Biomedical Advances in Alzheimer's Disease

CRS Report for Congress
Biomedical Advances in Alzheimer’s Disease
June 29, 2005
Michele M. Schoonmaker
Specialist in Genetics
Domestic Social Policy Division
Laura B. Shrestha
Specialist in Demography
Domestic Social Policy Division

Congressional Research Service ˜ The Library of Congress

Biomedical Advances in Alzheimer’s Disease
Alzheimer’s Disease (AD) is a severely debilitating neurodegenerative condition
that currently affects an estimated 4.5 million Americans, with a feasible range of 1.1
to 4.8 million. As the American population ages, the number of people with AD is
expected to increase dramatically to approximately 13.2 million affected individuals
by 2050 (range: 8.0-16.0 million). Medicare costs to treat a person with AD are
almost three times greater than the average for other beneficiaries, and are anticipated
to reach $49.3 billion by 2010. Similarly, costs to the Medicaid program could
increase from $18.2 billion in 2000 to $33 billion annually in less than 10 years. The
recent death of former President Ronald Reagan highlighted not only the challenges
of providing health services to an AD patient, but also the devastating impact the
disease has on family caregivers.
Since the late 1980s, the dramatic increase in funding for AD research has
rapidly expanded our understanding of the disease. However, unlike other important
chronic diseases we do not yet have any proven preventive interventions or effective
treatments for curing AD. In 1999, at the instruction of Congress, NIH established
the AD Prevention Initiative to accelerate basic research and the translation of
research findings into clinical practice.
Funding for AD research has been appropriated for many different activities:
basic research, clinical research, health services research, and education and training.
In addition to budgets that may include funding opportunities for AD research or
services, the Consolidated Appropriations Act, FY2005 (P.L. 108-447), appropriated
the following amounts to various agencies and projects supporting AD research
(subject to the 0.8% rescission adjustment):
!$1.06 billion to the National Institute on Aging (NIA) for
aging-related research (NIA spent about $680 million in AD
research in 2004);
!$11.8 million to the Administration on Aging (AOA) for AD
demonstration programs, $3.0 million for social research into AD
care options, best practices and other Alzheimer’s research
!$1.6 million to the Centers for Disease Control and Prevention
(CDC) specifically for AD activities.
Consistent with activity in the 108th Congress, early in the 109th a bill was
introduced to increase funding for AD research, and to authorize an education and
outreach program (H.R. 192, the La Cura Act of 2005).
This report provides an overview of the public health and financial impact of
AD, summarizes federal funding for AD research and clinical trials, and discusses
our current understanding of AD and promising avenues of AD research. Issues
relating to social services for AD patients and support for caregivers are covered in
a companion report. This report will not be updated.

In troduction ......................................................1
Demographics ....................................................3
New Cases per Year............................................3
Current and Future Prevalence....................................3
Age and Alzheimer’s Disease....................................5
Gender and AD...............................................6
AD and Co-Morbidity..........................................6
AD and Mortality..............................................8
Public and Private Funding for AD Research............................9
Federal ......................................................9
Private .....................................................10
Challenges to the Health Care System.................................11
Biomedical Aspects of Alzheimer’s Disease............................13
The Biology of Alzheimer’s Disease..............................13
Clinical Signs and Symptoms...............................13
Physiological Changes and Pharmaceutical Targets..............15
Environmental Risk Factors.................................24
Other Potential Interventions to Reduce Risk...................26
Diagnosis ...................................................29
Brain Imaging...........................................30
Genetic Associations in Familial and Sporadic Disease...........31
Genetic Tests............................................33
Investigational Treatments......................................35
New Compounds.........................................35
Gene Therapy............................................36
Stem Cells and Tissue Regeneration..........................36
Vacci nat i o n .............................................37
Appendix A. Glossary.............................................39
List of Figures
Figure 1. Alzheimer’s Deaths, 1979-2001, by Sex........................8
Figure 2. NIH Funding (All Agencies) for AD Compared to
Total Budget of the NIA, 1987-2004..............................10
Figure 3. Physical Changes in Brain with Alzheimer’s Disease.............15
Figure 4. Microscopic Image of the AD Brain..........................17
Figure 5. Neurotransmitter Function..................................19
Figure 6. Movement of a Signal Between Neurons......................19

List of Tables
Table 1. Four Estimates and Projections of the Prevalence of Alzheimer’s
Disease, by Stage, 2000-2050....................................5
Table 2. Alzheimer’s Disease: Age-Specific Incidence Rates, United States...6
Table 3. Prevalence of Co-Morbid Conditions in AD Patients,
Adjusted for Age and Gender....................................7
Table 4. Types of AD.............................................15
Table 5. FDA Approved Anti-Dementia Drugs for Treatment of AD........22
Table 6. Familial AD: Genetic Associations and Frequency of Occurrence...32

Biomedical Advances in
Alzheimer’s Disease
Alzheimer’s Disease (AD) is a severely debilitating neurodegenerative condition
that is currently estimated to affect 4.5 million Americans, though the actual range
may be 1.1 to 4.8 million. As the baby boomer population ages, the number of
people with AD is expected to increase dramatically to approximately 13.2 million
(feasible range: 8-16 million) affected individuals by the year 2050. Medicare costs
to treat a person with AD are almost three times greater than the average for other
beneficiaries, and are anticipated to reach $49.3 billion by 2010.1 Similarly, costs to
the Medicaid program could increase from $18.2 billion in 2000 to $33 billion
annually in less than 10 years. The recent death of former President Ronald Reagan
highlighted not only the challenges of providing health services to an AD patient, but
also the devastating impact the disease has on family caregivers. The enormous
impact will grow as the U.S. population ages.
Since the late 1980s, the dramatic increase in funding for AD research has
rapidly expanded our understanding of the disease. However, unlike other important
chronic diseases we do not yet have any proven preventive interventions or effective
treatments for curing AD. In 1999, at the instruction of Congress, the National
Institutes of Health (NIH) established the AD Prevention Initiative to accelerate basic
research and the translation of research findings into clinical practice.
The 2005 Omnibus Appropriations Act (P.L. 108-447) appropriated for the2
following agencies specific amounts for AD research:
!The National Institute on Aging (NIA). Congress appropriated
$1.06 billion to the NIA for aging-related research; a large fraction
of this total will be devoted to AD research.3 The conferees further
recommended that NIA expand its collaboration with the National
Institute of Mental Health (NIMH) as well as the National Institute

1 The Lewin Group, “Medicare and Medicaid Costs for People with Alzheimer’s Disease,”
(Washington, DC: Apr. 2001), as cited in Alzheimer’s Association, Alzheimer’s Disease:
Statistics, 2001. Medicare’s spending does not include nonmedical long-term care supports
provided in the community or in nursing homes.
2 Subject to the 0.8% recession adjustment. Note that these figures are specifically for AD
research; appropriations for AD social services are excluded.
3 In FY2004, NIH reported spending approximately $633 million on AD research, $496
million of which was from the NIA.” (Source: CRS personal communication with NIA, July

12, 2005).

for Nursing Research (NINR) on AD to include research related to
identifying effective treatments for elderly persons who suffer from
!The Administration on Aging (AOA). In 1998, Congress
authorized the Alzheimer’s Disease Demonstration Grants to States
programs. This program is administered by the AOA, within the
U.S. Department of Health and Human Services (HHS). The
program’s mission is to expand the availability of diagnostic and
support services for persons with AD, their families, and their
caregivers, as well as to improve the responsiveness of the home and
community based care system to persons with dementia. The
program focuses on serving hard-to-reach and underserved people
with Alzheimer’s Disease or related disorders (ADRDs).
In FY2005, Congress appropriated for AOA $12 million specifically for
AD demonstration programs. In addition, $3 million was given for social
research into AD care options, best practices and other Alzheimer’s
research priorities that include research into cause, cure and care, as well
as respite care, assisted living, and the impact of intervention by social
service agencies on victims.
!The Center for Disease Control and Prevention (CDC). Out of
CDC’s total appropriation of $1.4 billion for health promotion
programs, Congress appropriated approximately $1.6 million
specifically for AD activities.
Early in the 109th Congress, a bill was introduced to increase funding for AD
research, and to authorize an education and outreach program to promote public
awareness and risk reduction, with particular emphasis on education and outreach in
the Hispanic population (H.R. 192, the La Cura Act of 2005). This bill would
significantly increase the NIA budget for AD research to $1.4 billion and would
authorize $25 million for demonstration programs.
In the 108th Congress, two hearings on AD focused on defining the short-and
long-term biomedical and social implications of the disease and the need for
additional research.4 Several bills were introduced that would have increased funding
for research, medical services for patients, or caregiver support.5

4 U.S. Congress, Senate Committee on Appropriations, Subcommittee on the Departments
of Labor, Health and Human Services, and Education, and Related Agencies, Alzheimer’s
Disease, Apr. 1, 2003 (S.Hrg. 108-130), [
bin/getdoc.cgi?dbname=108_senate_hearings&docid=f:89018.wais.pdf]. Senate Committee
on Health, Education, Labor and Pensions, Subcommittee on Aging, Breakthroughs in
Alzheimer’s Research: News You Can Use, May 11, 2004,
[ bills/hlh_42_bill.html ].
5 H.R. 4595 and S. 2533 (the Ronald Reagan Alzheimer’s Breakthrough Act of 2004)that
would have increased NIH funding for AD research to $1.4 billion in 2005. These bills

This report provides an overview of the public health and financial impact of
AD, summarizes federal funding for basic AD research and clinical trials, and
discusses our current understanding of AD and promising avenues of AD research.
Issues relating to other congressional concerns, such as social services for AD
patients and support for caregivers, are covered in companion reports.6 A glossary
of terms is included at the end of this report to assist with terminology.
New Cases per Year
The incidence of Alzheimer’s is estimated at approximately 380,000 new cases
per year.7 In the absence of major medical breakthroughs, experts project that the
incidence will more than double to about 959,000 persons per year by 2050.8
Current and Future Prevalence
The most recently published estimates (figures being used by the NIA and the
Alzheimer’s Association) reported that approximately 4.5 million persons were living
with clinically-diagnosed AD in 2000.9 While there has been debate on the exact

5 (...continued)
would also have authorized funding for programs supporting family caregivers, lifespan
respite care, education of health professionals, and the safe return program. H.R. 3451 (the
Alzheimer’s Treatment and Caregiver Support Act) would have authorized the Secretary of
HHS to make grants available for health care providers to expand treatment services for AD
patients, and provide support services for families and caregivers. S. 2029 would have
allowed a tax deduction for home health care and adult day respite care for dependents of
taxpayers that suffer from AD or related disorder.
6 See CRS Report RL30664, Alzheimer’s Disease and Caregiver Burden, by Beverly
Johnson and Carol O’Shaughnessy; and CRS Report RL31755, Family Caregiving to the
Elderly by Employed Persons: The Effects on Working Caregivers, Employers, and Federal
Policy, by Linda Levine.
7 Ronald Brookmeyer, S. Gray, and Claudia Kawas estimated 360,000 in 1997 in
“Projections of Alzheimer’s Disease in the United States and the Public Health Impact of
Delaying Disease Onset,” American Journal of Public Health, 88(9), 1998 (hereafter cited
as Brookmeyer and colleagues, 1998). L.E. Hebert, L.A. Beckett, P.A. Scherr, and D.A.
Evans estimated 377,000 in 1995 in “Annual Incidence of Alzheimer’s Disease in the United
States Projected to the Years 2000 Through 2050,” Alzheimer Disease & Associated
Disorders, 15(4) ( Oct./Nov./Dec., 2001). (Hereafter cited as Hebert, et al., Annual
Incidence of Alzheimer’s Disease in the U.S.)
8 Ibid.
9 L.E. Hebert, P.A. Scherr, J.L. Bienias, D.A. Bennett, and D.A. Evans, “Alzheimer’s
Disease in the U.S. Population: Prevalence Estimates using the 2000 Census,” Archives of
Neurology, vol. 60, no. 8 (Aug. 2003). (Hereafter cited as Hebert et al., Prevalence

number, experts agree that the range is between 1.1 to 4.8 million.10 The number of
Americans with AD has more than doubled since 1980 and continued rapid growth
is expected over the next decades. Some experts project an almost three-fold
increase, to 13.2 million by 205011 (feasible range of 8.0 to 16.0 million).
Table 1 highlights the wide variation in estimates and projections of AD. The
table presents estimates from four major studies carried out by: (1) the Government
Accountability Office (referred to as GAO in table; previously known at the General12
Accounting Office); (2) Sloane and colleagues at the University of North Carolina
at Chapel Hill (referred to as Sloane in table);13 (3) Evans and colleagues at Rush14
University Medical Center (referred to as Evans in table); and (4) Hebert and
colleagues also at Rush University Medical Center (referred to as Hebert and15
colleagues in table). Estimates of the number of moderate or severe cases are also
provided. 16

10 W.B. Grant, “Year 2000 Prevalence of Alzheimer’s Disease in the United States,”
Archives of Neurology, vol. 61, May 2004. Grant asserts that the Hebert, et al., Prevalence
Estimates over-estimate the prevalence of AD. He highlights a few methodological
concerns and notes that research by Brookmeyer and colleagues, 1998, estimated only 2.3
million, with scientific possibility within the range of 1.1 to 4.6 million. In 1998, the
General Accounting Office (GAO) judged there to be only 2.1 million cases in 1995, a
figure that the Director of the NIA characterized as “substantially lower than those used by
NIA and others.” One of the main issues contributing to the uncertainty is the lack of
definitive diagnostic tests or biological markers of AD, though the accuracy of diagnosis has
significantly improved with the development and implementation of diagnostic criteria by
NINCDS-ADRDA. U.S. GAO, Alzheimer Disease: Estimates of Prevalence in the United
States, 1998, GAO/HEHS-98-16. (Hereafter cited as GAO, Alzheimer Disease: Estimates
of Prevalence.) See also Richard Mayeax, “Epidemiology of Neurodegeneration,” Annual
Reviews in Neuroscience, vol. 26, 2003.
11 Hebert, et al., Annual Incidence of Alzheimer’s Disease in the U.S. Estimate is based on
assumption that baby boomers will live longer, placing more persons into the older age
categories where AD rates are highest.
12 GAO, Alzheimer’s Disease: Estimates of Prevalence in the United States.
13 P.D. Sloane, et al. “The Public Health Impact of Alzheimer’s Disease, 2000-2005:
Potential Implications of Treatment Advances,” Annual Review of Public Health, 2002, vol.

