TLDR
A specific gene called APOE, especially its APOE4 version, plays a big role in raising the risk for Alzheimer's disease, but this risk changes depending on a person's ancestry and sex.
Summary
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1 Study Aim
The review aims to summarize 25 years of research on the apolipoprotein E (APOE) gene and its connection to Alzheimer's disease (AD), focusing on whether the APOE4 version increases AD risk by causing the protein to lose its normal function or gain a harmful one. The authors also seek to clarify how APOE4's effects differ by ancestry and sex, and to discuss what these findings mean for future treatments and research directions. The paper's main goal is to explain how APOE4 affects Alzheimer's risk and what this means for different people and future treatments.
2 Study Design
This is a narrative review that synthesizes findings from human genetic studies, biomarker research, and clinical observations related to APOE and Alzheimer's disease. The authors compare results from large population studies, meta-analyses, and case reports, and they discuss evidence from both human and animal research. The review also examines how APOE's effects vary by ethnicity and sex, and considers rare genetic cases to explore the consequences of having no APOE protein at all. The authors looked at many studies and patient cases to understand how APOE4 affects Alzheimer's risk in different groups of people.
3 Findings
The review demonstrates that carrying the APOE4 version of the gene greatly increases the risk of developing Alzheimer's disease, with risk rising further for people with two copies of APOE4. The risk is not the same for everyone: it is higher in women and in people of East Asian or European ancestry, but lower in those with African ancestry. APOE4 is also linked to earlier onset of Alzheimer's and affects other diseases like heart disease and stroke. The authors argue that APOE4 may cause Alzheimer's mainly by reducing the normal function of the APOE protein, rather than by adding a new harmful function. They recommend that future research and treatments should consider a person's ancestry and sex, and suggest that targeting APOE4 could be a promising way to prevent or treat Alzheimer's disease. The review finds that APOE4 raises Alzheimer's risk, especially in certain groups, and suggests that new treatments should focus on how this gene works differently in different people.