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Alzheimer's Disease Analysis Leads to Modifiable Causal Factors

NEW YORK – With the help of Mendelian randomization (MR), a large international research team has uncovered causal ties between Alzheimer's disease (AD) and modifiable risk factors, including blood cholesterol and blood pressure traits.

"Importantly, we have applied novel analytic techniques in the Mendelian randomization analysis that corrects for noise from other interfering factors — a strategy that has not been implemented in previous studies," corresponding author Ruth Frikke-Schmidt, chief physician in the Copenhagen University Hospital-Rigshospitalet's clinical biochemistry department and deputy head of the clinical medicine department at the University of Copenhagen, said in an email.

"By doing so, we now for the first time observe that high systolic blood pressure is a direct cause of future development of Alzheimer's disease," she explained, adding that that result "emphasizes the need for improved focus on early prevention and treatment."

The investigators noted that the results build on a European Alzheimer's and Dementia Biobank (EADB) genome-wide association study meta-analysis published in Nature Genetics in 2022 that identified new and known loci, genes, and pathways linked to AD and related dementias using data for almost 789,000 cases and controls.

The previous study "provides new possibilities to disentangle potential causal aspects of modifiable risk factors for AD," Frikke-Schmidt and her colleagues wrote in JAMA Network Open on Wednesday, noting that "the massively increasing availability of high-quality genotypic data in large consortia provides more powerful genetic instrumental variables."

With that in mind, members of EADB's MR (EADB-MR) collaboration set out to find AD-related risk factors that might be modified to dial down risk of the neurodegenerative disease and related forms of dementia.

"To recommend the most efficient preventive strategy, we need to pinpoint those modifiable risk factors that directly is a cause of dementia," Frikke-Schmidt said. "Here, genetic studies of large populations can help us, because a genetically determined modifiable risk factor is created at conception, and thus is a very clean estimate of the direct impact of that risk factor on future development of dementia."

Using GWAS summary statistic data, coupled with modifiable risk factor measurements, the team searched for modifiable traits or behaviors associated with AD in 39,106 individuals with clinically diagnosed AD and nearly 401,600 unaffected control individuals, unearthing ties between AD risk and genetically influenced blood traits, including high-density lipoprotein (HDL) cholesterol levels and systolic blood pressure.

In particular, the researchers saw increased AD risk in participants with higher-than-usual HDL cholesterol levels mediated by genetic factors, and in individuals with genetically linked systolic blood pressure increases — relationships that held after adjusting for diastolic blood pressure and leaving out cases and controls originating from the UK Biobank (UKB) project.

"The main strength of this study is the use of the largest genomic consortia to date, yielding ample statistical power and instrumental variables explaining much phenotypic variation," the authors noted, adding that "statistical correction for sample overlap between exposure and endpoint data, as well as the possibility to use the EADB data excluding the entire UKB, enabled us to produce robust findings."

In contrast, they saw reduced AD risk in individuals with genetic variants associated with increased educational attainment. Genetic variants involved in other traits or behaviors such as smoking, apoA1 lipid levels, or body mass index showed inconclusive ties to AD, on the other hand, while genetic predisposition to diabetes, alcohol consumption, apoB lipid levels, low-density lipoprotein cholesterol levels, and triglyceride levels were not associated with AD risk.

"These findings suggest that genetically determined increased high-density lipoprotein cholesterol and systolic blood pressure may be involved in AD pathogenesis," the authors suggested, "which may thus inspire new drug targeting and improved early dementia prevention."