AbstractBackgroundAlzheimerās disease (AD) is associated with widespread reductions in cerebral blood flow (CBF), but the precise link between AD pathology and CBF is unclear. Hypoperfusion is a lateāstage event associated with tau, but not amyloid, pathology. We assessed whether baseline levels of cerebrospinal fluid (CSF)āmeasured core AD pathology [Ī²āamyloid42 (AĪ²42), phosphorylated tau (pātau)] related to CBF changes over a 7āyear period and if associations differed by baseline cognitive status.MethodsVanderbilt Memory and Aging Project participants free of clinical dementia or stroke at enrollment [n = 153, 72Ā±6 years, 37% mild cognitive impairment (MCI), 33% female] underwent lumbar puncture to obtain CSF at study entry and serial multimodal 3T brain magnetic resonance imaging over a 7āyear followāup period (mean = 5.4 years). Enzymeālinked immunosorbent assays quantified CSF AĪ²42 and pātau181. Pseudoācontinuous arterial spinālabeling captured CBF in total and lobar grey matter regions of interest (ROI). Linear mixedāeffects models related biomarker x time to longitudinal CBF variables adjusting for baseline age and cognitive status, sex, race/ethnicity, education, Framingham Stroke Risk Profile (minus age), ROI volume, APOEāĪµ4 status, and time. Models were repeated testing a cognitive status x biomarker x time interaction term.ResultsIn main effect models, neither CSF AĪ²42 (pāvalues>0.31) nor pātau (pāvalues>0.28) related to CBF outcomes. AĪ²42 did not interact with cognitive status on CBF outcomes (pāvalues>0.37), but pātau interacted with baseline cognitive status on longitudinal frontal, temporal, parietal, occipital, and total grey matter CBF trajectories (pāvalues<0.005). Among cognitively unimpaired participants, higher pātau was associated with slower reductions in frontal (Ī² = 0.01, p = 0.03), parietal (Ī² = 0.01, p = 0.04), occipital (Ī² = 0.01, p = 0.02), and total grey matter CBF (Ī² = 0.01, p = 0.04). Among individuals with MCI, higher pātau was associated with faster reductions in frontal (Ī² = ā0.03, p = 0.008), temporal (Ī² = ā0.02, p = 0.01), parietal (Ī² = ā0.04, p = 0.002), occipital (Ī² = ā0.03, p = 0.0004), and total grey matter CBF (Ī² = ā0.03, p = 0.005).ConclusionsResults linking CSF pātau to CBF decline in MCI support the theory that grey matter hypoperfusion is a laterāstage event tied to neurofibrillary tangle pathology. Associations between higher pātau and slower rates of CBF decline among cognitively unimpaired individuals warrants further investigation. Funding: R01āAG034962, K24āAG046373, F31āAG079640, T32āAG058524, P20āAG068082