On the surface, it wouldn't seem as though cardiovascular disease and Alzheimer's disease would have anything in common other than their shared status as leading health issues, but new research has found that certain genes could impart a predisposition to both conditions. That research, published in Acta Neuropathologica under the title “Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease,” comes from an international team led by researchers from the University of California, San Francisco (UCSF) and Washington University School of Medicine in St. Louis.
While hints have previously existed that Alzheimer's disease and heart disease could be linked—namely the APOE gene and the role it plays in both lipid metabolism and Alzheimer's disease—a distinct connection has yet to be established. This recent work, which looked at genome-wide data from more than 1.5 million individuals, is offering a few more answers along those lines.
“These results imply that irrespective of what causes what, cardiovascular and Alzheimer’s pathology co-occur because they are linked genetically. That is, if you carry this handful of gene variants you may be at risk for not only heart disease but also Alzheimer’s,” explained Dr. Rahul Desikan, a UCSF neurodegeneration researcher.
The research team combined several large-scale genome-wide association studies (GWAS), thanks to statistical techniques developed by Desikan's lab—together with Dr. Ole Andreassen of the University of Oslo and Dr. Anders Dale of UC San Diego—to examine genetic markers linked to both diseases. Their studies consisted of five GWAS studies of more than one million people with cardiovascular disease risk and three GWAS studies of nearly 30,000 Alzheimer's disease patients and more than 50,000 age-matched control individuals.
With this approach, they discerned 90 locations in the genome where DNA variants meant a higher combined chance of developing Alzheimer's disease and increased blood levels of lipid molecules such as HDL/LDL cholesterol and triglycerides, well-known hallmarks of heart disease. Of those 90 locations, a UCSF press release by Nicholas Weiler noted that six presented with “genome-wide significant” impacts on Alzheimer's disease and higher blood lipid levels.
“In fold enrichment plots, we observed robust genetic enrichment in AD as a function of plasma lipids (TG, TC, LDL, and HDL); we found minimal AD genetic enrichment conditional on BMI, T2D, CAD, and WHR. Beyond APOE, at conjunction FDR < 0.05 we identified 90 SNPs on 19 different chromosomes that were jointly associated with AD and CV-associated outcomes,” the authors reported in the study. “In meta-analyses across three independent cohorts, we found four novel loci within MBLAC1 (chromosome 7, meta-p = 1.44 × 10−9), MINK1 (chromosome 17, meta-p = 1.98 × 10−7) and two chromosome 11 SNPs within the MTCH2/SPI1 region (closest gene = DDB2, meta-p = 7.01 × 10−7 and closest gene = MYBPC3, meta-p = 5.62 × 10−8).”
“These findings represent an opportunity to consider repurposing drugs that target pathways involved in lipid metabolism,” Dr. Celeste M. Karch, an assistant professor of psychiatry at Washington University School of Medicine and co-corresponding author of the study, said in a WUSL press release. “Armed with these findings, we can begin to think about whether some of those drugs might be useful in preventing or delaying Alzheimer’s disease. Our study emphasizes that there’s much to learn about how genes driving Alzheimer’s disease risk also increase the risk for other health problems, particularly cardiovascular disease, and vice versa. So we really need to think about these risks more holistically.”
“These results suggest that Alzheimer’s and cardiovascular disease could both be influenced by genetic defects that impair the body’s ability to processes lipids properly,” added the study's first author Dr. Iris Broce-Diaz, a postdoctoral researcher in Desikan’s lab. “But they also suggest that the link between Alzheimer’s and other cardiovascular risk factors are not likely due to common genetics, though they could be linked by diet or other lifestyle factors.
“This is exciting because we know that levels of cholesterol and other lipids in the blood are highly modifiable through changes in diet or with drugs. This raises the possibility that we might be able to help delay or even prevent the onset of Alzheimer’s in these patients, though we’ll need more data before we can say that for sure.”
The identified variants were also compared to a healthy control population of people with a family history of Alzheimer's disease, and those with no such history. The individuals with a family history of the disease—those with one or more parents who had been diagnosed—were more likely to have the variants in their genomes than those who had no disease history in their family. As reported by the authors, “In a large ‘AD-by-proxy’ cohort from the UK Biobank, we replicated three of the four novel AD/CV pleiotropic SNPs, namely variants within MINK1, MBLAC1, and DDB2.”
According to Desikan, “It’s remarkable that among these healthy adults with a family history of Alzheimer's, a subset of cardiovascular risk genes themselves appear to strongly influence risk of eventually developing Alzheimer’s. This is exactly the population we should study to see if reducing cardiovascular disease risk through lifestyle or medication can delay or prevent the onset of dementia later in life.”
Per Weiller's press release, these results were confirmed in work with Karch, whose team was able to demonstrate that “the novel genes most closely tied to Alzheimer’s/cardiovascular risk in the new study were differently expressed in the brains of Alzheimer's patients compared to control brains.”
As for the next phase of this work, Desikan and Broce-Diaz aim to add their results to the Alzheimer's disease polygenic risk test previously engineered by the Desikan lab.
SOURCE: UCSF press release by Nicholas Weiller, WUSL press release by Jim Dryden
