Vascular Risk Factors and Their Role in the Development of Alzheimer’s Disease
By Richard S. Isaacson, MD
Associate Professor of Neurology (Education), Weill Cornell Medical College
Dr. Isaacson reports no financial relationships relevant to this field of study.
SYNOPSIS: This study has found an association between mid-life, but not late-life, vascular risk factors and brain amyloid deposition as imaged on amyloid-labeled PET.
SOURCE: Gottesman RF, Schneider AL, Zhou Y, et al. Association between midlife vascular risk factors and estimated brain amyloid deposition. JAMA 2017;317:1443-1450.
The future of Alzheimer’s disease (AD) prevention most likely will rely on a combination of interventions that include pharmacologic as well as non-pharmacologic therapies. Several promising clinical trials are currently underway, with most focused on amyloid-beta lowering; yet, an increasing number of lifestyle-based interventions (e.g., physical exercise, nutrition) also are being studied. Numerous reports have suggested an association between cardiovascular and cerebrovascular risk factors and increased risk for AD, and prevention may be most effective when started as early as possible.
The most recent AD diagnostic criteria (described in 2011) most accurately reflects the current understanding of AD (National Institutes of Aging/Alzheimer’s Association criteria). These standards describe a spectrum of AD that starts many years before the first symptoms occur. This new model breaks down AD into three different stages. Before AD starts, patients can be classified in the prodromal stage, meaning the disease has not started, and no symptoms are present. In Stage 1, AD has started in the brain but there are no symptoms (preclinical AD). In Stage 2, patients have mild memory loss, but still can perform all their usual daily activities (mild cognitive impairment due to AD). In Stage 3, the patients have dementia caused by AD. To have the most optimal effect and offer the most clinically relevant neuroprotection, interventions will need to be initiated at a preclinical or prodromal stage.
Along these lines, a new study by Gottesman and colleagues has found an association between mid-life vascular risk factors (including hypertension, diabetes, total cholesterol > 200, body mass index > 30 kg/m2, and current smoking) and brain amyloid deposition as imaged on amyloid-labeled PET. The Atherosclerosis Risk in Communities — PET Amyloid Imaging Study was a prospective cohort study (n = 322) of subjects without dementia in three states (Maryland, North Carolina, and Mississippi). These subjects have been evaluated longitudinally for more than 30 years, with baseline demographics of a mean age of 52 years, 58% female, and 43% black. In 2011, subjects began receiving amyloid-labeled PET scans with florbetapir when they were between 67 and 88 years of age.
The study found that elevated body mass index in midlife was associated with elevated brain amyloid (odds ratio, 2.06; 95% confidence interval [CI], 1.16-3.65). At baseline, 65 participants had no vascular risk factors, 123 had one risk factor, and 134 had two or more risk factors. In alignment with hypotheses generated based on several past epidemiologic studies, a higher number of mid-life vascular risk factors were associated with elevated brain amyloid. Compared with no mid-life vascular risk factors, the odds ratio for elevated brain amyloid associated with one vascular risk factor was 1.88 (95% CI, 0.95-3.72) and for two or more vascular risk factors was 2.88 (95% CI, 1.46-5.69). Interestingly, late-life vascular risk factors were not associated with late-life brain amyloid deposition.
COMMENTARY
Prior studies have demonstrated that vascular risk factors contribute to brain amyloid deposition, particularly in blacks, as well as in the setting of the most common late-onset genetic risk factor for AD, carriage of the APOE4 gene. However, in this study, no relationship was found between race or APOE4 status. Taken together, these findings suggest that there is a role of vascular disease in the pathogenesis of AD across a broad spectrum of patient populations, and offer additional evidence toward the potential utility of cardio and cerebrovascular risk factor modification in mid-life in an effort to reduce risk and/or slow the progression toward dementia due to AD.
At this time, from a practical clinical perspective, vascular risk factor modification in mid-life seems to be a worthwhile approach toward addressing AD risk via possible attenuation of brain amyloid deposition across genotypes. However, more rigorous prospective, randomized studies are warranted to definitively prove that this hypothetical approach truly reduces AD risk over time.
This study has found an association between mid-life, but not late-life, vascular risk factors and brain amyloid deposition as imaged on amyloid-labeled PET.
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