Genetics in Medicine

April 2008 䡠 Vol. 10 䡠 No. 4

collaborative review

Genetic aspects of Alzheimer disease

Thomas D. Bird, MD
Alzheimer disease is the most common cause of dementia and represents a major public health problem. The
neuropathologic findings of amyloid-␤ plaques and tau containing neurofibrillary tangles represent important
molecular clues to the underlying pathogenesis. Genetic factors are well recognized, but complicated. Three rare
forms of autosomal-dominant early-onset familial Alzheimer disease have been identified and are associated with
mutations in amyloid precursor protein, presenilin 1, and presenilin 2 genes. The more common late-onset form
of Alzheimer disease is assumed to be polygenic/multifactorial. However, thus far the only clearly identified genetic
risk factor for Alzheimer disease is Apo lipoprotein E. The ⑀4 allele of Apo lipoprotein E influences age at onset of
Alzheimer disease, but is neither necessary nor sufficient for the disease. The search continues for the discovery
of additional genetic influences. Genet Med 2008:10(4):231–239.
Key Words: Alzheimer, dementia, amyloid, neurogenetics

Table of Contents

Overview ................................................................................................................. 231 Risk to family members– early-onset familial Alzheimer disease .............. 235
Clinical manifestations of Alzheimer disease ............................................... 231 Related genetic counseling issue ................................................................... 235
Establishing the diagnosis of Alzheimer disease ......................................... 231 Use of APOE genotyping for predictive testing ......................................... 235
Differential diagnosis of Alzheimer disease .................................................. 232 Down syndrome ............................................................................................. 236
Prevalence of Alzheimer disease .................................................................... 232 Testing of at-risk asymptomatic EOAD family members ............................. 236
Causes .................................................................................................................... 232 Testing of at-risk asymptomatic adults ...................................................... 236
Environmental causes ...................................................................................... 233 Testing of at-risk individuals during childhood ......................................... 236
Heritable causes .................................................................................................233 Prenatal testing ................................................................................................. 236
Chromosomal ................................................................................................. 233 Preimplantation genetic diagnosis ................................................................. 236
Down syndrome ......................................................................................... 233 Management .......................................................................................................... 236
Single gene ................................................................................................ 233 Treatment of manifestations ........................................................................... 236
Late-onset familial Alzheimer disease ................................................... 233 Therapies under investigation ......................................................................... 236
Early onset familial Alzheimer disease ...................................................... 233 Other ................................................................................................................... 236
Unknown cause ................................................................................................. 234 Genetics clinics ............................................................................................. 236
Evaluation Strategy ............................................................................................... 234 Support groups .............................................................................................. 236
Family history ..................................................................................................... 234 Summary ..................................................................................................................237
Molecular genetic testing ................................................................................ 234 Disease characteristics .................................................................................... 237
Late-onset familial AD .................................................................................. 234 Diagnosis/testing ............................................................................................. 237
Early-onset familial AD ................................................................................. 235 Management ...................................................................................................... 237
Genetic Counseling ............................................................................................... 235 Genetic counseling ........................................................................................... 237
Mode of inheritance .......................................................................................... 235 Resources .............................................................................................................. 237
Risk to family members–late-onset nonfamilial Alzheimer disease .......... 235

