Seven DNA regions differ in their associations with an Alzheimer’s disease diagnosis in APOE ε4 carriers

Seven DNA regions differ in their associations with an Alzheimer’s disease diagnosis in APOE ε4 carriers

On September 14, a study published in Nature Genetics grouped people with an established Alzheimer’s disease diagnosis by their APOE variants and compared the associations of other DNA variants with the diagnosis. The authors found differences between ε4 carriers and people with two copies of ε3.

APOE is a gene with three common variants, ε2, ε3 and ε4; ε4 is associated with an increased risk of Alzheimer’s disease. A conventional genetic analysis estimates the average association between each DNA variant and the diagnosis across the entire sample. Here, the authors first grouped participants by APOE: the ε3/ε3 group included 24 033 cases and 363 161 people without the diagnosis, while the ε4 carrier group included 29 122 cases and 164 206 people without the diagnosis.

Across the two main groups, they identified 25 DNA regions associated with the diagnosis: nine in both groups, nine only in ε4 carriers and seven only in the ε3/ε3 group. The authors then compared the strength of each region’s association with the diagnosis. In ε4 carriers, the association was weaker for three regions and stronger for four than in people with ε3/ε3.

One of the new signals in ε4 carriers was near the DDHD1 gene. An analysis accounting for the nearby, previously known FERMT2 signal showed that this was an independent association with the diagnosis. In samples from the brain’s frontal cortex, the rs10131116 variant was associated with lower levels of DDHD1 RNA, the molecules that cells produce from this gene. This finding led the authors to propose DDHD1 as a separate hypothesis for a mechanism underlying the disease.

The authors propose grouping participants in future Alzheimer’s drug trials by their APOE variants in advance.