Relationship between metabolic disease and Alzheimer’s disease

Abstract

AbstractBackgroundDiabetes is an enormous and growing global public health problem, associated with poor health outcomes including dementia. Mechanisms underlying the relationship of diabetes to dementia are less well understood.MethodsWe leveraged several large, ongoing community‐based cohorts of older women and men with and without diabetes, taking part in longitudinal, clinical‐pathologic studies of aging at the Rush Alzheimer’s Disease Center. Participants undergo annual clinical evaluations including detailed neuropsychological testing, and brain autopsy at time of death. We examined the relation of diabetes and related clinical variables (e.g., medications, body mass index [BMI], hypertension), and blood and brain biomarkers of insulin resistance and other measures (e.g., epigenetics), to brain outcomes. Level and change in global cognition and five cognitive domains were based on neuropsychological tests, and dementia status was classified. Postmortem human brain specimens of deceased persons were systematically evaluated for neuropathology, including neurodegenerative (e.g., Alzheimer’s disease [AD]) and cerebrovascular disease (e.g., infarcts).ResultsDiabetes, present in 15‐20% of our cohorts, is associated a two‐fold increased risk of dementia and relates to cognitive decline (particularly in some cognitive domains more than others), and these observations are found in both Black and White participants. Some diabetes‐related clinical variables (e.g., BMI) are associated with faster cognitive decline, while others such as medications (metformin) are associated with slower cognitive decline. Regarding human postmortem neuropathologic outcomes, diabetes is associated with cerebrovascular pathologies, and small subcortical infarcts in particular. But, while we have not found clear associations of diabetes with neurodegenerative pathologies such as AD, some brain molecular markers in the insulin signaling pathway (AKT1) are associated with AD (including amyloid‐beta and tau tangles) and cognition (memory). Recently, using blood and brain specimens, we show that genome‐wide 5‐hydroxymethylcytosine profiling uncovers epigenetic features and biologic pathways related to nucleotide sugar metabolism linking diabetes to diabetes‐associated AD.ConclusionDiabetes is a potentially‐modifiable risk factor for dementia and cognitive decline. Clinical, neuropathologic, and epigenetic factors are at play in the underlying mechanisms. A better understanding of mechanisms will inform future research and offer opportunities for precision medicine and dementia prevention (supported by NIH: R01NS084965, RF1AG059621, RF1AG074549, R01AG022018, P30AG10161, P30AG072975, R01AG15819, R01AG17917).