23, pp. 213-231.

14 Denis A. Evans, et al. “The Impact of Alzheimer’s Disease in the United States
Population,” in The Oldest Old, ed. Richard M. Suzman, David P. Willis, and Kenneth G.
Manton (New York: Oxford University Press, 1995).
15 Hebert, et al.,Prevalence Estimates.
16 The figures cited in the text as feasible ranges above do not match numbers in Table 1
precisely for two reasons. First, our analysis included the data and research from additional
sources. Second, Table 1 reports only middle-range projections, and there is greater
variability (i.e., a wider range) if the low- and high-range assumptions are used.

Table 1. Four Estimates and Projections of the Prevalence of
Alzheimer’s Disease, by Stage, 2000-2050
(in millions of cases)
All casesor severe cases
Year GAO Sloane Evans H ebert GAO Sloane Evans H ebert
2000 2.2 2.2 4.8 4.5 1.2 1.2 2.1 2.3
2010 2.7 3.1 5.6 5.1 1.5 2.0 2.5 N/A
2020 3.4 4.1 7.4 5.7 1.9 2.5 3.2 N/A
2030 4.6 5.5 9.7 7.7 2.6 3.4 4.2 N/A
2040 6.3 7.9 11.5 11.0 3.7 4.9 5.3 N/A
2050 8.0 10.2 13.0 13.2 4.7 6.5 6.3 N/A
Sources: CRS compilation based on four research studies.
Notes: Where Hebert et al., Prevalence Estimates, use low-, middle-, and high-series estimates of
population growth from the 2000 census, only the middle, or most likely, projections are shown here.
Projections differ because of both differences in the size of the estimated baseline populations and
assumptions about relevant future trends.
N/A= estimates by level 9 of severity are not available in this study.
Age and Alzheimer’s Disease
The risk of AD varies significantly by age. The disease is rare in persons under
the age of 65. Its onset increases dramatically in each five-year age category above
age 65. Of the estimated 4.5 million persons with Alzheimer’s,17 only 0.3 million
(7%) were between the ages of 65 and 74 years, 2.4 million (53%) were between the
ages of 75 and 84 years, and 1.8 million (40%) were 85 years of age or older.
The incidence of AD (new cases) increases dramatically with age — incidence
at age 65, for instance, is more than double that observed at age 60 (Table 2).18

17 Although the absolute numbers estimated differ across different data sets, the age pattern
is always one of increasing incidence and prevalence rates with age. The figures presented
are the most recently published, those by Hebert, et al., Annual Incidence of Alzheimer’s
Disease in the U.S. These figures are at the higher-end of the range of plausible estimates.
18 GAO, 1998, developed through integration of prevalence rates from 18 studies.

Table 2. Alzheimer’s Disease:
Age-Specific Incidence Rates, United States
(in percent)
Incidence (new cases)
EstimateFeasible range
95 12.10 6.36-18.57
Source: R. Brookmeyer and colleagues,Projections of Alzheimers Disease
in the U.S.” American Journal of Public Health, 88(9), Sept. 1998, based on
four U.S. epidemiologic studies: Framingham, East Boston, Rochester, and
B a ltimo r e.
Estimates of AD prevalence also vary widely, but experts agree that the pattern
is one of sharp increase with age, doubling about every five years over at least the age
range of 65 to 85 years (not shown in table). Estimates suggest that, in age group
80-84, about 18% of persons have AD, increasing to 53% of persons by age group

95 and above. Moderate or severe AD is seen in 10% of those aged 80-84 and 35%

in age group 95 and above.
Gender and AD
It is often reported that the number of women with AD and the incidence rates
for women exceed those of men. However, some experts attribute this to the gender
composition of the U.S. population and the longer life expectancy of women, rather19
than to sex-specific risk factors for the disease.
AD and Co-Morbidity
In addition to AD, patients suffer from many of the same chronic conditions as
the non-AD elderly population (see Table 3). Some conditions, such as congestive

19 Liese E. Hebert, Paul Scherr, Judith J. McCann, Laurel A. Beckett, and Denis A. Evans,
“Is the Risk of Developing Alzheimer’s Disease Greater for Women than for Men?”
American Journal of Epidemiology 153 (2) (2001), pp. 132-136

heart failure and cerebrovascular disease are two-three times more common in the
AD patients than the general elderly population. Because Alzheimer’s disease can
complicate co-morbid conditions, the hospital stay for a patient with AD averages
longer and is more costly than that of a patient without Alzheimer’s. For instance,
one study20 found that the average hospital stay was four days — and $4,000 — more
for a patient with dementia than a non-demented person of similar age Dementia also
complicates preventable medical situations by impairing patients’ abilities to follow
medical instructions and manage their own care, and predisposing patients to a two-
fold increase in the rates of fractures or other injuries.21
Table 3. Prevalence of Co-Morbid Conditions in AD Patients,
Adjusted for Age and Gender
Prevalence of co-morbidity
Co-morbidityAD patientsNon-AD elderlydifferent?
Cerebrovascular Disease34.6310.24Yes
Congestive Heart Failure23.9414.36Yes
Chronic Pulmonary Disease19.7719.96No
Diabetes, Uncomplicated18.8916.55Yes
Peripheral Vascular Disease14.068.71Yes
Malignancy 10.91 10.04 No
Myocardial Infarction9.665.44Yes
Renal Disease5.423.10Yes
Diabetes, with Chronic Complications5.203.81Yes
Peptic Ulcer Disease4.693.38Yes
Source: H. Fillit, J.W. Hill, and R. Futterman, Health Care Utilization and Costs of Alzheimer
Disease Stage, and Pharmacotherapy,Family Medicine, July-Aug. 2002.

20 C. Lyketsos, “Dementia in Elderly Persons in a General Hospital,” American Journal of
Psychiatry, 175(5), 2000, as cited in the Alzheimer’s Association, Medicare and Medicaid
Costs for People with Alzheimer’s Disease, Apr. 2001.
21 Note that this study was of persons with dementia, a clinical state characterized by loss
of function in multiple cognitive domains. There are approximately 70-80 types of
dementia, with the most common being Alzheimer’s disease. See American Psychiatricth
Association, Diagnostic and Statistical Manual of Mental Disorders, 4 ed. (DSM IV)
(Washington, D.C.: American Psychiatric Association, 1994).

AD and Mortality
Fifteen leading causes of death accounted for 83% of all deaths for all ages in
the United States in 2001, with deaths from diseases of the heart and malignant
neoplasms (with 700,000 and 554,000 deaths, respectively) far out-distancing other
causes of death. In 2001, AD was ranked at number 8 as a leading cause of death.22
There has been a dramatic increase in the number of reported deaths from AD
over the past two decades (Figure 1). In 1979, there were only 857 reported deaths23
from AD. In contrast, AD was reported as the underlying cause of death for a
record 53,852 persons in year 2001 (most recent data available), representing about24
2.2% of the 2.42 million deaths from all causes. The median survival from initial
diagnosis with AD was 4.2 years for men and 5.7 years for women with AD. Men25
had poor survival across all age groups compared with females.
Figure 1. Alzheimer’s Deaths, 1979-2001, by Sex

40a nds Me n
30T hou Wo me n
e r
20m b
9 981 983 985 9 8 7 98 9 991 993 9 5 99 7 99 9 001
1 97 1 1 1 1 1 1 1 19 1 1 2
Source: CRS compilation based on National Vital Statistics data.
22 National Center for Health Statistics (NCHS), National Vital Statistics Reports, vol. 52,
no. 3, Sept. 2003.
23 This number reflects, in part, lack of awareness of AD generally and unfamiliarity with
screening or diagnostic tools.
24 Official mortality data are compiled through the National Vital Statistics System. The
Standard Death Certificate is designed to elicit a single disease or injury that started the
morbid process that led to death — referred to as the underlying cause of death.
25 E.B. Larson, et al., “Survival after Initial Diagnosis of Alzheimer Disease,” Annals of
Internal Medicine, vol. 140, 2004.

In 2001, there were 38,090 (71%) AD deaths in females compared to only
15,762 (29%) for men, presumably reflecting the longer life expectancy of women
rather than sex-specific factors for the disease. The vast majority of all AD deaths
were to persons aged 65 years and older (53,245, or 98.9%) with a significant portion
to those aged 85 and above.
Age-adjusted death rates for the leading causes of death in the United States
have been falling for a number of conditions, most notably for diseases of the heart
and cerebrovascular disease.26 The trend for mortality due to AD, however, has been
one of rapid increase since 1979. While this trend may reflect changes in the
underlying risk of becoming affected by AD, other contributing factors should be
noted, including improvements in diagnosis (i.e., the development and wide-spread
implementation of diagnostic criteria); an increase in awareness of the condition by
physicians, coroners, or funeral directors (who determine the underlying cause of
death for the death certificate); and in formal acceptance of the term “Alzheimer’s
Disease.” A particularly large increase in 1999 was likely the result of the adoption
of the 10th Revision of the International Classification of Diseases (ICD-10) by the
U.S. National Center for Health Statistics (NCHS) for that year, which led to more
accurate identification of AD as a true cause of death compared to some other
designated cause (e.g., pneumonia, heart attack, or general dementia).27
Public and Private Funding for AD Research
Funding for Alzheimer’s research has been a growing priority for NIH since the
mid-1980s, and has more than doubled since 1997, keeping pace with the budget for
the NIA (Figure 2). However, the increase has been relatively modest compared to
the budget for all health research, with federal spending for AD comprising 1.23%
of the total NIH budget in 1987, growing to 2.44% in 2004. In 2004, NIH spent an
estimated $680 million on AD research.28 For 2005, Congress appropriated $1.06
billion to the NIA for aging-related research. The government current funds over 100
new or ongoing research studies on many topics, including the identification of risk

26 The figures for age-specific and age-adjusted death rates differ slightly. The latter
highlights cause-specific mortality trends after adjusting crude rates to eliminate the effect
of differences in population composition with respect to age and other variables.
27 Cause of death data from death certificates are the most widely available, timely, and
geographically comparable data on health available for the United States, but their reliability
and accuracy are dependent upon the ability of the physician or coroner to make the proper
diagnosis and the care with which he records this information on the death certificate.
NCHS See also D.C. Ewbank, “Deaths Attributable to Alzheimer’s Disease in the United
States,” American Journal of Public Health, Jan. 1999.
28 U.S. Department of Health and Human Services. Office of the Assistant Secretary for
Budget, Technology and Finance, “Alzheimer’s Disease,” FY2005 Moyer Material, Feb. 5,


factors and new early diagnostic markers for treating AD.29 While there has been
dramatic progress in understanding the disease process, researchers are still searching
for more effective means for earlier diagnosis, more effective treatments and
preventive strategies, as well as efficient mechanisms to transfer the fruits of research
into beneficial services for patients.
Figure 2. NIH Funding (All Agencies) for AD
Compared to Total Budget of the NIA, 1987-2004

