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].

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

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 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 [Khachaturian et al 2004].

• Several other potential genes under investigation:

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

  • A2M on chromosome 12 [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 APOE e4 allele [Reiman et al 2007]

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

  • TOMM40 located on chromosome 19q very close to the ApoE locus; TOMM40 has been implicated in late-onset AD both by linkage analysis [Potkin et al 2009] and by the presence of a variable length poly-T repeat within the gene [Roses et al 2009].

  • Clusterin (CLU, APOJ) [Lambert et al 2009]

  • CR1 and PICALM, implicated in two genome-wide association studies (GWAS) [Lambert et al 2009, Harold et al 2009]

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

  • 12 [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 suggesting 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

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Locus Name	Gene Symbol	Protein Name	Test Availability
AD2	APOE	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 [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 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

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Locus Name	Proportion of EOFAD	Gene Symbol	Protein Name	Test Availability
AD3	20%-70%	PSEN1	Presenilin-1	Clinical
AD1	10%-15%	APP	Amyloid beta A4 protein	Clinical
AD4	Rare	PSEN2	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 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.

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

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, 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].

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).

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].

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 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 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. (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 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. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk for some types of Alzheimer disease 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. For laboratories offering prenatal testing search by disease in the GeneTests Laboratory Directory or see

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 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 [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].

