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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Genet Med. Author manuscript; available in PMC 2009 June 3.
Published in final edited form as:
PMCID: PMC2690397

Genetic Aspects of Alzheimer Disease


Alzheimer’s disease (AD) is the most common cause of dementia and represents a major public health problem. The neuropathological findings of Aβ 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 AD have been identified and are associated with mutations in APP (amyloid precursor protein), PS1 (presenilin 1) and PS2 (presenilin 2) genes. The more common late onset form of AD is assumed to be polygenic/multifactorial. However, thus far the only clearly identified genetic risk factor for AD is Apo lipoprotein E. The ε4 allele of ApoE influences age at onset of AD, but is neither necessary nor sufficient for the disease. The search continues for the discovery of additional genetic influences.

Keywords: Alzheimer, Dementia, Amyloid, Neurogenetics


Clinical Manifestations of Alzheimer Disease

The clinical manifestation of Alzheimer disease (AD) is dementia that typically begins with subtle and poorly recognized failure of memory and slowly becomes more severe and, eventually, incapacitating. Other common findings include confusion, poor judgment, language disturbance, agitation, withdrawal, and hallucinations. Occasionally, seizures, Parkinsonian features, increased muscle tone, myoclonus, incontinence, and mutism occur1.

Death usually results from general inanition, malnutrition, and pneumonia. The typical clinical duration of the disease is eight to ten years, with a range of from one to 25 years.

Establishing the Diagnosis of Alzheimer Disease

Establishing the diagnosis of Alzheimer disease relies upon clinical-neuropathologic assessment1. Neuropathologic findings on autopsy examination remain the gold standard for diagnosis of AD. The clinical diagnosis of AD (prior to autopsy confirmation) is correct about 80%-90% of the time2.

  • Clinical signs: slowly progressive dementia
  • Neuroimaging: gross cerebral cortical atrophy3
  • Neuropathologic findings: microscopic extracellular Aβ-amyloid neuritic plaques, intraneuronal neurofibrillary tangles, and amyloid angiopathy at postmortem examination. The plaques should stain positively with Aβ-amyloid antibodies and negative for prion antibodies, which are diagnostic of prion diseases. The numbers of plaques and tangles must exceed those found in age-matched controls without dementia. Guidelines for the quantitative assessment of these changes exist4, 5. Aggregation of alpha-synuclein in the form of Lewy bodies may also be found in neurons in the amygdala6.

Differential Diagnosis of Alzheimer Disease

Differential diagnosis of Alzheimer disease includes other causes of dementia, especially treatable forms of cognitive decline, such as depression, chronic drug intoxication, chronic CNS infection, thyroid disease, vitamin deficiencies (especially B12 and thiamine), CNS angitis, and normal-pressure hydrocephalus1.

Other degenerative disorders associated with dementia, such as frontotemporal dementia including frontotemporal dementia with parkinsonism-17 (FTDP-17), Picks disease, Parkinson disease, diffuse Lewy body disease (LBD), Creutzfeldt-Jakob disease, and CADASIL, may also be confused with AD7.

CT and MRI are valuable for identifying some of these other causes of dementia, including neoplasms, normal-pressure hydrocephalus, frontotemporal dementia and cerebral vascular disease.

Prevalence of Alzheimer Disease

AD is the most common cause of dementia in North America and Europe, with an estimate of four million affected individuals in the US.

The prevalence of AD increases with age. Mild memory loss is often call mild cognitive impairment (MCI). In many persons MCI is considered an early stage of Alzheimer’s disease.

The incidence of AD rises from 2.8 per 1,000 person years in the 65-69 year age group to 56.1 per 1,000 person years in the older than 90 year age group8. Approximately 10% of persons over age 70 years have significant memory loss and more than half of these individuals have AD. An estimated 25%-45% of persons over age 85 years have dementia.


