Abstract
Aims/hypothesisType 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.MethodsFrom the population-based British 1946 birth cohort, a maximum number of 1780 participants had metabolic variables (type 2 diabetes, insulin resistance [HOMA2-IR] and HbA1c) 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.ResultsThe 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/interpretationAssociations 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.
Highlights
Cross-sectional and longitudinal studies have demonstrated associations between mid-life hyperglycaemia, insulin resistance and type 2 diabetes and increased risk of cognitive impairment, Alzheimer’s disease and all cause dementia [1,2,3,4,5,6,7,8,9,10,11,12,13]
We hypothesise that the association between mid-life type 2 diabetes, hyperglycaemia and insulin resistance and later-life cognitive function in a prospective analysis may be a consequence of these life course factors acting separately on these outcomes and subsequently confounding the relationship
We investigated the association between genetic risk of type 2 diabetes, insulin resistance and hyperglycaemia with later-life cognition (ACE-III score at age 69 years) and memory using linear regression models further adjusted for sex
Summary
Cross-sectional and longitudinal studies have demonstrated associations between mid-life hyperglycaemia, insulin resistance and type 2 diabetes and increased risk of cognitive impairment, Alzheimer’s disease and all cause dementia [1,2,3,4,5,6,7,8,9,10,11,12,13]. Genetic studies—Mendelian randomisation studies, which use genetic predictors of Diabetologia (2019) 62:1891–1900 diabetes as unconfounded instruments to directly assess causality—have reported null associations between the genetic risk of type 2 diabetes and cognitive ability [15] and laterlife cognitive impairment [15, 16], and between the genetic risk of type 2 diabetes, fasting glucose and insulin resistance and all-cause dementia and Alzheimer’s disease [17, 18] These compelling yet contradictory findings suggest that the relationship between type 2 diabetes and its associated features and later-life cognitive impairment may not be directly causal, and that other pathways related to type 2 diabetes, or processes occurring as a comorbidity or result of diabetes and its dysmetabolic precursors, may be aetiologically important in contributing to cognitive impairment/dementia risk. These genetic and life course relationships have not yet been studied comprehensively together
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