Clinical manifestations of Alzheimer disease features, increased muscle tone, myoclonus, incontinence, and
The clinical manifestation of Alzheimer disease (AD) is de- mutism occur.1
mentia that typically begins with subtle and poorly recognized Death usually results from general inanition, malnutrition,
failure of memory and slowly becomes more severe and, even- and pneumonia. The typical clinical duration of the disease is
tually, incapacitating. Other common findings include confu- 8 –10 years, with a range from 1 to 25 years.
sion, poor judgment, language disturbance, agitation, with-
Establishing the diagnosis of Alzheimer disease
drawal, and hallucinations. Occasionally, seizures, Parkinsonian
Establishing the diagnosis of Alzheimer disease relies on
clinical-neuropathologic assessment.1 Neuropathologic find-
From the University of Washington, Geriatric Research Education and Clinical Center, VA ings on autopsy examination remain the gold standard for di-
Puget Sound Health Care System, Seattle, Washington. agnosis of AD. The clinical diagnosis of AD (before autopsy
Thomas D. Bird, MD, University of Washington, Geriatric Research Education and Clinical confirmation) is correct about 80 –90% of the time.2
Center, VA Puget Sound Health Care System, Seattle, Washington. E-mail: tomnroz@
u.washington.edu. ● Clinical signs: slowly progressive dementia
Disclosure: Dr. Bird receives licensing fees from Athena Diagnostics, Inc. ● Neuroimaging: gross cerebral cortical atrophy3
Submitted for publication January 11, 2008.
● Neuropathologic findings: microscopic extracellular amy-
Accepted for publication January 29, 2008.
DOI: 10.1097/GIM.0b013e31816b64dc loid-␤ (A␤)-amyloid neuritic plaques, intraneuronal neu-

Genetics IN Medicine 231

Bird

Table 1
Causes of Alzheimer disease
Cause % of cases
Chromosomal (Down syndrome) ⬍1
Familial ⬃25
Late-onset familial (AD2) 15–25
Early-onset familial AD (AD1, AD3, AD4) ⬍2
Unknown (includes genetic/environment interactions) ⬃75

ist.4,5 Aggregation of alpha-synuclein in the form of Lewy

bodies may also be found in neurons in the amygdala.6

Differential diagnosis of Alzheimer disease

Differential diagnosis of AD includes other causes of de-
mentia, especially treatable forms of cognitive decline, such as
depression, chronic drug intoxication, chronic central nervous
system infection, thyroid disease, vitamin deficiencies (espe-
cially B12 and thiamine), central nervous system angitis, and
normal-pressure hydrocephalus.1
Other degenerative disorders associated with dementia, such as
frontotemporal dementia, including frontotemporal dementia
with parkinsonism-17, Picks disease, Parkinson disease, diffuse
Lewy body disease, Creutzfeldt-Jakob disease, and cerebral auto-
somal dominant arteriopathy with subcortical infarcts and leu-
koencephalopathy (CADASIL), may also be confused with AD.7
Computerized tomography and magnetic resonance imag-
ing are valuable for identifying some of these other causes of
Fig. 1. Normal adult brain (top) compared with Alzheimer brain (bottom) showing dementia, including neoplasms, normal-pressure hydroceph-
marked diffuse cortical atrophy and ventricular enlargement. alus, frontotemporal dementia, and cerebral vascular disease.

Prevalence of Alzheimer disease

AD is the most common cause of dementia in North Amer-
ica and Europe, with an estimate of 4 million affected individ-
uals in the United States.
The prevalence of AD increases with age. Mild memory loss
is often called mild cognitive impairment. In many persons
mild cognitive impairment is considered an early stage of AD.
The incidence of AD rises from 2.8 per 1000 person years in
the 65– 69 years age group to 56.1 per 1000 person years in the
older than 90-year age group.8 Approximately 10% of persons
older than 70 years have significant memory loss and more
than half of these individuals have AD. An estimated 25– 45%
of persons older than 85 years have dementia.
Fig. 2. Microscopic neuropathology of Alzheimer disease showing a neuritic plaque
(lower left hand corner) and neurofibrillary tangles (upper right hand corner). CAUSES
About 1– 6% of all AD is early onset (before age 60 – 65
rofibrillary tangles, and amyloid angiopathy at postmor- years) and about 60% of early-onset AD is familial, with 13%
tem examination (Figs. 1 and 2). The plaques should stain seeming to be inherited in an autosomal-dominant manner
positively with A␤-amyloid antibodies and negative for (Table 1).9,10
prion antibodies, which are diagnostic of prion diseases. The distinction between early-onset familial AD (EOFAD,
The numbers of plaques and tangles must exceed those onset before age 60 – 65 years) and late-onset familial AD (on-
found in age-matched controls without dementia. Guide- set after age 60 – 65 years) is somewhat arbitrary. Early-onset
lines for the quantitative assessment of these changes ex- cases can occur in families with generally late-onset disease.11

