Neurovascular-metabolic dysregulation, metabolic connectomics, and metabolic functional changes in Alzheimer's disease: A preclinical and clinical comparison.

Historically, imaging diagnostics in Alzheimer's disease (AD) have focused primarily on amyloid and tau accumulation; however, recent work suggests that neurometabolic and vascular dysregulation (MVD) may precede protein deposition and persist throughout the disease spectrum, preclinically and clinically. Translating these findings between human patients and preclinical mouse models remains challenging due to cross-species differences. To address this, regional MVD phenotypes were identified using cerebral metabolism and blood flow, and region-set enrichment analysis (RSEA) was conducted to assess brain functional category (BFC) changes based on metabolic variations, facilitating systematic cross-species comparisons. Clinically, MVD showed progressive alterations across the AD spectrum, while mouse models demonstrated similar genotype- and age-dependent changes. Although direct one-to-one regional correspondence is limited, RSEA revealed changes in comparable BFCs. Our findings suggest that imaging-based MVD mapping and RSEAs can bridge species differences, offering a translational framework to support early diagnostics of AD, enhance disease stratification, and enable therapeutic testing.