Objective: Subjects with diabetes are reported to have an increased risk of dementia and cognitive impairment. However, the underlying causes remain unknown. We investigated the longitudinal associations between midlife insulin secretion, glucose metabolism, and the subsequent development of Alzheimer disease (AD) and dementia.

Methods: The population-based Uppsala Longitudinal Study of Adult Men started 1970 when the 2,322 participants were 50 years old. Investigation at baseline included determinations of acute insulin response and glucose tolerance using the IV glucose tolerance test and Homeostasis Model Assessment insulin resistance index. During a median follow up of 32 years, 102 participants were diagnosed with AD, 57 with vascular dementia, and 394 with any dementia or cognitive impairment. Associations were analyzed using Cox proportional hazard models.

Results: A low insulin response at baseline was associated with a higher cumulative risk of AD (hazard ratio for 1 SD decrease, 1.31; 95% CI, 1.10–1.56) also after adjustment for age, systolic blood pressure, body mass index, serum cholesterol, smoking, education level, and insulin resistance. This association was stronger in subjects without the APOE 4 allele. Impaired glucose tolerance increased the risk of vascular dementia (hazard ratio for 1 SD decrease, 1.45; 95% CI, 1.05–2.00) but not AD. Impaired insulin secretion, glucose intolerance, and estimates of insulin resistance were all associated with higher risk of any dementia and cognitive impairment.

Conclusions: In this longitudinal study, impaired acute insulin response at midlife was associated with an increased risk of Alzheimer disease (AD) up to 35 years later suggesting a causal link between insulin metabolism and the pathogenesis of AD.