Niigata, Japan – Researchers at Niigata University have conducted the first comprehensive reappraisal in nearly 30 years of the risk of Alzheimer’s disease (AD) associated with APOE-e4 homozygosity ( e4*4 ) in the Japanese population. Their findings suggest that the risk, while still substantial, is lower than estimates that have been widely cited since the 1990s.
AD is the most common cause of dementia worldwide. Among the many factors that influence disease risk, the APOE gene is considered the strongest genetic risk factor for late-onset AD. Individuals who inherit two copies of the APOE-e4 variant are known to have a particularly high risk of developing the disease.
In 1997, a landmark international meta-analysis reported that Japanese e4*4 had a more than 30-fold higher risk of AD compared with individuals carrying the most common APOE genotype, e3*3 (Farrer LA, et al . JAMA [1997]). This estimate has been repeatedly cited in scientific literature for nearly three decades. However, many additional case-control studies have been published in Japan since then, raising the need for an updated assessment based on a much larger body of evidence.
To address this issue, the research team systematically reviewed and combined data from 21 Japanese case-control studies. By integrating the available evidence, they found that e4*4 is associated with an approximately 12- to 15-fold increase in AD risk. Although this still represents one of the strongest known genetic risk factors for the disease, it is substantially lower than the long-standing estimate exceeding 20- to 30-fold (Farrer LA, et al . JAMA [1997]; Bertram L, et al . Nat Genet [2007]).
“The e4*4 remains a very strong genetic risk factor for AD in Japanese populations,” explains Dr. Akinori Miyashita (Associate Professor) of Niigata University. “However, our findings indicate that the risk is not as extreme as previously believed. By incorporating evidence accumulated over the past three decades, we were able to provide a more robust and up-to-date estimate.”
The study also showed that the risk observed in Japanese populations is broadly comparable to estimates reported in large studies of people with European ancestry (Farrer LA, et al . JAMA [1997]; Bertram L, et al . Nat Genet [2007]; Belloy ME, et al . JAMA Neurol [2023]). This finding, together with evidence from Chinese populations showing comparable effect sizes (Liu M, et al . Sci Rep [2014]), suggests that the effect of e4*4 may be more consistent across populations than previously thought.
“Accurate risk estimates are essential for both research and clinical practice,” says Dr. Takeshi Ikeuchi (Professor) of Niigata University. “As the field moves toward earlier diagnosis and prevention of AD, reliable genetic risk information will become increasingly important.”
The researchers believe that their findings provide an updated foundation for genetic risk assessment and future studies aimed at disease prevention. They also emphasize that carrying the APOE-e4 variant does not guarantee that a person will develop AD, as many environmental and lifestyle factors also contribute to disease risk.
The study highlights the importance of periodically re-evaluating long-standing scientific assumptions as new evidence accumulates and demonstrates how updated analyses can refine our understanding of disease risk in diverse populations.
Molecular Neurodegeneration
A Reappraisal of APOE Genetic Effects on Alzheimer’s Disease Risk in the Japanese Population: A Meta-Analysis
24-Jun-2026