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

1. Atri A, Shaughnessy LW, Locascio JJ, Growdon JH. Long-term Course and Effectiveness of Combination Therapy in Alzheimer Disease. Alzheimer Dis Assoc Disord. 2008;22:209–21. [PMC free article: PMC2718545] [PubMed: 18580597]
2. Bacanu SA, Devlin B, Chowdari KV, DeKosky ST, Nimgaonkar VL, Sweet RA. Heritability of Psychosis in Alzheimer Disease. Am J Geriatr Psychiatry. 2005;13:624–7. [PubMed: 16009739]
3. Bensemain F, Chapuis J, Tian J, Shi J, Thaker U, Lendon C, Iwatsubo T, Amouyel P, Mann D, Lambert JC. Association study of the Ubiquilin gene with Alzheimer's disease. Neurobiol Dis. 2006;22:691–3. [PubMed: 16504527]
4. Bertram L, Tanzi RE. The current status of Alzheimer's disease genetics: what do we tell the patients? Pharmacol Res. 2004;50:385–96. [PubMed: 15304236]
5. Bertram L, Blacker D, Mullin K, Keeney D, Jones J, Basu S, Yhu S, McInnis MG, Go RC, Vekrellis K, Selkoe DJ, Saunders AJ, Tanzi RE. Evidence for genetic linkage of Alzheimer's disease to chromosome 10q. Science. 2000;290:2302–3. [PubMed: 11125142]
6. Bertram L, Hiltunen M, Parkinson M, Ingelsson M, Lange C, Ramasamy K, Mullin K, Menon R, Sampson AJ, Hsiao MY, Elliott KJ, Velicelebi G, Moscarillo T, Hyman BT, Wagner SL, Becker KD, Blacker D, Tanzi RE. Family-based association between Alzheimer's disease and variants in UBQLN1. N Engl J Med. 2005;352:884–94. [PubMed: 15745979]
7. Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE. Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat Genet. 2007;39:17–23. [PubMed: 17192785]
8. Bird TD, Miller BL (2008) Alzheimer's disease and primary dementias. In: Kasper D, Fauci A, Branwald E, et al (eds) Harrison's Principles of Internal Medicine, 17 ed. McGraw-Hill, NY, pp 2393-2406.
9. Borenstein AR, Copenhaver CI, Mortimer JA. Early-life risk factors for Alzheimer disease. Alzheimer Dis Assoc Disord. 2006;20:63–72. [PubMed: 16493239]
10. Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol (Berl). 1991;82:239–59. [PubMed: 1759558]
11. Breitner JC, Wyse BW, Anthony JC, Welsh-Bohmer KA, Steffens DC, Norton MC, Tschanz JT, Plassman BL, Meyer MR, Skoog I, Khachaturian A. APOE-epsilon4 count predicts age when prevalence of AD increases, then declines: the Cache County Study. Neurology. 1999;53:321–31. [PubMed: 10430421]
12. Brickell KL, Steinbart EJ, Rumbaugh M, Payami H, Schellenberg GD, Van Deerlin V, Yuan W, Bird TD. Early-onset Alzheimer disease in families with late-onset Alzheimer disease: a potential important subtype of familial Alzheimer disease. Arch Neurol. 2006;63:1307–11. [PubMed: 16966510]
13. Campion D, Dumanchin C, Hannequin D, Dubois B, Belliard S, Puel M, Thomas-Anterion C, Michon A, Martin C, Charbonnier F, Raux G, Camuzat A, Penet C, Mesnage V, Martinez M, Clerget-Darpoux F, Brice A, Frebourg T. Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999;65:664–70. [PMC free article: PMC1377972] [PubMed: 10441572]
14. Check E. Nerve inflammation halts trial for Alzheimer drug. Nature. 2002;415:462. [PubMed: 11823817]
15. Cupples LA, Farrer LA, Sadovnick AD, Relkin N, Whitehouse P, Green RC. Estimating risk curves for first-degree relatives of patients with Alzheimer's disease: the REVEAL study. Genet Med. 2004;6:192–6. [PubMed: 15266206]
16. Depboylu C, Lohmuller F, Du Y, Riemenschneider M, Kurz A, Gasser T, Muller U, Dodel RC. Alpha2-macroglobulin, lipoprotein receptor-related protein and lipoprotein receptor-associated protein and the genetic risk for developing Alzheimer's disease. Neurosci Lett. 2006;400:187–90. [PubMed: 16650578]
17. D'Introno A, Solfrizzi V, Colacicco AM, Capurso C, Amodio M, Todarello O, Capurso A, Kehoe PG, Panza F. Current knowledge of chromosome 12 susceptibility genes for late-onset Alzheimer's disease. Neurobiol Aging. 2006;27:1537–53. [PubMed: 16257095]
