Abstract
AIMS/HYPOTHESIS: Type 2 diabetes, hyperglycaemia and insulin resistance are associated with cognitive impairment and dementia, but causal inference studies using Mendelian randomisation do not confirm this. We hypothesised that early-life cognition and social/educational advantage may confound the relationship. METHODS: From the population-based British 1946 birth cohort, a maximum number of 1780 participants had metabolic variables (type 2 diabetes, insulin resistance [HOMA2-IR] and HbA(1c)) assessed at age 60-64 years, and cognitive state (Addenbrooke's Cognitive Examination III [ACE-III]) and verbal memory assessed at age 69 years. Earlier-life measures included socioeconomic position (SEP), cognition at age 8 years and educational attainment. Polygenic risk scores (PRSs) for type 2 diabetes were calculated. We first used a PRS approach with multivariable linear regression to estimate associations between PRSs and metabolic traits and later-life cognitive state. Second, using a path model approach, we estimated the interrelationships between earlier-life measures, features of mid-life type 2 diabetes and cognitive state at age 69 years. All models were adjusted for sex. RESULTS: The externally weighted PRS for type 2 diabetes was associated with mid-life metabolic traits (e.g. HOMA2-IR β = 0.08 [95% CI 0.02, 0.16]), but not with ACE-III (β = 0.04 [-0.02, 0.90]) or other cognitive outcomes. While there was an association between HOMA2-IR and subsequent ACE-III (β = -0.09 [-0.15, -0.03]), path modelling showed no direct effect (β = -0.01 [-0.06, 0.03]) after accounting for the association between childhood SEP and education with HOMA2-IR. The same pattern was observed for later-life verbal memory. CONCLUSIONS/INTERPRETATION: Associations between type 2 diabetes and mid-life metabolic traits with subsequent cognitive state do not appear causal, and instead they may be explained by SEP in early life, childhood cognition and educational attainment. Therefore, glucose-lowering medication may be unlikely to combat cognitive impairment in older age.