232 Genetics IN Medicine

 Genetic aspects of Alzheimer disease

Table 2 ● Well-documented association of late-onset familial AD

Late-onset familial Alzheimer’s disease: molecular genetics (FAD) with the APOE e4 allele. The APOE e4 allele, by
Locus Gene Chromosomal Protein Test unknown mechanisms, seems to affect age of onset by
name symbol locus name availability shifting the onset toward an earlier age.31,32
AD2 APOE 19q13.2 ApolipoproteinE Clinical ● Several other potential genes are under investigation:
● SORL1 on chromosome 11q23, a protein involved with
Environmental causes amyloid precursor protein (APP) trafficking33
● A2M on chromosome 1234 –37
No environmental agents (e.g., head trauma, viruses, toxins,
● GST01 and GST02 on chromosome 1038
low education level) have been proven to be directly involved
● GAB2 on chromosome 11q14 interacting with the
in the pathogenesis of AD. It is often speculated that late-onset
APOE e4 allele39
AD is the result of unknown environmental factors acting on a
predisposing genetic background.12 Twin studies have impli- ● Several other potential loci are under investigation on the
cated both genes and environment.13 following chromosomes:

Heritable causes ● 1240 – 43

● 1044 – 48
Chromosomal ● 2q, 9p, and 15q49,50
Down syndrome. Essentially, all persons with Down syndrome ● 19p1351
(DS) (trisomy 21) develop the neuropathologic hallmarks of ● 7q3652
AD after 40 years. More than half of individuals with DS also ● 9q22 (UBQLN1)53–56
show, if carefully observed or tested, clinical evidence of cog-
nitive decline.14 The presumed reason for this association is the ● Studies of late-onset AD in a genetically isolated Dutch
lifelong overexpression of the APP gene on chromosome 21 population have suggested linkage of AD to markers on
encoding the amyloid precursor protein and the resultant chromosome 1q22, 3q23, 10q22, and 11q25.57
overproduction of ␤-amyloid in the brains of persons who are
trisomic for this gene. Early-onset familial Alzheimer disease
The A␤ deposition in the brain may begin in the first decade
● Clinical features: EOFAD refers to families in which mul-
of life in persons with DS.15 AD was not noted clinically or
pathologically in a 78-year-old woman with partial trisomy 21, tiple cases of AD occur with the mean age of onset usually
who did not have an extra copy of the APP gene.16 Two studies before age 65 years, although some studies have used age
have found no association of Apo E genotype with age of onset 60 or 70 years. Age of onset is usually in the 40s or early
of dementia in DS,17,18 but one study did find an association of 50s, although onset in the 30s and early 60s has been re-
onset age with a polymorphism in the APP gene.18 Schupf et ported. Campion et al.10 found a prevalence of early-onset
al.19 found an unexplained increased risk for AD in mothers AD in the general population of 41.2 per 100,000 persons
younger than 35 years, who gave birth to children with DS. at risk (ages 40 –59 years). Sixty-one percent of these in-
dividuals with early-onset AD had a positive family history,
Single gene. About 25% of AD is familial (i.e., two or more and 13% met stringent criteria for autosomal-dominant in-
family members have AD). Familial cases seem to have the heritance (i.e., affected individuals in three generations).
same clinical and pathologic phenotypes as nonfamilial cases EOFAD cannot be clinically distinguished from nonfamilial
(i.e., an individual with AD and no known family history of AD except on the basis of family history and age of onset. The
AD)20,21 and are thus distinguished only by family history or by dementia phenotype is similar to that of late-onset AD,
molecular genetic testing. A large volume of research on the sometimes with a long prodrome.58 – 60
molecular and genetic basis of AD has been summarized by ● Molecular genetics: At least three subtypes of EOFAD (AD1,
Rosenberg,22 Sleegers and van Duijn,23 Nussbaum and Ellis,24 AD3, and AD4) have been identified based on the causative
Goedert and Spillantini,25 and Roses and Saunders.26 gene. The relative proportion of each subtype and the caus-
ative genes are summarized in Table 3.10,61– 63 The APP is
Late-onset familial Alzheimer disease. Many families have mul- cleaved by alpha- and gamma-secretases to form the A beta-
tiple affected members, most or all of whom have onset of peptide, which is the primary component of the extracellular
dementia after age 60 or 65 years (Table 2). Disease duration is amyloid plaque deposited in AD (Fig. 3). Presenilin 1 (PS1)
typically 8 –10 years, but ranges from 2 to 25 years. Investiga- is part of the gamma-secretase complex (and PS2 is a close
tions have supported the concept that late-onset AD is a com- homolog of PS1). Thus, the three primary genes associated
plex disorder that may involve multiple susceptibility genes with EOFAD are all related to APP and A beta-amyloid mo-
(reviewed and summarized by Kamboh,27 Bertram and lecular biology. It is likely that other genes will be identified as
Tanzi,28 Serretti et al.,29 and Roses and Saunders26). Bertram et a cause of EOFAD because kindreds with autosomal-domi-
al.30 have performed a meta-analysis on these data. The follow- nant FAD with no known mutations in presenilin 1
ing information are currently available: (PSEN1), PSEN2, or APP have been described.63,64