18. Dodel RC, Du Y, Bales KR, Gao F, Eastwood B, Glazier B, Zimmer R, Cordell B, Hake A, Evans R, Gallagher-Thompson D, Thompson LW, Tinklenberg JR, Pfefferbaum A, Sullivan EV, Yesavage J, Alstiel L, Gasser T, Farlow MR, Murphy GM, Paul SM. Alpha2 macroglobulin and the risk of Alzheimer's disease. Neurology. 2000;54:438–42. [PubMed: 10668709]
19. Dreses-Werringloer U, Lambert JC, Vingtdeux V, Zhao H, Vais H, Siebert A, Jain A, Koppel J, Rovelet-Lecrux A, Hannequin D, Pasquier F, Galimberti D, Scarpini E, Mann D, Lendon C, Campion D, Amouyel P, Davies P, Foskett JK, Campagne F, Marambaud P. A polymorphism in CALHM1 influences Ca2+ homeostasis, Abeta levels, and Alzheimer's disease risk. Cell. 2008;133:1149–61. [PMC free article: PMC2577842] [PubMed: 18585350]
20. Ertekin-Taner N, Graff-Radford N, Younkin LH, Eckman C, Baker M, Adamson J, Ronald J, Blangero J, Hutton M, Younkin SG. Linkage of plasma Abeta42 to a quantitative locus on chromosome 10 in late-onset Alzheimer's disease pedigrees. Science. 2000;290:2303–4. [PubMed: 11125143]
21. Farrer LA, O'Sullivan DM, Cupples LA, Growdon JH, Myers RH. Assessment of genetic risk for Alzheimer's disease among first-degree relatives. Ann Neurol. 1989;25:485–93. [PubMed: 2774490]
22. Feldman H, Gauthier S, Hecker J, Vellas B, Hux M, Xu Y, Schwam EM, Shah S, Mastey V. Economic evaluation of donepezil in moderate to severe Alzheimer disease. Neurology. 2004;63:644–50. [PubMed: 15326236]
23. Feldman HH, Lane R. Study 304 Group; Rivastigmine: a placebo controlled trial of twice daily and three times daily regimens in patients with Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2007;78(10):1056–63. [PMC free article: PMC2117538] [PubMed: 17353259]
24. Ferrer I, Boada Rovira M, Sanchez Guerra ML, Rey MJ, Costa-Jussa F. Neuropathology and pathogenesis of encephalitis following amyloid-beta immunization in Alzheimer's disease. Brain Pathol. 2004;14:11–20. [PubMed: 14997933]
25. Gatz M, Reynolds CA, Fratiglioni L, Johansson B, Mortimer JA, Berg S, Fiske A, Pedersen NL. Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry. 2006;63:168–74. [PubMed: 16461860]
26. Gibson AM, Singleton AB, Smith G, Woodward R, McKeith IG, Perry RH, Ince PG, Ballard CG, Edwardson JA, Morris CM. Lack of association of the alpha2-macroglobulin locus on chromosome 12 in AD. Neurology. 2000;54:433–8. [PubMed: 10668708]
27. Godbolt AK, Cipolotti L, Watt H, Fox NC, Janssen JC, Rossor MN. The natural history of Alzheimer disease: a longitudinal presymptomatic and symptomatic study of a familial cohort. Arch Neurol. 2004;61:1743–8. [PubMed: 15534185]
28. Goedert M, Spillantini MG. A century of Alzheimer's disease. Science. 2006;314:777–81. [PubMed: 17082447]
29. Green RC. Risk assessment for Alzheimer's disease with genetic susceptibility testing: Has the moment arrived? Alzheimer's Care Quarterly. 2002;3:208–14.
30. Green RC, Cupples LA, Go R, Benke KS, Edeki T, Griffith PA, Williams M, Hipps Y, Graff-Radford N, Bachman D, Farrer LA. Risk of dementia among white and African American relatives of patients with Alzheimer disease. JAMA. 2002;287:329–36. [PubMed: 11790212]
31. Green RC, Roberts JS, Cupples LA, Relkin NR, Whitehouse PJ, Brown T, Eckert SL, Butson M, Sadovnick AD, Quaid KA, Chen C, Cook-Deegan R, Farrer LA. REVEAL Study Group; Disclosure of APOE genotype for risk of Alzheimer's disease. N Engl J Med. 2009;361:245–54. [PMC free article: PMC2778270] [PubMed: 19605829]
32. Grupe A, Li Y, Rowland C, Nowotny P, Hinrichs AL, Smemo S, Kauwe JS, Maxwell TJ, Cherny S, Doil L, Tacey K, van Luchene R, Myers A, Wavrant-De Vrieze F, Kaleem M, Hollingworth P, Jehu L, Foy C, Archer N, Hamilton G, Holmans P, Morris CM, Catanese J, Sninsky J, White TJ, Powell J, Hardy J, O'Donovan M, Lovestone S, Jones L, Morris JC, Thal L, Owen M, Williams J, Goate A. A scan of chromosome 10 identifies a novel locus showing strong association with late-onset Alzheimer disease. Am J Hum Genet. 2006;78:78–88. [PMC free article: PMC1380225] [PubMed: 16385451]
33. Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Williams A, Jones N, Thomas C, Stretton A, Morgan AR, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Morgan K, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Love S, Kehoe PG, Hardy J, Mead S, Fox N, Rossor M, Collinge J, Maier W, Jessen F, Schürmann B, van den Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frölich L, Hampel H, Hüll M, Rujescu D, Goate AM, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Sleegers K, Bettens K, Engelborghs S, De Deyn PP, Van Broeckhoven C, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Tsolaki M, Singleton AB, Guerreiro R, Mühleisen TW, Nöthen MM, Moebus S, Jöckel KH, Klopp N, Wichmann HE, Carrasquillo MM, Pankratz VS, Younkin SG, Holmans PA, O'Donovan M, Owen MJ, Williams J. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat Genet. 2009;41:1088–93. [PMC free article: PMC2845877] [PubMed: 19734902]
34. Heston LL, Mastri AR, Anderson VE, White J. Dementia of the Alzheimer type. Clinical genetics, natural history, and associated conditions. Arch Gen Psychiatry. 1981;38:1085–90. [PubMed: 6457579]
35. Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JA. Long-term effects of Abeta42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet. 2008;372:216–23. [PubMed: 18640458]
36. Janssen JC, Beck JA, Campbell TA, Dickinson A, Fox NC, Harvey RJ, Houlden H, Rossor MN, Collinge J. Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Neurology. 2003;60:235–9. [PubMed: 12552037]
37. Jarvik G, Larson EB, Goddard K, Schellenberg GD, Wijsman EM. Influence of apolipoprotein E genotype on the transmission of Alzheimer disease in a community-based sample. Am J Hum Genet. 1996;58:191–200. [PMC free article: PMC1914964] [PubMed: 8554056]
38. Jayadev S, Steinbart EJ, Chi YY, Kukull WA, Schellenberg GD, Bid TD. Conjugal Alzheimer disease: risk in children when both parents have Alzheimer disease. Arch Neurol. 2008;65:373–378. [PubMed: 18332250]
39. Kamboh MI. Molecular genetics of late-onset Alzheimer's disease. Ann Hum Genet. 2004;68:381–404. [PubMed: 15225164]
40. Kamboh MI, Minster RL, Feingold E, DeKosky ST. Genetic association of ubiquilin with Alzheimer's disease and related quantitative measures. Mol Psychiatry. 2006;11:273–9. [PubMed: 16302009]
41. Khachaturian AS, Corcoran CD, Mayer LS, Zandi PP, Breitner JC. Apolipoprotein E epsilon4 count affects age at onset of Alzheimer disease, but not lifetime susceptibility: The Cache County Study. Arch Gen Psychiatry. 2004;61:518–24. [PubMed: 15123497]
42. Klafki HW, Staufenbiel M, Kornhuber J, Wiltfang J. Therapeutic approaches to Alzheimer's disease. Brain. 2006;129:2840–55. [PubMed: 17018549]
43. Kukull WA, Higdon R, Bowen JD, McCormick WC, Teri L, Schellenberg GD, van Belle G, Jolley L, Larson EB. Dementia and Alzheimer disease incidence: a prospective cohort study. Arch Neurol. 2002;59:1737–46. [PubMed: 12433261]
44. Lai F, Kammann E, Rebeck GW, Anderson A, Chen Y, Nixon RA. APOE genotype and gender effects on Alzheimer disease in 100 adults with Down syndrome. Neurology. 1999;53:331–6. [PubMed: 10430422]
45. Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, Combarros O, Zelenika D, Bullido MJ, Tavernier B, Letenneur L, Bettens K, Berr C, Pasquier F, Fiévet N, Barberger-Gateau P, Engelborghs S, De Deyn P, Mateo I, Franck A, Helisalmi S, Porcellini E, Hanon O. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat Genet. 2009;41:1094–9. [PubMed: 19734903]
46. Larner AJ, Doran M. Clinical phenotypic heterogeneity of Alzheimer's disease associated with mutations of the presenilin-1 gene. J Neurol. 2006;253:139–58. [PubMed: 16267640]
47. Leverenz JB, Raskind MA. Early amyloid deposition in the medial temporal lobe of young Down syndrome patients: a regional quantitative analysis. Exp Neurol. 1998;150:296–304. [PubMed: 9527899]
48. Li G, Higdon R, Kukull WA, Peskind E, Van Valen Moore K, Tsuang D, van Belle G, McCormick W, Bowen JD, Teri L, Schellenberg GD, Larson EB. Statin therapy and risk of dementia in the elderly: a community-based prospective cohort study. Neurology. 2004;63:1624–8. [PubMed: 15534246]