12 00
10 00
600 ($
ng l
* 5 *
1 987 19 8 8 1 98 9 1 990 1 99 1 1 992 19 9 3 1 994 1 99 5 1 996 19 9 7 1 998 19 9 9 2 000 2 001 2 002 2 003 2 004 2 00
AD budgetNIA budget
Source: AD funding, Alzheimer’s Disease Funding:NIH Budget Office,” Oct. 5, 2004.
See also [], accessed July 18, 2005.
NIA total budget, see [],
accessed July 18, 2005.
Note: Data for 1987-2003 are actual figures; data for 2004 and 2005 are estimates.
Clinical trials evaluating the safety and effectiveness of new diagnostic methods,
drugs or other treatments are expensive. Large scale trials of new medical products30
can cost $10-$30 million. It is difficult to determine the magnitude of private
industry investments in AD research, and to determine what clinical trials are
29 The exact number depends on whether the search includes only Alzheimer’s (as opposed
to broader dementia), the type of research supported (human studies, clinical trials, animal
models), and other factors. For a list and summary of current clinical trials, see the database at [].
30 Alzheimer’s Association, Additional Resources Needed to Speed Progress on Treating
and Preventing Alzheimer’s Disease, 2004. Also Alzheimer’s Association, personal
communication, Apr. 26, 2005.

conducted in the private sector that are not registered with the federal government.
The Alzheimer’s Association is the largest private funder of AD research, investing
over $165 million in 1,300 projects over the past 10 years, including $15.8 million
for 71 projects in 2004 alone.31 The Alzheimer’s Association estimates that
additional funding is needed in the following areas:
!$50 million for clinical trials;
!$60 million for research to understand risk factors, including $10
million to support the Genetics Initiative sponsored by NIA, and $50
million to examine the relative influence of environmental risk
!$30 million for identifying early markers of disease, including $10
million to support the neuroimaging initiative sponsored by NIA,
and $20 million to support community-based epidemiologic studies;
!$60 million for basic science research to increase the number of
studies funded from 15% of proposals submitted to NIA to 25% of
Challenges to the Health Care System
The number of affected persons, the complexity, and the chronic and long-term
nature of AD will present unique challenges to the U.S. health care system in the
coming decades. The failure of physicians — particularly those in primary care
where patients initially seek services — and family members to recognize symptoms
of dementia in the early stages, is a major barrier to appropriate care for many AD32
patients. One study found that general practitioners only identified 3.2% of patients
with mild cognitive impairment and 23.5% of patients with moderate to severe33
dementia. A related medical concern is that while remedies may reduce the
incidence (i.e., number of new cases each year) of disease,34 earlier diagnosis and
improved treatments increases the prevalence — or proportion of persons living with
AD out of the total population, while not influencing the incidence. According to the
Alliance for Aging Research, the United States will fall short of the 36,000
specialists35 needed by 2030 to meet the medical needs of the aging population.

31 Alzheimer’s Association at [].
32 Jeffrey L. Cummings, “Alzheimer’s Disease,” New England Journal of Medicine, vol.

351, July 1, 2004, pp. 56-67 (Hereafter cited as Cummings, “Alzheimer’s Disease.”)

33 C.M. Callahan, H.C. Hendrie, and W.M. Tierney, “Documentation and Evaluation of
Cognitive Impairment in Elderly Primary Care Patients,” Annals of Internal Medicine, vol.

122 (1995), pp. 422-429.

34 J.C.S. Breitner, “The End of Alzheimer’s Disease?” International Journal of Geriatric
Psychiatry, vol. 14 (1999), pp. 577-586.
35 Alliance for Aging Research, “Ten Reasons Why America Is Not Ready for the Coming

Even if better biological or genetic markers are developed to improve diagnosis,
patients will still need evaluation and testing to determine onset of dementia,
prognosis, progression, residual function and hopefully, response to therapy.
Identification of earlier markers of AD offers the opportunity to begin preventive
treatments to slow the progression of disease, giving patients more time with their
families to plan the course of their care and make other life decisions. Additional
markers may act to monitor the effectiveness of therapy. Identification of such
markers has been a priority for the NIH.36
While not a cure, delaying the onset of disease or the time to progression to
severe disease still has benefits. The Alzheimer’s Association indicated that
breakthroughs in medical research could result in nearly a 45% drop in the number
of cases (from 6.5 million to 3.6 million), potentially saving up to $149 billion in
annual Medicare and Medicaid costs by 2025.37 A recent study showed that using the
newly approved drug, memantine, alone could slow cognitive decline enough to
reduce the need for caregiving to 45.8 hours per month,38 with the potential for better
outcomes when combined with other interventions. Likewise, treatment with an
established drug (donepezil), may slow progression sufficiently to delay nursing
home care for an average of 30 months.39 While use of the drug would increase
treatment costs perhaps as much as four-fold, it may substantially reduce a patient’s
overall medical costs — in one study, total annual costs were reduced by $3,891 for
patients receiving donepezil.40

35 (...continued)
Age Boom,” 2002, available at [].
36 Testimony of NIA Director Richard Hodes, in U.S. Congress, Senate Committee on
Health, Education, Labor and Pensions, Subcommittee on Aging, Breakthroughs inthnd
Alzheimer’s Disease: News You Can Use, hearing, 108 Congress, 2 sess. May 11, 2004,
[ ].
37 Report of the Lewin Group to the Alzheimer’s Association, “Saving Lives Saving Money:
Dividends for Americans Investing In Alzheimer Research,” June 23, 2004, pp. 1-7, at
[]. This report is subject
to a number of important assumptions regarding the prevalence of disease, the rate of
technological advancement, and the projected costs of care. These assumptions may be in
part, a reason why the costs at baseline are higher (estimated at $189 billion in total
Medicare spending in 2015) compared to those cited earlier in this report (total Medicare
costs for Alzheimer’s were $49.3 billion in 2010). The costs cited earlier in this report were
from an earlier report by the Lewin Group (2001).
38 B. Reisberg, et al., “Memantine in Moderate-to-Severe Alzheimer’s Disease,” The New
England Journal of Medicine, vol. 348, no. 14 (2003), pp. 1333-1341.
39 George Provenzano, et al., “Delays in Nursing Home Placement for Patients with
Alzheimer’s Disease Associated with Donepezil May Have Health Care Cost Saving
Implications,” Value in Health vol. 4, no. 2 (2001), p. 158.
40 J.W. Hill, et al., “The Effect of Donepezil Therapy on Health Costs in a Managed Care
Plan,” Managed Care Interface. Mar. 2002, pp. 63-70.

Biomedical Aspects of Alzheimer’s Disease
In the absence of the disease, the human brain often can function well into the41
tenth decade of life. In 1906, Dr. Alois Alzheimer, a German doctor, noticed
changes in the brain tissue of a woman who had died of an unusual mental illness.
The amyloid plaques and neurofibrillary tangles that he discovered are now
considered hallmarks of AD.42 Until the 1970s, AD was considered a rare disorder,43
with only a small group of pioneers conducting research on the disease.
The biomedical aspects of Alzheimer’s Disease are considered in the next three
sections. The first section reviews the clinical symptoms of the disease and the
biology of AD progression. Though the precise cause of AD is still illusive, much
knowledge has been gained through basic research in the understanding of the
physical signs and progression of the disease. This section will review major
initiatives in basic and clinical research.44 As knowledge is gained about the process
of disease development, treatments can be designed to block or otherwise alter that
progression. For clarity, a discussion of current treatments follows the description
of the biological factors that they are designed to alter. None of the current
treatments provide a definitive or effective cure for AD, though a few may act to
slow the progression of cognitive decline.
In the next section (“Diagnosis”), an overview of current and promising means
of diagnosing AD based on the clinical signs and symptoms of the disease is
presented, along with a discussion of current treatments that target a risk factor and
aim to reduce the severity of symptoms and delay cognitive decline.
Finally, the third section will describe the latest research into the newest
potential treatments. Together these sections provide an overview of how research
dollars are being spent in various basic, clinical and behavioral research settings to
determine and affect cause, to prevent or reduce symptoms, and to reverse damage
accumulated during disease progression.
The Biology of Alzheimer’s Disease
Clinical Signs and Symptoms. AD is a progressive neurodegenerative
condition, and a common form of dementia in the elderly. The disease process

41 United States Department of Health and Human Services, National Institutes of Health
(NIH), National Institute on Aging (NIA), Alzheimer’s Disease: Unraveling the Mystery,

2002 (Hereafter cited as DHHS/NIH/NIA, Alzheimer’s Disease: Unraveling the Mystery.)

42 NIH Senior Health, Alzheimer’s Disease, Nov. 23, 2003, at [
alzheimersdisease/defined/04.html ].
43 DHHS/NIH/NIA, Alzheimer’s Disease: Unraveling the Mystery.
44 Basic research often uses animal or cell culture models to answer a specific research
question. In contrast, clinical (or applied) research involves investigation of a specific
intervention in human beings.

usually begins with mild cognitive impairment (MCI),45 and loss of instrumental
activities of daily living (IADLs), such as check writing or use of public
transportation. Patients may present with confusion, poor judgement, language
disturbances, agitation, and hallucinations.46 Depression is common in early disease.
As the disease progresses, patients experience difficulties in basic activities of daily
living (ADLs), such as eating, grooming, bathing, or using the toilet.47 In addition
to the loss of physical abilities, mood changes and apathy occur throughout the
course of the illness. During the middle and later phases, psychosis and agitation
become commonplace.48 The disease can last from 8-10 years, with a range of 1-25
years. Death typically results from general inanition (i.e., exhaustion due to
malnutrition), malnutrition, and pneumonia.49 Early onset AD is characterized by
appearance of symptoms before age 65, usually between the ages of 40 and 50;
however, onset can range from the 30s to early 60s. Late onset AD is characterized
by the appearance of symptoms at age 65 or older.
Studies of AD are difficult, because exact diagnosis is not possible without an
examination of brain tissue which is not available until after the patient has died. As
a result, the precise cause of AD remains unknown, but is postulated to be both
multifactorial (meaning that there are multiple causes) and polygeneic (i.e., multiple
genes50 are involved). Much of what is known has been derived from animal models,
such as transgenic (i.e., genetically modified) mice.
AD results from a disruption of normal brain structure and function. Table 4
summarizes the frequency of different types of AD. One thing that contributes to the
disruption is a buildup of protein called beta-amyloid. The majority of the cases
occur sporadically, with no familial influence or obvious exposure. However,

45 MCI is different from both AD and normal age-related memory change. People with MCI
have ongoing memory problems but do not have other losses like confusion, attention
problems, and difficulty with language. See the Alzheimer’s Disease Education and
Referral Center (ADEAR) at [].
46 Thomas D. Bird, Alzheimer Disease Overview, Sept. 12, 2003. Available at [http://www.] (Hereafter cited as Bird, Alzheimer Disease Overview).
47 D. Galasko, et al., “An inventory to Assess Activities of Daily Living for Clinical Trials
in Alzheimer’s Disease: the Alzheimer’s Disease Cooperative Study,” Alzheimer Disease
and Associated Disorders, vol. 11, suppl. 2 (1997), pp. S33-S39.
48 M.S. Mega, J.L. Cummings, T. Fiorello, and J. Gornbein, “The Spectrum of Behavioral
Changes in Alzheimer’s Disease,” Neurology, vol. 46 (1996), pp. 130-135.
49 American Psychiatric Association (APA), Diagnostic and Statistical Manual of Mental
Disorders, 4th ed. (Washington, D.C.: APA, 1994), pp. 139-145.
50 Genes are pieces of DNA which encode the biochemical sequence that can be translated
into proteins. Each person usually inherits two copies of a gene (one from their mother, one
from their father). The different forms of a gene are called alleles. Differences in the gene
sequences that differentiate the alleles can result in different versions — or isoforms — of
a protein. CRS Report RL32478, Genetic Testing: Scientific Background and
Nondiscrimination Legislation, by Michele Schoonmaker and Erin Williams, includes a
brief discussion of the relationship between genes and proteins.

approximately 25% of patients have relatives with AD (i.e., the disease ‘runs in their
families’). Clinically, familial cases look the same as sporadic cases.
The gene that codes for the amyloid protein is found on chromosome 21.
‘Normal’ individuals have two copies of chromosome 21, and therefore two copies
of the gene for amyloid protein. Down syndrome patients have three copies of
chromosome 21 (and therefore three copies of the gene for amyloid protein).
Because Down syndrome patients have three copies of chromosome 21, a rare few
of AD cases (less than 1%) can be associated with Down syndrome.
Table 4. Types of AD
Type of ADFrequency
Sporadic (e.g., no family history)75%
Late onset15-25%
Early onset< 2%
Chromosomal (e.g., trisomy 21)< 1%
Source: Bird, Alzheimers Disease Overview.
Physiological Changes and Pharmaceutical Targets. The damage to
the AD brain is selective and concentrated in the areas that are concerned with
memory, language, reasoning and judgement. The most striking damage is51
generalized atrophy (i.e., shrinking) of the brain and enlargement of cavities (known
as ventricles) which occurs when nerve cells begin to die (Figure 3).
Figure 3. Physical Changes in Brain with Alzheimer’s Disease

Source: Alzheimer’s Disease Education & Referral Center (ADEAR), “Alzheimer’s Disease: Unraveling
the Mystery, at [].
51 The University of California Los Angeles (UCLA) Laboratory of NeuroImaging (LONI)
website hosts a computer animation which demonstrates changes in the gross structure of
a normal human brain as it is transformed by AD. See “Elderly Normal to Elderly
Alzheimer’s Disease Warp” at [].