April 2008 䡠 Vol. 10 䡠 No. 4 233

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Table 3
Early-onset familial Alzheimer disease (EOFAD): molecular genetics
Locus name Proportion of EOFAD Gene symbol Chromosomal locus Protein name Test availability
AD3 20–70% PSEN1 14q24.3 Presenilin-1 Clinical
AD1 10–15% APP 21q21 Amyloid beta A4 protein Clinical
AD4 Rare PSEN2 1q31-q42 Presenilin-2 Clinical

EVALUATION STRATEGY
Family history
A three-generation family history with close attention to the
history of individuals with dementia should be obtained. For each
affected individual, the age of onset of dementia should be noted.
Generally, individuals with onset before age 65 years are consid-
ered to have early-onset AD and those with onset after age 65 years
are considered to have late-onset AD. Medical records of affected
family members, including reports of neuroimaging studies and
autopsy examinations, should be obtained.
● The diagnosis of EOFAD is made in families with multiple
cases of AD in which the mean age of onset is before age
60 – 65 years.
● The diagnosis of late-onset FAD is made in families with
multiple cases of AD in which the mean age of onset is
Fig. 3. Molecular aspects of the APP gene and protein showing the sites of cleavage by after age 60 – 65 years.
␣, ␤, and ␥ secretases, production of the A␤ peptide (upper right), and sites of several
disease causing mutations (bottom line).
Molecular genetic testing

