Region-specific cerebral blood flow differentiates cognitively impaired and unimpaired individuals with core Alzheimer's disease pathology

Background: Up to 30% of individuals harboring core Alzheimer's disease (AD) neuropathology, amyloid-beta (Abeta; A) and tau (T)-remain cognitively unimpaired. Objective: We examine whether MRI measures of cerebral blood flow (CBF) and white matter hyperintensities (WMH) differentiate cognitively impaired (AD or mild cognitive impairment (MCI);AD+MCI) from non-demented individuals with (NDAN) and without (Controls) core AD neuropathology. Methods: A retrospective cohort study (2018-2023) using data from The Wisconsin Registry for Alzheimer's Prevention and Wisconsin Alzheimer's Disease Research Center studies employed linear models comparing group differences in regional gray matter (GM) CBF and whole brain WMH volume. Participants (N=500) underwent 3T MRI, amyloid- (11C-Pittsburgh Compound B) and tau- (18F-MK6240) PET, and neuropsychological assessments. We categorized participants based on PET and cognitive status as Controls (n=416; cognitively unimpaired, A-T-), NDAN (n=38; cognitively unimpaired, A+T+), or AD+MCI (n=46; cognitively impaired, A+T+). Results: Participants were 67 years old (mean), 68% female, and 37% APOE 4+. NDAN, like Controls, had significantly higher CBF than AD+MCI in GM regions susceptible to neurofibrillary tangle formation in early AD (frontal and temporal cortices, and limbic regions (ps<0.05)). Largest CBF differences (22-34%) were observed in GM regions that accumulate amyloid early but remain largely tangle-free during early AD progression, namely the occipital and parietal cortices. WMH volume differentiated AD+MCI from Controls (p=0.002) but not NDAN (p=0.16). Conclusion: CBF differentiated NDAN from AD+MCI, highlighting vascular contributions to cognitive resilience. Most pronounced CBF preservation in NDAN was observed in parietal and occipital cortices, regions typically free of tau until late stages of AD progression.