Science Friday

How One Gene Affects Alzheimer’s Risk

February 25, 2026

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  • Variants in the APOE gene (specifically E3 and E4 forms) are estimated to contribute to 70% to over 90% of Alzheimer's disease cases, suggesting it is a disproportionately important single genetic target for research and therapeutics. 
  • Despite its significant role, the APOE gene's importance in Alzheimer's research has historically been overshadowed, evidenced by only one drug trial among approximately 140 currently targeting it. 
  • The APOE gene has three main types (E2, E3, E4), with E2 conferring low risk and E4 conferring high risk, but the gene's effect is not deterministic, as many individuals with high-risk variants do not develop the disease. 

Segments

Introduction and APOE Background
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(00:00:50)
  • Key Takeaway: APOE is a protein involved in shuttling fat that has diverse roles in the brain and is strongly linked to Alzheimer’s risk.
  • Summary: The episode of Science Friday focuses on untangling the genetic factors in Alzheimer’s disease, specifically the APOE gene. The APOE protein normally functions in shuttling fat around the body and has known roles in the brain. Individuals inherit one of three types: E2 (low risk), E3 (medium risk), or E4 (high risk) for Alzheimer’s disease.
Quantifying APOE’s Contribution
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(00:02:23)
  • Key Takeaway: Removing the effects of the medium (E3) and high-risk (E4) APOE variants could prevent 70% to over 90% of Alzheimer’s cases.
  • Summary: Researchers sought to quantify what proportion of Alzheimer’s cases would be prevented if the E3 and E4 gene forms were eliminated. This calculation revealed that the contribution of these two variants is massive compared to other known Alzheimer’s susceptibility genes. This finding strongly supports increased research funding toward APOE-related therapeutic development.
Future Research Directions
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(00:04:34)
  • Key Takeaway: Future research must investigate APOE’s role across different ethnic groups and study the protective mechanisms of the low-risk E2 variant.
  • Summary: Key questions remain regarding how APOE’s role might differ in non-European ancestry groups and what other genetic or environmental factors modify the risk. Furthermore, understanding the unique properties of the low-risk E2 variant is crucial for both prevention strategies and assessing the safety of potential therapeutics.
APOE and Disease Manifestation
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(00:07:15)
  • Key Takeaway: The APOE gene variants influence both the physical hallmarks (plaques and tangles) and the clinical symptoms of Alzheimer’s dementia.
  • Summary: The influence of APOE variants relates to both the buildup of characteristic proteins in the brain and the resulting memory and thinking problems seen in dementia. While traditional research focuses on removing these characteristic proteins, progress has been slow, suggesting a need to diversify approaches by focusing more on APOE.
Therapeutic and Screening Implications
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(00:08:40)
  • Key Takeaway: Therapeutic approaches could involve gene therapy to modify the gene directly or conventional pharmacology targeting the pathways driven by APOE risk factors.
  • Summary: Potential treatments include emerging gene therapy technologies to switch genes or insert beneficial ones, or using standard pharmacology to modify the disease pathways indicated by genetic risk. Screening individuals for APOE status is currently not recommended because the gene is not destiny and does not provide actionable information for prevention at this time.
APOE Risk Analogy and Status
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(00:11:00)
  • Key Takeaway: APOE’s role in Alzheimer’s is analogous to smoking’s role in lung cancer: a strong, predominant cause that is necessary but not sufficient on its own to guarantee the disease.
  • Summary: The risk conferred by APOE is significant but requires other factors to amplify or buffer its effect, meaning the disease would not occur for most people without it. Currently, only one of the approximately 140 Alzheimer’s drug trials in progress directly relates to targeting APOE.