Published on: August 9, 2020
by Madolyn Bowman Rogers for AlzForum:
Having established that poor cardiovascular health in midlife increases the risk of cognitive decline and dementia as a person ages, scientists are now pushing to see if the same relationship might hold true even earlier in life. Indeed, several presentations at the Alzheimer’s Association International Conference, held virtually July 27 to 31, reported that cardiovascular risk factors present even at the beginning of adulthood might also affect the risk of developing Alzheimer’s disease. Researchers linked conditions such as hypertension, high cholesterol, obesity, and diabetes in young adults to smaller brain volumes, poor performance on cognitive tests, and a higher risk of AD decades later. Altogether, the findings highlight the importance of starting preventative lifestyle interventions as early as possible.
Previous studies have built a broad consensus among researchers that hypertension in one’s 40s or 50s boosts risk of dementia later in life (e.g., Whitmer et al., 2005; Aug 2017 news; Jun 2018 news). Cardiovascular disease in the 50s ups the likelihood of amyloid plaques after age 70, and obesity in the 50s seems to bring on dementia sooner (Apr 2017 news; Whitmer et al., 2005; Mar 2009 news; Sep 2015 news).
But how early in life do the processes underlying these risk associations start? This is difficult to study because it requires cohorts that record health data over decades. At AAIC, Kristen George, University of California, Davis, pushed the age when vulnerability can be detected back to the 30s. She analyzed MRI data from 220 participants in the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) study. All were enrolled in the Kaiser Permanente health care system in northern California and were 65 or older and dementia-free. The cohort was racially diverse, with approximately equal numbers of whites, blacks, Latinos, and Asians. All had had a health checkup decades earlier, at an average age of 32, that measured blood pressure, cholesterol, and body-mass index. At that age, about a third of the cohort had hypertension, a third high cholesterol, and a quarter obesity.
Participants who at that young age had had a BMI of 25 or greater had a smaller hippocampal volume on average in late life than did their peers without a history of obesity. A BMI of 25 or more is considered overweight, while 30 or higher is considered obese. Likewise, a young-adult blood pressure of 130/80 or greater, or total cholesterol of 200 or more, associated with a smaller cerebral volume after age 65.
This brain shrinkage had functional consequences. Across the cohort, smaller hippocampal volume was associated with worse episodic memory, as assessed by the Spanish and English Neuropsychological Assessment Scales (SENAS) cognitive composite. Participants took this test at an average age of 75. Similarly, smaller cerebral volume associated with worse working memory and executive function on the SENAS, George reported.
The risk to the brain from obesity may start even younger than that. Chillingly, a previous study linked high BMI to smaller brain volume even in children. Researchers led by Jennifer Laurent at the University of Vermont, Burlington, analyzed data from the ABCD study of 3,190 children at 21 sites across the U.S. All were 9 or 10 years old. The higher their BMI, the thinner their cortex was, particularly in prefrontal regions. This thinning correlated with worse performance on tests of executive function (Laurent et al., 2019).
The KHANDLE imaging sample was too small to determine if risk varied by race. However, the National Health and Nutrition Examination Survey (NHANES) 2015–2016 data previously found the highest prevalence of hypertension to be among blacks, while blacks and Latinos were more likely to be overweight or have diabetes than whites and Asians.
At AAIC, Rachel Peterson at UC Davis reported cognitive data from the Study of Healthy Aging in African Americans (STAR), which examined the effect of cardiovascular risk factors on late-life brain health specifically in this population. STAR enrolled 710 African Americans from the Kaiser Permanente healthcare system. All were 50 or older when recruited in 2018–2020. Importantly, whether they had had hypertension, cholesterol, obesity, or diabetes in young adulthood had been previously assessed, at around age 19 for 165 participants, age 25 for 435, and age 39 for 110.
The researchers assessed cognition in STAR participants at a mean age of 68, using the SENAS. Participants who had two or more of these risk factors at a young age performed worse on tests of executive function and semantic and episodic memory. In addition, there was a trend for diabetes in adolescence to associate with poor executive function late in life, and hypertension in early adulthood to associate with poor episodic memory.
Other presentations at AAIC reinforced these findings. Adina Zeki Al Hazzouri of Columbia University in New York analyzed data from 2,909 participants in the Cardiovascular Health Study and 2,195 from the Health, Aging, and Body Composition study. Both are diverse cohorts, with an overall mean age of 73. Women whose BMI topped 25 between the ages of 20 and 49 had nearly twice the risk of dementia as their leaner peers. In contrast, for women weighed in their 50s and 60s, BMI had no measurable effect on later dementia risk. For men, a high BMI at any point from ages 20 to 69 boosted dementia risk by 35 to 50 percent. For both sexes, a high BMI after age 70 associated with lower risk, as others have found (Fitzpatrick et al., 2009; Strand et al., 2013; Pedditzi et al., 2016; Singh-Manoux et al., 2018).
Similarly, Xiaoling Zhang at Boston University linked unhealthy cholesterol between the ages of 35 and 50 to Alzheimer’s risk decades later. Among 3,224 participants in the Framingham Heart Study Offspring cohort, those who had high levels of LDL, the “bad” cholesterol, and low levels of HDL, the “good” cholesterol, in this age range were more likely to have AD after age 60. Statin treatment at the earlier time point lessened the risk, but the relationship between early life cholesterol and late-life AD remained statistically significant.
Researchers don’t fully know how metabolic factors heighten AD risk. One possibility is inflammation. At AAIC, Kristine Yaffe at the University of California, San Francisco, linked systemic inflammation at young ages to late-life cognitive problems. She analyzed data from 1,920 participants in the Coronary Artery Risk Development in Young Adults study. Their mean age was 33. All had repeated measurements of plasma C-reactive protein, a clinical marker of systemic inflammation, over the course of two decades. Those whose C-reactive protein crept up over time, or was high throughout adult life, were twice as likely to perform poorly on tests of executive function and processing speed at age 55 as were those with consistently low C-reactive protein.
Intriguingly, a recent mouse study from Tony Wyss-Coray and colleagues at Stanford University found that activated B and T cells begin to accumulate in adipose tissue during middle age, suggesting a possible link between obesity and inflammation (Schaum et al., 2020). Obesity is also emerging as a major risk factor for a severe course of SARS-CoV2 infection, which, in turn, is marked by an excessive, dysregulated inflammatory response.
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