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Key Points

  • Disease summary:

    • Alzheimer disease (AD) is the most common form of dementia. It is characterized by debilitating and progressive episodic memory loss, difficulty with language and decision making, and (in advanced stages) loss of motor control, incontinence, and mutism.

    • The neuropathologic hallmarks of the AD brain include an abundance of senile plaques largely composed of beta-amyloid (Aβ) deposits and neurofibrillary tangles made up of tau protein. While these features are consistently observed in autopsies of AD patients, the exact role that these proteins play in AD pathogenesis is still unclear.

    • Most patients with AD begin developing symptoms after 60 years of age, although in the rare cases of autosomal dominantly inherited AD symptoms typically manifest at an earlier age.

    • Although risk for AD increases with age, AD is not a symptom of normal aging.

  • Differential diagnosis:

    • Treatable diagnoses: depression, chronic drug intoxication, chronic central nervous system (CNS) infection, thyroid disease, vitamin deficiencies (particularly B12 and thiamine), CNS angiitis, and normal-pressure hydrocephalus (NPH)

    • Other neurodegenerative disorders: vascular dementia, diffuse Lewy body syndrome, Parkinson disease, Pick disease, Creutzfeldt-Jakob disease, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

  • Monogenic forms:

    • Rare cases of very early-onset familial AD (FAD) follow a Mendelian autosomal dominant inheritance pattern.

    • Approximately 70% of FAD cases can be explained by mutations in one of three genes: PSEN1, PSEN2, and APP.

  • Family history:

    • The average person has a 10% to 12% chance of developing AD in his or her lifetime. First-degree relatives of patients with AD have a 20% to 44% lifetime risk for the disease.

  • Twin studies:

    • Monozygotic twins show a 60% concordance rate for AD.

  • Environmental factors:

    • Risk factors include female gender, lower level of education, and history of head trauma.

  • Genome-wide Associations:

    • Recent large-scale genome-wide association studies (GWASs) have identified multiple genetic loci associated with AD risk (Table 124-1). Of these results however, even the most robust marker for AD susceptibility, the ε4 allele of APOE, is neither necessary nor sufficient for AD diagnosis.

  • Pharmacogenomics:

    • While several studies have begun stratifying AD patients based on genetic markers to test for differential response to treatment, at present no consistently replicated pharmacogenomic associations have been observed for AD therapies.

Table 124-1Molecular Genetic Testing For Alzheimer Disease

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