Summary: Researchers have identified specific points on chromosome 11 and other genomic regions that increase risks for both cardiovascular disease and Alzheimer’s disease. The study suggests that managing cholesterol and triglyceride levels could help reduce Alzheimer’s risk in some people.
Source: WUSTL
Overview
Analyzing DNA from more than 1.5 million people, an international team led by Washington University School of Medicine in St. Louis and the University of California, San Francisco has identified genetic variants that raise the risk of both cardiovascular disease and Alzheimer’s disease. The findings, published in the journal Acta Neuropathologica, highlight how genes linked to lipid metabolism and blood lipids are also implicated in Alzheimer’s risk beyond the well-known APOE gene.
Researchers have long recognized that APOE, a gene involved in cholesterol and lipid metabolism, strongly affects Alzheimer’s risk—raising risk twofold in some people and up to 12-fold in others. This new, large-scale genetic analysis uncovers additional DNA locations across the genome that appear to influence both cardiovascular risk factors and Alzheimer’s disease, offering fresh insight into shared biological pathways.
Study design and major findings
The study is the largest genetic investigation of Alzheimer’s disease to date. Co-senior authors include Celeste M. Karch, PhD, of Washington University and Rahul S. Desikan, MD, PhD, of UCSF. The lead author is Iris Broce-Diaz, PhD. The team compared genetic data from people with cardiovascular risk factors and people with Alzheimer’s disease to identify single-nucleotide polymorphisms (SNPs) associated with both conditions.
They identified 90 genomic locations across 19 chromosomes that were associated with risk for both Alzheimer’s and cardiovascular-related outcomes. Of particular interest were six regions with very strong effects on Alzheimer’s risk and elevated blood lipid levels. Several of these regions had not previously been linked to dementia. Notably, the study pinpointed several variants within the CELF1/MTCH2/SPI1 region on chromosome 11—an area previously associated with immune system function—that also appear to influence lipid biology and Alzheimer’s risk.
The researchers confirmed the most promising associations in a large genetic dataset of healthy adults, showing these same risk variants were more common among people who reported a family history of Alzheimer’s, even if the individuals had not developed dementia or memory loss themselves.
Cardiovascular risk factors and genetic overlap
The team specifically examined established cardiovascular risk factors—body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist-hip ratio (WHR), total cholesterol (TC), triglycerides (TG), low-density (LDL) and high-density lipoprotein (HDL) cholesterol—to test whether the genetic drivers of those traits also related to Alzheimer’s risk.
Results showed that genetic variants tied to lipid metabolism and circulating blood lipid levels (TG, TC, LDL, HDL) had the strongest genetic overlap with Alzheimer’s disease. In contrast, genes associated with BMI, T2D, CAD and WHR showed minimal shared genetic enrichment with Alzheimer’s. In other words, the connection between cardiovascular risk and Alzheimer’s appears concentrated in pathways that regulate blood lipids.
“The genes that influenced lipid metabolism were the ones that also were related to Alzheimer’s disease risk,” Karch said. “Genes that contribute to other cardiovascular risk factors, like body mass index and type 2 diabetes, did not seem to contribute to genetic risk for Alzheimer’s.”
Desikan emphasized that while additional research is needed, these findings suggest a potential opportunity to repurpose or target existing drugs that affect cholesterol and triglyceride levels to lower Alzheimer’s risk in certain individuals. “These results imply that cardiovascular and Alzheimer’s pathology co-occur because they are linked genetically,” he said. “If you carry certain gene variants, you may be at risk not only for heart disease but also for Alzheimer’s.”
Replication and biological relevance
Beyond identifying shared SNPs, the researchers replicated several novel loci in independent cohorts and observed altered expression of implicated genes in postmortem Alzheimer’s brain tissue. Notable novel loci include variants near or within MBLAC1, MINK1 and within the MTCH2/SPI1 region on chromosome 11. These findings strengthen the case that a subset of cardiovascular-associated genes plays a direct role in Alzheimer’s pathogenesis.
Implications
Collectively, the results support a model in which cardiovascular biology—especially lipid metabolism—is integral to the development of clinical Alzheimer’s disease in a subset of people. The study highlights the importance of considering Alzheimer’s risk in a broader health context and suggests that managing blood lipids could be a valuable preventive strategy for some individuals, pending further clinical research.
Reference: Broce I, Karch C, Desikan R, et al. Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease. Acta Neuropathologica. Published online November 9, 2018.
Funding: Supported by the National Institute on Aging at the National Institutes of Health (NIH), including grant numbers NIH-AG046374 and K01 AG049152, along with additional awards from research foundations and Norwegian funding bodies.
Original research citation and DOI: Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease. DOI: 10.1007/s00401-018-1928-6
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