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Researchers analyzed genetic data from nearly 450,000 people and identified 42 DNA regions associated with Alzheimer’s risk among APOE4 carriers, including 29 regions not previously reported in this context. The findings point to oligodendrocytes and genes including TNS3 and CISD1 as possible research targets, but the signals need validation and do not establish a treatment or guarantee protection.
Researchers analyzing genetic data from nearly 450,000 people identified DNA regions that may help explain why some people who carry the Alzheimer’s risk gene APOE4 do not develop the disease, complementing research into other factors that may influence Alzheimer’s risk. The study, published in Alzheimer’s & Dementia, highlights genes active in oligodendrocytes as possible clues for future research, but it does not show that these genes prevent Alzheimer’s or provide a treatment.
Michael Belloy, an assistant professor at Washington University in St. Louis, and colleagues focused on people with one or two copies of APOE4 who had not developed Alzheimer’s. The research identified 42 DNA regions associated with APOE4 status: 13 previously reported and 29 newly identified in this analysis. The source report describes APOE4 as raising Alzheimer’s risk roughly four- to 12-fold, depending on the circumstances.
The team also examined gene activity in post-mortem brain tissue from 424 donors. Several candidate protective genes were active in oligodendrocytes, cells that produce the fatty coverings around nerve fibers and help electrical signals travel efficiently. Belloy pointed to TNS3 and CISD1 as genes that may modify risk: TNS3 has a role in oligodendrocyte maturation and survival, while CISD1 is involved in their metabolism.
The findings do not establish that changing activity in any of these genes would prevent disease. Belloy said the individual genetic effects may be small, and the signals need further validation. The report also notes that there are no FDA-approved drugs targeting TNS3 or CISD1 that could currently be repurposed for Alzheimer’s.
Why Oligodendrocytes Are in Focus
The study adds evidence that Alzheimer’s risk associated with APOE4 may be influenced by other genetic factors, rather than determined by the risk gene alone. Finding people who carry APOE4 but remain free of diagnosed disease can help researchers search for biological pathways that might explain resilience and, eventually, point toward treatment research.
The emphasis on oligodendrocytes may broaden investigation beyond the cell types and processes more commonly associated with Alzheimer’s. If later studies confirm that these cells or the candidate genes affect risk, researchers could explore whether their pathways are suitable for drug development. That possibility remains a research direction, not a clinical recommendation or a demonstrated therapy.
The report also describes interest in a finding involving MAPT, the gene that encodes the tau protein. Laura Nisenbaum, chief scientific officer of the Alzheimer’s Drug Discovery Foundation and not involved in the study, said higher MAPT activity appearing protective was intriguing. She noted a possible connection to diranersen, a gene-silencing therapy aimed at reducing tau that is heading toward Phase 3 trials, but the study does not establish that the drug’s approach will benefit APOE4 carriers.
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How APOE4 Shapes Alzheimer’s Risk
APOE4 is described in the report as the strongest common genetic risk factor for Alzheimer’s, but carrying it is not the same as having the disease. The source report says that over a lifetime, about 60 percent of people with two copies develop Alzheimer’s, meaning many do not. The researchers used this variation in outcomes to look for genetic factors that could alter risk among carriers.
Other proposed protective genetic findings have attracted attention, including the Christchurch variant. The report recounts a Colombian woman with inherited Alzheimer’s risk who remained cognitively healthy until her 70s and carried two copies of that variant. It also says a recent investigation raised doubts about the legitimacy of some studies related to Christchurch, underscoring why proposed protective effects require careful confirmation.
“Ultimately, we found a set of genes that look promising to counter Alzheimer’s disease risk due to APOE4.”
— Michael Belloy, assistant professor at Washington University in St. Louis, speaking to Being Patient
What the Genetic Signals Cannot Show
The study’s findings are associations that require validation; they do not prove that the identified genes caused protection. Most participants were of European ancestry, so it is not clear whether the results apply to other populations. The source also reports that participants had clinical diagnoses, but only 40 percent had biomarker confirmation, leaving open the possibility that some diagnoses were incorrect.
The gene-activity analysis used brain tissue donated after death, and Nisenbaum cautioned that samples from people who died in later stages of disease may not represent earlier stages. It also remains unknown how large the effects of the individual genes are, whether they operate similarly in living people, and whether any could be safely altered to change Alzheimer’s risk.
The report does not provide evidence that people can use genetic testing for these candidate genes to predict their personal outcomes. Nor does it establish a drug target ready for clinical use. The research describes possible avenues for study; it does not show that APOE4 carriers can avoid Alzheimer’s by changing gene activity.
Validation Before Treatment Research
Belloy said further experimental and validation studies are needed. Researchers will need to test whether the genetic associations hold in independent groups, including people from ancestries underrepresented in this analysis, and investigate how the candidate genes function in relevant brain cells and across disease stages.
Any move toward treatment would require additional work to establish whether modifying genes such as TNS3 or CISD1 is feasible and safe, followed by clinical testing. The report gives no timetable for such studies. Separately, diranersen’s reported path toward Phase 3 trials concerns tau reduction; the connection raised by Nisenbaum is a potential relevance, not evidence that the current study validates that therapy.
Key Questions
Does carrying APOE4 mean someone will develop Alzheimer’s?
No. APOE4 increases risk, but it does not determine an individual outcome. The source report says about 60 percent of people with two copies develop Alzheimer’s over their lifetime.
Which genes did the study identify as possible risk modifiers?
The study identified 42 DNA regions associated with APOE4 status. Belloy highlighted TNS3 and CISD1 as candidate modifiers, but their possible protective effects need further testing.
Does this research offer a way to prevent Alzheimer’s?
No. The findings are early genetic research, not a prevention method or treatment. The study does not show that changing these genes reduces disease risk.
Can the findings be applied to everyone?
That is not yet clear. Most participants were of European ancestry, so researchers need to test whether the results hold in other populations.
Are there approved drugs that target TNS3 or CISD1?
The source report says there are no FDA-approved medications targeting TNS3 or CISD1 that could currently be repurposed for Alzheimer’s.
Source: rss