Table 4 Late-onset familial AD

Percent of APOE genotypes in controls and individuals with AD The association of one or two copies of the APOE allele e4
Individuals with AD (i.e., genotypes e2/e4, e3/e4, e4/e4) with late-onset AD is well
All individuals and positive family documented (Table 4).32,66,67
APOE Normal controls with AD history of dementiaa
genotype (n ⫽ 304) (n ⫽ 233) (n ⫽ 85) ● The association between APOE e4 and AD is greatest
e2/e2 1.3% 0% 0% when the individual has a positive family history of de-
e2/e3 12.5% 3.4% 3.5% mentia. The last column of Table 4 largely represents late-
onset familial AD.
e2/e4 4.9% 4.3% 8.2%
● The strongest association between the APOE e4 allele and
e3/e3 59.9% 38.2% 23.5% AD, relative to the normal control population, is with the
e3/e4 20.7% 41.2% 45.9% e4/e4 genotype. That genotype occurs in about 1% of the
e4/e4 0.7% 12.9% 18.8% normal control population and in nearly 19% of the fa-
milial AD population.
Modified from Jarvik G, Larson EB, Goddard K, Schellenberg GD, et al. Influ-
ence of apolipoprotein E genotype on the transmission of Alzheimer disease in ● In individuals who have the clinical diagnosis of AD, the
a community-based sample. Am J Hum Genet 1996;58:191–200. probability that AD is the correct diagnosis is increased to
a
Most families would be considered to have late-onset familial AD. about 97% in the presence of the APOE e4/e4 genotype.68
● The increased risk of AD associated with one APOE e4
Unknown causes allele or two APOE e4 alleles is also found in African-
Individuals with nonfamilial AD meet the diagnostic criteria Americans69 and Caribbean Hispanics.70
for AD and have a negative family history. Onset can be any- ● Approximately 42% of persons with AD do not have an
time in adulthood. The exact pathogenesis of the disease is APOE e4 allele. Thus, APOE genotyping is not specific for
unknown. A common hypothesis is that nonfamilial AD is AD. The absence of an APOE e4 allele does not rule out
multifactorial and results from a combination of aging, genetic the diagnosis of AD2.
predisposition, and exposure to one or more environmental ● Breitner et al.71 have estimated lifetime risks for devel-
agents, such as head trauma, viruses, and/or toxins65 although oping AD based on gender and APOE genotype (see
no environmental agents have been proven to be directly in- Testing of At-risk Asymptomatic Individuals under
volved in the pathogenesis of AD. Genetic Counseling).

