APOE Gene Variant Increases Alzheimer's Risk, But Many Without It Still Show Signs of the Disease
A recent study presented at the NSGC 2025 conference reveals a fascinating yet complex relationship between genetics and Alzheimer's disease. While the APOE ϵ4/ϵ4 gene variant is a strong predictor of higher Alzheimer's risk, the study shows that many individuals without this allele still exhibit true Alzheimer's disease (AD) pathology.
But here's where it gets intriguing: The study, led by Matt Tschirgi, analyzed biomarker testing results from a large cohort and found that APOE ϵ4/ϵ4 carriers were more likely to have biomarkers indicating mild cognitive impairment or AD-associated dementia. However, a significant number of people without this gene variant also showed signs of AD, complicating the interpretation of biomarker results.
The study included 21,267 individuals who underwent beta-amyloid testing, with 27.1% classified as higher risk, aligning with previous research. Interestingly, no significant differences were found between individuals homozygous for APOE ε3 and APOE ε4.
Researchers delved into the complexities of biomarker testing, with 49.5% of 7313 individuals showing biomarker results consistent with mild cognitive impairment or AD-related dementia. The study also revealed that APOE ε4 homozygosity was significantly associated with these biomarkers.
And this is the part most people miss: Among 743 individuals who received p-tau 217 testing, 56.0% had results indicating mild cognitive impairment or dementia due to AD. Surprisingly, this proportion was similar between APOE ε3 and APOE ε4 homozygotes, emphasizing the need for expert interpretation of such results.
The study highlights the crucial role of certified genetic counselors in deciphering complex biomarker and genetic test results, especially as new AD therapies emerge. With the growing focus on AD, discussions about the role of genetic counselors in testing are becoming more prominent, as they can provide valuable insights into discordant or ambiguous results.
The authors note that while APOE allele status is a significant risk factor, the availability of newer blood biomarker assays adds complexity to counseling discussions. This study underscores the importance of comprehensive genetic counseling in navigating the intricate landscape of Alzheimer's disease risk assessment and management.