49. Li Y, Grupe A, Rowland C, Nowotny P, Kauwe JS, Smemo S, Hinrichs A, Tacey K, Toombs TA, Kwok S, Catanese J, White TJ, Maxwell TJ, Hollingworth P, Abraham R, Rubinsztein DC, Brayne C, Wavrant-De Vrieze F, Hardy J, O'Donovan M, Lovestone S, Morris JC, Thal LJ, Owen M, Williams J, Goate A. DAPK1 variants are associated with Alzheimer's disease and allele-specific expression. Hum Mol Genet. 2006;15:2560–8. [PubMed: 16847012]
50. Li YJ, Oliveira SA, Xu P, Martin ER, Stenger JE, Scherzer CR, Hauser MA, Scott WK, Small GW, Nance MA, Watts RL, Hubble JP, Koller WC, Pahwa R, Stern MB, Hiner BC, Jankovic J, Goetz CG, Mastaglia F, Middleton LT, Roses AD, Saunders AM, Schmechel DE, Gullans SR, Haines JL, Gilbert JR, Vance JM, Pericak-Vance MA. Glutathione S-transferase omega-1 modifiesage-at-onset of Alzheimer disease and Parkinson disease. Hum Mol Genet. 2003;12:3259–67. [PubMed: 14570706]
51. Liu F, Arias-Vásquez A, Sleegers K, Aulchenko YS, Kayser M, Sanchez-Juan P, Feng BJ, Bertoli-Avella AM, van Swieten J, Axenovich TI, Heutink P, van Broeckhoven C, Oostra BA, van Duijn CM. A genomewide screen for late-onset Alzheimer disease in a genetically isolated Dutch population. Am J Hum Genet. 2007;81:17–31. [PMC free article: PMC1950931] [PubMed: 17564960]
52. Margallo-Lana M, Morris CM, Gibson AM, Tan AL, Kay DW, Tyrer SP, Moore BP, Ballard CG. Influence of the amyloid precursor protein locus on dementia in Down syndrome. Neurology. 2004;62:1996–8. [PubMed: 15184603]
53. Martins CA, Oulhaj A, de Jager CA, Williams JH. APOE alleles predict the rate of cognitive decline in Alzheimer disease: a nonlinear model. Neurology. 2005;65:1888–93. [PubMed: 16380608]
54. Masters CL, Beyreuther K. Alzheimer's centennial legacy: prospects for rational therapeutic intervention targeting the Abeta amyloid pathway. Brain. 2006;129:2823–39. [PubMed: 17012295]
55. Mayeux R, Saunders AM, Shea S, Mirra S, Evans D, Roses AD, Hyman BT, Crain B, Tang MX, Phelps CH. Utility of the apolipoprotein E genotype in the diagnosis of Alzheimer's disease. Alzheimer's Disease Centers Consortium on Apolipoprotein E and Alzheimer's Disease. N Engl J Med. 1998;338:506–11. [PubMed: 9468467]
56. Mega MS, Dinov ID, Porter V, Chow G, Reback E, Davoodi P, O'Connor SM, Carter MF, Amezcua H, Cummings JL. Metabolic patterns associated with the clinical response to galantamine therapy: a fludeoxyglucose f 18 positron emission tomographic study. Arch Neurol. 2005;62:721–8. [PubMed: 15883258]
57. McKee AC, Cantu RC, Nowinski CJ, Hedley-Whyte ET, Gavett BE, Budson AE, Santini VE, Lee HS, Kubilus CA, Stern RA. Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J Neuropathol Exp Neurol. 2009;68:709–35. [PMC free article: PMC2945234] [PubMed: 19535999]
58. Mintzer J, Greenspan A, Caers I, Van Hove I, Kushner S, Weiner M, Gharabawi G, Schneider LS. Risperidone in the treatment of psychosis of Alzheimer disease: results from a prospective clinical trial. Am J Geriatr Psychiatry. 2006;14:280–91. [PubMed: 16505133]
59. Mulnard RA, Cotman CW, Kawas C, van Dyck CH, Sano M, Doody R, Koss E, Pfeiffer E, Jin S, Gamst A, Grundman M, Thomas R, Thal LJ. Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. Alzheimer's Disease Cooperative Study. JAMA. 2000;283:1007–15. [PubMed: 10697060]
60. Myers A, Holmans P, Marshall H, Kwon J, Meyer D, Ramic D, Shears S, Booth J, DeVrieze FW, Crook R, Hamshere M, Abraham R, Tunstall N, Rice F, Carty S, Lillystone S, Kehoe P, Rudrasingham V, Jones L, Lovestone S, Perez-Tur J, Williams J, Owen MJ, Hardy J, Goate AM. Susceptibility locus for Alzheimer's disease on chromosome 10. Science. 2000;290:2304–5. [PubMed: 11125144]
61. National Institute on Aging-Alzheimer’s Association Working Group; Apolipoprotein E genotyping in Alzheimer's disease. National Institute on Aging/Alzheimer’s Association Working Group. Lancet. 1996;347:1091–5. [PubMed: 8602063]