234 Genetics IN Medicine

 Genetic aspects of Alzheimer disease

The usefulness of APOE genotyping in clinical diagnosis and overall lifetime risk to any individual of developing dementia is
risk assessment remains unclear (Statements and Policies Re- approximately 10 –12%.
garding Genetic Testing). First-degree relatives of a person with AD have a cumulative
lifetime risk of developing AD of about 15–30%, which is typ-
● Although the presence of one APOE e4 allele or two APOE
ically reported as a 20 –25% risk.77,78 This risk is about 2.5 times
e4 alleles is neither necessary nor sufficient to establish a
that of the background risk (⬃27% vs. 10.4%).79,80
diagnosis of AD, APOE genotyping may have an adjunct
Disagreement exists as to whether the age of onset of the
role in the diagnosis of AD because a large proportion of
affected person changes the risk to first-degree relatives. One
individuals with one APOE e4 allele or two APOE e4 al-
study found that early-onset AD increased the risk,78 whereas
leles who are demented have been found to have neuro-
another study did not.77
pathologic confirmation of AD at autopsy.2,66,72,73
The number of additional affected family members proba-
● In contrast, APOE genotyping was not found to be of
bly increases the risk to close relatives, but the magnitude of
significant diagnostic use in identifying AD in a commu-
that increase is unclear unless the pattern in the family is char-
nity-based sample with late-onset dementia.74
acteristic of autosomal-dominant inheritance. Having two,
There is some evidence that the APOE e2 allele may have a three, or more affected family members probably raises the risk
protective effect in regard to risk for AD (Table 4). to other first-degree relatives in excess of that noted above for
Another way to look at this association between AD and an nonfamilial cases, although the exact magnitude of the risk is
APOE e4 allele is with APOE e4 allele frequencies (Table 5). not clear. Heston et al.81 found a 35– 45% risk of dementia in
individuals who had a parent with AD and a sib with onset of
Early-onset familial AD AD before age 70 years. Jayadev et al.82 also report data sug-
The three known subtypes of EOFAD, called AD3, AD1, and gesting that offspring of parents with conjugal AD (i.e., both
AD474,75 can only be distinguished by molecular genetic testing parents affected) had an increased risk of dementia.
(Table 3). Genetic testing of individuals who are simplex cases
(i.e., a single occurrence of early-onset AD in a family) is con- Risk to family members— early-onset familial Alzheimer disease
troversial and should be undertaken in the context of formal Many individuals diagnosed as having early-onset AD have
genetic counseling.76 A small proportion (⬍5%) of such cases another affected family member, although family history is
will have a mutation in PS1. negative 40% of the time.10 Family history may be “negative”
because of early death of a parent, failure to recognize the dis-
GENETIC COUNSELING order in family members, or, rarely, a de novo mutation. The
risk to sibs depends upon the genetic status of the affected
Mode of inheritance
proband’s parent. If one of the proband’s parents has a mutant
Because AD is genetically heterogeneous, genetic counseling allele, then the risk to the sibs of inheriting the mutant allele is
of persons with AD and their family members must be tailored 50%. Individuals with EOFAD (and a mutation in APP, PS1, or
to the information available for that family. AD is usually con- PS2) have a 50% chance of transmitting the mutant allele to
sidered polygenic and multifactorial. EOFAD is inherited in an each child. The risk to other family members depends upon the
autosomal-dominant manner. status of the proband’s parents. If a parent is found to be af-
fected, his or her family members are at risk.
Risk to family members—late-onset nonfamilial Alzheimer disease
Genetic counseling for people with nonfamilial AD and Related genetic counseling issues
their family members must be empiric and relatively nonspe-
cific. It should be pointed out that AD is common and that the Use of APOE genotyping for predictive testing
In contrast to the use of APOE testing as an adjunct diagnos-
tic test in individuals with dementia, there is general agreement
that APOE testing has limited value used for predictive testing
Table 5
APOE allele frequencies in controls and individuals with AD
for AD in asymptomatic persons. Data suggest that a young
asymptomatic person with the APOE e4/e4 genotype may have
Individuals with AD an approximately 30% lifetime risk of developing AD.83 Fur-
Normal All individuals and positive family
APOE controls with AD history of dementiaa ther refinement of this risk reveals that women with an APOE
allele (n ⫽ 304) (n ⫽ 233) (n ⫽ 85) e4/e4 genotype have a 45% probability of developing AD by
e2 9.0% 3.9% 5.9% age 73 years, whereas men have a 25% risk.71 These risks are
lower—and the likely age of onset later—for persons with only
e3 76.5% 60.5% 48.2%
one APOE e4 allele (peak age 87 years) or no APOE e4 allele
e4 13.7% 35.6% 45.9% (peak age 95 years). These estimates are not generally consid-
Modified from Jarvik G, Larson EB, Goddard K, Schellenberg GD, et al. Influ- ered clinically useful; however, a research study to assess the
ence of apolipoprotein E genotype on the transmission of Alzheimer disease in
a community-based sample. Am J Hum Genet 1996;58:191–200. potential use of APOE testing in relatives of individuals with
a
Most families would be considered to have late-onset familial AD. late-onset AD is under way.79,84