Though still unproven, the “amyloid hypothesis” is the most well-supported
theory of how AD develops. In this theory, the cascade of biological events leading
to AD are (1) beta-amyloid accumulates in the brain in the form of plaques; (2)
neurofibrillary tangles form, (3) inflammation occurs around the plaques and tangles
and finally, (4) cell death is initiated. At some point in the cascade, the neurons (i.e.,
nerve cells) become dysfunctional in their ability to communicate with one another.
Scientists do not always agree which of these steps are causal or which are effects of
Established treatments have focused on multiple stages in the AD disease
process. Some target the process of plaque formation. Other therapies attempt to
inhibit the inflammatory response that occurs in response to the plaques, or attempt
to improve function by replenishing neurotransmitters, growth factors or hormonal
therapies.52 Each of the steps in the disease process will be discussed below along
with the corresponding opportunities for therapeutic interventions.
Amyloid Protein. On a microscopic level, the AD brain is characterized by
the accumulation of amyloid plaques and neurofibrillary tangles. A large protein
called amyloid precursor protein (APP) is broken down (i.e., cleaved) into smaller
amyloid proteins, called beta-amyloid-40 and beta-amyloid-42. The number signifies
how many amino acids (i.e., the chemical building blocks of proteins) are in each.
Of these cleavage products, beta-amyloid-42 is more likely to be in plaques and be
toxic to cells. APP and its cleavage products may occur in normal cells and
cerebrospinal fluid,53 but their function is not known.54
In Alzheimer’s, the beta-amyloid product builds up around nerve cells in a bad
form (known as a beta-pleated sheet) and eventually forms the characteristic plaque
(Figure 4). The mechanisms of how the beta-amyloid protein is allowed to
accumulate are still unclear. In some cases, mutations in the APP gene (i.e., the
genetic material that is the blueprint for the protein) or abnormal processing of the
APP by enzymes called secretases may result in the overproduction of beta-amyloid.
In other instances, the accumulation may be mediated by another unknown factor, or
may be due to the brain’s inability to clear toxic forms of the protein.55

52 DHHS, Mental Health: A Report of the Surgeon General, Chapter 5: Older Adults and
Mental Health, Section 4: Alzheimer’s Disease at [
mentalhealth/chapter5/sec4.html ].
53 Dennis J. Selkoe, “Alzheimer’s Disease: Mechanistic Understanding Predicts Novel
Therapies,” Annals of Internal Medicine, vol. 140, 2004, pp. 627-38 (Hereafter cited as
Selkoe, Alzheimer’s Disease: Mechanistic Understanding.)
54 A. Kamal, et al., “Kinesin-Mediated Axonal Transport of a Membrane Compartment
Containing Beta-secretase and Presenilin-1 Requires APP,” Nature, vol. 414, 2001, pp. 643-


55 R.N. Rosenberg, “The Molecular and Genetic Basis of AD: The End of the Beginning,”
Neurology, vol. 54, 2000, pp. 2045-2054. (Hereafter cited as Rosenberg, The Molecular and
Genetic Basis of AD.)

Figure 4. Microscopic Image of the AD Brain

Source: CNS Pathology at [
CNS090.html], accessed May 26, 2005.
Notes: The large dark spots are the amyloid plaques and the smaller, darker, irregular
shaped structures are the tangles.
The presence of plaques is not limited to AD. In fact, in normal aging there is
some neuronal loss, and some healthy individuals even develop a few scattered
plaques and tangles, making an early diagnosis of AD difficult.
To date, there are no therapies available to effectively reduce or eliminate beta-
amyloid from the brain.56 Researchers are investigating strategies to inhibit secretase57
(and therefore inhibit beta-amyloid synthesis) as potential therapies. One vaccine
clinical trial was stopped in 2003 when 6% of the patients experienced serious side58
Neurofibrillary Tangles. Neurofibrillary tangles are the dense, irregularly
shaped structures in Figure 4. They are made of microtubules. The microtubules are
the structures that neurons use to carry substances within the body of the cell and to
its many projections, called dendrites. These microtubules are made up of proteins
called tau proteins. In AD, a change in the chemical make up of the tau proteins
56 Cummings, “Alzheimer’s Disease,”, pp. 56-57.
57 Rosenberg, The Molecular and Genetic Basis of AD.
58 Jean-Marc Orgogozo, et al., “Subacute Meningoencephalitis in a Subset of Patients with
AD After Abeta42 Immunization,” Neurology, vol. 61, 2003, pp. 46-54, in Cummings,
“Alzheimer’s Disease.”

causes them to rearrange and weaken the support system for the nerve cell. The cell
then changes shape and loses its ability to communicate with other nerve cells. The
cell eventually dies, but the tangles remain. Tangles can occur in the absence of beta-
amyloid plaques, and do so in other diseases such as frontotemporal dementia.59
Inflammatory Response. As plaques and tangles form, the brain launches
a localized inflammatory response against the dying nerve cells and abnormal
proteins. Studies show that signs of inflammation occur from early to late disease.
These signs include the association of inflammatory proteins with plaques, and the
accumulation and activation of microglial cells60 around the plaques. While
inflammation is a normal response to injury or disease, chronic inflammation can be
harmful to tissues.
Some researchers suggest that the inflammatory proteins may be involved in the
regulation of APP synthesis and actually aggravate the disease. In this model, the
APP is made and cleaved into the beta-amyloid protein. The toxic form of beta-
amyloid then activates microglial cells to produce inflammatory proteins. The
inflammatory proteins then stimulate production of more APP, which then is
converted to beta-amyloid, and so on, eventually leading to the build-up of beta-
amyloid into a plaque.61
Anti-Inflammatory Medications. Regardless of the mechanism by which
inflammation acts (i.e., whether chronic inflammation causes general damage to brain
tissue or the inflammatory proteins are somehow more specifically involved in
plaque formation), researchers are investigating whether non-steroidal anti-
inflammatory drugs (NSAIDs), such as ibuprofen, can slow the disease progression
as suggested by epidemiologic studies. Despite the epidemiologic evidence, negative
results have been reported for trials of diclofenac, rofecoxib (Vioxx),62 and naproxen63
(e.g., Aleve, Naprosyn). As a result insufficient evidence exists to support long-
term treatment with NSAIDs. Some researchers argue that comparisons between
different NSAIDs are difficult because they have different mechanisms of action.
Current studies are evaluating the value of new NSAIDs (such as celecoxib, human
recombinant interferon-alpha, and cyclophosphamine) in preventing AD.
Neurotransmitters. A neurotransmitter is a chemical made by a nerve cell.
It is used to transmit signals from one neuron to either another neuron or other cell
(such as a skeletal muscle cell or heart muscle cell). When a neuron is stimulated,
it releases a neurotransmitter from the ends of the dendrites (Figure 5). The

59 Selkoe, Alzheimer’s Disease: Mechanistic Understanding.
60 Microglial cells are immune cells that engulf and clear dead cells and debris in the brain.
61 J. M. Hoozemans, et al., “Immunological Aspects of Alzheimer’s Disease,” BioDrugs, vol.

15, no. 5 (2001), pp. 325-337.

62 Vioxx was recently removed from the market due to excessive adverse cardiac events
associated with its use for rheumatoid arthritis. Public health advisories have been issued
for other NSAIDs, including some sold over-the-counter, such as ibuprofen. See
[]. Accessed Apr. 26, 2005.
63 Cummings, “Alzheimer’s Disease.”

neurotransmitter rapidly travels the small gap (called the synapse) between the first
neuron (called the pre-synaptic neuron), and binds to a special receptor on the
dendrite of a neighboring neuron (post-synaptic). The binding of the
neurotransmitter to its receptor elicits an electrochemical response (called
depolarization) in the second neuron, which stimulates it to release a neurotransmitter
to stimulate the next neuron. The movement of electrochemical signals and the
release of neurotransmitters occur in one direction along a nerve, and are what allows
neurons to communicate with each other (Figure 5).
Figure 5. Neurotransmitter Function
Source: [].
When the signal has been transmitted, the neurotransmitter must be removed
from the synapse. For almost all neurotransmitters, removal occurs by a process
called reuptake. In reuptake, the neurotransmitter is actively re-absorbed by the
presynaptic neuron.
Figure 6. Movement of a Signal Between Neurons
Source: Instituto de Fisiología Celular, The Neuron at [
Brain/neuron. htm].

Neurotransmitters can be small molecules (such as acetylcholine (ACH),
dopamine, norepinephrine, serotonin, histamine, and epinephrine), amino acids (such
as gamma-aminobutyric acid (GABA), glycine, glutamate, and aspartate), peptides
(such as insulin, neuropeptide Y, or somatostatin among others) or even soluble gases
(carbon monoxide or nitric oxide).
Acetylcholine. The cholinergic system consists of all of the neurons that use
acetylcholine (ACH) as their neurotransmitter. ACH has been shown to have a
central role in information processing, memory, and learning. It is made from other
chemicals by an enzyme called choline acetyltransferase. The degenerative
progression in AD has been associated with deficits in the cholinergic system. The
deficits could be due to the death of cholinergic neurons (i.e, neurons that make or
use ACH) which reduces the amount of ACH that is available.
ACH can be released into the synapse by two different receptors, called the
muscarinic and nicotinic receptors.64 These receptors can also bind other molecules.
Depending on the molecule encountered, the receptor will signal the increased or
decreased release of ACH into the synapse. When the signal has been transmitted,
the neurotransmitter must be deactivated. Unlike most other neurotransmitters which
are deactivated by a reuptake mechanism, ACH is broken down into inactive
fragments by an enzyme called acetylcholinesterase.
Glutamate. Glutamate is a neurotransmitter that binds to another kind of
receptor, called the NMDA (N-methyl-D-aspartate) receptor. When glutamate binds
to the NMDA receptor, it triggers calcium to flow into the neuron. Calcium flow into
and out of the neuron is important for depolarization to occur. For the brain to store
information and function properly, there must be a balance between the levels of
glutamate and calcium. If there is not enough glutamate to bind NMDA receptors,
calcium cannot enter the cell and information cannot be stored. On the other hand,
if too much glutamate is available, too much calcium enters the neuron, and the65
neuron may die.
Treatment with Neurotransmitter Modulators. The ACH system has
long been the target for therapeutic intervention. Drugs have sought to increase the
amount of ACH that is available by stimulating its production, by inhibiting the
enzymes that break it down, or by affecting the receptors to which ACH binds. Four

64 Muscarinic receptors are found between the junction of nerve cells and cardiac or smooth
muscles, and between nerve cells that control sympathetic nervous function. Sympathetic
nervous function is responsible for the body’s response to stress. Stimulation of sympathetic
nerves causes the heartbeat to increase, blood pressure to rise, and digestive movement to
slow. Nicotinic receptors are found at the junction between nerve cells and skeletal muscle,
and between neurons that control parasympathetic nervous function. Parasympathetic
nervous function is responsible for returning the body to normal after a stressful encounter
(e.g., lowers blood pressure, lowers heart beat, increase digestive movement).
65 Namanda (memantine) Information for Consumers, available at [http://www.namenda.
com/treating/ how.asp].

drugs66 that act to influence neurotransmitter function have been approved by the
Food and Drug Administration (FDA) for the treatment of AD (Table 5). Donepezil
(Aricept™), rivastigmine (Exelon™) and galantamine (Reminyl™) inhibit
acetylcholinesterase, leaving more acetylcholine in the synapse to foster
communication between neurons. In addition, galantamine actually stimulates the
nicotinic receptors of the nerve cells to make more acetylcholine.
The most frequent side effects of cholinesterase inhibitors are nausea and
vomiting, diarrhea, stomach cramps and headaches, dizziness, fatigue, insomnia and
loss of appetite.67 Evidence suggests that treatment with cholinesterase inhibitors68
may delay the onset of AD symptoms by 6-24 months. While cholinesterase
inhibitors have demonstrated effectiveness for improving cognition and/or attention
associated with mild to moderate disease, the effects still are not clear in later
stages.69 There have been no direct comparisons of these drugs, and the main
differences in utilization may be due to the ease of administration and side effect
profiles rather than their efficacy.70

66 A fifth drug, tacrine, was one of the first approved by the Food and Drug Administration
(FDA), but now is rarely used due to increased adverse side effects in the liver.
67 Alzheimer’s Society, “After the Diagnosis: Drug Treatments for Alzheimer’s Disease -
Aricept, Exelon, Reminyl and Ebixa,” Nov. 2000. Available at [
uk/After_diagnosis/T reat ments/info_drugs.htm] .
68 E. Giacobini, “Cholinesterase Inhibitor Therapy Stabilizes Symptoms of Alzheimer
Disease,” Alzheimer Disease and Associated Disorders, vol. 14, 2000, pp. S3-S10.
69 Most trials have only measured the effects of the cholinesterase inhibitor for 6-12 months,
and one, using extrapolated data for the placebo group, suggested that patients continued to
benefit from therapy for two-three years. See Cummings, Alzheimer’s Disease.
70 R.S. Doody, et al., “Practice Parameter: Management of Dementia, Report of the Quality
Standards Subcommittee of the American Academy of Neurology,” Neurology, vol. 56,

2001, pp. 1154-1166. (Hereafter cited as Doody et al., Practice Parameter).

