Basic Science and Pathogenesis

Autosomal dominant Alzheimer's disease (ADAD) provides a unique model to study early cognitive changes associated with Alzheimer's disease (AD) pathological hallmarks. Although APOE ε4 is the main genetic risk factor for sporadic AD, related to the apparition of amnestic phenotypes, its relationship with cognitive features in ADAD remains unclear. This study investigates the influence of the co-occurrence of APOE ε4 with APP_V717I or PSEN1_A431E mutations on cognitive performance in the preclinical phase of ADAD.

A total of 81 Mexican-mestizo individuals at risk of inheriting one of these mutations, underwent genetic analysis, including PSEN1_A431E/APP_V717I mutation screening and APOE genotyping, as well as neuropsychological evaluation using the CERAD-MX battery. Based on genetic results, participants were divided into carriers (C; n = 39 [14 APP_V717I and 25 PSEN1_A431E]) and non-carriers (NC; n = 42). Further stratification by APOE genotype (ε4+ or ε4-) resulted in four subgroups: ε4+/ε4- carriers (Cε4+ n = 6 /Cε4- n = 33), and ε4+/ε4- non-carriers (NCε4+ n = 5 /NCε4- n = 37). Normalized z-scores from 12 tasks of the CERAD-MX were taken as measures of global cognition, memory, language, attention, visuospatial skills, and executive functions. The Clinical Dementia Rating (CDR) was used to determine preclinical staging. Group differences were analyzed using Mann-Whitney U, Kruskal-Wallis, and Dunn's post hoc tests.

Comparisons revealed that mutation carriers exhibited lower performance in Constructional Praxis-Recall (NC>C, U = 582, p = .02) and Rey-Osterrieth Complex Figure-Recall (RCF; NC>C U = 503, p = .002) visual memory tasks. When stratified by APOE, Cε4- participants showed a significant difference in RCF-recall compared to NCε4- (k = 10.32, p = .009).

Our findings indicate early visual memory impairment preceding the ADAD clinical stage in this carrier population. However, no evidence was found to indicate a negative impact of APOE ε4 on memory performance. Future efforts to expand the sample size will be essential to confirm whether the observed pattern persists and to uncover potential effects on other cognitive domains. Additionally, factors such as proximity to symptom onset and APOE ancestry may also influence cognitive performance. This study contributes to understanding early cognitive changes in ADAD and suggests that factors modifying the clinical phenotype may also play a role in shaping preclinical cognitive variations.