Niigata University study updates Alzheimer's risk for APOE-e4 homozygotes

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]).