Table 5. FDA Approved Anti-Dementia Drugs for
Treatment of AD
Date of approval
Common (trade)andApprovedMechanism of
nam e manuf acturer i ndi cat i ons action
Donepezil11/25/1996; EisaiFor treatment ofInhibits
(Aricept)and Pfizermild to moderateAcetylcholin-
dementia ofesterase
Alzheimer’s type.
Rivastigmine 4/21/2000;For treatment ofInhibits
(Exelon)Novartis mild to moderateAcetylcholin-
dementia ofesterase
Alzheimer’s type.
Galantamine 2/28/2001; Shire,For treatment ofInhibits
(Reminyl)Inc.mild to moderateAcetylcholin-
dementia ofesterase; stimulates
Alzheimer’s type.acetylcholine
Memantine 10/27/2003;For the treatment ofBlocks glutamate
(Namenda, akaMerzmoderate to severebinding to NMDA-
Ebixa in UK)dementia of thereceptors
Alzheimer’s type
Source: CRS compilation.
A recently approved drug, memantine (Namenda™) helps to regulate the
activity of glutamate by binding to the NMDA receptor. While memantine is mildly
effective in stabilizing or improving cognition at the middle to later stages of AD,
there is no evidence at this time to show that it slows or prevents
neurodegeneration.71 Memantine therapy may be combined with other therapies like
vitamin E or a cholinesterase inhibitor, since they have a different mechanism of
action. Combination therapy may result in some cognitive and behavioral
improvement compared to placebo. Like other drugs, the effects of memantine,
however, are temporary (i.e., does not stop, cure, or reverse the disease).72
Though still at a very early stage, pharmacogenomic data may eventually prove
useful in identifying which patients are likely to respond to different medications, and
which may experience serious adverse events. For example, FDA approved labeling

71 Namanda (memantine) FDA-approved product labeling, available at [
72 P.N. Tariot, et al., “Memantine Treatment in Patients with Moderate to Severe Alzheimer
Disease Already Receiving Donepezil: A Randomized Controlled Trial,” Journal of the
American Medical Association, vol. 291(2004), pp. 317-324.

for Reminyl states that 7% of patients treated may have a genetic variation which
would slow the rate that the drug is cleared from their bodies (i.e., poor metabolizer),
potentially leading to toxic build-ups.73 The implication of this information is that
these patients may receive either a lower than recommended dosage or a different
drug to minimize their risks of adverse events.
Apoliprotein E. Apolipoprotein E (ApoE) is a well characterized lipoprotein74
that is normally found in plasma and cerebrospinal fluid. ApoE is involved in lipid
metabolism. It is particularly important for bringing cholesterol into neurons during
brain development and in response to neuronal injury. ApoE normally recycles
cholesterol from dying neurons by forming a complex with it and other lipoproteins
inside the dying cell. The complex is then released into circulation where it can bind
with a receptor site (the low density lipoprotein receptor: LPR) on a healthy cell and
become internalized. The cholesterol is released and used to make new neuronal75
dendrites or in re-building synapses.
The LPRs can also interact with APP, beta-amyloid, and other proteins involved
in lipid metabolism (such as alpha-2 macroglobulin), and may mediate the clearance76
of ApoE/beta-amyloid or protein/beta-amyloid complexes from the brain. LPR is
also found in the beta-amyloid plaque.77
There are three main forms of the ApoE lipoprotein: ApoE2, E3 and E4 which
result from variation in the ApoE gene locus. In 1993, research demonstrated that
the ApoE4 allele (i.e., form of the gene) was more frequent in AD patients compared78
to those without AD, particularly in cases with an early age of onset. In AD, ApoE4
may produce increased risk through abnormal cholesterol metabolism.79 It has been
hypothesized that ApoE4 may be involved with the degradation of amyloid or may
disrupt the removal of beta-amyloid from brain tissue leading to accelerated buildup

73 Reminyl (galantamine) FDA-approved labeling, available at [
74 A lipoprotein is a combination of a fat and a protein that usually carries other lipids —
such as cholesterol — through the blood.
75 Judes Poirier, “ApolipoproteinE: A Pharmacogenetic Target for the Treatment of
Alzheimer’s Disease,” Molecular Diagnosis, vol. 4, no. 4 (1999), pp. 335-341.
76 Rosenberg, The Molecular and Genetic Basis of AD.
77 Bradley T. Hyman, Dudley Strickland, and William Rebeck, “The Role of Low Density
Lipoptotein Receptor Related Protein (LPR) in beta-Amyloid Metabolism and Alzheimer’s
Disease,” Archives of Neurology, vol. 57, 2000, pp. 646-650.
78 See references 9-11 in Poirier, “ApolipoproteinE: A Pharmacogenetic Target for the
Treatment of Alzheimer’s Disease,” Molecular Diagnosis, vol. 4, no. 4 (1999).
79 Rosenberg, The Molecular and Genetic Basis of AD.

of the toxic protein.80 ApoE4 has been associated with other diseases, such as HIV-
associated dementia,81 cerebral palsy,82 and cardiovascular disease.83
Statins. (Cholesterol Lowering Drugs). Because cholesterol metabolism may
be linked to the generation of the beta-amyloid plaques, researchers have suggested
that cholesterol-lowering drugs (statins84) may be beneficial in reducing the85
accumulation of beta-amyloid. However, because studies to date have been
relatively small, professional groups do not recommend that a patient take statins86
solely to combat Alzheimer’s. One study investigating the ability of a statin
(simvastitin) to slow disease progression in 400 individuals with mild to moderate87
AD was recruiting patients as of September 2004.
Environmental Risk Factors. The majority of AD patients do not have a
family history. Even though it has often been speculated that late onset disease
results from exposure to an unknown environmental agent on a predisposing genetic
background, no environmental agents have been definitively proven to cause AD.88
Many of the studies linking risk factors to AD are epidemiologic (i.e., population-
based); conclusions usually support evidence of an association, but not of causality.
Additional research controlling for potential bias or unmeasured risk factors is
necessary to separate true associations from spurious ones, and to confirm the
epidemiologic findings.89 Trauma, smoking, and exposure to pesticides may increase

80 Peter H. St. George-Hyslop, “Molecular Genetics of Alzheimer’s Disease,” Biological
Psychiatry, vol. 47, 2000, pp. 183-199.
81 E.H. Coder, et al., “HIV-Infected Subjects with the E4 Allele for ApoE Have Excess
Dementia and Peripheral Neuropathy,” Nature Medicine, vol. 10, 1998, pp. 1182-1184.
82 Erika Meirelles Kalil Pessoa de Barros; Rodrugues, Consuela Junqueira; Pessoa de
Barros, Tarcisio; Bevilacqua, and Ruy Geraldo, “Presence of Apolipoprotien E4 Allele in
Cerebral Palsy,” Journal of Pediatric Orthopedics, vol. 20, 2000, pp. 786-789.
83 F.M. Van Bockxmeer, C.D. Mamotte, F.R. Gibbons, and R.R. Taylor,, “Apoliprotein
Epsilon 4 Homozygosity — A Determinant of Restinosis after Coronary Angioplasty,”
Atherosclerosis, vol. 110, 1994, pp. 195-202.
84 FDA approved statins include Atorvastatin (Lipitor®), Fluvastatin (Lescol®), Lovastatin
(Mevacor®), Pravastatin (Pravachol®), Simvastitin (Zocor®), among others, see
[ h t t p : / / www.f d a . go v/ c d e r / ] .
85 Suzana S. Petanceska; S. DeRosa; V. Olm, N Diaz, A. Sharma, T. Thomas-Bryant, K.
Duff, M. Pappolla, and L.M. Refolo, “Statin Therapy for Alzheimer’s Disease: Will It
Work?” Journal of Molecular Neuroscience, vol. 19, 2002, pp. 155-161.
86 Alzheimer’s Association, “Facts About Statins and Alzheimer’s Disease,” Feb. 10, 2003,
available at [].
87 See [].
88 Bird, Alzheimer Disease Overview.
89 Steven D. Edland, Susan Slager, and Matthew Farrer, “Genetic Association Studies in
Alzheimer’s Disease Research: Challenges and Opportunities,” Statistics in Medicine, vol.

23, 2004, pp. 169-178.

risk of developing AD.90 Other risk factors are similar to those for heart disease and
stroke (i.e., high cholesterol, high blood pressure, diabetes).91 However, it is unclear
if these risks are specific for other types of dementia or for conditions that may co-
exist with or accelerate the AD.
On the protective side, higher education, and time spent in physical or mental
activities during life have been associated with a lower risk of AD.92 Though
alcoholism has been associated with dementia, a few studies have demonstrated that
light to moderate drinking may have a beneficial effect in reducing Alzheimer’s risk,
possibly related to the antioxidant properties of alcohol or its effect on lipid
metabolism.93 Other studies suggest that dietary folic acid may protect neurons
against DNA damage by lowering levels of homocysteine.94 Folic acid can also cause
cholesterol to become oxidized into low-density lipoprotein, which is damaging to
the arteries. Low calorie diets may protect against aging in general.95 To date, none
of these potential neuroprotective dietary agents or interventions have been shown
to be of benefit for people who already have symptoms.
Infectious agents have also been investigated as having a possible role in
sporadic cases of AD. Herpes simplex virus (HSV-1) is a neurotropic infectious
agent that has been shown to be a risk factor for AD, potentially predisposing
individuals to increased inflammation, plaque and tangle formation. Most (80%-
90%) humans have antibodies to HSV-1, indicating that they have been exposed to
the virus (mostly in the form of oral cold sores). Many exposures will result in mild
or asymptomatic disease. HSV-1 reproduces in the sensory nerves near the site of
infection. It can lay dormant in the nervous system. The theory is that HSV-1
reactivation causes neuronal injury which can predispose an individual to AD. No
clinical trials have been initiated that would investigate the effectiveness of antiviral
treatments, such as acyclovir, in treating AD. A few studies have shown an increased
frequency of the ApoE4 allele in patients that test positive for HSV-1, indicating a
possible interaction between ApoE and herpes disease recurrence.96

90 Though nicotine as a treatment (binding to the nicotinic receptors) may offer some benefit,
smoking does not seem to reduce risk. See Richard Mayeux, “Epidemiology of
“Neurodegeneration,” Annual Reviews of Neuroscience, vol. 26, 2003, pp. 81-104 (Hereafter
cited as Mayeux, Epidemiology of Neurodegeneration.)
91 Monique M. Breteler, “Vascular Risk Factors for Alzheimer’s Disease: An Epidemiologic
Perspective,” Neurobiology of Aging, vol. 21, 2000, pp. 153-160.
92 Mayeux, Epidemiology of Neurodegeneration.
93 Ibid.
94 Homocysteine is an amino acid that is produced in the body. If allowed to accumulate,
it can irritate blood vessels and cause blockage.
95 Mark P. Mattson, “Gene-Diet Interactions in Brain Aging and Neurodegenerative
Disorders,” Annals of Internal Medicine, vol. 135, 2003, pp. 441-444.
96 Richard B. Pyles, “The Association of Herpes Simplex Virus and Alzheimer’s Disease:
A Potential Synthesis of Genetic and Environmental Factors,” Herpes, vol. 8, 2001, p. 64-


Some researchers have postulated links between AD and prion diseases97 due
to similarities in the biochemical mechanisms by which the disease-associated
proteins are processed.98
A major genetics initiative is now underway, sponsored by NIA in collaboration
with the Alzheimer’s Association to locate families with two or more affected
members. Histories are taken and specimens are banked for genetic testing. The
Genetics Initiative seeks to understand the relative influence of genetic and
environmental interactions contributing to AD.99
Other Potential Interventions to Reduce Risk.
Hormone Therapy. Epidemiologic studies have shown that postmenopausal
women who were taking estrogen replacement therapy had a lower incidence of AD.
However, to date, randomized trials have not confirmed any benefit. Other hormones
— such as progesterone, dehydroepiandrosterone (DHEA), and melatonin have
produced similar negative effects.100 Five trials are currently underway investigating
different hormone formulations. Until these trials are concluded, hormone therapy
is not recommended solely for treatment of AD.
Vitamins and Dietary Supplements. Free radicals are highly reactive,
chemically unstable molecules that interact with cell structures causing damage. The
most common free radical in biological systems is the radical form of oxygen. A
main theory of aging states that free radical damage occurs constantly within a cell.
When the cell can no longer repair the damage caused by free radicals, the cell dies.
Antioxidants are compounds that prevent damage to cells due to free radicals
by helping the cell eliminate them. Several studies support the concept that vitamins,
particularly vitamin E (an antioxidant) and vitamin C, may delay the onset of
symptoms of AD which are thought — in part — to result from oxidative damage.101
Some physicians recommend high dose vitamin E supplements along with standard

97 Prion diseases (also known as transmissible spongiform encephalopathies such as Mad
Cow Disease) are rapidly progressive, and uniformly fatal diseases that can affect humans
and animals. Cases of the disease are thought be either acquired (sporadic) through
infection or may be inherited. Evidence suggests that ‘prions’ are not viruses, but may be
abnormal proteins that, once in the body, have the ability to affect normal organ function.
98 Frédéric Checler and Bruno Vincent, “Alzheimer’s and Prion Diseases: Distinct
Pathologies, Common Proteolytic Denominators,” Trends in Neurosciences, vol. 25, no. 12,
Dec. 2002, pp. 616-620.
99 See [].
100 Brian R. Ott and Norma J. Owens, “Complementary and Alternative Medicines for
Alzheimer’s Disease,” Journal of Geriatric Psychiatry and Neurology, vol. 11, 1998, pp.

