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.

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.

Background: Early-onset Alzheimer’s disease (EOAD) caused by autosomal dominant mutations provides a deterministic framework for investigating genetic modifiers of neurodegeneration. Telomere biology has emerged as a central regulator of genomic stability, cellular ageing, and stress response integration, yet its role in EOAD, particularly in under-represented populations, remains poorly defined. Methods: We conducted a cross-sectional case–control study to evaluate the genetic distribution, disease association, and predicted regulatory consequences of common variants in the telomere maintenance genes TERT and TERC in individuals from Western Mexico. The EOAD group comprised genetically confirmed carriers of the PSEN1 p.Ala431Glu (A431E) founder mutation with clinical EOAD (n = 69), and controls were unrelated individuals without dementia (n = 179). Five common variants were analyzed: rs2242652, rs2853677, rs2736100, and rs10069690 (TERT), and rs12696304 (TERC). Results: Genotype distributions in controls conformed to the Hardy–Weinberg equilibrium. Single-variant analyses showed no significant allele-level associations. Most TERT variants did not show significant allele-level associations with EOAD. However, a preliminary genotype-level enrichment for the GC allele at rs12696304 (TERC) was observed among EOAD cases compared with controls; allele-level associations were not significant. Linkage disequilibrium analysis revealed low r² values (<0.20), supporting variant independence. Population-level allele frequency comparisons revealed ancestry-dependent divergence across loci; in silico functional annotation localised all variants to non-coding regulatory regions. GTEx-based analyses indicated that rs12696304 acts as an eQTL for ACTRT3 in whole blood and pituitary, as well as for LRRC34 in the cerebellar hemisphere, suggesting a potential regulatory network within the TERC locus (3q26.2). Conclusions: Overall, common regulatory variants in TERT did not show strong independent effects on EOAD susceptibility in PSEN1 A431E carriers. However, the convergence of association patterns, functional annotation, and regulatory evidence provides hypothesis-generating support for the TERC locus (3q26.2), particularly rs12696304, as a candidate region for further investigation. Additional studies integrating telomere dynamics, functional validation, and multi-omics analyses are needed to clarify the role of telomere biology in the pathogenesis of autosomal dominant EOAD.

Background: Alzheimer's disease (AD) is the most common neurodegenerative disorder, characterized by neuropathological hallmarks such as amyloid β‐protein plaques, leading to neuronal loss. Early‐Onset Alzheimer's Disease (EOAD), which manifests before the age of 65, is a rare condition often associated with specific genetic variants. Patients carrying the PSEN1 A431E mutation typically present with symptoms at an average age of 42.5 years, with rapid disease progression leading to death within an average of 7.5 years. This mutation represents the second‐largest population of EOAD cases caused by a single mutation. Given the clinical variability observed among affected families with the same mutation, we investigated the influence of additional genetic factors, such as APOE alleles, on disease phenotype. Method: A total of 89 patients with familial EOAD were evaluated at the CMNO‐IMSS genetics service. Autosomal dominant inheritance patterns and clinical features consistent with AD were identified. The PSEN1 A431E mutation was confirmed by Sanger sequencing, and APOEε2 and APOEε4 alleles were genotyped using real‐time PCR. Data analysis included descriptive statistics, Kruskal‐Wallis, and simple linear regression to assess clinical correlations. Result: A significant association was identified between the age at symptom onset and APOE alleles. APOEε4 carriers showed a delayed symptom onset of 4.15 years ( p = 0.00035), whereas APOEε2 carriers showed an earlier onset of 2.34 years ( p = 0.037). However, no association was observed between APOE alleles and the nature of the first clinical manifestation. Conclusion: This study highlights an apparently inverse effect of APOEε4 and APOEε2 in EOAD patients with the PSEN1 A431E mutation, compared to late‐onset AD. Specifically, APOEε4 delays the age of symptom onset, whereas APOEε2 accelerates it. These findings suggest that APOE alleles play a dual role as genetic modifiers in EOAD, offering potential avenues for personalized risk assessment and targeted interventions.