Cardiovascular risk factors and regional neuropathology in autopsy-confirmed Alzheimer disease

Cardiovascular risk factors are implicated in Alzheimer disease (AD) progression and its neuropathological hallmarks but their specific contributions to regional brain pathology within AD remain understudied. In this cohort study (n = 276), we examined associations between diabetes, hypertension, and hypercholesterolemia (present vs absent), and neuropathologies in decedents with pathologically confirmed Intermediate/High AD from 3 Alzheimer's Disease Research Centers. Regional arteriolosclerosis, cerebral amyloid angiopathy (CAA), cored plaques (CPs), diffuse plaques (DPs), neurofibrillary tangles (NFTs), neuritic plaques (NPs), and neuropil threads (NTs) were semi-quantitatively assessed by adapting established scoring schemes. Differences in neuropathology by cardiovascular risk factor status were assessed using Wilcoxon rank-sum tests and ordinal logistic regression models adjusted for ethnicity, sex, age at death, and center. In adjusted analyses, diabetes was associated with higher frontal NTs (odds ratio, 3.2 [95% CI, 1.2-8.4]). Hypercholesterolemia was associated with higher CAA in the parietal lobe (odds ratio, 2.7 [95% CI, 1.3-5.8]) and posterior hippocampus (odds ratio, 2.8 [95% CI, 1.3-6.1]). None of these associations remained statistically significant following false discovery rate (FDR) correction. These findings suggest vascular risk factors do not substantially modify the burden of AD pathology once advanced disease is present and any independent effects on AD-related lesions are likely modest within this select cohort.