62. National Institute on Aging-Reagan Working Group; Consensus recommendations for the postmortem diagnosis of Alzheimer's disease. The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer’s Disease. Neurobiol Aging. 1997;18 Suppl 4:S1–2. [PubMed: 9330978]
63. Nochlin D, van Belle G, Bird TD, Sumi SM. Comparison of the severity of neuropathologic changes in familial and sporadic Alzheimer's disease. Alzheimer Dis Assoc Disord. 1993;7:212–22. [PubMed: 8305189]
64. Nussbaum RL, Ellis CE. Alzheimer's disease and Parkinson's disease. N Engl J Med. 2003;348:1356–64. [PubMed: 12672864]
65. Overshott R, Burns A. Treatment of dementia. J Neurol Neurosurg Psychiatry. 2005;76 Suppl 5:v53–9. [PMC free article: PMC1765710] [PubMed: 16291922]
66. Petersen RC, Thomas RG, Grundman M, Bennett D, Doody R, Ferris S, Galasko D, Jin S, Kaye J, Levey A, Pfeiffer E, Sano M, van Dyck CH, Thal LJ. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med. 2005;352:2379–88. [PubMed: 15829527]
67. Popescu A, Lippa CF, Lee VM, Trojanowski JQ. Lewy bodies in the amygdala: increase of alpha-synuclein aggregates in neurodegenerative diseases with tau-based inclusions. Arch Neurol. 2004;61:1915–9. [PubMed: 15596612]
68. Potkin SG, Guffanti G, Lakatos A, Turner JA, Kruggel F, Fallon JH, Saykin AJ, Orro A, Lupoli S, Salvi E, Weiner M, Macciardi F. Alzheimer's Disease Neuroimaging Initiative; Hippocampal atrophy as a quantitative trait in a genome-wide association study identifying novel susceptibility genes for Alzheimer's disease. PLoS One. 2009;4:e6501. [PMC free article: PMC2719581] [PubMed: 19668339]
69. Prasher VP, Farrer MJ, Kessling AM, Fisher EM, West RJ, Barber PC, Butler AC. Molecular mapping of Alzheimer-type dementia in Down's syndrome. Ann Neurol. 1998;43:380–3. [PubMed: 9506555]
70. Quaid KA, Murrell JR, Hake AM, Farlow MR, Ghetti B. Presymptomatic genetic testing with an APP mutation. J Genet Counsel. 2000;9:327–45.
71. Rademakers R, Cruts M, Sleegers K, Dermaut B, Theuns J, Aulchenko Y, Weckx S, De Pooter T, Van den Broeck M, Corsmit E, De Rijk P, Del-Favero J, van Swieten J, van Duijn CM, Van Broeckhoven C. Linkage and association studies identify a novel locus for Alzheimer disease at 7q36 in a Dutch population-based sample. Am J Hum Genet. 2005;77:643–52. [PMC free article: PMC1275613] [PubMed: 16175510]
72. Raskind MA, Peskind ER, Wessel T, Yuan W. Galantamine in AD: A 6-month randomized, placebo-controlled trial with a 6-month extension. The Galantamine USA-1 Study Group. Neurology. 2000;54:2261–8. [PubMed: 10881250]
73. Raux G, Guyant-Marechal L, Martin C, Bou J, Penet C, Brice A, Hannequin D, Frebourg T, Campion D. Molecular diagnosis of autosomal dominant early onset Alzheimer's disease: an update. J Med Genet. 2005;42:793–5. [PMC free article: PMC1735922] [PubMed: 16033913]
74. Reiman EM, Webster JA, Myers AJ, Hardy J, Dunckley T, Zismann VL, Joshipura KD, Pearson JV, Hu-Lince D, Huentelman MJ, Craig DW, Coon KD, Liang WS, Herbert RH, Beach T, Rohrer KC, Zhao AS, Leung D, Bryden L, Marlowe L, Kaleem M, Mastroeni D, Grover A, Heward CB, Ravid R, Rogers J, Hutton ML, Melquist S, Petersen RC, Alexander GE, Caselli RJ, Kukull W, Papassotiropoulos A, Stephan DA. GAB2 Alleles Modify Alzheimer's Risk in APOE varepsilon4 Carriers. Neuron. 2007;54:713–20. [PMC free article: PMC2587162] [PubMed: 17553421]
75. Reisberg B, Doody R, Stoffler A, Schmitt F, Ferris S, Mobius HJ. Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med. 2003;348:1333–41. [PubMed: 12672860]
76. Reisberg B, Doody R, Stöffler A, Schmitt F, Ferris S, Möbius HJ. A 24-week open-label extension study of memantine in moderate to severe Alzheimer disease. Arch Neurol. 2006;63:49–54. [PubMed: 16401736]
