Scientists have analyzed DNA from diverse populations and identified 16 new regions of the genome linked to Alzheimer’s. These genes are involved in communication between neurons, brain metabolism and inflammation, helping to better understand the disease and enabling advances in treatments and diagnostics.
Alzheimer’s disease (AD) is a neurodegenerative condition that affects memory, thinking and behavior. Globally, it is estimated that 315 million people live with this disease, representing approximately 22% of individuals over the age of 50.
In addition, the prevalence of Alzheimer’s disease has increased dramatically over the past three decades. This means that more people are being diagnosed with this condition as the population’s life expectancy increases.
An important factor to consider is that Alzheimer’s disease has a strong genetic influence. Twin studies show that approximately 70% of the risk of developing the disease is linked to heredity. This means that certain genetic variations inherited from parents can significantly increase a person’s chance of developing Alzheimer’s.
To identify these variations, scientists use a technique called genome-wide association studies (GWAS). This approach analyzes millions of small differences in the DNA of thousands of individuals to find regions of the genome associated with Alzheimer’s disease.
To date, these studies have identified more than 70 regions of DNA (called genomic loci) that are linked to Alzheimer’s, especially in populations of European descent. Alzheimer’s disease studies generally use two main approaches:
Clinically diagnosed Alzheimer’s disease: This includes patients who have been diagnosed by doctors based on symptoms and tests.
Alzheimer’s disease by proxy: This includes individuals who have not been directly diagnosed but who have first-degree relatives (parents or siblings) or even grandparents with Alzheimer’s.
This approach allows more individuals to be included in studies, increasing sample sizes and improving the accuracy of the findings.
The data used in these studies come from large genetic banks, such as NIAGADS (National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site), NIMH (National Institute of Mental Health) and the UK Biobank, which store genetic information from thousands of participants.
However, one problem with these studies is that most of the participants analyzed to date are of European descent. This means that the findings may not apply equally to people of other backgrounds, such as black or Hispanic individuals, who are often at higher risk of developing Alzheimer’s.
To address this limitation, a new meta-analysis was conducted using a more diverse database called All of Us (AoU), created by the National Institutes of Health (NIH) in the United States.
AoU was launched in 2018 with the goal of including groups that have been historically underrepresented in biomedical research. It currently has 315,000 participants, 78% of whom belong to diverse ethnic groups and half identify as non-white.
This database collects detailed medical and genetic information, allowing studies to be more representative of population diversity.
In the new study, researchers analyzed whole genome sequencing (WGS) data from 49,149 individuals with Alzheimer’s disease (12,074 clinically diagnosed cases and 37,075 proxy cases) and 383,225 healthy controls.
The study included data from NIAGADS, NIMH, UK Biobank, and All of Us, with nearly half of the NIAGADS and AoU participants having non-European ancestry.
The research identified 16 new DNA regions (loci) associated with Alzheimer's disease, 14 in clinically diagnosed cases and 2 in cases of Alzheimer's disease by proxy. Below is a summary list of the genes identified and their possible functions.
Genes identified in clinically diagnosed Alzheimer's disease:
FBN2/SLC27A6 – Involved in the structure of elastic fibers in tissues and in lipid metabolism.
AC090115.1 – Function still poorly understood, but may be involved in gene regulation.
DYM – Related to the development of the nervous system and cellular processes in the brain.
KCNG1/AL121785.1 – Associated with the electrical activity of nerve cells.
TIAM1 – Participates in communication between neurons and may be linked to synaptic plasticity, essential for memory.
Rare genes identified in clinically diagnosed Alzheimer's disease:
VWA5B1 – Possibly involved in cell adhesion and communication between neurons.
RNU6-755P/LMX1A – LMX1A plays an important role in brain cell development.
MOB1A – Related to cell survival and neuronal function.
MORC1-AS1 – Little studied gene, but may play a role in DNA regulation in the brain.
LINC00989 – Possibly involved in the regulation of genes linked to neurodegenerative diseases.
PDE4D – Involved in the regulation of neurotransmitters and already associated with the risk of brain diseases.
RNU2-49P/CDO1 – CDO1 may be related to oxidative stress, a risk factor for neurodegenerative diseases.
NEO1 – Important for neuron development and regeneration of nervous tissue.
SLC35G3/AC022916.1 – Possibly involved in the transport of substances within brain cells.
Rare genes identified in Alzheimer’s disease by proxy:
RPL23/LASP1 – Related to the functioning of ribosomes, cellular structures essential for the production of proteins.
CEBPA/AC008738.6 – CEBPA plays an important role in the inflammatory response and may be involved in neuroinflammation in Alzheimer’s.
The results of this study show that there are differences between the genes associated with clinically diagnosed Alzheimer's disease and those identified in Alzheimer's disease by proxy.
This suggests that methods for identifying Alzheimer's disease by family history may not fully capture the genetic factors involved in the disease.
However, the discovery of these 16 new genetic loci expands our knowledge of the mechanisms of the disease and reinforces the importance of using genetically diverse populations to identify new genes associated with Alzheimer's disease.
This study also highlights the relevance of GWAS based on whole genome sequencing (WGS), a more advanced technique that allows the identification of rare mutations that could be missed in conventional analyses.
In the future, the inclusion of diverse population groups and the use of new genetic technologies may lead to even more significant discoveries, helping to develop early diagnosis strategies and new treatments for Alzheimer's disease.
READ MORE:
Identification of 16 novel Alzheimer’s disease loci using multi-ancestry meta-analyses
Julian Daniel Sunday Willett, Mohammad Waqas, Younjung Choi, Tiffany Ngai, Kristina Mullin, Rudolph E. Tanzi and Dmitry Prokopenko
Alzheimer’s & Dementia. 25 February 2025
Abstract:
Alzheimer's disease (AD) is the most prevalent form of dementia. While many AD-associated genetic determinants have been identified, few studies have analyzed individuals of non-European ancestry. We conducted a multi-ancestry genome-wide association study (GWAS) of clinically diagnosed AD and AD-by-proxy using whole genome sequencing data from the National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS), National Institute of Mental Health, UK Biobank (UKB), and All of Us (AoU) consisting of 49,149 cases (12,074 clinically diagnosed and 37,075 AD-by-proxy) and 383,225 controls. Nearly half of NIAGADS and AoU participants were of non-European ancestry. For clinically diagnosed AD, we identified 14 new loci—five common (FBN2/SCL27A6, AC090115.1, DYM, KCNG1/AL121785.1, TIAM1) and nine rare (VWA5B1, RNU6-755P/LMX1A, MOB1A, MORC1-AS1, LINC00989, PDE4D, RNU2-49P/CDO1, NEO1, and SLC35G3/AC022916.1). Meta-analysis of UKB and AoU AD-by-proxy cases yielded two new rare loci (RPL23/LASP1 and CEBPA/AC008738.6), also nominally significant in NIAGADS. In summary, we provide evidence for 16 novel AD loci and advocate for more studies using whole genome sequencing–based GWAS of diverse cohorts.
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