The interplay of PICALM with APOE ε4 on Alzheimer’s disease: clues from two longitudinal cohorts and proteomic studies

APOE and PICALM are prominent risk genes for late-onset Alzheimer’s disease (AD). We previously reported that the protective PICALM rs3851179 A allele was associated with slower cognitive and pathological progression among APOE ε4 carriers. However, whether this interaction affects incident AD, and through what mechanisms, remains unclear. We tested the interaction between PICALM rs3851179 and APOE ε4 on incident AD risk using multi-variable Cox models in two independent cohorts: the UK Biobank (UKB) and the Alzheimer’ s Disease Neuroimaging Initiative (ADNI). Plasma and cerebrospinal fluid (CSF) proteomics were used to explore mechanisms. In UKB, additive-scale interaction measures indicated antagonism (AP = −0.13; RERI = −0.52; SI = 0.86). Consistently, rs3851179 AG and AA genotypes were associated with lower AD risk only among APOE ε4 carriers (HR = 0.89 and 0.80, respectively). Plasma proteomics identified synaptosomal-associated protein 25 (SNAP25) as a protein associated with both APOE ε4 and PICALM rs3851179. In UKB, plasma SNAP25 levels were lower in rs3851179 AA than GG carriers (P = 0.003) and positively associated with APOE ε4 status (P < 0.001). Consistent though nominal associations were found in ADNI, with higher SNAP25 levels in APOE ε4 carriers (P = 0.079) and lower levels in rs3851179 AA (P = 0.030). No CSF protein survived the multiple-testing correction. These findings suggest that the protective effect of rs3851179 A on AD risk may be confined to APOE ε4 carriers, with SNAP25-related synaptic modulation potentially contributing to this effect