In one of the largest studies of its type, researchers confirm a link between midlife vascular disease and late-life dementia. As reported in the April 11 Journal of the American Medical Association, 50-year-olds with two or more vascular risk factors were almost three times more likely to have amyloid in the brain in their 70s as were those with no signs of cardiovascular disease in middle age. Researchers said that the study, led by Rebecca Gottesman at Johns Hopkins University School of Medicine, Baltimore, was impressive for the number of subjects and its prospective design. However, scientists are still unsure how vascular disease begets amyloid.
Gottesman and colleagues analyzed data collected from the Atherosclerosis Risk in Communities (ARIC) study, which has been following almost 16,000 volunteers recruited from four communities since 1987 (see ARIC Investigators, 1989). A subset of 346 people from three of those communities (in Maryland, North Carolina, and Mississippi) underwent 3T MRI and amyloid PET scanning with florbetapir between 2011 and 2013, when they were about 76 years old on average. Using a standard uptake value ratio (SUVR) of 1.2 as a cutoff for tracer uptake, Gottesman correlated amyloid positivity with earlier cardiovascular factors, including body mass index, high blood pressure, diabetes, plasma cholesterol, and smoking history.
When comparing individual risk factors, only people with a body mass index of 3.0 or higher at midlife were more likely to have amyloid in their 70s, with an odds ratio of 2.06. This included 38 percent of whites and 32 percent of blacks. A stronger correlation emerged when the researchers accounted for multiple cardiovascular risk factors. Those with two or more were 2.8 times as likely to have amyloid in late life as those with fewer than two. Almost 42 percent of people in the study had more than two risk factors.
The findings make a lot of sense, said Charles DeCarli, University of California, Davis. He noted that while prior studies have linked midlife cardiovascular disease to late-life dementia, researchers have debated whether vascular dementia occurred independently of amyloid (e.g., Launer et al., 2000; Kivipelto et al., 2001; Whitmer et al., 2005). “It’s interesting here in this ARIC cohort that midlife vascular risk factors increased amyloid retention in the brain.”
William Jagust, University of California at Berkeley, agreed. “Other studies have measured vascular risk at the same time they measured amyloid,” he told Alzforum (see Reed et al., 2014; Rodrigue et al., 2013; Reed et al., 2012). “From epidemiological and public health perspectives, the midlife risk factor correlation here is very important,” he said.
Jagust also praised the community-based nature of the study, which makes it more representative of the general population than similar studies, which have tended to be more selective. He welcomed the high proportion of African-Americans (43 percent), for example, who are historically under-recruited relative to whites.
However, both Jagust and DeCarli emphasized the lack of a clear mechanism linking vascular risk factors to cortical amyloid. “We could never find a relation between cortical amyloid and measures of vascular disease such as stroke, infarct, and white-matter hyperintensities,” said Jagust. In fact, at this year’s Human Amyloid Imaging meeting, held in January in Miami Beach, Gottesman herself reported finding no correlation between elevated florbetapir SUVR and white-matter hyperintensities or infarcts in the ARIC cohort, though she noted that her study was probably underpowered to draw those links out. Likewise, the JAMA paper reports no statistically significant influence of race or ApoE genotype on the vascular-amyloid correlation, but here again, the study may have been underpowered, write the authors.
While growing evidence links vascular disease with dementia and now amyloid, the lack of a clear mechanism puzzles Jagust. While Gottesman and colleagues suggest that poor clearance of Aβ from the brain may be the link, a scenario DeCarli considers reasonable, hard evidence is wanting. Jagust thinks better animal models may help scientists understand Aβ clearance, while in people, high field strength imaging may reveal correlations between amyloid and microscopic damage that cannot be seen on 3T MRI (e.g., Bouvy et al., 2017).—Tom Fagan
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- Bouvy WH, Kuijf HJ, Zwanenburg JJ, Koek HL, Kappelle LJ, Luijten PR, Ikram MK, Biessels GJ, Utrecht Vascular Cognitive Impairment (VCI) Study group. Abnormalities of Cerebral Deep Medullary Veins on 7 Tesla MRI in Amnestic Mild Cognitive Impairment and Early Alzheimer's Disease: A Pilot Study. J Alzheimers Dis. 2017;57(3):705-710. PubMed.
No Available Further Reading
- Gottesman RF, Schneider AL, Zhou Y, Coresh J, Green E, Gupta N, Knopman DS, Mintz A, Rahmim A, Sharrett AR, Wagenknecht LE, Wong DF, Mosley TH. Association Between Midlife Vascular Risk Factors and Estimated Brain Amyloid Deposition. JAMA. 2017 Apr 11;317(14):1443-1450. PubMed.