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 <i>PSEN1, PSEN2</i>, or <i>APP</i> 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 <i>APOE</i> and <i>DAOA</i> genotypes, previously described as modifiers of clinical phenotypes in LOAD and EOAD in 88 individuals clinically diagnosed with AD-EOAD due to the <i>PSEN1</i> A431E variant (39 females, 49 males). We classified the population according to their genotype (<i>APOEε2, APOEε3</i>, and <i>APOEε4</i> and <i>DAOA</i> 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 <i>APOE</i> genotype and AoO (<i>p</i> < 0.001), with the <i>APOEε4</i> allele being linked to a delayed onset (β = 4.04, SE = 1.11, <i>p</i> = 0.0003). Similarly, individuals with the <i>DAOA</i> rs2391191 A/A genotype showed a significantly later AoO compared to G/G carriers (β = 2.13, SE = 0.96, <i>p</i> = 0.0301). No significant association was found between <i>APOE</i> or <i>DAOA</i> genotypes and FCM. The findings suggest that both the <i>APOEε4</i> allele and <i>DAOA</i> 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 <i>APOE</i> and <i>DAOA</i> influence AD-EOAD progression.