Reacción a "A single copy of a protective gene variant helps delay early Alzheimer's disease"

The study they present is very well designed and clearly justified, as it is a natural continuation of the group's previous studies that had demonstrated the gene's protective role in homozygosity. They now show that the APOE3 Christchurch allele in heterozygosity is also protective for the clinical manifestation of Alzheimer's disease. This study benefits from the world's largest cohort of PSEN1 mutation carriers, specifically the E280A mutation that causes autosomal dominant Alzheimer's disease (ADAD) with presenile onset (age of symptoms at 48 years). ADAD, despite its rarity, has been extensively studied because it offers unique opportunities for studying the pathophysiology of Alzheimer's disease, primarily due to its complete penetrance and predictable age of symptom onset. However, there is variability in the age of onset due to genetic and environmental factors. This study demonstrates that APOE3 Christchurch is a protective genetic factor.   

The study complements previous studies of a homozygous APOE3 Christchurch allele carrier group in which the age of symptom onset was more than 20 years later. They now show a more modest protective role of the allele in heterozygosity, suggesting a dose-response of the protective factor. Coming also from a well-studied cohort, the study shows that this mutation affects tau accumulation and delays symptoms rather than affecting amyloid accumulation which is still occurring, suggesting a later effect within the amyloid cascade.  

A limitation of the study is the relatively small size of the APOE3 Christchurch carriers who also come from the same extended family (a founder effect that justifies a relatively large number of carriers in a particular geographical area). This means that studies in more diverse populations, and possibly in other populations such as Down's syndrome, are needed to validate the magnitude of the protective effect conferred by this variant. Furthermore, this study, despite the relevance of the biomarker data mentioned above, does not provide data on the biological mechanisms conferring protection. This is essential for the future development of protective therapies based on these findings.