April 2008 䡠 Vol. 10 䡠 No. 4 235

Bird

Down syndrome Preimplantation diagnosis has been reported in a mother with

Family members of persons with DS are not at increased risk an APP mutation.87,88
for AD.
MANAGEMENT
Testing of at-risk asymptomatic EOAD family members
Treatment of manifestations
Testing of at-risk asymptomatic adults
The mainstay of treatment for AD is necessarily supportive
Testing of asymptomatic adults at risk for EOFAD caused by
and each symptom is managed on an individual basis.1 In gen-
mutations in the PSEN1, PSEN2, or APP gene is available clin-
eral, affected individuals eventually require assisted living ar-
ically. Testing results for at-risk asymptomatic adults can only
rangements or care in a nursing home.
be interpreted after an affected family member’s disease-caus-
Although the exact biochemical basis of AD is not well un-
ing mutation has been identified. It should be remembered
derstood, it is known that deficiencies of the brain cholinergic
that testing of asymptomatic at-risk individuals with nonspe-
system and of other neurotransmitters are present. Drugs that
cific or equivocal symptoms is predictive testing, not diagnos-
increase cholinergic activity by inhibiting acetylcholinesterase
tic testing.
produce a modest but useful behavioral or cognitive benefit in
Preliminary results have shown that although relatively few
some affected individuals. The first such drug was tacrine;
family members choose such testing, they usually cope well
however, this agent is also hepatotoxic. Newer such drugs with
with the results, which can affect personal relationships and
similar pharmacologic action, such as Aricept® (donepezil),89 –91
emotional well-being.85 However, significant depression after
Exelon® (rivastigmine),92 and galantamine,93–95 are not hepato-
such testing has been reported.86
toxic.
Testing of at-risk individuals during childhood Memantine, an NMDA receptor antagonist, has shown some
effectiveness in the treatment of moderate to severe AD.96 –99
Consensus holds that individuals at risk for adult-onset dis-
Antidepressant medication may improve associated de-
orders should not have testing during childhood in the absence
pression.
of symptoms. The principal arguments against testing asymp-
tomatic individuals during childhood are that it removes their Therapies under investigation
choice to know or not know this information, it raises the
Treatment trials evaluating use of anti-inflammatory agents
possibility of stigmatization within the family and in other so-
(NSAIDs), estrogens, nerve growth factors, ginkgo biloba, st-
cial settings, and it could have serious educational and career
atins, beta-site cleaving enzyme (BACE) inhibitors, and anti-
implications.
oxidants are under way or recently reviewed.100 –102
Prenatal testing Other
Prenatal diagnosis for pregnancies at increased risk for mu- Vitamins and other over-the-counter medications have
tations in the PSEN1 gene is possible by analysis of DNA ex- been used in the treatment of AD.103
tracted from fetal cells obtained by amniocentesis usually per- Some, but not all, reports suggest that affected individuals
formed at about 15–18 weeks’ gestation or chorionic villus taking 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A re-
sampling at about 10 to 12 weeks’ gestation. The disease-caus- ductase inhibitors for hypercholesteralemia have a reduced in-
ing allele of an affected family member must be identified be- cidence of dementia.104 –106
fore prenatal testing can be performed. Immunization of an AD mouse model with ␤-amyloid has
No laboratories offering molecular genetic testing for pre- attenuated the AD pathology and stimulated the search for a
natal diagnosis of EOFAD caused by APP or PSEN2 mutations possible vaccination approach to the treatment of human
are listed in the GeneTests Laboratory Directory. However, AD.107 A human trial of this approach was halted because of
prenatal testing may be available for families in which the dis- encephalitis in a few subjects.108 –110 Alternative approaches to
ease-causing mutation has been identified. immunization therapy have been proposed.111
Requests for prenatal diagnosis of adult-onset diseases are Thus far, treatment of symptomatic AD with estrogens has
uncommon. Differences in perspective may exist among med- not proven beneficial.112,113
ical professionals and within families regarding the use of pre-
natal testing, particularly if the testing is being considered for Genetics clinics
the purpose of pregnancy termination. Although most centers Genetics clinics are a source of information for individuals
would consider decisions about prenatal testing to be the and families regarding the natural history, treatment, mode of
choice of the parents, careful discussion of these issues is ap- inheritance, and genetic risks to other family members as well
propriate. as information about available consumer-oriented resources.

Preimplantation genetic diagnosis Support groups

Preimplantation genetic diagnosis may be available for fam- Support groups have been established for individuals and
ilies in which the disease-causing mutation has been identified. families to provide information, support, and contact with

