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A 52-year-old woman develops progressive memory loss and cognitive decline. Her mother and two maternal aunts died of early-onset dementia in their 50s.
- Early-onset Alzheimer's disease genes (AD): APP (21q), PSEN1 (14q), PSEN2 (1q)
- Risk factor: APOE ε4 allele (dosage-dependent)
- Protective factor: APOE ε2 allele
- Early-onset: <65 years (often 40s-50s with AD genes)
- Progressive memory loss, cognitive decline
- Behavioral/personality changes
- PSEN1 variants: most common AD cause of early-onset familial AD
- Patients with Down syndrome are at increased risk for Alzheimer's because APP is on chromosome 21
- Clinical diagnosis supported by cognitive testing; early-onset autosomal dominant disease warrants molecular testing of APP, PSEN1, PSEN2
- Biomarkers: CSF (low amyloid-beta 42, elevated phospho-tau/total tau) and amyloid PET support the diagnosis
- APOE genotyping is a susceptibility marker, not diagnostic, and is generally not used for predictive testing
- Predictive testing of at-risk relatives for a known familial deterministic variant follows a formal Huntington-style protocol with genetic counseling
- No disease-modifying cure; cholinesterase inhibitors (donepezil) and memantine for symptomatic support
- Anti-amyloid monoclonal antibodies are an option in select early-stage disease (require MRI monitoring for ARIA)
- Treat behavioral and psychiatric symptoms; caregiver support, safety planning, and advance care planning
- Cascade counseling for at-risk relatives when a deterministic variant is identified
"APP on chromosome 21 = Down syndrome link": Patients with trisomy 21 (Down syndrome) have 3 copies of APP, leading to increased amyloid-beta production and early-onset Alzheimer's.
"Alzheimer's vs Huntington's vs Parkinson's": Alzheimer's = strict memory loss first. Huntington's = chorea (involuntary movements). Parkinson's = rigidity and resting hand tremor.