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Alzheimer Disease Overview

, MD
Seattle VA Medical Center
Departments of Neurology and Medicine
University of Washington
Seattle, Washington

Initial Posting: ; Last Revision: April 3, 2014.

Summary

Clinical 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. Approximately 25% of all AD is familial (i.e., ≥2 persons in a family have AD) of which approximately 95% is late onset (age >60-65 years) and 5% is early onset (age <65 years).

Diagnosis/testing.

Establishing the diagnosis of Alzheimer disease relies on clinical-neuropathologic assessment. Neuropathologic findings of 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 approximately 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. While APOE genotyping may have an adjunct role in the diagnosis of AD in symptomatic individuals, it appears to have little 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.

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 approximately 15%-30%, which is typically reported as a 20%-25% risk. This risk is approximately 2.5 times that of the background risk (~27% vs 10.4%). In contrast, early-onset familial Alzheimer disease (EOFAD) is inherited in an autosomal dominant manner.

Management.

Treatment of manifestations: 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 a minority of affected individuals (e.g., donepezil [Aricept®], rivastigmine [Exelon®], galantamine). Memantine, an NMDA receptor antagonist, is also used. Antidepressant medication may improve associated depression.

Definition

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. Bacanu et al [2005] have shown evidence for heritability of psychotic features in AD (delusions and hallucinations).

Occasionally, seizures, Parkinsonian features, increased muscle tone, myoclonus, incontinence, and mutism occur [Bird & Miller 2008].

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. 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 on CT or MRI
    • Diffuse cerebral hypometabolism on PET
  • Neuropathologic findings. Microscopic β-amyloid neuritic plaques, intraneuronal neurofibrillary tangles (containing tau protein), 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].
  • Cerebrospinal fluid (CSF). Decreased Aβ amyloid 42 and increased tau [Snider et al 2009].

Differential Diagnosis of Alzheimer Disease

Differential diagnosis of Alzheimer disease includes other causes of dementia, especially treatable forms of cognitive decline including depression, chronic drug intoxication, chronic CNS infection, thyroid disease, vitamin deficiencies (especially B12 and thiamine), CNS angitis, and normal-pressure hydrocephalus [Bird & Miller 2008].

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].

Causes

Table 1.

Causes of Alzheimer Disease

Cause% of Cases
Chromosomal (Down syndrome)<1%
All familial~25%
15%-25%
<2%
Unknown (includes genetic/environment interactions)~75%

Approximately 1%-6% of all Alzheimer disease (AD) is early onset (age <60-65 years) and approximately 60% of early-onset AD is familial, with 13% appearing to be inherited in an autosomal dominant manner [Campion et al 1999].

The distinction between early-onset familial Alzheimer disease (onset age <60-65 years) and late-onset familial Alzheimer disease (onset age >60-65 years) is somewhat arbitrary. Note: Early-onset cases can occur in families with generally late-onset disease [Brickell et al 2006].

Environmental Causes

No environmental agents (e.g., 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]. Repeated head trauma has been associated with dementia having excessive neurofibrillary tangle formation [McKee et al 2009].

Heritable Causes

Chromosomal

Down syndrome (DS). Essentially all persons with Down syndrome (trisomy 21) develop the neuropathologic hallmarks of AD after age 40 years. If carefully observed or tested, more than half of individuals with DS also show clinical evidence of cognitive decline. The presumed reason for this association is the lifelong over-expression of APP 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 DS [Leverenz & Raskind 1998]. 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 APP [Prasher et al 1998]. Two studies have found no association of APOE genotype with age of onset of dementia in Down syndrome [Lai et al 1999, Margallo-Lana et al 2004], but one study did find an association of onset age with a polymorphism in APP [Margallo-Lana et al 2004].

Schupf et al [2001] found an unexplained increased risk for AD in mothers who gave birth to children with DS prior to age 35 years.

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) [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 Bertram & Tanzi [2004], Kamboh [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:

Table 2.

Late-Onset Familial Alzheimer Disease: Molecular Genetics

Locus NameGene SymbolProtein Name
AD2APOE Apolipoprotein E

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 gene in which mutation is causative. The relative proportion of each subtype and the related genes are summarized in Table 3 [Campion et al 1999, Janssen et al 2003, Raux et al 2005]. See also Early-Onset Familial Alzheimer Disease. It is likely that mutation in other genes will be identified as causative of EOFAD because kindreds with autosomal dominant FAD with no known mutations in PSEN1, PSEN2, or APP have been described [Raux et al 2005].

Table 3.

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

Locus NameProportion of EOFADGene SymbolProtein Name
AD320%-70%PSEN1 Presenilin-1
AD110%-15%APP Amyloid beta A4 protein
AD4RarePSEN2 Presenilin-2

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 3 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 [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 including head trauma, low education level, viruses, and/or toxins, 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) [Jarvik et al 1996, Khachaturian et al 2004, Martins et al 2005]:

  • 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.

