Alzheimer Disease Overview

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 occur [Cummings et al 1998].

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 on clinical-neuropathologic assessment [Cummings et al 1998]. Neuropathologic findings on autopsy examination remain the gold standard for diagnosis of AD. The clinical diagnosis of AD (prior to autopsy confirmation) is correct approximately 80%-90% of the time [Mayeux et al 1998]:

• Clinical signs: slowly progressive dementia

• Neuroimaging: gross cerebral cortical atrophy [Kaye 1998]

• Neuropathologic findings: microscopic β-amyloid neuritic plaques, intraneuronal neurofibrillary tangles, and amyloid angiopathy at postmortem examination. The plaques should stain positively with β-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 exist [Braak & Braak 1991, National Institute on Aging-Reagan Working Group 1997]. Aggregation of alpha-synuclein in the form of Lewy bodies may also be found in neurons in the amygdala [Popescu et al 2004].

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 hydrocephalus [Bird & Miller 2004].

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 AD [Rogan & Lippa 2002].

CT and MRI are valuable for identifying some of these other causes of dementia, including neoplasms, normal-pressure hydrocephalus, 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:

• 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.

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 group [Kukull et al 2002].

Environmental Causes

No environmental agents (e.g., head trauma, viruses, toxins) 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 background [Borenstein et al 2006]. Twin studies have implicated both genes and environment [Gatz et al 2006].

Heritable Causes

Single Gene

Approximately 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) [Haupt et al 1992, Nochlin et al 1993] 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 Rosenberg [2000], Sleegers & Van Duijn [2001], Nussbaum & Ellis [2003], Goedert & Spillantini [2006], and Roses & Saunders [2006].

Late-onset familial AD (AD2) (See Table 2)

• Molecular genetics. Investigations have supported the concept that late-onset AD is a complex disorder that may involve multiple susceptibility genes (reviewed and summarized by Kamboh [2004], Bertram & Tanzi [2004], Serretti et al [2005], and Roses & Saunders [2006]). Bertram et al [2007] 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 age [Meyer et al 1998, Khachaturian et al 2004].

  • Several other potential genes are under investigation:

    • SORL1 on chromosome 11q23, a protein involved with APP protein trafficking [Rogaeva et al 2007]

    • A2M on chromosome 12 [Blacker et al 1998, Dodel et al 2000, Gibson et al 2000, Depboylu et al 2006]

    • GST01 and GST02 on chromosome 10 [Li et al 2003]

    • GAB2 on chromosome 11q14 interacting with the ApoE4 allele [Reiman et al 2007]

    • CALHM1 on chromosome 10q24 influences calcium homeostasis and has a single nucleotide polymorphism (SNP) associated with late-onset AD [Dreses-Werringloer et al 2008].

  • Several other potential loci are under investigation on the following chromosomes:

    • 12 [Pericak-Vance et al 1997, Rogaeva et al 1998, Wu et al 1998, D'Introno et al 2006]

    • 10 [Bertram et al 2000, Ertekin-Taner et al 2000, Myers et al 2000, Grupe et al 2006, Riemenschneider et al 2006]

    • 2q, 9p, and 15q [Scott et al 2003, Li et al 2006]

    • 19p13 [Wijsman et al 2004]

    • 7q36 [Rademakers et al 2005]

    • 9q22 (UBQLN1) [Bertram et al 2005, Bensemain et al 2006, Kamboh et al 2006, Smemo et al 2006]

  • Studies of LOAD in a genetically isolated Dutch population have suggested linkage of AD to markers on chromosome 1q22, 3q23, 10q22 and 11q25 [Liu et al 2007].

Table 2. Late-Onset Familial Alzheimer Disease: Molecular Genetics

Locus Name	Gene Symbol	Chromosomal Locus	Protein Name	Test Availability	Genomic Databases
AD2	APOE	19q13.2	Apolipoprotein E	Clinical

• Clinical features. 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.

Early-onset familial AD (EOFAD)

• 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 [Sherrington et al 1996, Campion et al 1999, Janssen et al 2003, Raux et al 2005]. EOFAD and the molecular genetic testing available are described in more detail in Early-Onset Familial Alzheimer Disease. 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 [Cruts et al 1998, Raux et al 2005].

Table 3. Early-Onset Familial Alzheimer Disease (EOFAD): Molecular Genetics

Locus Name	Proportion of EOFAD	Gene Symbol	Chromosomal Locus	Protein Name	Test Availability	Genomic Databases
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

• 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 al [1999] 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 [Lampe et al 1994, Godbolt et al 2004, Larner & Doran 2006].

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 toxins [Cummings et al 1998] although no environmental agents have been proven to be directly involved in the pathogenesis of AD.

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

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.

• 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 approximately 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 approximately 97% in the presence of the APOE e4/e4 genotype [Saunders et al 1996].