About 1%-6% of all Alzheimer disease (AD) is early onset (before age 60-65 years) and about 60% of early-onset AD is familial, with 13% appearing to be inherited in an autosomal dominant manner9,10.

The distinction between early-onset familial Alzheimer disease (onset before age 60-65 years) and late-onset familial Alzheimer disease (onset after age 60-65 years) is somewhat arbitrary. Early-onset cases can occur in families with generally late-onset disease11.

Environmental Causes

No environmental agents (e.g., head trauma, viruses, toxins, low education level) have been proven to be directly involved in the pathogenesis of AD. It is often speculated that late-onset AD is the result of unknown environmental factors acting on a predisposing genetic background12. Twin studies have implicated both genes and environment13.

Heritable Causes


Down syndrome (DS)

Essentially all persons with Down syndrome (trisomy 21) develop the neuropathologic hallmarks of AD after age 40 years. More than half of individuals with DS also show, if carefully observed or tested, clinical evidence of cognitive decline14. The presumed reason for this association is the lifelong over-expression of the APP gene on chromosome 21 encoding the amyloid precursor protein and the resultant overproduction of β-amyloid in the brains of persons who are trisomic for this gene.

The amyloid-β (Aβ) deposition in the brain may begin in the first decade of life in persons with DS15. AD was not noted clinically or pathologically in a 78-year-old woman with partial trisomy 21 who did not have an extra copy of the APP gene16. Two studies have found no association of Apo E genotype with age of onset of dementia in Down syndrome17,18, but one study did find an association of onset age with a polymorphism in the APP gene18. Schupf et al19 found an unexplained increased risk for AD in mothers who gave birth to children with DS prior to age 35 years.

Single Gene

About 25% of AD is familial (i.e., two or more family members have AD). Familial cases appear to have the same clinical and pathologic phenotypes as non-familial cases (i.e., an individual with AD and no known family history of AD)20, 21 and are thus distinguished only by family history or by molecular genetic testing. A large volume of research on the molecular and genetic basis of AD has been summarized by Rosenberg22, Sleegers & Van Duijn23, Nussbaum & Ellis24, Goedert & Spillantini25, and Roses & Saunders26.

Late-onset familial AD (AD2)

Many families have multiple affected members, most or all of whom have onset of dementia after age 60 or 65 years. Disease duration is typically eight to ten years, but ranges from two to 25 years. Investigations have supported the concept that late-onset AD is a complex disorder that may involve multiple susceptibility genes (reviewed and summarized by Kamboh27, Bertram & Tanzi28, Serretti et al29, and Roses & Saunders26). Bertram et al30 have performed a meta-analysis on these data. The following information is currently available:

  • Well-documented association of late-onset familial AD (FAD) with the APOE e4 allele. The APOE e4 allele, by unknown mechanisms, appears to affect age of onset by shifting the onset toward an earlier age31, 32.
  • Several other potential genes are under investigation:
    • SORL1 on chromosome 11q23, a protein involved with APP protein trafficking33
    • A2M on chromosome 1234, 35, 36, 37
    • GST01 and GST02 on chromosome 1038
    • GAB2 on chromosome 11q14 interacting with the ApoE4 allele39
  • Several other potential loci are under investigation on the following chromosomes:
  • Studies of LOAD in a genetically isolated Dutch population have suggested linkage of AD to markers on chromosome 1q22, 3q23, 10q22 and 11q25 57.

