Neurometabolic and vascular dysfunction as an early diagnostic for Alzheimer's disease and related dementias

INTRODUCTION: Recent studies suggest that the brain undergoes anatomical and functional restructuring, resulting in neurometabolic and vascular dysregulation (MVD) prior to amyloid beta accumulation, which begins at an early age and leads to the onset of Alzheimer's disease (AD). METHODS: Using a retrospective clinical population (n = 403) from the Alzheimer's Disease Neuroimaging Initiative, cerebral perfusion and metabolism changes across 59 brain regions were evaluated from clinical studies. Results were verified by transcriptomic signatures and clinical cognitive assessments. RESULTS: Our findings suggest that disease progression follows a stage-dependent MVD pattern that can identify at-risk regions. Although each region progresses at a different pace, regions related to memory, cognition, and motor function showed significant early dysregulation. Importantly, these changes aligned with transcriptomic and cognitive signatures. DISCUSSION: This study underscores that MVD in brain regions varies by sex and disease stage, making it a sensitive tool for early AD diagnosis. This approach could improve patient monitoring, stratification, and therapeutic testing. HIGHLIGHTS: The potential of metabolic and vascular dysfunction as an early biomarker was assessed. An analytical method to assess dysregulation via imaging was developed. An analytical and graphical method to visualize the changes across disease spectrum was developed. Brain regions progress at different rates across Alzheimer's disease progression. Results were aligned with transcriptomics and cognitive signatures.