Mid‐life and late‐life vascular risk factor burden and neuropathology in old age

Abstract

ObjectiveTo determine whether vascular risk factor burden in mid‐ or late‐life associates with postmortem vascular and neurodegenerative pathologies in a community‐based sample.MethodsWe studied participants from the Framingham Heart Study who participated in our voluntary brain bank program. Overall vascular risk factor burden was calculated using the Framingham Stroke Risk Profile (FSRP). Mid‐life FSRP was measured at 50 to 60 years of age. Following death, brains were autopsied and semi‐quantitatively assessed by board‐certified neuropathologists for cerebrovascular outcomes (cortical infarcts, subcortical infarcts, atherosclerosis, arteriosclerosis) and Alzheimer’s disease pathology (Braak stage, cerebral amyloid angiopathy, and neuritic plaque score). We estimated adjusted odds ratios between vascular risk burden (at mid‐life and before death) and neuropathological outcomes using logistic and proportional‐odds logistic models.ResultsThe median time interval between FSRP and death was 33.4 years for mid‐life FSRP and 4.4 years for final FSRP measurement before death. Higher mid‐life vascular risk burden was associated with increased odds of all cerebrovascular pathology, even with adjustment for vascular risk burden before death. Late‐life vascular risk burden was associated with increased odds of cortical infarcts (OR [95% CI]: 1.04 [1.00, 1.08]) and arteriosclerosis stage (OR [95% CI]: 1.03 [1.00, 1.05]). Mid‐life vascular risk burden was not associated with Alzheimer’s disease pathology, though late‐life vascular risk burden was associated with increased odds of higher Braak stage (OR [95% CI]: 1.03 [1.01, 1.05]).InterpretationMid‐life vascular risk burden was predictive of cerebrovascular but not Alzheimer’s disease neuropathology, even after adjustment for vascular risk factors before death.

Association of cardiovascular risk burden with risk of dementia and brain pathologies: A population‐based cohort study

“…However, the association of diabetes or hypertension with AD pathology was not found in other studies 18–20 . Moreover, mid‐life vascular risk burden assessed by the Framingham Stroke Risk Profile was predictive of cerebrovascular pathologies, but not AD pathology 22 . In addition, another autopsy study showed the association between dementia risk score (incorporating age, sex, education, SBP, BMI, cholesterol, physical activity, and APOE ε4 status) and cerebral infarcts 32 .…”

“…Few studies have shown the association of diabetes or hypertension with AD pathology such as neuritic plaques and neurofibrillary tangles 17,21 . However, other studies have shown that diabetes, hypertension, or the Framingham Stroke Risk Profile (including age, systolic blood pressure, current smoking status, antihypertensive medication use, prevalent diabetes, prevalent CVD, and prevalent atrial fibrillation) is related to cerebrovascular pathologies (including cortical infarctions and arteriosclerosis stage) but not AD pathology 18–20,22 . Possible explanations for the discrepancies could be explained by the differences in age of the study populations, study settings, ascertainment of the exposure, assessment of brain pathologies, follow‐up time, and major causes of death among these studies.…”

“…In aging and dementia research, post mortem neuropathological evaluation generally includes a uniform and structured assessment of AD pathology, vascular pathology, Lewy body disease, and other pathologies 16 . Several neuropathological studies have focused on individual cardiovascular risk factor and brain pathologies with some inconsistent findings 17–22 . Few studies have shown the association of diabetes or hypertension with AD pathology such as neuritic plaques and neurofibrillary tangles 17,21 .…”

Risk Factors, Lifestyle Behaviors, and Vascular Brain Health

“…13 Vascular risk factors have been associated with amyloid and tau deposition, by positron emission tomography, or other Alzheimer disease (AD) biomarkers, in some 14 but not all studies. 15,16 Because overlapping pathologies are common in dementia, vascular mechanisms are often relevant. In the Religious Order Study/Rush Memory and Aging Project, individuals clinically diagnosed with mild cognitive impairment (MCI) or AD frequently had infarcts and mixed pathology on postmortem evaluation.…”

RNA-sequencing of human post-mortem hypothalamus and nucleus accumbens identifies expression profiles associated with obesity

“…Brain donation is part of the ROS and MAP study protocols and each participant signed an Anatomic Gift Act in addition to informed consent and a repository consent allowing their biospecimens and data to be repurposed. Details of study design for each of these cohorts has been previously published [28][29][30]. Dissection of frozen hypothalamus and nucleus accumbens was done by a single pathologist at each site.…”