Early-onset familial AD (EOFAD)
  • Clinical features. Early-onset familial AD refers to families in which multiple cases of AD occur with the mean age of onset usually before age 65 years, although some studies have used age 60 years or 70 years. Age of onset is usually in the 40s or early 50s, although onset in the 30s and early 60s has been reported. Campion et al10 found a prevalence of early-onset AD in the general population of 41.2 per 100,000 persons at risk (ages 40-59 years). Sixty-one percent of these individuals with early-onset AD had a positive family history and 13% met stringent criteria for autosomal dominant inheritance (i.e., affected individuals in three generations). EOFAD cannot be clinically distinguished from non-familial AD except on the basis of family history and age of onset. The dementia phenotype is similar to that of late-onset AD, sometimes with a long prodrome 58-60.
  • Molecular genetics. At least three subtypes of EOFAD (AD1, AD3, AD4) have been identified based on the causative gene. The relative proportion of each subtype and the causative genes are summarized in Table 3 10, 61-63. The amyloid precursor protein (APP) is cleaved by alpha and gamma secretases to form the A beta peptide which is the primary component of the extracellular amyloid plaque deposited in AD. Presenilin 1 (PS1) is part of the gamma secretase complex (and PS2 is a close homolog of PS1). Thus, the three primary genes associated with EOFAD are all related to APP and A beta amyloid molecular biology. It is likely that other genes will be identified as a cause of EOFAD because kindreds with autosomal dominant FAD with no known mutations in PSEN1, PSEN2, or APP have been described 63-64.
    Table 3
    Early-Onset Familial Alzheimer Disease (EOFAD): Molecular Genetics

Unknown Causes

Individuals with non-familial AD meet the diagnostic criteria for AD and have a negative family history. Onset can be anytime in adulthood. The exact pathogenesis of the disease is unknown. A common hypothesis is that non-familial AD is multifactorial and results from a combination of aging, genetic predisposition, and exposure to one or more environmental agents, such as head trauma, viruses, and/or toxins65 although no environmental agents have been proven to be directly involved in the pathogenesis of AD.

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 considered to have early-onset Alzheimer disease (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 to 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 after age 60 to 65 years.

Molecular Genetic Testing

Late-onset familial AD. The association of one or two copies of the APOE allele e4 (i.e., genotypes e2/e4, e3/e4, e4/e4) with late-onset Alzheimer disease (AD) is well documented (Table 4) 32, 66, 67.

  • ○ The association between APOE e4 and AD is greatest when the individual has a positive family history of dementia. The last column of Table 4 largely represents late-onset familial AD.
  • ○ The strongest association between the APOE e4 allele and AD, relative to the normal control population, is with the e4/e4 genotype. That genotype occurs in about 1% of the normal control population and in nearly 19% of the familial AD population.
  • ○ In individuals who have the clinical diagnosis of AD, the probability that AD is the correct diagnosis is increased to about 97% in the presence of the APOE e4/e4 genotype68.
  • ○ The increased risk of AD associated with one APOE e4 allele or two APOE e4 alleles is also found in African-Americans69 and Caribbean Hispanics70.
  • ○ Approximately 42% of persons with AD do not have an APOE e4 allele. Thus, APOE genotyping is not specific for AD. The absence of an APOE e4 allele does not rule out the diagnosis of AD2.
  • ○ Breitner et al71 have estimated lifetime risks for developing AD based on gender and APOE genotype. See Testing at-risk asymptomatic individuals under Genetic Counseling.
Table 4
Percent of APOE Genotypes in Controls and Individuals with AD

The usefulness of APOE genotyping in clinical diagnosis and risk assessment remains unclear [Statements and Policies Regarding Genetic Testing].

  • ○ Although the presence of one APOE e4 allele or two APOE e4 alleles is neither necessary nor sufficient to establish a diagnosis of AD, APOE genotyping may have an adjunct role in the diagnosis of AD because a large proportion of individuals with one APOE e4 allele or two APOE e4 alleles who are demented have been found to have neuropathologic confirmation of AD at autopsy2, 66, 72, 73.
  • ○ In contrast, APOE genotyping was not found to be of significant diagnostic use in identifying AD in a community-based sample with late-onset dementia74.

There is some evidence that the APOE e2 allele may have a protective effect in regard to risk for AD (Table 4).

Another way to look at this association between AD and an APOE e4 allele is with APOE e4 allele frequencies (Table 5).

