Researchers at University College London have found that up to 93 percent of Alzheimer's cases may be linked to variants of the APOE gene, far more than previously estimated. The analysis, published in npj Dementia, also indicates that nearly half of all dementia cases could depend on this gene. The discovery underscores APOE as a key target for future treatments.
A comprehensive study led by Dr. Dylan Williams at University College London reveals that the APOE gene plays a central role in Alzheimer's disease, potentially influencing over 90 percent of cases. The research, which analyzed data from more than 450,000 participants across four large studies, estimates that between 72 percent and 93 percent of Alzheimer's would not occur without the ε3 and ε4 variants of APOE. This is higher than prior assessments, which focused mainly on the harmful ε4 allele while overlooking ε3's contributions.
APOE has three common alleles—ε2, ε3, and ε4—with individuals inheriting two copies, leading to six possible combinations. The ε4 variant increases risk significantly, while ε2 offers some protection compared to ε3, long viewed as neutral. Dr. Williams noted, "We have long underestimated how much the APOE gene contributes to the burden of Alzheimer's disease... much disease would not occur without the additional impact of the common ε3 allele."
The findings extend to broader dementia, with about 45 percent of cases possibly tied to APOE. Variations in study results stemmed from differences in diagnosing Alzheimer's—via medical records, other classifications, or brain scans for amyloid buildup—as well as follow-up durations and recruitment methods. Despite APOE's dominance, it is not the only factor; even those with two ε4 copies face less than 70 percent lifetime risk, influenced by other genetic and environmental elements like social isolation, high cholesterol, or smoking.
Dr. Williams emphasized therapeutic potential: "Intervening on the APOE gene specifically, or the molecular pathway between the gene and the disease, could have great... potential for preventing or treating a large majority of Alzheimer's disease." Dr. Sheona Scales of Alzheimer's Research UK added, "Further research into APOE will be important for developing future prevention and treatment strategies."
Funded by organizations including Alzheimer's Research UK and the Medical Research Council, the study calls for prioritizing APOE in drug development, including gene editing and conventional therapies targeting cholesterol or inflammation pathways linked to the gene.