236 Genetics IN Medicine

 Genetic aspects of Alzheimer disease

other affected individuals. The Resources section may include (i.e., single occurrence in a family) have a cumulative lifetime
disease-specific and/or umbrella support organizations. risk of developing AD of about 15–30%, which is typically re-
ported as a 20 –25% risk. This risk is about 2.5 times that of the
background risk (⬃27% vs. 10.4%). In contrast, EOFAD with
SUMMARY
mutations in APP, PS1 or PS2 is inherited in an autosomal-
Disease characteristics dominant manner.
AD is characterized by dementia that typically begins with
subtle and poorly recognized failure of memory and slowly
RESOURCES
becomes more severe and, eventually, incapacitating. Other
common findings include confusion, poor judgment, lan- Alzheimer’s Association National Headquarters, 225 North
guage disturbance, agitation, withdrawal, and hallucinations. Michigan Avenue Fl 17, Chicago, IL 60601-7633, Phone:
Occasionally, seizures, Parkinsonian features, increased mus- 800-272-3900, 312-335-8700, Fax: 312-335-1110, E-mail:
cle tone, myoclonus, incontinence, and mutism occur. Death [email protected], www.alz.org.
usually results from general inanition, malnutrition, and Alzheimer’s Disease Education and Referral Center, PO Box 8250,
pneumonia. The typical clinical duration of the disease is 8 to SilverSpring,MD20907-8250,Phone:800-438-4380;301-495-
10 years, with a range from 1 to 25 years. About 25% of all AD 3334, Fax: 301-495-3334, E-mail: adear@ alzheimers.org,
is familial (i.e., two or more persons in a family have AD) of www.alzheimers.org.
which about 95% is late-onset (after age 60 – 65 years) and 5% National Library of Medicine Genetics Home Reference,
is early-onset (before age 65 years). Alzheimer Disease.
NCBI Genes and Disease, Alzheimer Disease.
Diagnosis/testing National Institute on Aging, Building 31, Room 5C27, 31
Establishing the diagnosis of AD relies upon clinical-neuro- Center Drive MSC 2292, Bethesda, MD 20892, Phone:
pathologic assessment. Neuropathologic findings of extracel- 301-496-1752, E-mail: [email protected], www.nia.nih.
lular ␤-amyloid plaques and intraneuronal neurofibrillary gov.
tangles remain the gold standard for diagnosis. The clinical
diagnosis of AD, based on signs of slowly progressive dementia PUBLISHED STATEMENTS AND POLICIES REGARDING GENETIC
and findings of gross cerebral cortical atrophy on neuroimag- TESTING
ing, is correct about 80 –90% of the time. The association of the
● American College of Medical Genetics/American Society of
APOE e4 allele with AD is significant; however, APOE geno-
Human Genetics Working Group on ApoE and Alzheimer’s Dis-
typing is neither fully specific nor sensitive. APOE genotyping
ease. Statement on use of apolipoprotein E testing for Alzhei-
may have an adjunct role in the diagnosis of AD in symptom-
mer’s disease. 1995.
atic individuals and a limited role at this time in predictive
● American Society of Human Genetics and American College of
testing of asymptomatic individuals. Three forms of EOFAD
Medical Genetics. Points to consider: ethical, legal, and psycho-
caused by mutations in one of three genes (APP, PSEN1, and
social implications of genetic testing in children and adolescents.
PSEN2) are recognized. Molecular genetic testing of the three
1995.
genes is available in clinical laboratories.
● National Institute on Aging/Alzheimer’s Association Working
Management Group. Apolipoprotein E genotyping in Alzheimer’s disease.
Lancet 1996;347:1091–1095.
Treatment is supportive. Each symptom is managed on an
● National Society of Genetic Counselors. Resolution on prenatal
individual basis. Assisted living arrangements or care in a nurs-
and childhood testing for adult-onset disorders. 1995.
ing home is usually necessary. Drugs that increase cholinergic
● Post SG, Whitehouse PJ, Binstock RH, Bird TD, et al. The clinical
activity by inhibiting acetylcholinesterase produce a modest
introduction of genetic testing for Alzheimer’s disease: an ethical
but useful behavioral or cognitive benefit in some affected in-
perspective. JAMA 1997;277:832– 836.
dividuals. Antidepressant medication may improve associated
depression. An NMDA receptor antagonist is also FDA ap- ACKNOWLEDGMENTS
proved.
This work was supported by funding from Veterans Affairs
Genetic counseling Research Funds and NIA/NIH Grant P50 AG 005136-22.
Because AD is genetically heterogeneous, genetic counseling
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