Table 5
APOE Allele Frequencies in Controls and Individuals with AD

Early-onset familial Alzheimer disease

The three known subtypes of EOFAD, called AD3, AD1, and AD474, 75 can only be distinguished by molecular genetic testing (Table 3). Genetic testing of individuals who are simplex cases (i.e., a single occurrence of early-onset AD in a family) is controversial and should be undertaken in the context of formal genetic counseling76. A small proportion (<5%) of such cases will have a mutation in PS1.

Genetic Counseling

Mode of Inheritance

Because Alzheimer disease (AD) is genetically heterogeneous, genetic counseling of persons with AD and their family members must be tailored to the information available for that family. AD is usually considered polygenic and multifactorial. Early-onset familial Alzheimer disease is inherited in an autosomal dominant manner.

Risk to Family Members — Late-Onset Non-Familial Alzheimer Disease

Genetic counseling for people with non-familial AD and their family members must be empiric and relatively nonspecific. It should be pointed out that AD is common and that the overall lifetime risk to any individual of developing dementia is approximately 10%-12%.

First-degree relatives of a person with AD have a cumulative lifetime risk of developing AD of about 15%-30%, which is typically reported as a 20%-25% risk77, 78. This risk is about 2.5 times that of the background risk (~27% vs 10.4%)79, 80.

Disagreement exists as to whether the age of onset of the affected person changes the risk to first-degree relatives. One study found that early-onset AD increased the risk78, while another study did not77.

The number of additional affected family members probably increases the risk to close relatives, but the magnitude of that increase is unclear unless the pattern in the family is characteristic of autosomal dominant inheritance. Having two, three, or more affected family members probably raises the risk to other first-degree relatives in excess of that noted above for non-familial cases, although the exact magnitude of the risk is not clear. Heston et al81 found a 35%-45% risk of dementia in individuals who had a parent with AD and a sib with onset of AD before age 70 years. Jayadev et al82 also report data suggesting that offspring of parents with conjugal AD (i.e., both parents affected) had an increased risk of dementia.

Risk to Family Members — Early-Onset Familial Alzheimer Disease

Many individuals diagnosed as having early-onset Alzheimer disease have another affected family member, although family history is negative 40% of the time10. Family history may be “negative” because of early death of a parent, failure to recognize the disorder in family members, or, rarely, a de novo mutation. The risk to sibs depends upon the genetic status of the affected proband’s parent. If one of the proband’s parents has a mutant allele, then the risk to the sibs of inheriting the mutant allele is 50%. Individuals with early-onset familial Alzheimer disease (and a mutation in APP, PS1 or PS2) have a 50% chance of transmitting the mutant allele to each child. The risk to other family members depends upon the status of the proband’s parents. If a parent is found to be affected, his or her family members are at risk.

Related Genetic Counseling Issues

Use of APOE genotyping for predictive testing. In contrast to the utility of APOE testing as an adjunct diagnostic test in individuals with dementia, there is general agreement that APOE testing has limited value used for predictive testing for AD in asymptomatic persons. Data suggest that a young asymptomatic person with the APOE e4/e4 genotype may have an approximately 30% lifetime risk of developing AD83. Further refinement of this risk reveals that females with an APOE e4/e4 genotype have a 45% probability of developing AD by age 73 years, whereas males have a 25% risk71. These risks are lower — and the likely age of onset later — for persons with only one APOE e4 allele (peak age 87 years) or no APOE e4 allele (peak age 95 years). These estimates are not generally considered clinically useful; however, a research study to assess the potential utility of APOE testing in relatives of individuals with late-onset AD is under way79, 84.

Down syndrome. Family members of persons with Down syndrome are not at increased risk for AD.

