Amyloid and Tau Pathology are Associated with Cerebral Blood Flow in a Mixed Sample of Nondemented Older Adults with and without Vascular Risk Factors for Alzheimer’s Disease

Alzheimer’s disease (AD) is the leading cause of dementia in individuals over 65 in the U.S. Prevalence is projected to double by 2050, but current treatments cannot stop the progression of AD. Treatments administered before severe cognitive decline may be effective; identification of biomarkers for preclinical and prodromal stages of AD is therefore imperative. Cerebral blood flow (CBF) is a potential early biomarker for AD; generally, older adults with AD have decreased CBF compared to normally aging peers. Characterization should include the relationships between CBF and AD risk factors and pathologies. We assessed the relationships between CBF quantified by arterial spin labeled MRI, hypertension, APOE ε4, and tau and amyloid PET in 77 older adults: cognitively normal, subjective cognitive decline, and mild cognitive impairment. Tau and amyloid aggregation were related to altered CBF, and some of these relationships were dependent on hypertension or APOE ε4 status. Our findings suggest a complex relationship between risk factors, AD pathologies, and CBF that warrants future studies of CBF as a potential early biomarker for AD. ### Competing Interest Statement Dr. Apostolova receives support in the form of consulting fees from Biogen, Two Labs, IQVIA, NIH, Florida Department of Health, NIH Biobank, Eli Lilly, GE Healthcare, and Eisai, in the form of payment for lectures, etc. from AAN, MillerMed, AiSM, and Health and Hospitality, and in the form of travel and meeting support from Alzheimer's Association. She also participates on Data Safety Monitoring or Advisory boards for IQVIA, NIA R01 AG061111, UAB Nathan Shock Center, and New Mexico Exploratory ADRC, in leadership roles for Medical Science Council Alzheimer Association Greater IN Chapter, Alzheimer Association Science Program Committee, and FDA PCNS Advisory Committee, stock or stock options Cassava Neurosciences and Golden Seeds, and receipt of materials, etc. from AVID Pharmaceuticals, Life Molecular Imaging, and Roche Diagnostics. Dr. Saykin has received support for consultation to Bayer Oncology (Scientific Advisory Board), Eisai (Scientific Advisory Board), Siemens Medical Solutions USA, Inc. (Dementia Advisory Board), and Springer-Nature Publishing (Editorial Office Support as Editor-in-Chief, Brain Imaging and Behavior). Dr. Wang has received book royalties from American Psychiatric Publishing, Inc., and consultant fees for serving on a Data Safety Monitoring Board. Dr. Clark receives royalties for two UpToDate articles on aphasia and has done paid consulting for Eli Lilly and Company on the topic of amyloid scans. Dr. Brosch discloses the following: AbbVie [Progressive supranuclear palsy], AbbVie [Alzheimer disease], Avanir [Alzheimer disease], Biogen [Alzheimer disease], Biogen [Prodromal or mild Alzheimer disease], Dominantly Inherited Alzheimer Network [Alzheimer disease], Eisai [Early Alzheimer disease], Eisai [Dementia with Lewy bodies], Eli Lilly [Alzheimer disease], Eli Lilly [Parkinson disease dementia], Genentech [Alzheimer disease], Novartis [Alzheimer disease], Roche [Alzheimer disease], Suven [Alzheimer disease]. All other authors report no disclosures. ### Funding Statement This study was funded in part by the following grants from the National Institute on Aging: K01 AG049050, R01 AG061788, P30 AG010133, P30 AG072976, R01 AG019771, R01 AG057739, U01 AG024904, R01 AG068193, T32 AG071444, U01 AG068057, and U01 AG072177 and the National Library of Medicine: R01 LM013463. In kind support for tau PET tracer precursor was provided by Avid Radiopharmaceuticals, a subsidiary of Eli Lilly and Company. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Institutional Review Board of Indiana University School of Medicine gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors. * Aβ : amyloid beta AAL : Automated Anatomical Labeling AD : Alzheimer’s disease ADNI : Alzheimer’s Disease Neuroimaging Initiative APOE : apolipoprotein E ANCOVA : analysis of covariance ANOVA : analysis of variance ASL : arterial spin labeled CBF : cerebral blood flow CCI : Cognitive Change Index CN : cognitively normal CSF : cerebrospinal fluid FWE : Family-Wise Error FWHM : full width at half maximum MCI : mild cognitive impairment MNI : Montreal Neurological Institute MRI : magnetic resonance imaging MTL : medial temporal lobe pCASL : psuedocontinuous arterial spin labeled PET : positron emission tomography PIB : Pittsburgh compound B ROI : region of interest SCD : subjective cognitive decline SPM : Statistical Parametric Mapping SPSS : Statistical Package for the Social Sciences SUVR : standardized uptake value ratio