Scientists find 16 new Alzheimer’s-linked genes using multi-ancestry genome data

A new study published in Alzheimer’s & Dementia has identified 16 novel genetic regions associated with Alzheimer’s disease by analyzing whole genome sequencing data from a large, ethnically diverse group of individuals. The findings emphasize the importance of including underrepresented populations in genetic research and point to new biological pathways that may play a role in the development of the disease.

Alzheimer’s disease is the most common form of dementia, affecting millions of people around the world. While the disease is known to have a strong genetic component, most studies of its genetic basis have focused on individuals of European ancestry. This limits understanding of the disease’s full genetic architecture and may leave important variants undiscovered. The researchers behind this new study sought to address that gap by analyzing genomic data from over 430,000 individuals of diverse backgrounds, including participants of African, Hispanic/Latino, and other ancestries.

“Alzheimer’s disease is a complex disease with contributions from both genetics and environment,” said Dmitry Prokopenko of the Genetics and Aging Research Unit and the McCance Center for Brain Health at Massachusetts General Hospital. “Most of the previous genome-wide association studies were focused on cohorts with subjects of European descent. Here we have studied diverse cohorts and biobanks with about 50% of non-European descent.”

The team drew on data from four major sources: the National Institute on Aging Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS), the National Institute of Mental Health (NIMH), the UK Biobank, and the All of Us Research Program. The combined dataset included more than 49,000 Alzheimer’s cases—12,074 with a clinical diagnosis and 37,075 defined by a family history of the disease—and over 383,000 controls. Notably, nearly half of the participants from the NIAGADS and All of Us cohorts were of non-European ancestry, providing a much-needed level of diversity.

To identify genetic variants linked to Alzheimer’s, the researchers conducted a genome-wide association study, a method that scans the genome for variants more common in people with the disease than in those without. For clinical Alzheimer’s diagnoses, they uncovered 14 new genetic loci, five of which were common variants and nine of which were rare. These loci were located near or within genes that play roles in brain function, immune response, and cellular signaling.

Among the newly identified common variants were those near the genes FBN2, SLC27A6, DYM, KCNG1, and TIAM1. These genes are involved in processes such as neural connectivity, fatty acid metabolism, and synaptic signaling. For example, FBN2 and SLC27A6 were found to be more active in neurons of individuals with Alzheimer’s pathology, suggesting they may contribute to disease development or progression. KCNG1, a gene related to potassium channels, showed altered expression in both neurons and astrocytes, hinting at a potential role in brain electrical signaling.

The study also identified nine rare variants in genes such as VWA5B1, PDE4D, and NEO1, among others. These rare variants may have strong effects on disease risk, even though they are present in only a small portion of the population. Identifying such variants is especially important for understanding Alzheimer’s in populations that have been historically underrepresented in genetic studies.

In addition to studying people with confirmed clinical diagnoses, the researchers also examined a group of individuals categorized as having “Alzheimer’s disease by proxy”—that is, people with a family history of the disease but no personal diagnosis. Using data from the UK Biobank and All of Us, they conducted a similar genetic analysis and found two new rare loci associated with increased Alzheimer’s risk. These were located near the genes RPL23/LASP1 and CEBPA, both of which are involved in cellular functions that may influence brain health. CEBPA, for instance, plays a role in regulating immune responses in the brain.

The team then compared the findings from the two analyses—clinical Alzheimer’s cases and Alzheimer’s-by-proxy cases. While some overlap existed, most of the new loci identified in one dataset did not replicate in the other. This suggests that the two approaches may capture different aspects of the disease’s genetic architecture, particularly across populations of varying ancestry.

Importantly, the researchers assessed whether the newly discovered genetic regions were located near genes with altered activity in the brains of people with Alzheimer’s. They used previously published single-cell data that mapped gene expression in various brain cell types, such as neurons and astrocytes. Many of the newly identified genes, including DYM, TIAM1, and PDE4D, were indeed differentially expressed in individuals with cognitive impairment and hallmark Alzheimer’s pathology.

These findings offer promising leads for future research into the mechanisms of Alzheimer’s disease. By revealing new genetic associations and linking them to biological changes in the brain, the study helps lay the groundwork for new strategies to predict, prevent, and treat the disease. It also underscores the importance of including participants from a wide range of genetic backgrounds in research.

Despite its strengths, the study has some limitations. The definition of Alzheimer’s-by-proxy relies on self-reported family history, which may introduce errors or inconsistencies, especially in more diverse populations where diagnosis rates may vary due to disparities in healthcare access. Additionally, many of the variants identified in the more diverse All of Us dataset did not replicate in the clinical dataset, raising the possibility of false positives or ancestry-specific effects that require further investigation.

Future research should focus on validating these newly identified loci in independent cohorts and exploring how they influence brain biology. Functional experiments, including laboratory studies of gene expression and protein function, will be necessary to determine the roles these variants play in Alzheimer’s disease.

“Our paper underscores the importance of using diverse cohorts with well-defined phenotypes for discovery and validation,” Prokopenko told PsyPost. “Our study can help discover new precision medicine approaches in diverse populations. Such genetic studies help scientists to discover new biological pathways and disease mechanisms. However, additional studies are needed to fully replicate these novel findings. As next steps, we plan to use gene-based testing to combine signals from multiple rare variants within a gene or functional elements to test for disease association.”

The study, “Identification of 16 novel Alzheimer’s disease loci using multi-ancestry meta-analyses,” was authored by Julian Daniel Sunday Willett, Mohammad Waqas, Younjung Choi, Tiffany Ngai, Kristina Mullin, Rudolph E. Tanzi, and Dmitry Prokopenko.