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Researchers analyzing genetic data from nearly 450,000 people identified 42 DNA regions associated with Alzheimer’s risk among APOE4 carriers, including 29 not previously reported in this analysis. The findings point to genes active in oligodendrocytes as possible protective factors, but they do not establish that these genes prevent Alzheimer’s or that treatments targeting them would work.
Researchers analyzing genetic data from nearly 450,000 people identified DNA regions associated with Alzheimer’s risk among carriers of APOE4, including genes that may help explain why some carriers do not develop the disease, alongside other research into Alzheimer’s risk factors. The study, published in Alzheimer’s & Dementia, highlights oligodendrocytes—cells that support communication between neurons—as a possible focus for future research, but it does not show that the identified genes prevent Alzheimer’s or provide a proven treatment.
The team led by Michael Belloy, an assistant professor at Washington University in St. Louis, examined people who carried one or two copies of APOE4, a genetic variant linked to elevated Alzheimer’s risk. The report says the variant is associated with a four- to 12-fold increase in risk; that range describes the risk associated with APOE4, not the protective effect of any particular gene identified in this study. Researchers looked for other genetic differences that might modify risk among carriers.
The analysis identified 42 DNA regions linked to APOE4 status: 13 had been identified previously and 29 were new in this analysis. The researchers also examined gene activity in post-mortem brain tissue from 424 donors. Several genes highlighted by the analysis were active in oligodendrocytes, which form insulating sheaths around nerve fibers and help electrical signals travel efficiently between neurons.
Belloy pointed to TNS3 and CISD1 as possible risk modifiers. TNS3 is involved in the maturation and survival of oligodendrocytes, while CISD1 has a role in their metabolism. The report describes both as potential drug targets, but says there are no FDA-approved medicines that target them and can be repurposed for Alzheimer’s. Researchers have not established that changing either gene’s activity would reduce disease risk.
Oligodendrocytes Emerge as Research Targets
The findings add to evidence that APOE4 does not act alone: other genetic factors may influence whether a carrier develops Alzheimer’s. Understanding those differences could help researchers identify biological processes that lower risk and, eventually, investigate whether those processes can be targeted with medicines. This is a research lead, not a clinical result or a basis for changing an individual’s care.
The focus on oligodendrocytes may widen investigations beyond the brain cells and processes most commonly discussed in Alzheimer’s research. If further studies confirm that these cells contribute to protection in APOE4 carriers, they could offer additional directions for drug development. The study does not establish how large any protective effect is, whether it applies across populations, or whether a treatment could reproduce it.
The report also notes a finding involving MAPT, the gene that encodes tau, a protein that forms tangles in Alzheimer’s. Higher MAPT activity appeared potentially protective in the analysis, a result Laura Nisenbaum of the Alzheimer’s Drug Discovery Foundation said she found intriguing. That observation does not prove that increasing MAPT activity is beneficial; it will need to be interpreted and tested in further work.
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How Researchers Searched for Protection
APOE4 is widely described as the strongest common genetic risk factor for Alzheimer’s, but carrying it does not make the disease inevitable. The supplied report says that, over a lifetime, about 60 percent of people with two APOE4 copies develop Alzheimer’s. The figure illustrates that outcomes vary even among people with the same major risk variant; it does not quantify the effect of the newly identified regions.
To investigate that variation, Belloy and colleagues searched for genetic differences associated with Alzheimer’s risk in APOE4 carriers, then examined whether genes identified in the analysis were active in particular brain cell types. Combining population-scale genetic data with post-mortem tissue can help generate hypotheses about both which genes may matter and where they may act. It cannot, by itself, establish the cause of protection or show that manipulating a gene would prevent disease.
Other research has described rare genetic variants that may protect some people at unusually high inherited risk, including the Christchurch variant discussed in earlier studies. The current report presents a broader search for risk modifiers among APOE4 carriers. Those lines of research are related, but a finding about one rare variant does not validate the effects of the regions identified in this study.
“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, as quoted by Being Patient
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Key Findings Still Need Validation
The results remain associations and candidate signals, not proof that specific genes shield APOE4 carriers from Alzheimer’s. The report says individual genes may have small effects, and further experimental and validation studies are needed to determine whether the signals are reproducible and how they might work.
The study population was made up mostly of people of European ancestry, so it is not yet clear whether the findings apply to people from other ancestry groups. The report also says participants had clinical diagnoses, but only about 40 percent had biomarker confirmation. Misdiagnosis among some participants could affect the analysis.
There are limits to the brain-tissue evidence as well. The post-mortem samples came from donors who died in later stages of disease, according to the report, and may not reflect gene activity earlier in Alzheimer’s. It is also unclear whether TNS3, CISD1, MAPT, or the other identified regions have a causal protective role, how large any effect might be, and whether a medicine could safely reproduce it.
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Validation Before Treatment Claims
The next step is replication and experimental testing to check whether the genetic signals hold up and to clarify how the genes affect brain cells and Alzheimer’s risk. Belloy said further validation is needed. The supplied report does not give a timetable for those studies or describe a clinical trial testing medicines directed at TNS3 or CISD1.
Researchers will also need to assess whether the findings generalize beyond predominantly European-ancestry participants and whether better confirmation of Alzheimer’s diagnoses changes the results. Those questions matter before the signals can guide treatment development or patient decisions.
Nisenbaum noted that the MAPT finding could be relevant to diranersen, a gene-silencing therapy from Biogen that the report says is heading toward Phase 3 trials to reduce tau levels. The study does not test diranersen or establish that its approach is supported by these findings. Any connection between the genetic observation and a therapy remains a research question.
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Key Questions
Does APOE4 mean someone will develop Alzheimer’s?
No. APOE4 is associated with increased Alzheimer’s risk, but it does not make the disease inevitable. The supplied report says about 60 percent of people with two copies develop Alzheimer’s over their lifetime; the outcome varies among individuals.
Which genes did the study identify as possible protective factors?
The report highlights TNS3 and CISD1 as possible risk modifiers and notes a potentially protective association involving MAPT gene activity. These are research candidates, not confirmed protective genes or proven treatment targets.
Does the study show that a medicine can prevent Alzheimer’s in APOE4 carriers?
No. The study identified genetic regions associated with risk, but it did not test a preventive medicine. The report says there are no FDA-approved drugs targeting TNS3 or CISD1 that can be repurposed for Alzheimer’s.
Do the findings apply to people of every ancestry?
That is not yet clear. Most participants were of European ancestry, and researchers will need further studies to determine whether the results generalize to other populations.
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