Longitudinal Association of Mid-Life Ten Year Cardiovascular Disease Risk Score with Brain Biomarkers of Alzheimer's Disease, Neurodegeneration and White Matter Hyper Intensities in Cognitively Unimpaired Older Adults: Heart SCORE Brain Study

Introduction: Atherosclerotic cardiovascular disease (ASCVD) risk factors in mid-life have been associated with cognitive decline and late-life dementia. However, the role of these risk factors in preclinical Alzheimer's disease (AD) pathophysiology remains elusive. We investigated whether mid-life 10-year pooled cohort equations (PCE) based ASCVD risk is associated with late-life amyloid, tau, neurodegeneration [AT(N)] measures and white matter hyperintensities (WMHI). Methods: Participants enrolled in the Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) study between 2003-2005 (mid-life) and underwent brain MRI and PET scans in 2018-2022 (age >65 years, late-life) to detect and quantify amyloid (A, PiB-PET) and tau (T, Flortaucipir (FTP) PET) deposition, cortical thickness (N) and white matter hyperintensities (WMHIs). Mid-life PCE ASCVD risk was categorized as; borderline (5%-7.4%), intermediate (7.5%- <15%), or high (≥15%). Association of midlife ASCVD risk HR (5% CI) was assessed using logistic and linear regressions with A, T, or N and chi square beta coefficients for WMHI in latelife. Results: Over a ~16y follow up, in 135 participants (mean age 73y), A and T showed no significant association with mid-life ASCVD risk. Neurodegeneration had a graded association with mid-life ASCVD risk categories (ORASCVD high vs low risk% 6.98 [2.44-19.95]; p<0.05) driven by self-identified Black race and age. In a subset n=60, ASCVD risk score was also associated with WMHIs ((β=0.42 plusmn; 0.22; p=0.05) in a model adjusted for inflammation and education. Conclusions: In this asymptomatic, diverse cohort, 10y ASCVD risk was predictive of late-life neurodegeneration and white matter hyperintensities but not amyloid or tau. These data suggest that ASCVD risk factors in midlife may lead to a state of vulnerability (through increased neurodegeneration and white matter hyperintensities) which may progress to cognitive decline and dementia. Further mechanistic studies are warranted to test this hypothesis. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement SOURCES OF FUNDING This work was funded by grants R01-AG072641, R01-AG052446 and R01-AG064877 from the National Institute on Aging. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. ### 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 permission by the University of Pittsburgh was obtained. CONSENT STATEMENT All human participants provided informed consen 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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data are available upon reasonable request.