Genes May Protect Against APOE4 Alzheimer’s Risk

TL;DR

Prime Big Deal Days · Oct 6–7Offer from Amazon

Get self-care and calm essentials delivered free — and shop member deals

• Fast, free delivery on millions of items
• Access to Prime Big Deal Days deals on October 6–7
• Prime Video, Amazon Music and more included

Start your free Prime trial →Free trial for eligible customers · Cancel anytime

As an affiliate, we earn on qualifying purchases.Hide

Researchers analyzing genetic data from nearly 450,000 people identified 42 DNA regions associated with Alzheimer’s risk among APOE4 carriers, including 29 regions not previously reported in this analysis. Follow-up brain-tissue analysis pointed to oligodendrocytes and genes including TNS3 and CISD1, but the findings need validation and may not apply across ancestries.

Researchers have identified 42 DNA regions associated with Alzheimer’s risk among people carrying the APOE4 risk gene, including signals that may help explain why some carriers do not develop the disease. The study, published in Alzheimer’s & Dementia, points to brain-support cells called oligodendrocytes and genes including TNS3 and CISD1 as possible research targets, but it does not establish that these genes prevent Alzheimer’s or provide a treatment.

Michael Belloy, an assistant professor at Washington University in St. Louis, and colleagues analyzed genetic data from nearly 450,000 people, focusing on those with one or two copies of APOE4. The researchers looked for genetic variants associated with changes in Alzheimer’s risk among these carriers. They reported 42 linked DNA regions: 13 had been identified previously, while 29 were new in the analysis.

The team also examined gene activity in post-mortem brain tissue from 424 donors. Many of the genes identified as potentially protective were active in oligodendrocytes, which form insulating sheaths around nerve cells and support efficient transmission of electrical signals. The researchers highlighted TNS3 and CISD1 as possible risk modifiers: TNS3 is involved in oligodendrocyte maturation and survival, while CISD1 has a role in the cells’ metabolism.

These results identify associations and candidate biological pathways, not confirmed causes of protection. Belloy told Being Patient that the signals need further experimental work and validation. The report also notes that there are no FDA-approved medicines targeting TNS3 or CISD1 that could currently be repurposed for Alzheimer’s.

Oligodendrocytes Enter the Risk Picture

The findings add to evidence that APOE4 does not determine an individual outcome on its own. Identifying genetic factors linked to lower risk among carriers could help researchers understand why risk varies and point toward biological processes that might be studied for future therapies. The oligodendrocyte signal suggests that research into Alzheimer’s risk may need to include cells that support neurons, not only the neurons themselves.

Any treatment implications remain distant. The identified genes are potential leads, and the study did not test a drug, show that activating these genes prevents disease, or measure whether a specific intervention changes outcomes. Belloy told Being Patient that individual genes may have small effects, while targeting several pathways could potentially strengthen benefits; that is a research possibility, not a demonstrated clinical result.

The report also described interest in MAPT, the gene that encodes tau. Laura Nisenbaum, chief scientific officer of the Alzheimer’s Drug Discovery Foundation, told Being Patient that higher MAPT activation in the analysis was an intriguing finding. She noted a possible connection to diranersen, a gene-silencing therapy aimed at lowering tau levels that the report said was heading toward Phase 3 trials. The study does not show that its MAPT result predicts diranersen’s effectiveness.

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 does not mean a person will inevitably develop the disease. The article reports that about 60 percent of people with two APOE4 copies develop Alzheimer’s over their lifetime, meaning many do not. The study set out to examine genetic differences that might help account for that variation.

Researchers have previously investigated other genetic examples of possible protection, including the Christchurch variant in people with inherited forms of Alzheimer’s. The Being Patient report describes a Colombian woman who remained cognitively healthy until her 70s despite a genetic form that typically causes symptoms in the 40s, and says she had two copies of the variant. The report also notes that more recent work has questioned the reliability of some research in this area, underscoring why protective signals require independent 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

Signals Still Need Independent Testing

The study’s associations do not prove that the identified genes directly protect against Alzheimer’s. The report says most participants were of European ancestry, so it remains unclear whether the findings apply to other populations. Researchers also relied on clinical diagnoses for participants in the genetic data; the report says only 40 percent had biomarker confirmation, leaving a possibility that some diagnoses were incorrect.

The brain-tissue analysis has a separate limitation: the donors’ brains were examined after death, and Nisenbaum cautioned that tissue from people who died in later stages of disease may not represent what happens earlier. It is also unclear how large the effects of individual genes are, whether their activity can be safely changed, and whether modifying them would reduce disease risk. The study does not establish a timeline for turning its candidates into therapies.

Validation Before Treatment Claims

The next steps are experimental studies and independent validation to test whether the genetic signals are reproducible and to determine how the candidate genes relate to Alzheimer’s biology. Research will also need to examine participants from more varied ancestry groups and address the limits of clinical diagnoses and late-stage post-mortem tissue.

Until those questions are addressed, TNS3, CISD1, MAPT and the other regions should be treated as research leads, not as proven ways to prevent or treat Alzheimer’s. The report does not identify a scheduled follow-up result or a clinical trial testing medicines that target TNS3 or CISD1.

Key Questions

Does carrying APOE4 mean someone will develop Alzheimer’s?

No. APOE4 raises risk but does not determine the outcome. The report says about 60 percent of people with two copies develop Alzheimer’s over their lifetime; it does not mean all carriers will develop the disease.

Which genes did the study identify as possible risk modifiers?

The researchers highlighted TNS3 and CISD1 as possible modifiers among APOE4 carriers. They also identified 42 associated DNA regions in total, but the study does not prove that any one gene prevents Alzheimer’s.

Do the findings point to an available Alzheimer’s treatment?

No. The report says there are no FDA-approved medicines targeting TNS3 or CISD1 for this purpose. The findings are research leads, and the study did not test a treatment.

How certain are the results?

The results are preliminary associations that require further validation. Most participants were of European ancestry, only 40 percent of the clinical diagnoses in the genetic data had biomarker confirmation, and the post-mortem tissue may reflect later disease stages.

Source: rss