77. Riemenschneider M, Konta L, Friedrich P, Schwarz S, Taddei K, Neff F, Padovani A, Kolsch H, Laws SM, Klopp N, Bickeboller H, Wagenpfeil S, Mueller JC, Rosenberger A, Diehl-Schmid J, Archetti S, Lautenschlager N, Borroni B, Muller U, Illig T, Heun R, Egensperger R, Schlegel J, Forstl H, Martins RN, Kurz A. A functional polymorphism within plasminogen activator urokinase (PLAU) is associated with Alzheimer's disease. Hum Mol Genet. 2006;15:2446–56. [PubMed: 16825285]
78. Roberts JS, Cupples LA, Relkin NR, Whitehouse PJ, Green RC. Genetic risk assessment for adult children of people with Alzheimer's disease: the Risk Evaluation and Education for Alzheimer's Disease (REVEAL) study. J Geriatr Psychiatry Neurol. 2005;18:250–5. [PubMed: 16306249]
79. Rogaeva E, Meng Y, Lee JH, Gu Y, Kawarai T, Zou F, Katayama T, Baldwin CT, Cheng R, Hasegawa H, Chen F, Shibata N, Lunetta KL, Pardossi-Piquard R, Bohm C, Wakutani Y, Cupples LA, Cuenco KT, Green RC, Pinessi L, Rainero I, Sorbi S, Bruni A, Duara R, Friedland RP, Inzelberg R, Hampe W, Bujo H, Song YQ, Andersen OM, Willnow TE, Graff-Radford N, Petersen RC, Dickson D, Der SD, Fraser PE, Schmitt-Ulms G, Younkin S, Mayeux R, Farrer LA, St George-Hyslop P. The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet. 2007;39:168–77. [PMC free article: PMC2657343] [PubMed: 17220890]
80. Rogan S, Lippa CF. Alzheimer's disease and other dementias: a review. Am J Alzheimers Dis Other Demen. 2002;17:11–7. [PubMed: 11831415]
81. Romas SN, Santana V, Williamson J, Ciappa A, Lee JH, Rondon HZ, Estevez P, Lantigua R, Medrano M, Torres M, Stern Y, Tycko B, Mayeux R. Familial Alzheimer disease among Caribbean Hispanics: a reexamination of its association with APOE. Arch Neurol. 2002;59:87–91. [PubMed: 11790235]
82. Rosenberg RN. The molecular and genetic basis of AD: the end of the beginning: the 2000 Wartenberg lecture. Neurology. 2000;54:2045–54. [PubMed: 10851361]
83. Roses AD, Saunders AM. Perspective on a pathogenesis and treatment of Alzheimer's disease. Alzheimers Dement. 2006;2:59–70. [PubMed: 19595857]
84. Roses AD, Lutz MW, Amrine-Madsen H, Saunders AM, Crenshaw DG, Sundseth SS, Huentelman MJ, Welsh-Bohmer KA, Reiman EM (2009) A TOMM40 variable-length polymorphism predicts the age of late-onset Alzheimer's disease. Pharmacogenomics J. [Epub ahead of print]
85. Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Liao Z, Lieberburg I, Motter R, Mutter L, Soriano F, Shopp G, Vasquez N, Vandevert C, Walker S, Wogulis M, Yednock T, Games D, Seubert P. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature. 1999;400:173–7. [PubMed: 10408445]
86. Schupf N, Kapell D, Nightingale B, Lee JH, Mohlenhoff J, Bewley S, Ottman R, Mayeux R. Specificity of the fivefold increase in AD in mothers of adults with Down syndrome. Neurology. 2001;57:979–84. [PubMed: 11571320]
87. Scott WK, Hauser ER, Schmechel DE, Welsh-Bohmer KA, Small GW, Roses AD, Saunders AM, Gilbert JR, Vance JM, Haines JL, Pericak-Vance MA. Ordered-subsets linkage analysis detects novel Alzheimer disease Loci on chromosomes 2q34 and 15q22. Am J Hum Genet. 2003;73:1041–51. [PMC free article: PMC1180484] [PubMed: 14564669]
88. Seltzer B, Zolnouni P, Nunez M, Goldman R, Kumar D, Ieni J, Richardson S. Efficacy of donepezil in early-stage Alzheimer disease: a randomized placebo-controlled trial. Arch Neurol. 2004;61:1852–6. [PubMed: 15596605]
89. Serretti A, Artioli P, Quartesan R, De Ronchi D. Genes involved in Alzheimer's disease, a survey of possible candidates. J Alzheimers Dis. 2005;7:331–53. [PubMed: 16131736]
90. Silverman JM, Li G, Zaccario ML, Smith CJ, Schmeidler J, Mohs RC, Davis KL. Patterns of risk in first-degree relatives of patients with Alzheimer's disease. Arch Gen Psychiatry. 1994;51:577–86. [PubMed: 8031231]
91. Sleegers K, Van Duijn CM. Alzheimer's Disease: Genes, Pathogenesis and Risk Prediction. Community Genet. 2001;4:197–203. [PubMed: 12107347]
