DAOA and APOEε4 as Modifiers of Age of Onset in Autosomal-Dominant Early-Onset Alzheimer's Disease Caused by the PSEN1 A431E Variant.

While most of the Alzheimer's disease (AD) cases are sporadic and manifest after age 65 (late-onset AD, LOAD), a subset of patients develop symptoms earlier in life (early-onset, EOAD) due to mutations in the PSEN1, PSEN2, or APP genes with an autosomal-dominant inheritance pattern (AD-EOAD). In this study, we examined the association between age of onset (AoO) and first clinical manifestation (FCM) with the APOE and DAOA genotypes, previously described as modifiers of clinical phenotypes in LOAD and EOAD in 88 individuals clinically diagnosed with AD-EOAD due to the PSEN1 A431E variant (39 females, 49 males). We classified the population according to their genotype (APOEε2, APOEε3, and APOEε4 and DAOA G/G, G/A, and A/A) and FCM (cognitive, behavioral, motor, and memory impaired). Memory impairment was the most frequent symptom (51%), followed by motor disturbances (31.8%), cognitive symptoms other than memory (10.4%), and behavioral changes (6.8%). We found a significant association between APOE genotype and AoO (p < 0.001), with the APOEε4 allele being linked to a delayed onset (β = 4.04, SE = 1.11, p = 0.0003). Similarly, individuals with the DAOA rs2391191 A/A genotype showed a significantly later AoO compared to G/G carriers (β = 2.13, SE = 0.96, p = 0.0301). No significant association was found between APOE or DAOA genotypes and FCM. The findings suggest that both the APOEε4 allele and DAOA rs2391191 A/A genotype may act as genetic modifiers of AoO, delaying symptom onset in individuals with AD-EOAD. Further research is needed to elucidate the molecular pathways through which APOE and DAOA influence AD-EOAD progression.