Effects of BACE2 polymorphisms on verbal memory in the general population.

UNLABELLED: Emerging evidence highlights the potential role of BACE2 (beta-site APP cleavage enzyme 2) in influencing Alzheimer’s disease (AD) risk and cognitive impairment, particularly due to its ability to cleave amyloid precursor protein (APP) at the θ-site in a non-amyloidogenic manner without the accumulation of neurotoxic Aβ42. Using data from the German population-based Study of Health in Pomerania (SHIP-TREND), we applied general linear regression models to evaluate the associations between 231 genetic variants within BACE2 and two verbal memory scores in a cross-sectional (N = 3791) and a longitudinal setting (N = 2215). Additionally, we examined the moderating effect of APOE ε4 on the relationship between BACE2 variants and memory performance. Three genetic clumps were significantly associated with verbal memory scores in the cross-sectional setting (pFDR<0.05). The minor T-allele of rs61736857 and the minor C-allele of rs1072869 were inversely associated with verbal memory, while the minor C-allele of rs6517661 showed a positive association. No interaction term with APOE ε4 reached statistical significance in the cross-sectional setting. In longitudinal analyses, rs8133778 demonstrated a significant (pFDR<0.05) interaction effect with APOE ε4 on memory. Genotype GG exhibited a more pronounced decline in verbal memory among ε4 carriers, while genotypes AA and AG represented a risk factor for non-carriers. We replicated some BACE2 variants previously reported as potential risk factors in AD at a nominal significance level. In addition, our results identify novel variants that may contribute to cognitive impairment in the general population, some of which have been previously associated with altered BACE2 expression.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00406-026-02208-y.