DNA variants linked to inherited Alzheimer’s disease risk
One DNA variant was associated with higher disease odds, with an odds ratio of 11.99, when 101 symptomatic mutation carriers were compared with 5,050 unaffected controls.
Our read
Mechanisms- Studied:
- Genetic association study of 5,151 non-Hispanic White ADAD cases and controls
- What changed:
- Inherited Alzheimer’s disease risk was higher with the CNIH4 variant than without it (odds ratio 11·99)
- The catch:
- Only 101 symptomatic cases, raising concerns about inflated CNIH4 risk estimates
Editor of record: Boris Djordjevic · AgingResearch.News
The 101 people with symptomatic autosomal dominant Alzheimer’s disease, an inherited form, were unrelated and non-Hispanic White. An observational genome-wide association study searched their DNA for disease-linked differences by comparing them with 5,050 unaffected controls. Women accounted for 46 cases and 3,019 controls. Median dementia onset was 47 years; controls’ median age at their last healthy visit was 80.
Three DNA regions were associated with disease, regardless of which disease-causing mutation participants carried. One associated variant was also linked to earlier dementia onset among people with inherited disease. Those carrying this variant had a median onset age of 40, compared with 48 among those not carrying it.
Why it matters
Variation in when inherited Alzheimer’s disease begins raises questions about the role of other genes. The authors said these associations could inform family genetic counseling and future clinical trial designs.
Caveats
The main analysis compared symptomatic mutation carriers with controls without those mutations, rather than with unaffected carriers. It included only 101 cases, and all participants were non-Hispanic White.
From the paper
- Participants
We included 1992 participants from Knight-ADRC, 472 from DIAN, and 16 549 from ADSP R4 (control participants and participants with ADAD).
- Result
The most significant locus was observed on chromosome 14 led by rs141931440 (p<0·0001, odds ratio [OR] 5·96 [95% CI 3·42–10·36]; MAFcohort 0·027; χ² OR 4·94) and located near the RHOJ gene.
- Events by group
The APOE ε4 allele was present in 34 (34%) case participants and 1411 (28%) control participants.
- Limitation
First, despite having the largest cohort to date, the rarity of ADAD results in a relatively small sample size, which might potentially reduce the statistical power of our analysis.
Quoted word for word from the full text on PubMed Central.
The paper
Washington University in St. Louis; Universidad de Antioquia
The Lancet Neurology, May 14, 2026, Open access
Presented at AAIC 2025 as an abstract
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