ALZHEIMER RESEARCH PROJECT: Brain aging and cardiovascular risk factors and disease

National Institute On Aging

Investigators

Linked publications, trials & patents

Abstract

Summary: Research Resources Much of this research is based on three large epidemiologic observational cohorts the AGES-RS (Age Gene/Environment Susceptibility-Reykjavik Study), and the HAAS (Honolulu Asia Aging Study), the Coronary Artery Risk Development in Young Adults Study (CARDIA). AGES-RS includes men and women born 1907-1935 and the HAAS includes Japanese American men born 1900-1919. Both AGES-RS and HAAS cohorts were established in the mid-1960s to answer questions about the heart disease epidemic that became a public health priority during that decade. CARDIA began in 1985-6 with a group of 5115 black and white men and women aged 18-30 years. The MRI sub-study in CARDIA fills the gap in the other cohorts by providing the opportunity to study prospectively changes in brain structure and function that occur during middle age. All studies have similar measures of cardiovascular risk factors in middle-age, which is invaluable when trying to understand epidemiologic studies designed to investigate etiology. Since the mid-life data are similar, and both studies identify dementia cases, this provides an excellent opportunity to replicate findings from one cohort, in the other cohort. The studies also have complementary measures of brain aging; whereas the HAAS includes a rich autopsy sub-study, AGES-RS has a wealth of cognitive, MRI and clinical data, while CARDIA has state-of-the-art measures on brain MRI. Based on this suite of studies we will gain a better understanding of what, when, who, and why certain groups should be targeted in the prevention and early management of CVD before irreversible damage and functional consequences occurs. They will also provide data on early MRI markers that may predict later age cognitive disorders. In order to increase the power of our studies, we are participating in the NINDS funded initiative, MARK_VCID, designed to identify blood and imaging based biomarkers of cerebro-vascular disease, and which can be used in trials to test new interventions. As a part of this research program, the Neuroepidemiology Section contributed to the NHLBI/NIA/NINDS major therapeutic strategy trial -- SPRINT MIND-- to determine whether blood pressure lowering reduces the risk for mild cognitive impairment or dementia. As a follow-up to the SPRINT trial we have investigated the genetically defined pathways that underlie the association of blood pressure to brain changes We have also added on to the CARDIA study, a sub-study of the gut microbiome to look at these characteristics in relation to cognitive function and risk factors for poor cognitive function. In another project we are examining the relationship of cardiovascular risk factors to AD biomarkers that have in recent studies shown to be associated with MRI and PET imaging of neurodegeneration. Findings Cardiovascular disease is an important and major component of the dementia that afflicts older age people. We have found that even in a middle age cohort, total brain volume, white matter lesion load, white matter tissue integrity and cerebral blood flow are associated with one or more cardiovascular risk factors, including elevated blood pressure, diabetes, smoking, and sedentary behavior, and that these risk factors lead to measurably lower scores on cognitive function tests. Control of one single cardiovascular risk factor, mid-life hypertension, could significantly reduce the 25% of the burden of ADRD. The data also suggest that without more research on this vascular aspect of dementia, meaningful interventions will not be identified and a portion of the dementia epidemic not addressed. The following have recently been identified in the MARK_VCID as potentially useful plasma biomarkers that may be indicative of small vessel disease: Glial Fibrillary Acid Protein (GFAP), Neurofilament Light ( NFL), and Tau-181. Novel MRI measures reflective of small vessel disease include DTI-sequence based Free Water and PSMD. In a 2021 publication we reported on the role of cerebral perfusion as an important correlate of brain structure and function, and importantly, the data suggested cerebral perfusion was more important than blood pressure level. In another publication we described the hemodynamics of the major and secondary coronary and carotid vessels that leads to a protection of the small arteries in the brain. The SPRINT MIND trial was the first to show lowering of systolic blood pressure to <120 mmHG significantly reduced the risk of a combined mild cognitive impairment / dementia outcome, as well as slowing the progression of white matter lesions. Work on BP pathways, the microbiome and AD biomarkers is on-going. Recent studies based on epigenetically defined Biologic aging suggest cardiovascular risk factors are associated with a faster pace of aging in middle and older cohorts. In another study using machine learning approaches we found a Hemoglobin and red blood cell distribution cluster associates significantly with levels of Alzheimer's disease biomarker levels and that incorporating diverse peripheral factors modestly enhances incident dementia prediction accuracy in community settings. We also replicated previous research showing poor cardiovascular health in early midlife is associated with faster decline in cognition across 10 years overall and in specific domains as well as brain MRI markers of cerebrovascular and neurodegenerative damage. To There has also been progress in identifying more sensitive to vascular damage. To date, our studies shown the most robust cardiovascular factors associated with brain aging and dementia are elevated blood pressure,smoking, diabetes, and high BMI.