Neuro-Vascular-Metabolic Dysregulation, Metabolic Connectomics, and Metabolic Functional Changes in Alzheimer’s Disease: A Preclinical and Clinical Comparison

Clinical imaging diagnostics in AD primarily focus on amyloid and tau accumulation; however, recent work suggests that neuro-metabolic and vascular dysregulation (MVD) begins prior to protein deposition. MVD changes persist in preclinical and clinical cases across the disease spectrum; therefore, comparing them could provide valuable insight into disease onset and progression. Regional MVD phenotypes were determined using imaging readouts as surrogates for cerebral metabolism and blood flow, and region-set enrichment analysis (RSEA) was performed to determine brain functional category (BFC) changes based on metabolic variations. Clinically, MVD showed changes across the disease spectrum, while mice showed similar trajectories, though these were genotype- and age-dependent. Although there is no one-to-one relationship between BFC across species, RSEA showed significant changes in comparable categories. Our findings indicate that clinical MVD and RSEA changes can be mapped to preclinical models, aiding the development of early diagnostic techniques, improving disease stratification, and enabling therapeutic testing.