A new study by researchers at The University of Texas Health Science Center at San Antonio (UT Health San Antonio) has linked obesity with changes in the expression of 21 Alzheimer’s disease (AD)-related genes,  and offered up a potential mechanism that may explain why Alzheimer’s is sometimes more frequent among adults who experienced obesity in midlife.

The findings, from a large sample of 5,619 participants in the Framingham Heart Study, implicated a number of genes that are known to be part of multiple pathways involved in AD neurobiology.

The team reported its findings in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, in a paper titled “Obesity impacts the expression of Alzheimer’s disease-related genes: The Framingham Heart Study,” in which corresponding author Claudia Satizabal, PhD, of the Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases at UT Health San Antonio and colleagues, concluded, “Our findings suggest that obesity might be contributing to AD risk through modulating effects in the expression of genes regulating the underlying neurodegenerative process.” Satizabal is assistant professor of population health sciences in UT Health’s Joe R. and Teresa Lozano Long School of Medicine.

It is estimated that the number of people living with dementia will reach 131 million by 2050, which, the authors wrote, will have “momentous social and financial implications for patients, caregivers and healthcare systems.” Obesity, they continued, is similarly a growing public health concern, with projections suggesting that by 2030, up to 85% of adults in the U.S. may be overweight or obese.

Obesity has been linked to late-onset AD, and it has been hypothesized that obesity creates an environment of chronic low-grade systemic inflammation and increased oxidative stress that may contribute to neurodegeneration. However, the researchers further noted, while it’s possible that obesity—a known risk factor type 2 diabetes, heart disease and stroke—may contribute to dementia by increasing vascular pathology in the brain, “the exact biological substrate” of the relationship between obesity and AD isn’t understood.

It is also not known whether obesity is associated with the differential expression of AD-related genes. For their newly reported study, the investigators analyzed 74 Alzheimer’s-related genes from Framingham data. They found that of those genes, 21 were either under-expressed or over-expressed in obesity. “After adjustment for cardiovascular risk factors, 14 associations remained significant, indicating that obesity might be modulating the expression of AD-related genes both directly and indirectly through vascular pathways,” the team noted. Also after adjustment for cardiovascular risk factors, 13 Alzheimer’s-related genes were associated with body mass index (BMI), and eight genes were associated with a second metric of obesity, waist-to-hip ratio (WHR).

“Several of the genes were more strongly related to obesity in midlife versus in late life, and also to obesity in women versus men,” said Satizabal. As the authors noted, “Stratified analyses by sex revealed that four out of the 18 identified associations between BMI and AD-related gene expression were only present in women … In the models further adjusted for cardiovascular risk factors, five out of 13 associations were only present in women,” Those observations are in line with prior epidemiological studies that suggested midlife obesity may be a factor in Alzheimer’s disease risk in women, Satizabal added.

Interestingly, people who develop dementia tend to lose weight about five to 10 years before the onset of the disease. This may be unhealthy weight loss driven by the disease. “We think it is more important to address obesity and begin healthy weight loss in midlife, in one’s 40s and 50s, when obesity may be impacting expression of the genes we studied,” Satizabal said.

BMI is the classical marker for obesity, but some studies suggest that waist-to-hip ratio, which measures abdominal obesity (belly fat), is a more sensitive marker of metabolic dysregulation in individuals. Obesity is a component of metabolic syndrome and among the chief risk factors for cardiovascular disease and stroke.

The 21 dementia-related genes associated with obesity in the new analysis are implicated in several Alzheimer’s disease processes, including neuro-inflammation, programmed cell death and deposition of amyloid-beta protein in neurons, said study first author Sokratis Charisis, MD, resident physician in the Department of Neurology and Biggs Institute at the Long School of Medicine.

Obesity has been linked to Alzheimer’s disease in late life, and understanding the connection between brain health and body weight is crucial. In the newly reported study, after accounting for cardiovascular risk factors, obesity was associated with upregulated expression of 10 genes. “CLU, CD2AP, FCER1G, and KLC3 exhibited the most robust associations in terms of effect size as well as significance, and were present across all obesity metrics” Interestingly the team noted, “the largest body of evidence regarding a potential role in AD pathogenesis exists for the CLU gene.” This gene is the third most associated risk factor for late-onset AD, explaining approximately nine percent of the attributable risk for the disease. “Interestingly, the CD2AP gene is also among the top 10 genetic predisposition factors for AD,” the authors continued, while there is evidence from GWAS, DNA sequencing, and network expression analysis of a role fin AD pathogenesis for the microglial-specific gene FCER1G, which is expressed at a greater level in the adipose tissues of obese individuals compared with non-obese individuals.

Conversely, after adjustment for cardiovascular risk factors, obesity was associated with downregulation of four genes, PVRIG, ZNF646, ZNF768, ABCA7. The gene ABCA7 encodes a protein that is expressed in neurons, astrocytes, and microglia, and notably, the authors wrote, “Strong genetic evidence suggests that ABCA7 protects from AD pathogenesis.” And remarkably, they continued, “Remarkably, prior studies in European ancestry populations have shown that Ad-associated variants at the ABCA7 locus raise the risk of late-onset AD by approximately 20%, whereas ABCA7 loss-of-function mutations raise the risk of early-onset AD by 100% to 400%.” A loss-of-function mutation present in African ancestry populations has also been shown to increase AD risk by approximately 80%.

The Framingham Heart Study has been conducted in a mostly white population. “We think the associations between Alzheimer’s-related genes and obesity might be even more relevant in Hispanics, who have a higher prevalence of obesity, but that is yet to be tested,” Satizabal commented. “We need to increase the sampling of diverse populations to find more genetic markers related to dementia.”

Acknowledging limitations of their study, the authors nevertheless pointed out that the associations of obesity with AD-related gene expression indicated by their study identified genes that previous work has also implicated in AD pathobiology, further increasing the biological plausibility of their findings. In conclusion, the team wrote, “The present findings provide important insights into the mechanistic intermediates of the pathway leading from obesity to dementia.  Furthermore, they could assist public health and dementia prevention policies to target lifestyle interventions, such as weight loss, to population groups that might have the most benefit.”

Co-author and long-time Framingham researcher Sudha Seshadri, MD, professor of neurology and director of the Glenn Biggs Institute at UT Health San Antonio, commented, “A team led by Dr. Satizabal, and including others such as Helen Hazuda, PhD, professor in the Long School of Medicine, will soon lead a study similar to the Framingham Heart Study. This research project will be called the San Antonio Heart Mind Study and will explore brain and heart functions in persons who were previously enrolled in UT Health San Antonio studies of diabetes, including persons who are normal weight as well as persons who are obese.

A genetic studies team at the Biggs Institute is working to expand the institute’s biobank. “Members of the public can volunteer to provide a blood sample, and we biobank that and of course keep it private,” Satizabal said. “We recommend also participating in cognitive testing, having an MRI and completing other questionnaires. This is a study conducted by our South Texas Alzheimer’s Disease Research Center (ADRC). We are collecting information and following people over time.”

“I am so grateful for the altruism, the time and the trouble taken by our volunteer research participants in Framingham and in San Antonio,” Seshadri said. “They are truly selfless champions helping us uncover the dark secrets of dementia, understand how lifestyle factors change dementia risk, and find new ways to prevent and treat it.”

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