Testing of At-Risk Asymptomatic EOAD Family Members

  • Testing of at-risk asymptomatic adults. Testing of asymptomatic adults at risk for early-onset familial Alzheimer disease (EOFAD) caused by mutations in the PSEN1, PSEN2, or APP gene is available clinically. Testing results for at-risk asymptomatic adults can only be interpreted after an affected family member’s disease-causing mutation has been identified. It should be remembered that testing of asymptomatic at-risk individuals with nonspecific or equivocal symptoms is predictive testing, not diagnostic testing.

Preliminary results have shown that while relatively few family members choose such testing, they usually cope well with the results, which can affect personal relationships and emotional well-being85. However, significant depression following such testing has been reported86.

Testing of at-risk individuals during childhood. Consensus holds that individuals at risk for adult-onset disorders should not have testing during childhood in the absence of symptoms. The principal arguments against testing asymptomatic individuals during childhood are that it removes their choice to know or not know this information, it raises the possibility of stigmatization within the family and in other social settings, and it could have serious educational and career implications.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk for mutations in the presenilin 1 (PSEN1) gene is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks’ gestation or chorionic villus sampling (CVS) at about ten to 12 weeks’ gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed. No laboratories offering molecular genetic testing for prenatal diagnosis of EOFAD caused by APP or PSEN2 mutations are listed in the GeneTests Laboratory Directory. However, prenatal testing may be available for families in which the disease-causing mutation has been identified.

Requests for prenatal diagnosis of adult-onset diseases are uncommon. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination. Although most centers would consider decisions about prenatal testing to be the choice of the parents, careful discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. Preimplantation diagnosis has been reported in a mother with an APP mutation87, 88.


Treatment of Manifestations

The mainstay of treatment for Alzheimer disease (AD) is necessarily supportive and each symptom is managed on an individual basis1. In general, affected individuals eventually require assisted living arrangements or care in a nursing home.

Although the exact biochemical basis of AD is not well understood, it is known that deficiencies of the brain cholinergic system and of other neurotransmitters are present. Drugs that increase cholinergic activity by inhibiting acetylcholinesterase produce a modest but useful behavioral or cognitive benefit in some affected individuals. The first such drug was tacrine; however, this agent is also hepatotoxic. Newer such drugs with similar pharmacologic action, such as Aricept® (donepezil)89-91, Exelon® (rivastigmine)92, and galantamine93-95, are not hepatotoxic.

Memantine, an NMDA receptor antagonist, has shown some effectiveness in the treatment of moderate to severe AD96-99.

Antidepressant medication may improve associated depression.

Therapies Under Investigation

Treatment trials evaluating use of anti-inflammatory agents (NSAIDs), estrogens, nerve growth factors, ginkgo biloba, statins, BACE inhibitors, and antioxidants are under way or recently reviewed100-102.


Vitamins and other over-the-counter medications have been used in the treatment of AD103.

Some, but not all, reports suggest that affected individuals taking HMG-coenzyme A reductase inhibitors for hypercholesteralemia have a reduced incidence of dementia104-106.

Immunization of an AD mouse model with β-amyloid has attenuated the AD pathology and stimulated the search for a possible vaccination approach to the treatment of human AD107. A human trial of this approach was halted because of encephalitis in a few subjects 108-110. Alternative approaches to immunization therapy have been proposed111.

Thus far, treatment of symptomatic AD with estrogens has not proven beneficial112-113.

Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources.

Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.


Disease characteristics. Alzheimer disease (AD) is characterized by dementia that typically begins with subtle and poorly recognized failure of memory and slowly becomes more severe and, eventually, incapacitating. Other common findings include confusion, poor judgment, language disturbance, agitation, withdrawal, and hallucinations. Occasionally, seizures, Parkinsonian features, increased muscle tone, myoclonus, incontinence, and mutism occur. Death usually results from general inanition, malnutrition, and pneumonia. The typical clinical duration of the disease is eight to ten years, with a range from one to 25 years. About 25% of all AD is familial (i.e., two or more persons in a family have AD) of which about 95% is late-onset (after age 60-65 years) and 5% is early-onset (before age 65 years).