92. Smemo S, Nowotny P, Hinrichs AL, Kauwe JS, Cherny S, Erickson K, Myers AJ, Kaleem M, Marlowe L, Gibson AM, Hollingworth P, O'Donovan MC, Morris CM, Holmans P, Lovestone S, Morris JC, Thal L, Li Y, Grupe A, Hardy J, Owen MJ, Williams J, Goate A. Ubiquilin 1 polymorphisms are not associated with late-onset Alzheimer's disease. Ann Neurol. 2006;59:21–6. [PubMed: 16278862]
93. Snider BJ, Fagan AM, Roe C, Shah AR, Grant EA, Xiong C, Morris JC, Holtzman DM. Cerebrospinal fluid biomarkers and rate of cognitive decline in very mild dementia of the Alzheimer type. Arch Neurol. 2009;66:638–45. [PMC free article: PMC2759394] [PubMed: 19433664]
94. Steinbart EJ, Smith CO, Poorkaj P, Bird TD. Impact of DNA testing for early-onset familial Alzheimer disease and frontotemporal dementia. Arch Neurol. 2001;58:1828–31. [PubMed: 11708991]
95. Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, Gergel I. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA. 2004;291:317–24. [PubMed: 14734594]
96. Tariot PN, Solomon PR, Morris JC, Kershaw P, Lilienfeld S, Ding C. A 5-month, randomized, placebo-controlled trial of galantamine in AD. The Galantamine USA-10 Study Group. Neurology. 2000;54:2269–76. [PubMed: 10881251]
97. Teri L, Logsdon RG, Peskind E, Raskind M, Weiner MF, Tractenberg RE, Foster NL, Schneider LS, Sano M, Whitehouse P, Tariot P, Mellow AM, Auchus AP, Grundman M, Thomas RG, Schafer K, Thal LJ. Alzheimer's Disease Cooperative Study; Treatment of agitation in AD: a randomized, placebo-controlled clinical trial. Neurology. 2000;55:1271–8. [PubMed: 11087767]
98. Towner D, Loewy RS. Ethics of preimplantation diagnosis for a woman destined to develop early-onset Alzheimer disease. JAMA. 2002;287:1038–40. [PubMed: 11866654]
99. Tsuang D, Larson EB, Bowen J, McCormick W, Teri L, Nochlin D, Leverenz JB, Peskind ER, Lim A, Raskind MA, Thompson ML, Mirra SS, Gearing M, Schellenberg GD, Kukull W. The utility of apolipoprotein E genotyping in the diagnosis of Alzheimer disease in a community-based case series. Arch Neurol. 1999;56:1489–95. [PubMed: 10593304]
100. van der Cammen TJ, Croes EA, Dermaut B, de Jager MC, Cruts M, Van Broeckhoven C, van Duijn CM. Genetic testing has no place as a routine diagnostic test in sporadic and familial cases of Alzheimer's disease. J Am Geriatr Soc. 2004;52:2110–3. [PubMed: 15571552]
101. Verlinsky Y, Rechitsky S, Verlinsky O, Masciangelo C, Lederer K, Kuliev A. Preimplantation diagnosis for early-onset Alzheimer disease caused by V717L mutation. JAMA. 2002;287:1018–21. [PubMed: 11866650]
102. Wang PN, Liao SQ, Liu RS, Liu CY, Chao HT, Lu SR, Yu HY, Wang SJ, Liu HC. Effects of estrogen on cognition, mood, and cerebral blood flow in AD: a controlled study. Neurology. 2000;54:2061–6. [PubMed: 10851363]
103. Wijsman EM, Daw EW, Yu CE, Payami H, Steinbart EJ, Nochlin D, Conlon EM, Bird TD, Schellenberg GD. Evidence for a novel late-onset Alzheimer disease locus on chromosome 19p13.2. Am J Hum Genet. 2004;75:398–409. [PMC free article: PMC1182019] [PubMed: 15248153]
104. Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel G. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3- methyglutaryl coenzyme A reductase inhibitors. Arch Neurol. 2000;57:1439–43. [PubMed: 11030795]
105. Yaffe K, Clemons TE, McBee WL, Lindblad AS. Impact of antioxidants, zinc, and copper on cognition in the elderly: a randomized, controlled trial. Neurology. 2004;63:1705–7. [PMC free article: PMC1473037] [PubMed: 15534261]

Published Statements and Policies Regarding Genetic Testing

1. American College of Medical Genetics/American Society of Human Genetics Working Group on ApoE and Alzheimer's disease (1995) Statement on use of apolipoprotein E testing for Alzheimer's disease.
2. American Society of Human Genetics and American College of Medical Genetics (1995) Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents.
3. National Society of Genetic Counselors (1995) Resolution on prenatal and childhood testing for adult-onset disorders.
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]

Revision History

• 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