167-173 (Hereafter cited as Ott and Owens, Complementary and Alternative Medicines.)

101 Cummings, “Alzheimer’s Disease.”

FDA approved therapy,102 while others are not convinced.103 Studies of the potential
benefits of other vitamins, such as B1 and B12, have not been conclusive.104
Before 1994, dietary supplements were regulated by the FDA. However, since
the Dietary Supplements Health and Education Act of 1994, FDA overview of
supplements has been limited to ensuring good manufacturing practices and labeling
review. Unlike traditional medicines, FDA does not review or approve the safety and
effectiveness of a supplement before they are marketed. Thus, though the
manufacturer is responsible for ensuring the safety of dietary supplement products,
FDA can take regulatory action if a supplement represents a significant risk of illness
or injury to an individual. Labeling for supplements is limited to general statements;
manufacturers cannot portray the product as being able to “diagnose, prevent,
mitigate, treat, or cure a disease.” Both FDA and the Federal Trade Commission
(FTC) have jurisdiction over labeling and advertising of dietary supplements.105
Herbal remedies are commonly used by patients and their families. Ginkgo
Biloba is a herbal remedy that has been used in Europe for treatment of a variety of
cerebrovascular conditions. Studies have shown that gingko biloba may have
positive effects on cholinergic neurotransmission by increasing the number of
muscarinic receptors and the rate of acetylcholine turnover,106 and may act as an
antioxidant.107 Because ginkgo biloba is comprised of many active ingredients, it is
difficult to standardize compounds from different manufacturers for study, and to
optimize dosage for a study. Other studies have demonstrated no effect of herbal
remedies like ginseng and ginkgo biloba on improving cognition or memory.108
Ginseng has been used in Chinese medicine for 5000 years as a treatment for
many different conditions, such as fatigue, diabetes, and other disorders of aging. It
acts to release adrenocorticotropic hormone, which stimulates nerve growth factor
and exerts estrogen-like activity. Animal models have shown that it may stimulate

102 Doody et al., Practice Parameter. Also see [
articles/alz3.cfm], accessed Apr. 26, 2005.
103 Deborah Blacker, Mild Cognitive Impairment — No Benefit from Vitamin E, Little from
Donepezil, published at [] Apr. 13, 2005.
104 Ott and Owens, Complementary and Alternative Medicines.
105 FDA, Center for Food Safety and Applied Nutrition, “Overview of Dietary
Supplements,” at [].
106 Turan Itil and David Martorano, “Natural Substances in Psychiatry (Ginkogo Biloba in
Dementia),” Psychopharmacological Bulletin, vol. 31, 1995, pp. 147-158.
107 M. Zimmermann, et al., “Ginkgo Biloba Extract: from Molecular Mechanisms to the
Treatment of Alzheimer’s Disease,” Cellular and Molecular Biology, vol. 48, no. 6, 2002,
pp. 613-623.
108 J. Persson, et al., “The Memory-Enhancing Effects of Ginseng and Ginkgo Biloba in
Healthy Volunteers,” Psychopharmacology, vol. 172, 2004, pp. 430-434.

acetylcholine release, and have some anti-inflammatory effects. Ginseng has not
been studied specifically for AD.109
Huperzine A is a compound isolated from club moss. The dried herb has long
been used as an alternative medicine in China for the treatment of several conditions,
including schizophrenia.110 Huperzine A is a potent inhibitor of aceytlcholinesterase
that crosses the blood-brain barrier. Compared to synthetic acetylcholinesterase
inhibitors, it may have a longer duration of action and higher therapeutic index. An
early clinical trial of huperzine A and AD in China demonstrated positive results,111
and since has been approved and used clinically in China to relieve symptoms.112 A
trial of 150 patients is currently underway in the United States.
Other compounds have been evaluated for their potential to impact AD
progression, including dietary choline (in the form of lecithin, which is an emulsifier
found in processed foods) and other chemicals in food. However, well designed
clinical studies have failed to show improvements in cognition with these agents.113
Other Medications. AD patients also take a number of other drugs in an
attempt to reduce symptoms, including tranquillizers, antidepressants, mood
stabilizers, anti-anxiety drugs, hypnotics and anti-convulsants.114 The use of these
drugs primarily occurs “off-label,” meaning that few of these drugs have been
approved by FDA for use in patients with dementia or AD.115
Nonpharmacologic Intervention. Many studies have investigated the
effectiveness of behavioral modifications, and cognitive rehabilitation in delaying the
onset of cognitive decline. Interventions include the use of memory aids, music,
videotapes, sensory stimulation and relaxation. These strategies have been applied
and shown to be of varied effectiveness for patients in nursing homes or long-term116
care facilities, and are beginning to be evaluated in community and home care

109 Ott and Owens, Complementary and Alternative Medicines.
110 D.L. Bai, X.C. Tang, and X.C. He, “Huperzine A, A Potential Therapeutic Agent for
Treatment of Alzheimer’s Disease,” Current Medicinal Chemistry, vol. 7, 2000, pp. 355-374
(Hereafter cited as Bai et al., A Potential Therapeutic Agent).
111 Ott and Owens, Complementary and Alternative Medicines.
112 Bai et al., A Potential Therapeutic Agent.
113 Ott and Owens, Complementary and Alternative Medicines.
114 Ian G. McKeith, Alzheimer’s Society Information Sheet, Nov. 2000. Available at
[ ht t p: / / zhei me r s .or pr i nt _i nf o/ p_dr ugsbehavi our .ht m] .
115 Cummings, “Alzheimer’s Disease.”
116 Ibid.

Definitive diagnosis of AD is only possible upon death of the individual and
confirmation of the physical signs of AD pathology. These findings include gross or
microscopic evidence of beta-amyloid plaques, neurofibrillary tangles, degeneration
of small blood vessels, and neuronal loss.
Diagnosis of probable or possible AD while an individual is alive is based on
differential exclusion of other possible causes for the symptoms.117
Neuropsychological evaluation and cognitive testing by psychologists are the
preferred differential diagnostic methods to discriminate organic dementia from age-
related cognitive decline, cognitive difficulties related to depression and other related
disorders.118 Initial assessments typically include evidence of functional decline in
multiple cognitive domains (not just memory); a focused history and physical
examination (to take into account any sensory impairment or confounding factors);
informant reports (family, friends and caregivers); mental tests; and an evaluation of
mental health status.119 These laboratory, functional, and cognitive tests are
conducted to first rule out other causes of dementia, such as: vascular dementia,
Picks Disease, HIV infection, head trauma, substance abuse, or other mental or
systemic illness.
“Probable” AD is determined by a diagnosis of progressive dementia on the
basis of the Mini-Mental State Test or similar examination of cognitive function that
cannot be explained by the presence of another disorder based on neuropsychological
tests. Probable AD patients have deficits in at least two areas of cognition.
“Possible” AD is used when the a patient has dementia that cannot be explained by
another cause, and a deficit in only one area of cognition.120 Using the criteria of
McKhann (1984), probable AD is confirmed at autopsy with 85%-90% accuracy.121
These criteria were reviewed by the Quality Standards Subcommittee of the
American Academy of Neurology in 2001 and found to be reliable.122

117 M.B. First, ed., “Delerium, Dementia, and other Cognitive Disorders,” Diagnostic and
Statistical Manual of Mental Disorders, 4th edition (Washington, DC: American Psychiatric
Association, 1994), pp. 134-155.
118 APA Presidential Task Force on the Assessment of Age-Consistent Memory Decline and
Dementia, Guidelines for the Evaluation of Dementia and Age-Related Cognitive Decline,
Feb. 1998. Available at [].
119 Early Alzheimer’s Disease: Recognition and Assessment, Sept. 1996. Available at
[ h t t p : / / www.a h c p r . go v/ c l i n i c / a l zove r .ht m] .
120 G. McKhann, et al., “Clinical diagnosis of Alzheimer’s Disease: Report of the NINCDS-
ADRDA Work Group,” Neurology, vol. 34, July 1984, pp. 939-944.
121 D. Galasko, et al., “Clinical-Neuropathological Correlations in Alzheimer’s Disease and
related dementias.” Archives of Neurology, vol. 51, no. 9, Sept. 1994, pp. 888-895.
122 D.S. Knopman, et al., “Practice parameter: Diagnosis of Dementia, Report of the Quality
Standards Subcommittee of the American Academy of Neurology,” Neurology, vol. 56,

2001, pp. 1143-1153.

Current research efforts are largely focused on improving mechanisms of patient
assessment such as imaging techniques, genetic testing, and assessment of
environmental risk factors to better understand physical changes in the AD brain, and
their association with familial risk and environmental exposures. The goal is earlier
identification of patients at greatest risk believing that earlier identification may
afford earlier opportunities for intervention.
Brain Imaging. Structural imaging of the brain is generally recommended in
the routine initial evaluation of patients diagnosed with dementia to increase the
accuracy of the clinical diagnosis. In many cases, brain atrophy (i.e., shrinking) can
be seen on imaging tests that show structure, such as computed tomography (CT) or
magnetic resonance imaging (MRI). Given that normal aging brains can have
evidence of plaques and tangles, some are questioning the value of imaging (at least
with the current state of technology) in diagnosing early Alzheimer’s. Without an
effective treatment, doctors are not likely to recommend using imaging to screen
nonsymptomatic individuals for AD, despite widespread availability and marketing123
by commercial firms. Some of the available imaging techniques are discussed
Computed Tomography (CT) scanning uses special x-ray equipment to produce
cross sections of the body, providing detailed images of organs, bones, and other
tissues. The cross-sections eliminate much of the overlap of structures and increases
the resolution of imaging over traditional x-rays. Sometimes a special dye is used to
increase the contrast between soft and solid body parts. The CT is used to evaluate
the structure of the brain, including an assessment of its size. AD may be indicated
if brain atrophy (i.e., shrinking) is seen.
Magnetic Resonance Imaging (MRI) uses radio-frequency waves and a strong
magnetic field to provide remarkably clear and detailed pictures of internal organs
and tissues. MRI requires specialized equipment and expertise and allows evaluation
of some body structures that may not be as visible with other imaging methods.124
The MRI also evaluates brain structure and size. While it can have better resolution
than a CT scan and does not use ionizing radiation, other factors (such as the effect
on implanted metal electronic devices or the long time needed to capture an image)
may make MRI less desirable for some patients.
Positron Emission Tomography (PET) scans produce images based on how the
brain uses glucose (sugar). In a PET scan, areas of the brain that are actively
functioning or using sugar show up as red-orange spots. Dark blue or violet spots
indicate little activity. AD is suspected if a dark spot shows up in an area of the brain

123 John Fauber, “Doctors See Brain Scans as Ripe for Abuse. Alzheimer’s Fears Could
Lead to Unnecessary Procedures, They Say,” Milwaukee Journal Sentinel, July 4, 2004, at
[], accessed July 18, 2005.
124 Radiology information, at [].