Diagnosis/testing. Establishing the diagnosis of Alzheimer disease relies upon clinical-neuropathologic assessment. Neuropathologic findings of extracellular β-amyloid plaques and intraneuronal neurofibrillary tangles remain the gold standard for diagnosis. The clinical diagnosis of AD, based on signs of slowly progressive dementia and findings of gross cerebral cortical atrophy on neuroimaging, is correct about 80%-90% of the time. The association of the APOE e4 allele with AD is significant; however, APOE genotyping is neither fully specific nor sensitive. APOE genotyping may have an adjunct role in the diagnosis of AD in symptomatic individuals and a limited role at this time in predictive testing of asymptomatic individuals. Three forms of early-onset familial AD (EOFAD) caused by mutations in one of three genes (APP, PSEN1, PSEN2) are recognized. Molecular genetic testing of the three genes is available in clinical laboratories.

Management. Treatment is supportive. Each symptom is managed on an individual basis. Assisted living arrangements or care in a nursing home is usually necessary. Drugs that increase cholinergic activity by inhibiting acetylcholinesterase produce a modest but useful behavioral or cognitive benefit in some affected individuals. Antidepressant medication may improve associated depression. An NMDA receptor antagonist is also FDA approved.

Genetic counseling. Because AD is genetically heterogeneous, genetic counseling of persons with AD and their family members must be tailored to the information available for that family. It should be pointed out that AD is common and that the overall lifetime risk for any individual of developing dementia is approximately 10%-12%. Genetic counseling for people with non-familial AD and their family members must be empiric and relatively nonspecific. First-degree relatives of a simplex case of AD (i.e., single occurrence in a family) have a cumulative lifetime risk of developing AD of about 15%-30%, which is typically reported as a 20%-25% risk. This risk is about 2.5 times that of the background risk (~27% vs 10.4%). In contrast, early-onset familial Alzheimer disease (EOFAD) with mutations in APP, PS1 or PS2 is inherited in an autosomal dominant manner.

Figure 1
Normal adult brain (top) compared with Alzheimer brain (bottom) showing marked diffuse cortical atrophy and ventricular enlargement.
Figure 2
Microscopic neuropathology of Alzheimer’s disease showing a neuritic plaque (lower left hand corner) and neurofibrillary tangles (upper right hand corner).
Figure 3
Molecular Aspects of the APP gene and protein showing the sites of cleavage by α, β and γ; secretases, production of the Aβ peptide (upper right) and sites of several disease causing mutations (bottom line).
Table 1
Causes of Alzheimer Disease
Table 2
Late Onset Familial Alzheimer’s Disease: Molecular Genetics


This work was supported by funding from Veterans Affairs Research Funds and NIA/NIH grant #P50 AG 005136-22.

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Published Statements and Policies Regarding Genetic Testing

•. American College of Medical Genetics. American Society of Human Genetics Working Group on ApoE and Alzheimer’s disease Statement on use of apolipoprotein E testing for Alzheimer’s disease. 1995. [PubMed]
•. American Society of Human Genetics and American College of Medical Genetics Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. 1995. [PubMed]
•. National Institute on Aging. Alzheimer’s Association Working Group Apolipoprotein E genotyping in Alzheimer’s disease. Lancet. 1996;347:1091–5. [PubMed]
•. National Society of Genetic Counselors Resolution on prenatal and childhood testing for adult-onset disorders. 1995.
•. Post SG, Whitehouse PJ, Binstock RH, Bird TD, Eckert SK, Farrer LA, Fleck LM, Gaines AD, Juengst ET, Karlinsky H, Miles S, Murray TH, Quaid KA, Relkin NR, Roses AD, St George-Hyslop PH, Sachs GA, Steinbock B, Truschke EF, Zinn AB. The clinical introduction of genetic testing for Alzheimer’s disease: an ethical perspective. JAMA. 1997;277:832–6. [PubMed]