    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 Genetic Counseling, Testing of at-risk asymptomatic family members.

The usefulness of APOE genotyping in clinical diagnosis and risk assessment remains unclear [Published Guidelines/Consensus Statements]:

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

Table 4.

Percent of APOE Genotypes in Controls and Individuals with AD

APOE GenotypeNormal Controls (n=304)All Individuals with AD (n=233)Individuals with AD and Positive Family History of Dementia 1 (n=85)
e2/e21.3%0%0%
e2/e312.5%3.4%3.5%
e2/e44.9%4.3%8.2%
e3/e359.9%38.2%23.5%
e3/e420.7%41.2%45.9%
e4/e40.7%12.9%18.8%

Modified from Jarvik et al [1996]

1. Most families would be considered to have late-onset familial AD.

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

APOE AlleleNormal Controls (n=304)All Individuals with AD (n=233)Individuals with AD and Positive Family History of Dementia 1 (n=85)
e29.0%3.9%5.9%
e376.5%60.5%48.2%
e413.7%35.6%45.9%

Modified from Jarvik et al [1996]

1. Most families would be considered to have late-onset familial AD.

Early-onset familial Alzheimer disease. The three known subtypes of EOFAD, called AD3, AD1, and AD4 [Tsuang et al 1999] can only be distinguished by molecular genetic testing (Table 3). (See Early-Onset Familial Alzheimer Disease for details about molecular genetic testing.) 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 counseling [van der Cammen et al 2004].

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

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. Jayadev et al [2008] 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, 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 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 be used cautiously 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. 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, Green et al 2009].

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 PSEN1, PSEN2, or APP is possible. 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 such testing 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. For more information, see also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

DNA banking is the storage of DNA (typically 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.

Prenatal Testing

If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation). Such testing may be available through laboratories that offer either testing for the gene of interest or custom testing.

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

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, discussion of these issues is appropriate [Quaid et al 2000].

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified. Preimplantation diagnosis has been reported in a mother with an APP mutation [Towner & Loewy 2002, Verlinsky et al 2002].

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Alzheimer's Association
    225 North Michigan Avenue
    Fl 17
    Chicago IL 60601-7633
    Phone: 800-272-3900 (Toll-free 24/7 Helpline); 866-403-3073 (Toll-free 24/7 Helpline - TDD); 312-335-8700
    Fax: 866-335-5886 (toll-free)
    Email: info@alz.org
  • Alzheimer's Disease Education and Referral Center (ADEAR)
    PO Box 8250
    Silver Spring MD 20907
    Phone: 800-438-4380 (toll-free)
    Fax: 301-495-3334
    Email: adear@alzheimers.org
  • National Library of Medicine Genetics Home Reference
  • NCBI Genes and Disease
  • National Institute on Aging
    31 Center Drive
    Building 31, Room 5C27
    MSC 2292
    Bethesda MD 20892
    Phone: 301-496-1752; 800-222-2225 (toll-free); 800-222-4225 (toll-free TTY)
    Fax: 301-496-1072

Management

Treatment of Manifestations

The mainstay of treatment for Alzheimer disease (AD) is necessarily supportive and each symptom is managed on an individual basis [Bird & Miller 2008]. 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 donepezil (Aricept®) [Feldman et al 2004, Seltzer et al 2004, Petersen et al 2005], rivastigmine (Exelon®) [Feldman et al 2007], and galantamine [Raskind et al 2000, Tariot et al 2000, Mega et al 2005, Reisberg et al 2006, Atri et al 2008], 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.

Agitation is especially difficult to control [Teri et al 2000, Mintzer et al 2006]

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, Holmes et al 2008]. Other approaches to this model are under investigation.

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

References

Published Guidelines/Consensus Statements

  1. 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. Available online. 1995. Accessed 3-31-14.
  2. Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 2-18-15. [PubMed: 23428972]
  3. National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2012. Accessed 3-31-14.
  4. 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: 9052715]

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Chapter Notes

Revision History

  • 3 April 2014 (tb) Revision: PLD3 included [Cruchaga et al 2014]
  • 30 January 2014 (tb) Revision: addition of information about new AD susceptibility loci
  • 3 July 2013 (tb) Revision: CD33 included [Griciuc et al 2013]
  • 13 December 2012 (tb) Revision: p.Arg47His allelic variant in TREM2 found to be a risk factor for late-onset AD [Guerreiro et al 2012, Jonsson et al 2012b]
  • 2 August 2012 (tb) Revision: addition of information about APP mutation p.Ala673Thr
  • 30 March 2010 (me) Comprehensive update posted live
  • 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
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