Low fasting values of serum insulin in a cohort of nondiabetic women followed over 34 years: Evidence for an alternative pathway to dementia

Background A previous study reported a U-shaped association between fasting insulin and dementia in a 5-year follow-up of a male cohort [1] . More recently, a cross-sectional study of 262 older adults free of diabetes and cognitively normal showed that decreased blood insulin below optimal levels was associated with higher beta amyloid deposition and neurodegeneration [2] . The purpose of the present study was to investigate the prospective association between fasting serum insulin and dementia in a representative population of women followed over 34 years, taking into account the incidence of diabetes. Methods Fasting values for insulin and glucose were obtained from serum samples in 1212 nondiabetic women aged 38–60 at the 1968 baseline. Risk of dementia was assessed by Cox proportional hazard regression adjusting for insulin, glucose, and other covariates, and, in a second model, after censoring for incident cases of diabetes. Incident diabetes was considered as a third endpoint, for comparison with dementia. Results Over 34 years, we observed 142 incident cases of dementia. The lowest tertile of insulin was associated with excess risk for dementia, hazard ratio (HR) = 2.33, 95% confidence interval = (1.52, 3.58), compared to the intermediate tertile, but the highest tertile of insulin was not, HR = 1.27 (0.81, 2.02). These associations were also seen for dementia without diabetes comorbidity. In contrast, high but not low insulin predicted incident diabetes (115 cases), HR = 1.69 (1.08, 2.66) and HR = 0.76 (0.43, 1.36), respectively. Conclusion This study provides epidemiological evidence for a new pathway to dementia that is characterized by low fasting serum insulin and differs from the metabolic pathway via hyperinsulinemia or diabetes. The identification of the tails of the U-shaped risk curve for insulin and dementia with distinct pathways was possible due to the long follow-up, and by comparing the associations of insulin with different dementia endpoints and diabetes. The distinction between alternative pathways will explain inconsistent epidemiological findings regarding risk factors of dementia and its subtypes.