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.

Bee venom (BV) contains bioactive peptides with potent antioxidant, anti-inflammatory, and neuroprotective properties, yet its direct therapeutic use is limited by cytotoxicity, instability, and uncontrolled release. This study aimed to develop and evaluate bee venom-loaded nanoliposomes (BV-LN) as an innovative Antioxidant and erythroprotective delivery platform with controlled in vitro release and enhanced gastrointestinal stability for potential applications in neurodegenerative disease management. BV’s antioxidant activity, erythroprotective potential, hemocompatibility, and membrane-stabilizing capacity were systematically assessed, alongside assays for antihemolytic activity against AAPH-induced oxidative hemolysis. BV-LN were synthesized via thin-film hydration and extensively characterized for encapsulation efficiency (84.43 ± 2.26%), water solubility (1.83 µg/mL), centrifugal stability (94.13 ± 3.53%), morphological integrity, and thermal/structural properties (XRD, DSC). Simulated digestion tests confirmed gradual peptide release under gastric and intestinal conditions. Results highlight BV’s strong antioxidant activity (≈70% DPPH inhibition) and marked erythroprotective effects, including >98% hemocompatibility at safe concentrations and significant membrane stabilization under heat and osmotic stress. Encapsulation in nanoliposomes slightly modulated immediate radical scavenging but enhanced safety by preventing excessive hemolysis and enabling controlled melittin release. The robust nanoliposomal structure, driven by peptide–phospholipid hydrophobic anchoring and cholesterol-mediated bilayer ordering, ensured stability under mechanical and digestive stress. This research is highly innovative as it pioneers BV encapsulation for neuroprotective nutraceutical applications, offering a safe, sustained-release platform that could mitigate oxidative stress and inflammation, key drivers of disorders like epilepsy, Alzheimer’s, and Parkinson’s. BV-LN demonstrate strong potential as next-generation carriers for functional foods or therapeutic formulations targeting neurodegenerative diseases, warranting further in vitro validation and translational studies.