  Note: The increased risk of AD associated with one APOE e4 allele or two APOE e4 alleles is also found in African-Americans [Green et al 2002] and Caribbean Hispanics [Romas et al 2002].

• 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 AD [Mayeux et al 1998].

• Breitner et al [1999] have estimated lifetime risks for developing AD based on gender and APOE genotype. See Testing at-risk asymptomatic individuals under Genetic Counseling.

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 autopsy [National Institute on Aging-Alzheimer’s Association Working Group 1996, Saunders et al 1996, Welsh-Bohmer et al 1997, Mayeux et al 1998].

• In contrast, APOE genotyping was not found to be of significant diagnostic use in identifying AD in a community-based sample with late-onset dementia [Tsuang et al 1999].

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. Early-onset familial Alzheimer disease is inherited in an autosomal dominant manner. AD is considered polygenic and multifactorial.

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%.

Parents, sibs, and offspring of a proband

• First-degree relatives of a person with AD have a cumulative lifetime risk of developing AD of approximately 15%-30%, which is typically reported as a 20%-25% risk [Farrer et al 1989, Silverman et al 1994]. This risk is approximately 2.5 times that of the background risk (~27% vs 10.4%) [Green et al 2002, Cupples et al 2004].

• 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 risk [Silverman et al 1994], while another study did not [Farrer et al 1989].

• 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 al [1981] 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. Bird et al [1993] also reported preliminary 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

Parents of a proband

• Many individuals diagnosed as having early-onset Alzheimer disease have another affected family member, although family history is negative 40% of the time [Campion et al 1999].

• 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.

Sibs of a proband

• The risk to sibs depends on the genetic status of the 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%.

Offspring of a proband. Individuals with early-onset familial Alzheimer disease have a 50% chance of transmitting the mutant allele to each child.

Other family members of a proband. The risk to other family members depends on 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 should not be 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 AD [Breitner 1996]. 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% risk [Breitner et al 1999]. 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 way [Green 2002, Roberts et al 2005].

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

Testing of At-Risk Asymptomatic 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-being [Steinbart et al 2001]. However, significant depression following such testing has been reported [Quaid et al 2000].

• 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. (See also the National Society of Genetic Counselors resolution on genetic testing of children and the 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.)

DNA banking. DNA Banking is the storage of DNA (typically been extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See for a list of laboratories offering DNA banking.

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 approximately 15-18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

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. For laboratories offering custom prenatal testing, see .

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. For laboratories offering PGD, see . Preimplantation diagnosis has been reported in a mother with an APP mutation [Towner & Loewy 2002, Verlinsky et al 2002].

Treatment of Manifestations

The mainstay of treatment for Alzheimer disease (AD) is necessarily supportive and each symptom is managed on an individual basis. 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 a minority of 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) [Feldman et al 2004, Seltzer et al 2004, Petersen et al 2005], Exelon^® (rivastigmine) [Rogers & Friedhoff 1996], and galantamine [Raskind et al 2000, Tariot et al 2000, Mega et al 2005], are not hepatotoxic.

Memantine, an NMDA receptor antagonist, has shown some effectiveness in the treatment of moderate to severe AD [Reisberg et al 2003, Tariot et al 2004].

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 reviewed [Overshott & Burns 2005, Klafki et al 2006, Masters & Beyreuther 2006].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Vitamins and other over-the-counter medications have been used in the treatment of AD [Yaffe et al 2004].

Some, but not all, reports suggest that affected individuals taking HMG-coenzyme A reductase inhibitors for hypercholesteralemia have a reduced incidence of dementia [Wolozin et al 2000, Li et al 2004].

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 AD [Schenk et al 1999]. A human trial of this approach was halted because of encephalitis in a few subjects [Check 2002, Ferrer et al 2004].

Thus far, treatment of symptomatic AD with estrogens has not proven beneficial [Mulnard et al 2000, Wang et al 2000].

Genetics clinics, staffed by genetics professionals, provide 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. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Literature Cited

Published Statements and Policies Regarding Genetic Testing

Revision History

• 24 July 2008 (cd) Revision: single nucleotide polymorphism (SNP) in CALHM1 associated with increased risk for late onset AD.

• 13 June 2007 (tb) Revision: sequence analysis for APP available on a clinical basis; new gene identified for late-onset familial AD

• 9 May 2007 (me) Comprehensive update posted to live Web site

• 10 February 2005 (me) Comprehensive update posted to live Web site

• 22 December 2003 (tb) Author revisions

• 12 September 2003 (tb) Revision: clinical testing available for APP

• 29 January 2003 (me) Comprehensive update posted to live Web site

• 22 June 2001 (tb) Author revisions

• 24 September 1999 (tb) Author revisions

• 31 August 1999 (tb) Author revisions

• 23 October 1998 (me) Overview posted to live Web site

• Spring 1996 (tb) Original submission