LAUSR

OBJECTIVE To examine associations of molecular markers of brain insulin signaling with Alzheimer's disease (AD) and cognition, among older persons with or without diabetes. METHODS This clinical-pathologic study was derived from a community-based cohort study, the Religious Orders Study. We studied 150 individuals (mean age-at-death =87 years, 48% women): 75 with and 75 without diabetes (matched by sex on age-at-death and education). Using ELISA, immunohistochemistry and ex vivo stimulation of brain tissue with insulin, we assessed insulin signaling in the postmortem middle frontal gyrus cortex. Postmortem data documented AD neuropathology. Clinical evaluations documented cognitive function proximate-to-death, based on 17 neuropsychological tests. In adjusted regression analyses, we examined associations of brain insulin signaling with diabetes, AD and level of cognition. RESULTS Brain IRS1 phosphorylation (pS307 IRS1 /total IRS1) and AKT phosphorylation (pT308 AKT1 /total AKT1) were similar in persons with or without diabetes. AKT phosphorylation was associated with the global AD pathology score (p = 0.001). In contrast, IRS1 phosphorylation was not associated with AD (p = 0.536). No other associations of insulin signaling were found with the global AD score, including when using the ex vivo brain insulin stimulation method. In secondary analyses, normalized pT308 AKT1 was positively correlated with both the amyloid burden and tau tangle density, and no other associations of brain insulin signaling with neuropathology were observed. Moreover, normalized pT308 AKT1 was associated with a lower level of global cognitive function (estimate = -0.212, SE = 0.097; p = 0.031). INTERPRETATION Brain AKT phosphorylation, a critical node in the signaling of insulin and other growth factors, is associated with AD neuropathology and lower cognitive function. This article is protected by copyright. All rights reserved.