Genetic loci linked to onset-age variability in autosomal dominant Alzheimer's disease

Evidence before this study

We searched PubMed on March 1, 2023, for publications published from database inception to March 1, 2023, using the terms “APP” OR “PSEN1” OR “PSEN2” AND “onset age variability”, without language restrictions. We identified 79 studies, which reported large variability in age at onset (AAO) of autosomal dominant Alzheimer's disease (ADAD) among individuals carrying PSEN1, PSEN2, or APP mutations, suggesting that genetic modifiers might be in part responsible for the phenotypic presentation. We also searched PubMed using various terms including “genome-wide association study”, “Alzheimer's disease”, and “genetics”, and curated relevant publications aimed at genetic modifier identification, yielding six studies. These studies on large families identified potential genetic modifiers, such as APOE Christchurch and RELN, that influence AAO of ADAD. Other studies leveraged founder mutations and identified potential genetic modifiers, which influence key pathological processes such as amyloid deposition, neuronal resilience, and synaptic function. However, replication is still insufficient, the effect of these potential genetic modifiers across ADAD mutations remains to be assessed, and additional modifiers remain to be identified.

Added value of this study

In our study, to the best of our knowledge, we gathered the largest ADAD cohort in the world, increasing not only the size of ADAD studies for genetic modifiers but also the diversity of mutations compared with previously reported studies. Through a genome-wide association study, we identified three new genetic loci acting as risk modifiers of the three ADAD genes. Among these loci, one variant is located in the coding region of the CNIH4 gene. The sentinel variant at the CCNG1 locus was associated with earlier AAO, potentially through TDP-43 pathology. The sentinel variant at the RHOJ locus was associated with CSF Alzheimer's disease biomarkers, highlighting its role in the progression of the disease.

Implications of all the available evidence

The identification of these genetic variants offers promising new pathways for developing biomarkers and therapeutic strategies for individuals with ADAD. Additionally, the variants could significantly improve genetic counselling for affected families and aid in the planning of future clinical trials. This research enhances our understanding of the genetic factors that drive Alzheimer's disease progression and paves the way for further study and therapeutic innovation.

Source: The Lancet Neurology