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

Abstract

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.

Blood biomarker profiles in young-onset neurocognitive disorders: a cohort study

“…Overall, the transferability of a PRS derived from a LOAD population to an EOAD population is mixed, with some studies demonstrating poor correlation. 54,55 Other studies have shown a potential role of a LOAD-derived PRS in predicting EOAD cases, though differences in age of participants and APOE status may confound direct comparisons. [56][57][58][59] Our findings, along with those previously published, indicate the need for an EOAD-derived PRS, especially in individuals with non-familial cases.…”

Single-nucleus multiomics reveals the disrupted regulatory programs in three brain regions of sporadic early-onset Alzheimer’s disease

“…sEOAD have unveiled both common and rare variants in genes associated with LOAD, alongside novel variants, suggesting a partially overlapping genetic framework between sEOAD and LOAD [14][15][16] . Several genome-wide association studies (GWAS) have identified over 75 common variants linked to LOAD, with the APOE ε4 allele being the most significant genetic risk factor [17][18][19][20][21][22] .…”