Genes May Protect Against APOE4 Alzheimer’s Risk

TL;DR

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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 oligodendrocytes and genes such as TNS3 and CISD1 as possible research leads, but they do not establish protective treatments or prove the genes prevent the disease.

Researchers have identified 42 DNA regions associated with Alzheimer’s risk in people carrying APOE4, including 29 regions not previously identified in this analysis, in a study of nearly 450,000 people. The findings, published in Alzheimer’s & Dementia, point to genes active in oligodendrocytes as possible clues to why some APOE4 carriers develop Alzheimer’s while others do not; they do not show that the genes prevent the disease or offer a treatment.

Michael Belloy, an assistant professor at Washington University in St. Louis, and colleagues examined genetic data from people who carried one or two copies of APOE4, focusing on factors that could modify their Alzheimer’s risk. The study identified 42 associated DNA regions: 13 had been reported previously, while 29 were new in this analysis. The researchers looked for genetic differences linked to whether APOE4 carriers had received a clinical Alzheimer’s diagnosis.

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

Being Patient reported that the researchers consider proteins encoded by these genes potential drug targets, but no FDA-approved medicines target TNS3 or CISD1 for Alzheimer’s. The study also found a signal involving MAPT, the gene that encodes tau. Laura Nisenbaum, chief scientific officer of the Alzheimer’s Drug Discovery Foundation, told Being Patient that the result was intriguing, while cautioning that tissue from people who died in later disease stages may not reflect earlier processes.

Oligodendrocytes Offer a New Research Lead

The findings add to evidence that APOE4 does not determine an individual’s outcome on its own. Identifying genetic factors associated with lower risk among carriers could help researchers study the biology behind that variation and identify pathways for future drug development. The oligodendrocyte signal gives scientists a specific cell type to investigate alongside the better-known processes involving neurons and tau.

That possibility is a research direction, not a clinical result. An association between a gene and a diagnosis does not establish that increasing the gene’s activity would prevent Alzheimer’s, nor that a medicine could do so safely. Belloy told Being Patient that individual genes may have small effects, and that further experimental work is needed before any treatment implications can be drawn.

The report also noted Nisenbaum’s interest in the MAPT finding because a tau-lowering gene-silencing therapy, diranersen, is heading toward Phase 3 trials. The study does not establish that its genetic result predicts the therapy’s effectiveness; any relationship would need direct testing.

APOE4 Raises Risk, Not Certainty

APOE4 is a strong common genetic risk factor for Alzheimer’s, but carrying it does not mean a person will necessarily develop the disease. The Being Patient report says the risk associated with APOE4 is about four to 12 times higher, depending on factors including whether a person has one or two copies. It also notes that about 60 percent of people with two copies develop Alzheimer’s over their lifetimes, meaning many do not.

Scientists have previously investigated genetic variants that may confer protection, including the Christchurch variant in research on inherited Alzheimer’s. This new study addresses a broader question: which genetic differences may modify risk among APOE4 carriers? Its results are candidates for follow-up, rather than a settled explanation of why some carriers remain unaffected.

The analysis used clinical diagnoses, but only 40 percent of participants had biomarker confirmation, according to the source report. That matters because some diagnoses may have been incorrect, which could affect the genetic signals identified. The brain-tissue analysis was a separate component based on samples from 424 donors.

“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

Findings Need Broader Validation

The study’s results remain associations, not proof of protection. The researchers need further validation and experiments to establish whether the candidate genes affect Alzheimer’s biology and, if so, how. It is also unclear whether the findings would apply to people outside the populations represented in the dataset: most participants were of European ancestry.

Clinical diagnoses were not confirmed with biomarkers for most participants, leaving open the possibility of misclassification. The post-mortem tissue came from people who had died after developing disease, so, as Nisenbaum told Being Patient, gene activity in those brains may not capture what happens earlier. The report does not provide evidence that changing TNS3, CISD1, or MAPT activity would reduce a person’s risk.

Replication and Experiments Are Needed

The next steps are independent validation and experimental studies to test whether the genetic regions and genes identified here have a causal role in risk. Researchers will also need to examine the findings in more ancestrally diverse populations and determine whether the candidate pathways matter at earlier stages of disease.

For now, the findings are research leads, not a basis for changing medical care or estimating an individual’s personal outlook. The report does not give a timeline for follow-up studies or clinical trials targeting TNS3 or CISD1. Whether the MAPT signal has any relevance to tau-directed treatments, including diranersen, also remains to be established.

Key Questions

What did the study find?

Researchers identified 42 DNA regions associated with Alzheimer’s risk among APOE4 carriers, including 29 not previously identified in this analysis. They also found that many candidate genes were active in oligodendrocytes, and highlighted TNS3 and CISD1 for further study.

Does carrying APOE4 mean someone will develop Alzheimer’s?

No. APOE4 raises risk, but does not determine whether a person will develop the disease. The source report says about 60 percent of people with two copies develop Alzheimer’s over their lifetimes.

Have researchers found a treatment based on these genes?

No. The study identified possible biological leads, but the source report says there are no FDA-approved medicines targeting TNS3 or CISD1 for Alzheimer’s. The findings need further validation and testing.

How certain are the results?

The results are preliminary associations. Most participants were of European ancestry, and only 40 percent had biomarker confirmation of their clinical diagnosis, according to Being Patient. Researchers say more validation and experimental studies are needed.

Source: rss