ObjectiveIn a representative population of women followed over 34 years, we investigated the prospective association between fasting serum insulin and dementia, taking into account the incidence of diabetes mellitus.MethodsFasting values for serum insulin and blood glucose were obtained in 1,212 nondiabetic women 38 to 60 years of age at the 1968 baseline. Risk of dementia was assessed by Cox proportional hazard regression with adjustment for insulin, glucose, and other covariates and, in a second model, after censoring for incident cases of diabetes mellitus. Incident diabetes mellitus was considered as a third endpoint for comparison with dementia.ResultsOver 34 years, we observed 142 incident cases of dementia. The low tertile of insulin displayed excess risk for dementia (hazard ratio [HR] 2.34, 95% confidence interval [CI] 1.52–3.58) compared to the medium tertile, but the high tertile of insulin did not (HR 1.28, 95% CI 0.81–2.03). These associations were also seen for dementia without diabetes comorbidity. In contrast, high but not low insulin predicted incident diabetes mellitus (115 cases) (HR 1.70, 95% CI 1.08–2.68 and HR 0.76, 95% CI 0.43–1.37, respectively).ConclusionA previous study reported a U-shaped association between fasting insulin and dementia in a 5-year follow-up of elderly men. Our results confirmed a nonlinear association in a female population, with high risk at low insulin values that was not attributable to preclinical dementia or impaired insulin secretion. This condition suggests a new pathway to dementia, which differs from the metabolic pathway involving diabetes mellitus.