Associations and interactions between premorbid cognitive health, apolipoprotein e4 genotype, and incident Alzheimer’s disease in UK Biobank (N=252,340)

Background: It is unclear to what extent genetic risk offsets the protective effects of better premorbid cognitive health, on risk of Alzheimer’s disease (AD). To address this, we tested for associations between measures of premorbid cognitive health, apolipoprotein (APOE) e4 ‘risk’ genotype, and their interaction, with risk of incident AD and age of diagnosis. Methods: We leveraged data on UK Biobank participants aged ≥55 years at baseline. Cox and linear regressions were used to test associations between cognitive scores (reasoning, information processing speed, memory) versus incidence of AD, and age at diagnosis. These were adjusted for age at time of assessment (prior to AD diagnosis), sex, deprivation, educational attainment, history of cardiometabolic diseases, 10 genetic principal components, genotypic array, and APOE e4 genotype. Results: During follow-up, 3,505/252,340 (1.39%) participants received an incident diagnosis of AD. There were significant associations between better performance on each cognitive test and lower risk of incident AD (e.g. overall hazard ratio [HR] = 0.73 per standard deviation [SD] better verbal-numerical reasoning; 95% confidence interval [CI] 0.68-0.79, P<0.001), and later age at diagnosis (0.58 years later per one SD). However, the benefit of better baseline cognitive scores on AD risk was attenuated in APOE e4 carriers (e.g. verbal-numerical reasoning: HR = 0.64 per SD in non-e4 carriers, versus HR = 0.79 in e4 carriers). Conclusion: These data demonstrate that the association between premorbid cognitive health and subsequent risk of AD is influenced by APOE e4 genotype. This has implications for risk stratification and targeted intervention.