Neuropathological links between T2DM and LOAD: systematic review and meta-analysis

Recent decades have described parallel neuropathological mechanisms increasing the risk for developing late-onset Alzheimer's dementia (LOAD) in type 2 diabetes mellitus (T2DM); however, still little is known of the role of diabetic encephalopathy and brain atrophy in LOAD. The aim of this systematic review is to provide a comprehensive view on diabetic encephalopathy/cerebral atrophy, taking into account neuroimaging data, neuropathology, metabolic and endocrine mechanisms, amyloid formation, brain perfusion impairments, neuroimmunology, and inflammasome activation. Key switches were identified, to further meta-analyze genomic candidate loci and epigenetic modifications. For the qualitative meta-analysis of genomic bases extracted, human linkage studies were examined; for epigenetic mechanisms, data from both human and animal studies are described. For the systematic review of pathophysiological mechanisms, 1,259 publications were evaluated and 93 gene loci extracted for candidate risk linkages. Sixty-six publications were evaluated for genomic association and descriptions of epigenomic modifications. Overall accumulated results highlight the insulin signaling system, vascular markers, inflammation and inflammasome pathways, amylin interactions, and glycosylation mechanisms. The protocol was registered with PROSPERO (ID: CRD42023440535).