Early-onset Alzheimer’s disease explained by polygenic risk of late-onset disease?

Author(s): Mantyh, WG; Cochran, JN; Taylor, JW; Broce, IJ; Geier, EG; Bonham, LW; Anderson, AG; Sirkis, DW; Joie, RL; Iaccarino, L; Chaudhary, K; Edwards, L; Strom, A; Grant, H; Allen, IE; Miller, ZA; Gorno-Tempini, ML; Kramer, JH; Miller, BL; Desikan, RS; Rabinovici, GD; Yokoyama, JS;
Year: 2023;  
Journal: Alzheimer's & Dementia (Amsterdam, Netherlands);  
Volume: 15;  
Issue: 4;  

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.