where language and memory processing occurs. PET scans may detect early signs
up to 93% of the time, at a cost of about $1,500 each.125
Single photon emission computed tomography (SPECT) is another test of brain
function. SPECT evaluates blood flow in the brain following the injection of a
special imaging solution into a patient. SPECT may be more comfortable to
administer than other imaging techniques, which require that a patient be enclosed
inside the detection device. Functional tests, such as PET and SPECT, can
complement structural tests, like CT or MRI.
Despite promise for earlier diagnosis, most current imaging studies are limited
to detecting damage which has already begun. The challenge is to untangle the early
effects that are predictive for AD, while excluding normal aging or other disorders.
Some new studies are focusing on using neuroimaging techniques to untangle the
genetic and environmental influences of normal brain structure. Surprisingly, many
physical brain features — such as the distribution of gray matter in the cerebral
cortex — are under significant genetic control; where there is genetic similarity
between individuals, there is similarity in brain structure during the normal aging
process and in certain disease processes.126 Structural changes — such as brain
atrophy over time in patients with mild cognitive impairment — may improve
diagnosis. However, the clinical value of the information over the battery of tests
that are currently available remains to be established.127
Other studies are focusing on identifying and evaluating new early biomarkers
of AD that will improve the imaging process. Biomarkers are molecules that can be
tagged with a dye that can be traced through the brain with imaging studies. For
example, NIA is currently recruiting for a large Neuroimaging Initiative. This study
is the product of a public and private partnership to develop more biomarkers for AD.
It is estimated that the research will cost approximately $12 million per year. As of
July 2004, 24 companies had agreed to contribute.
Genetic Associations in Familial and Sporadic Disease. Familial AD
comprises about 25% of all cases of the disease. Heritable causes of AD are still
largely unknown. In early onset familial AD, the disease appears to be inherited in
an autosomal dominant fashion, where the risk of transmission between a parent with
AD to his/her child is 50%.128 Early onset AD has three subtypes of disease,
depending on what gene is involved. AD1 is caused by a mutation in the amyloid
precursor protein (APP) gene, AD3 by a mutation in the presenilin-1 (PSEN1) gene,

125 Daniel H.S. Silverman, et al., “Positron Emission Tomography in Evaluation of
Dementia: Regional Brain Metabolism and Long-term Outcome,” Journal of the American
Medical Association, vol. 286, no. 17, Nov. 7, 2001, pp. 2120-2127.
126 Paul Thompson, et al., “Genetic Influences on Brain Structure,” Nature Neuroscience,
Dec., vol. 4, no. 12, 2001, pp. 1-6.
127 P.J. Nestor, P. Scheltens, and J.R. Hodges, “Advances in the Early Detection of
Alzheimer’s Disease,” Nature Reviews Neuroscience, July 2004, pp. S34-S41.
128 Bird, Alzheimer Disease Overview.

and AD4 by a mutation in the presenilin-2 (PSEN2) gene.129 All of these genes may
impact how beta-amyloid is produced or cleared.130 “Presenilin” is a generic term for
a family of proteins that are found in all cell types and are highly conserved between
species. Though not proven, the gene for presenilin is thought to code for secretase,
an enzyme(s) that cleaves APP to produce the beta-amyloid peptide found in AD
plaques131 or for an unidentified protein that may regulate secretase.132
Table 6. Familial AD: Genetic Associations
and Frequency of Occurrence
Major associated gene (genea
Disease subtypelocus )Frequency
Early Onset Subtypes
AD1APP (21q21)10%-15%
AD3PSEN1 (14q24.3)20%-70%
AD4PSEN2 (1q31-q42)rare
Late Onset AD
AD2ApoE4 (19q13.2)46%b
Source: Bird, Alzheimer Disease Overview.
a. The gene locus refers to the physical location of a gene on a chromosome. Standard
nomenclature is to put the chromosome number first, followed by the chromosome
arm, and then by band where the gene is located. For example, the APP gene locus
is 21q21. This means that the gene is located on chromosome 21, the q (or long) arm,
band number 21. Knowing the gene locus can be important for researching what other
disease or health-related genes may be located in the same area (i.e., some genetic
damage can affect multiple genes and cause multiple conditions simply because the
genes are close together).
b. This statistic is interpreted as 46% of patients with AD and a family history of AD have
at least one ApoE4 allele, in either a homozygous e4/e4 (i.e., the e4 allele is on both
chromosomes) or heterozygous state (i.e, e4 on one chromosome, and another ApoE
allele on the other).

129 Summarized in On-line Mendelian Inheritance in Man (OMIM), #104300, Alzheimer
Disease, July 31, 2003. Available at [] (Hereafter cited
as OMIM, #104300 Alzheimer Disease.)
130 Kristel Sleegers and Cornelia M. van Duijn, “Alzheimer’s Disease: Genes, Pathogenesis
and Risk Prediction,” Community Genetics, vol. 4, 2001, pp. 197-203.
131 Selkoe, Alzheimer’s Disease: Mechanistic Understanding.
132 Rosenberg, The Molecular and Genetic Basis of AD.

For late onset familial AD, the mode of inheritance is unknown. Late onset AD
is thought to involve multiple susceptibility (i.e., risk increasing) genes. If someone
in a family is identified as having late onset AD, the risk to other first degree relatives
is 15%-30%.133 The major gene involved with late onset familial disease is ApoE.
ApoE does not cause AD, but is associated with an increased risk for developing AD.
People with two copies of the ApoE4 allele represent only 2%-3% of the general
population, but 15%-20% of the AD population.134 Another allele, ApoE2, is rarely
found in AD patients, and may confer a protective effect.135 ApoE3 is most
commonly found in the non-AD population. Individuals with two copies of ApoE4
allele have an eight-fold risk of developing AD by age 75 while individuals with one
copy of the allele have a three-fold increase in risk.136
Candidate genes for sporadic late onset disease have been elusive. It is possible
that the genes for the proteins involved in cholesterol metabolism in the neuron —
such as alpha-2-macroglobulin, low density lipoprotein receptor, ApoE4 and amyloid
precursor protein described earlier — may participate in a common pathway that
leads to the AD-related neurodegeneration.137 The genes for alpha-2-macroglobulin
and the low density lipoprotein receptor are on chromosome 12. Several studies have
shown linkage between sporadic AD and chromosome 12, but the actual gene
involved has been elusive.138 A gene on chromosome 10 may influence the age of
onset of AD.139 So far, there have been no associations between mutations in the tau
gene (associated with neurofibrillary tangles) and familial AD;140 however, in a
mouse model, a gene called PIN1 has been recently identified that may protect
against AD, coding for a protein that may ‘untangle’ tangles caused by the tau
protein. 141
Genetic Tests. Genetic testing can offer benefits as well as risks. Perhaps
the greatest benefit of using predictive testing in asymptomatic (i.e., healthy) adults
is the opportunity to prevent damage before it occurs. As more genes are found to

133 Bird, Alzheimer Disease Overview.
134 American College of Medical Genetics (ACMG), “Statement on Use of Apolipoprotein
E Testing for Alzheimers Disease,” Journal of the American Medical Association , vol. 274,

1995, pp. 1627-1629. Available at [],

accessed July 18, 2005 (Hereafter cited as ACMG, Statement on Use of Apolipoprotein ).
135 Bird, Alzheimer Disease Overview.
136 Rosenberg, The Molecular and Genetic Basis of AD.
137 OMIM, #104300 Alzheimer Disease.
138 Rosenberg, The Molecular and Genetic Basis of AD.
139 Testimony of NIA Director Richard Hodes, in U.S. Congress, Senate Committee on
Health, Education, Labor and Pensions Subcommittee on Aging, Breakthroughs inthnd
Alzheimer’s Disease: News You Can Use, hearing, 108 Congress, 2 session, May 11,

2004, at [].

140 Some studies have shown that mutations in the tau gene are associated with a form of
frontotemporal dementia. See Selkoe, Alzheimer’s Disease: Mechanistic Understanding.
141 Y.C. Liou, et al., “Role of the Prolyl Isomerase PIN1 in Protecting Against
Age-dependent Neurodegeneration,” Nature, vol. 424, no. 6948, 2003, pp. 556-561.

cause disease, testing may allow an individual to prepare for the eventual disability
associated with disease, and studying them will improve the understanding of disease
etiology, progression and pathology. Susceptibility testing does not identify which
individuals will eventually get the disease, but it can provide information about
individuals who are at higher risk for developing AD, so that those individuals may
avoid other environmental factors that may further increase their risk.
Pharmacogenetic or pharmacogenomic testing142 may eventually help to identify
people who could benefit from new drugs, or from genotype specific dosing regimens
for old or new drugs.
The risks of testing asymptomatic adults include a possible negative effect on
personal relationships and emotional well-being for those who test positive, and may
offer a false sense of security for those who test negative. Clinical laboratory tests
are available for ApoE4, APP, PSEN1 and PSEN2.
A consensus statement of the American College of Medical Genetics (ACMG),
the American Society of Human Genetics (ASHG), the American Academy of
Neurology (AAN) and the American Pediatric Association (APA) agreed that
although there is strong association between AD and ApoE4, testing is not
recommended for the general population. The statement stressed that susceptibility
or predictive testing is only valuable if the course of the condition can be affected by
lifestyle changes or early drug intervention (prevention or alleviation).143 Others feel
that although testing for the ApoE4 allele is not widely recommended, identification
of the e4/e4 genotype may increase the sensitivity of traditional diagnosis up to 97%
in a symptomatic patient with family history of dementia. Diagnostic testing of
asymptomatic family members for PSEN1, APP, or PSEN2 is only recommended if
a mutation has already been identified in a family member with Alzheimer’s.144
Once a mutation is known in a family to be associated with a disease, testing in
other situations — such as in prenatal or preimplantation diagnostic testing145 — is
possible. Prenatal testing for PSEN1, PSEN2 and APP mutations is possible for
families where a mutation has been identified in association with disease. However,

142 Pharmacogenetic testing investigates variations that are inherited in a person’s DNA that
are associated with how that individual’s body reacts to drugs. Studies in pharmacogenetics
generally look for markers that will predict whether an individual will have an adverse
reaction to a drug, but can also investigate other aspects of drug metabolism.
Pharmacogenomic testing looks at the entire complement of gene products (including
proteins and enzymes) that are expressed in association with an individual’s reaction to
specific drugs.
143 ACMG, Statement on Use of Apolipoprotein.
144 Bird, Alzheimer Disease Overview.
145 Prenatal diagnosis is a process by which a sample of fetal cells is collected from a
pregnant woman through a procedure called amniocentesis, which relies on a needle being
inserted into the uterus during pregnancy. The cells can be cultured and analyzed for
genetic diseases or conditions for which the cause is known. Preimplantation diagnosis
involves the examination of products of conception (such as an early cell from a developing
embryo) or other by-product of in vitro fertilization (IVF), for genetic diseases or conditions.
Only embryos lacking the genetic disease gene are implanted in the uterus.

GeneTests (an online resource for locating genetic testing laboratories and associated
services) reports that no labs are offering testing for that purpose. Generally, requests
for prenatal testing for adult conditions is uncommon, and is not supported by
professional associations.146 Despite the recommendations, there was a report of a
case of preimplantation diagnosis in a mother with an APP mutation. The consensus
of the professional community is not to test children for adult onset diseases because
of the possibility of stigmatization, or serious educational and career implications.
Investigational Treatments
New Compounds. PhRMA, a leading association for pharmaceutical
manufacturers, indicates that there are 25 drugs under investigation for AD
(excluding the agents used in gene therapy); five have been approved by FDA either147
for AD or other indications (i.e., they are already on the market). Of the 20
unapproved products, only three (Alzhemed, Ampalex/CX516, and NS 2330) are148
registered with the federal government. See []. It is
too soon to tell which, if any of these new treatments will be effective in treating AD.
However, to put this research in the context of what is already available (refer to
section Physiological Changes and Pharmaceutical Targets), of the remaining 17 new
compounds currently under investigation:
!2 compounds target beta-amyloid formation, aggregation or
clearance (one is an alternate form of an anti-inflammatory drug);
!1 compound is thought to inhibit neuroinflammation;
!1 compound modulates calcium channel activity;
!2 compounds affect the acetylcholine neurotransmitter system;
!2 compounds are neurotrophic (i.e., “nerve growing”) agents;
!2 compounds are monoamine oxidase inhibitors (one of which also
has anti-acetylcholinesterase activity and neuroprotective activity);
!3 compounds target mood, anxiety and/or behavioral symptoms; and
!4 have an unknown, unspecified or unpublished mechanism of

146 ACMG, Statement on Use of Apolipoprotein.
147 PhRMA Medicines in Development for Older Americans, at [
148 Companies are required to inform the federal government that they plan to conduct
clinical trials by filing an Investigational New Drug (IND) application with the FDA. Once
approved, companies are also supposed to disclose the existence of many ongoing clinical
studies to the federal government in a database, such as [].
Despite this requirement, few companies actually submit information to the database. A
Washington Post article noted that only 13% of the 5,754 trials listed in the federal clinical
trials database,, were industry sponsored, in contrast to estimates that
over 80% of trials are funded by for-profit companies. See Shankar Vedantam,
“Drugmakers Prefer Silence on Test Data,” Washington Post, July 6, 2004, p. A01. See
CRS Report RL32832, Clinical Trials Reporting and Publication, by Erin Williams.

