Early‐onset Alzheimer's disease explained by polygenic risk of late‐onset disease?

Early‐onset Alzheimer's disease (AD) is highly heritable, yet only 10% of cases are associated with known pathogenic mutations. For early‐onset AD patients without an identified autosomal dominant cause, we hypothesized that their early‐onset disease reflects further enrichment of the common risk‐conferring single nucleotide polymorphisms associated with late‐onset AD. We applied a previously validated polygenic hazard score for late‐onset AD to 193 consecutive patients diagnosed at our tertiary dementia referral center with symptomatic early‐onset AD. For comparison, we included 179 participants with late‐onset AD and 70 healthy controls. Polygenic hazard scores were similar in early‐ versus late‐onset AD. The polygenic hazard score was not associated with age‐of‐onset or disease biomarkers within early‐onset AD. Early‐onset AD does not represent an extreme enrichment of the common single nucleotide polymorphisms associated with late‐onset AD. Further exploration of novel genetic risk factors of this highly heritable disease is warranted. HIGHLIGHTS: There is a unique genetic architecture of early‐ versus late‐onset Alzheimer's disease (AD). Late‐onset AD polygenic risk is not an explanation for early‐onset AD. Polygenic risk of late‐onset AD does not predict early‐onset AD biology. Unique genetic architecture of early‐ versus late‐onset AD parallels AD heterogeneity.