To examine the association of renin-angiotensin system (RAS) inhibitor use with postmortem brain insulin signaling and dementia-related neuropathology.

RAS inhibitor use has been associated with both improved peripheral insulin resistance and a reduced risk of dementia. However, whether RAS inhibitor use also improves brain insulin resistance and reduces neuropathology of dementia remains unclear.

Among Religious Orders Study participants,150 deceased and autopsied older individuals (75 with diabetes matched to 75 without by age at death, sex, and education) had measurements of insulin receptor substrate 1 (IRS-1) and RAC alpha serine/threonine protein kinase (AKT1) collected in the prefrontal cortex using ELISA and immunohistochemistry. Alzheimer’s disease (AD), brain infarcts, and cerebral vessel pathologies data were assessed by systematic neuropathologic evaluations. RAS inhibitor use was determined based on visual inspection of medication containers during study visits and coded using Medi-Span. Using regression analyses adjusted for age at death, sex, and diabetes, we examined the associations of RAS inhibitor use with brain insulin signaling measures and neuropathology.

RAS inhibitor users (N=90) included 54 with diabetes and 36 without. RAS inhibitor use was associated with lower pT³⁰⁸AKT1/total AKT1 (estimate=-0.397, p=0.019), a marker for brain insulin resistance, but not with pS³⁰⁷IRS-1/total IRS-1 or the density of pS⁶¹⁶IRS-1 positive cells. RAS inhibitor use was not associated with the level of global AD pathology, nor with amyloid beta burden. However, RAS inhibitor use was associated with a lower neurofibrillary tangle density (estimate=-0.425, p=0.022). Furthermore, we found a significant interaction between diabetes and RAS inhibitors on tangle density (estimate=-1.174, p=0.001). Lastly, RAS inhibitor use was associated with more atherosclerosis (estimate=0.721, p=0.047), but not other cerebral blood vessel pathologies or cerebral infarcts.

These findings suggest that late-life RAS inhibitor use is associated with less insulin resistance and less accumulation of tau tangles in postmortem brain of older individuals.