Early-Onset Familial Alzheimer Disease – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY

Excerpt

NOTE: THIS PUBLICATION HAS BEEN RETIRED. THIS ARCHIVAL VERSION IS FOR HISTORICAL REFERENCE ONLY, AND THE INFORMATION MAY BE OUT OF DATE.

Clinical characteristics: Alzheimer disease (AD) is characterized by adult-onset progressive dementia associated with cerebral cortical atrophy, beta-amyloid plaque formation, and intraneuronal neurofibrillary tangles. AD typically begins with subtle memory failure that becomes more severe and is eventually incapacitating. Other common findings include confusion, poor judgment, language disturbance, agitation, withdrawal, hallucinations, seizures, Parkinsonian features, increased muscle tone, myoclonus, incontinence, and mutism. Familial AD (FAD) characterizes families that have more than one member with AD and usually implies multiple affected persons in more than one generation. Early-onset FAD (EOFAD) refers to families in which onset is consistently before age 60 to 65 years and often before age 55 years.

Diagnosis/testing: EOFAD is diagnosed in families with multiple affected individuals with mean age of onset before 65 years and/or with a documented pathogenic variant in one of the genes known to be associated with EOFAD. The three clinically indistinguishable subtypes of EOFAD based on the underlying genetic mechanism are: Alzheimer disease type 1 (AD1), caused by mutation of APP (10%-15% of EOFAD); Alzheimer disease type 3 (AD3), caused by mutation of PSEN1, (30%-70% of EOFAD); and Alzheimer disease type 4 (AD4), caused by mutation of PSEN2 (<5% of EOFAD). Kindreds with autosomal dominant EOFAD with no identifiable pathogenic variants in PSEN1, PSEN2, or APP have been described; thus, it is likely that variants in additional genes are causative.

Management: Treatment of manifestations: Supportive; symptoms of depression, aggression, sleep disturbance, seizures, and hallucinations are managed on an individual basis; affected individuals eventually require assisted living/nursing home care; agents that increase cholinergic activity, such as Aricept^® (donepezil), Exelon^® (rivastigmine), and Reminy^® (galatamine), show modest but variable benefit; memantine, an NMDA receptor antagonist, is approved for use in AD; physical and occupational therapy help manage activities of daily living.

Surveillance: Monthly monitoring to identify and manage secondary complications.

Agents/circumstances to avoid: Sudden changes in environment; over-sedation.

Genetic counseling: EOFAD is inherited in an autosomal dominant manner. Most individuals with EOFAD had an affected parent; occasionally, neither parent is identified as having had the disease, but a second-degree relative (e.g., an uncle, aunt, and/or grandparent) has or had EOFAD. Each child of an individual with EOFAD has a 50% chance of inheriting the pathogenic variant and developing EOFAD. Prenatal testing for pregnancies at increased risk for is possible if the pathogenic variant in the family is known; however, prenatal testing for adult-onset disorders is uncommon.