Brain insulin signaling in persons with and without diabetes is associated with cognitive decline

Abstract

AbstractBackgroundPeripheral insulin resistance is associated with increased risk of AD dementia, and postmortem measures of reduced insulin signaling in the brain have been linked to poorer cognition in AD‐related domains proximal to death. However, the relationship between brain insulin signaling and longitudinal cognitive decline over the years leading up to death is under‐studied. This study assessed the relationship between longitudinal change in domain‐specific cognition and brain insulin signaling in a clinical‐pathologic, community‐based cohort.MethodUsing a subsample of participants in the Religious Orders Study (75 with diabetes matched to 75 without diabetes), we examined data derived from annual cognitive assessments (mean age (years) baseline: 77.25 ± 6.34; final: 86.03 ± 6.14) and postmortem measures of brain insulin signaling. Neuropsychological testing was grouped to form a primary measure of global cognition, and five separate cognitive domains. Brain insulin receptor signaling was quantified via ELISA for the ratio of pS307IRS1 /total IRS1 (insulin receptor substrate‐1) “IRS1 phosphorylation”, ratio of pT308AKT1/total AKT1 (serine/threonine‐protein kinase) “AKT phosphorylation”, and immunohistochemistry for IRS1 cells/mm2, and pIRS1 at S616. Mixed effects regression models assessed per‐person mean level and rate of change (slope) in each cognitive domain, along with effects of brain variables, age at death, sex, and education on mean level, and effects of brain variables on change (the α was set at 0.025).ResultGreater AKT phosphorylation had a trend‐level association with faster decline in global cognition (‐0.02 (0.01) 0.035). Greater AKT phosphorylation was associated with faster declines in working memory (‐0.02 (0.01) 0.015) and visuospatial ability (‐0.01 (0.01) 0.023) and at a trend level with faster episodic memory decline (‐0.03 (0.01) 0.026). Greater IRS1 phosphorylation was associated with slower decline in perceptual speed (0.02 (0.01) 0.023). Greater staining for pS616IRS1 was associated with faster visuospatial ability decline (‐0.02 (0.01) 0.020).ConclusionBrain insulin signaling measures are associated with cognitive decline in the years prior to death. Future work should further characterize these relationships and explore links of peripheral insulin resistance and cognitive decline and dementia.