Gene Therapy. Gene therapy is a procedure that uses genetically modified
cells (from the patient or another source) or infectious agents to: introduce normal
genetic sequences to replace deficient ones; to selectively kill certain cells (e.g.,
diseased cells); to make a body cell resistant to different types of infection (e.g., HIV149
infection) or to stimulate a patient’s immune function. Gene therapy trials must
be approved by both the FDA (for use of the investigational therapeutic agent) and
the NIH Recombinant DNA Advisory Commitee (RAC) (for important human factor
considerations and technical review) prior to initiation.
In 2001, doctors at the University of California, San Diego (UCSD) performed
the first surgery to implant genetically modified tissue into the brain of an AD
patient. In the therapy, skin samples from the patient (who had early-stage
Alzheimer’s) were collected and modified in the laboratory to introduce genes for
nerve growth factor (NGF). After the researcher verified that the cells produced the
NGF, they used a surgical procedure to implant the modified cells in damaged areas
of the brain. A total of eight people underwent the procedure, and were followed for150
a year. No adverse events were noted in any of the patients one year after surgery.
PET imaging of the patients showed increased metabolic activity in the areas of the
brains of patients after the treatment with NGF, and an autopsy of a patient who died
(death not related to treatment) showed active NGF production in the brain, with a151
growth response of brain cells to the NGF delivery.
A second trial is underway by researchers at Rush University Medical Center
and sponsored by Ceregene, Inc. to evaluate the safety, tolerability, and efficacy of
a new agent, CERE-110, in subjects with mild to moderate AD. CERE-110 is a
commercially developed agent that uses an adeno-associated virus to deliver NGF to152
brain cells. The CERE-110 trial is listed with the federal government, at
[] .
Stem Cells and Tissue Regeneration. Stem cells are cells within the
body that have not yet become specialized to perform a single function (i.e., they are
not blood, nerve, skin, muscular, etc). There are two types of stem cells: adult and
embryonic. Adult stem cells circulate the body in low numbers, and retain the ability
to become a specialized cell if needed. Much research has focused on harvesting and
using adult stem cells to repair tissue damage (such as spinal cord injury and brain
damage). Embryonic stem cells are derived from an early stage embryo. Though

149 P.M. Cannon and W.F. Anderson, “Retroviral Vectors for Gene Therapy,” in NS
Templeton and D.D. Lasic eds., Gene Therapy Therapeutic Mechanisms and Strategies
(New York, NY: Marcel Dekker, Inc., 2000), pp. 1-16.
150 See Gene Therapy for Alzheimer’s Disease — Clinical Trial Information, at
[] .
151 See Preliminary Results Are Promising in Alzheimer’s Gene Therapy Trial, online at
[ — pra042204.php].
152 See protocol number 0401-623, “A Phase I/II, Dose-Escalating, Randomized and
Controlled Study to Assess the Safety, Tolerability, and Efficacy of Cere-110
[Adeno-associated Virus (Aav)-based, Vector-mediated Delivery of Beta-nerve Growth
Factor (Ngf)] in Subjects with Mild to Moderate Alzheimer’s Disease,” at
[ h t t p : / / mc r i] .

they may have a greater potential to become different types of cells than adult stem
cells, research using them is highly controversial, currently prohibited to existing
lines, and is the subject of heated debate in Congress.153
Despite the controversy, some scientists believe there is potential for use of
stem cells in AD.154 Much of the federally funded research aims at further
understanding the mechanisms and regulation of how neural stem cells (NSC)
differentiate into specialized neurons. There are major barriers to overcome before
stem cell therapy can become a clinical reality in the treatment of AD. Because
memory deterioration involves the degeneration of specific cells (cholinergic
neurons), scientists have to figure out how to replace a specific cell type (see also the
section, “Neurotransmitters”). This is complicated because the beta-amyloid
formation process in the diseased brain may create an environment that influences
what type of cell the NSC becomes.155 Two studies currently underway are focusing
on using NSCs to repair damage to AD brains in an animal model.156 Given the
scientific and political barriers, clinical therapies using stem cells — while promising
— are not likely to be available in the near term.
The National Human Neural Stem Cell Resource provides neural stem cells
harvested from the post-natal, post-mortem, human brain to the research community
for stem cell research. Several brain areas as well as cultures from normal and
genetically mutant specimens are represented in the Resource.157
Vaccination. Because evidence suggests that the formation of plaques may
elicit an immune response, researchers have hypothesized that antibodies against
beta-amyloid may either prevent its accumulation or facilitate its clearance by
launching an immune attack against the plaque. Despite early promise, a clinical trial
of active vaccination against beta-amyloid had to be stopped due to complications.
Following the trial, analysis of a small group of patients suggested that vaccination
resulted in a reduction in disease progression in patients whose bodies generated158
antibodies against the beta-amyloid. Given this promise, some scientists believe

153 More a more detailed discussion of stem cells and the debate concerning the use of stem
cells in research, see CRS Report RL31015, Stem Cell Research, by Judith A. Johnson and
Erin Williams.
154 Statement of Richard J. Hodes, Director, National Institute on Aging, in U.S. Congress,
Senate, Subcommittee of the Committee on Appropriations, Alzheimer’s Disease, 2003th
hearings, 108 Cong., Mar. 23, 2004, S.Hrg. 108-130, [
cgi-bin/ge tdoc.cgi ?dbname =108_senat e_hearings &docid=f:89018.wais.pdf].
155 Kiminobu Sugaya, “Neuroreplacement Therapy and Stem Cell Biology under Disease
Conditions,” Cellular and Molecular Life Sciences, vol. 60, 2003, pp. 1891-1902.
156 Based on a search of the CRISP (Computer Retrieval of Information on Scientific
Projects) database, search terms “Alzheimer’s” and “Stem Cells,” accessed Aug. 25, 2004,
at [].
157 See [].
158 C. Hock, et al., “Antibodies Against Beta-Amyloid Slow Cognitive Decline in
Alzheimer’s Disease,” Neuron, vol. 38, 2003, pp. 547-554 in Cummings, Alzheimer’s

that passive immunization159 may be safer. Even if immunization were successful in
helping the body prevent beta-amyloid accumulation by facilitating clearance of the
peptide, it is unclear whether vaccination in later life will be able to reverse cognitive
defects or brain pathology.
Currently, there are no human trials of AD vaccines registered with the federal
government. However, there are 15 federally funded research studies investigating
new formulations of AD vaccines in mouse models.160

158 (...continued)
159 Active immunization is when a patient is given a vaccination consisting of an
administered dose of either an infectious agent or small molecule (such as a protein) before
exposure to the element, in an attempt to get the patient’s immune system to make
antibodies. At some future point when the patient contacts the agent (beta-amyloid), the
antibodies will then fight the agent to rid the body of the harmful agent. Passive
immunization is when a patient is given antibodies directly to fight an agent or molecule.
Passive immunization is usually given when the patient has already been exposed to the
160 CRISP search of “Alzheimer’s Vaccine,” at [http://crisp.cit.nih. gov].

Appendix A. Glossary
Allele — The specific version of a gene that is located on a chromosome. Normally,
individuals will have two alleles for each gene, one located on each chromosome in
a set.
Amygadala — The amygdala is an almond-shaped mass of gray matter, one in each
hemisphere of the brain, that is associated with feelings of fear and aggression and
is important for visual learning and memory.
Amyloid precursor protein — A large protein which is cleaved into smaller
proteins (or peptides), one of which is the beta-amyloid form that accumulates in the
brains of patients with AD as beta-amyloid plaques.
Autosomal dominant — A mode of inheritance in which a child has a 50% chance
of inheriting a particular trait, condition or disease from their parent.
Beta-amyloid — A cleavage product of amyloid precursor protein, this peptide
forms a beta-pleated sheet which accumulates in the brains of AD patients as plaques.
Chromosome — A long stretch of DNA that contains genes and other information.
Humans have 46 chromosomes, which arrange during cell division in pairs of two
(23 sets). During reproduction, each parent contributes one set of 23 chromosomes
to their offspring.
Dementia — A clinical state characterized by loss of mental function.
DNA — Deoxyribonucleic acid; a large, double-stranded nucleic acid molecule
arranged like a staircase (double helix); the chemical substance of which genes are
Early onset AD — When symptoms appear before age 65.
Enzyme — A special kind of protein that can cause biochemical reactions to occur.
Familial AD — Alzheimer’s disease that runs in family.
Family history — A record of diseases, conditions, or traits in a nuclear (parents,
children) or extended (grandparents, aunts, uncles, cousins, etc.) family.
FDA — United States Food and Drug Administration.
First degree relative — A first degree relative is defined as a parent, brother, sister
or child of an individual. A second degree relative would include grandparents,
aunts, uncles, nephews or nieces (children of aunts and uncles).
Gene — A stretch of DNA that carries information from one generation to the next
and codes for a specific protein.

Genotype — The specific alleles (forms of genes) in a cell. For example, everyone
has a gene(s) for eye color. The genotype would be the specific alleles that resulted
in a particular phenotype like blue eyes.
Heterozygous — When the alleles (forms of a gene) on both chromosomes (one
inherited from mother, one from father) are different.
HHS — United States Department of Health and Human Services.
Hippocampus — The hippocampus is part of the lower brain, one part within each
of the cerebral hemispheres. It is concerned with basic drives, emotions, and
short-term memory.
Homozygous — When the alleles (forms of a gene) on both chromosomes (one
inherited from mother, one inherited from father) are the same.
Late onset AD — When symptoms appear at or after age 65.
Mode of inheritance — The pattern by which a trait, characteristic, disease, disorder
or condition is transmitted from a parent to a child.
Mutation — In contrast to a chromosome abnormality, a mutation is an individual
change in a DNA sequence that accounts for genetic variations. Mutations may be
harmful if they prevent genes from making normal gene products. These mutations
can cause, or increase susceptibility to, specific diseases or conditions. A mutation
can be inherited from a person’s parents, or acquired from exposure to a toxic
environmental condition
Multifactorial — Multiple causes.
Neocortex — The neocortex is a thin layer of nerve cells that covers the cerebral
cortex (top brain) that is involved with higher brain functions such as learning.
Neurofibrillary tangles — Neurofibrillary tangles are characteristic “flame shaped”
structures in the AD brain. The tangles are accumulations of abnormal forms of tau
proteins, which make up microtubules in a normal nerve cell. The microtubules are
The microtubules are the structures that neurons use to carry substances within the
body of the cell and to its many projections.
Neurotransmitter — A neurotransmitter is a chemical made by a nerve cell that is
used to transmit signals from one neuron to either another neuron or other cell (such
as a skeletal muscle cell or heart muscle cell).
Neuron — Another name for a nerve cell.
Peptide — A short or truncated protein.
Pharmacogenetic — Variations that are inherited in a person’s DNA that are
associated with how that individual’s body reacts to drugs. Studies in
pharmacogenetics generally look for markers that will predict whether an individual

will have an adverse reaction to a drug, but can also investigate other aspects of drug
Pharmacogenomic — The entire complement of gene products that are expressed
in association with an individual’s reaction to specific drugs. Studies in
pharmacogenomics investigate many aspects of the drug metabolism process; and
many focus on identifying patterns of gene product expression that change in
response to drug treatment, and whether those changes indicate that the drug is
Phenotype — Observable characteristics (appearance) of an individual that are
determined by the interaction of genes, gene products and the environment.
Phenotypic testing identifies genetic variation by looking at the structure or function
of a gene products rather than looking directly at the gene.
Plaques — A buildup of the abnormal form of beta-amyloid in the brain which also
contains various lipids and inflammatory proteins. The buildup makes a dark round
spot in the brain tissue, called the plaque.
Polygenic — Multiple genes.
Predictive testing — Testing a currently healthy or asymptomatic individual’s DNA
for variations that may be associated with future disease.
Preimplantation diagnosis — A testing procedure performed on human eggs, sperm
or embryos before implantation in the uterus to determine whether or not certain
genetic disease, conditions, or traits are present.
Prenatal diagnosis — A testing procedure done on cells that are shed from a
developing fetus, usually between the third and fourth month of pregnancy, to
determine if the fetus has a genetic disease, condition or trait.
Protein — A string of amino acids that form a three-dimensional structure to carry
out the functions of a cell. Proteins can be structural (give the cell shape), regulatory
(act to turn genes “on or off”), or enzymatic (cause biochemical reactions to occur).
Secretase — An enzyme or family of enzymes that are thought to cleave amyloid
precursor protein into smaller peptides, one of which is the beta-amyloid peptide
found in AD plaques.
Stem cells — Unspecialized cells in an adult organism or embryo that have the
potential to become differentiated into any kind of functional cell (e.g., nerve,
muscle, blood).
Susceptibility — A possibility of disease caused or influenced by a genotype. Most
diseases result from a complex set of both genetic and environmental causes. Some
harmful gene mutations increase the likelihood that a person will develop a specific