Frida Rosales-Leycegui

Background: 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. Method: 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. Result: 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). Conclusion: 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.

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.

Early-onset Alzheimer’s disease (EOAD), defined as Alzheimer’s disease onset before 65 years of age, has been significantly less studied than the “classic” late-onset form (LOAD), although EOAD often presents with a more aggressive disease course, caused by variants in the APP, PSEN1, and PSEN2 genes. EOAD has significant differences from LOAD, including encompassing diverse phenotypic manifestations, increased genetic predisposition, and variations in neuropathological burden and distribution. Phenotypically, EOAD can be manifested with non-amnestic variants, sparing the hippocampi with increased tau burden. The aim of this article is to review the different genetic bases, risk factors, pathological mechanisms, and diagnostic approaches between EOAD and LOAD and to suggest steps to further our understanding. The comprehension of the monogenic form of the disease can provide valuable insights that may serve as a roadmap for understanding the common form of the disease.

In Alzheimer’s disease (AD), the age of onset (AoO) exhibits considerable variability, spanning from 40 to 90 years. Specifically, individuals diagnosed with AD and exhibiting symptoms prior to the age of 65 are typically classified as early onset (EOAD) cases. Notably, the apolipoprotein E (APOE) ε4 allele represents the most extensively studied genetic risk factor associated with AD. We clinically characterized and genotyped the APOEε4 allele from 101 individuals with a diagnosis of EOAD, and 69 of them were affected carriers of the autosomal dominant fully penetrant PSEN1 variant c.1292C>A (rs63750083, A431E) (PSEN1+ group), while there were 32 patients in which the genetic cause was unknown (PSEN1− group). We found a correlation between the AoO and the APOEε4 allele; patients carrying at least one APOEε4 allele showed delays, in AoO in patients in the PSEN1+ and PSEN1− groups, of 3.9 (p = 0.001) and 8.6 years (p = 0.012), respectively. The PSEN1+ group presented higher frequencies of gait disorders compared to PSEN1− group, and apraxia was more frequent with PSEN1+/APOE4+ than in the rest of the subgroup. This study shows what appears to be an inverse effect of APOEε4 in EOAD patients, as it delays AoO and modifies clinical manifestations.