Uncovering Resilience to Alzheimer's Disease

A recent publication highlights the discovery of the second case demonstrating exceptional resilience to autosomal dominant Alzheimer's disease (ADAD). This male patient, carrying a PSEN1-E280A mutation, remained cognitively intact until the age of 67, despite the presence of highly elevated amyloid plaque burden. Interestingly, the patient did not possess the protective APOE3 Christchurch variant but instead had a rare variant in the RELN gene (H3447R), termed COLBOS. This gain-of-function variant showed enhanced ability to activate its protein target Dab1, leading to reduced human Tau phosphorylation. These findings suggest a potential role for RELN signaling in resilience to dementia, highlighting the importance of genetic variants in ADAD protection. 

The apolipoprotein E (APOE) gene, specifically the APOE ε4 allele, is the most well-established genetic risk factor for late-onset Alzheimer's disease. Inheriting one or two copies of the APOE ε4 allele increases the risk of developing Alzheimer's and may influence the age of onset. Other genes, such as the presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes, have been linked to early-onset familial Alzheimer's disease, which is a rare form of the condition that runs in families. However, it's important to note that having these genetic risk factors doesn't guarantee the development of Alzheimer's, and many other factors, including lifestyle and environmental factors, also play a role in the disease.

Mutations in the PSEN1 gene are associated with early-onset familial Alzheimer's disease, which is a rare form of the condition that tends to run in families. Presenilin 1. The PSEN1 gene codes for a crucial component of the gamma-secretase enzyme complex. This enzyme plays a role in the processing and production of beta-amyloid, a protein fragment that forms plaques in the brains of individuals with Alzheimer's disease. Mutations in the PSEN1 gene, E280A in particular, can lead to the production of abnormal presenilin 1 protein, which in turn can disrupt the normal processing of beta-amyloid and contribute to the development of early-onset familial Alzheimer's disease.


Lopera, F., Marino, C., Chandrahas, A.S. et al. Resilience to autosomal dominant Alzheimer’s disease in a Reelin-COLBOS heterozygous man. Nat Med (2023). https://doi.org/10.1038/s41591-023-02318-3

Researchers discover second case of person resistant to Alzheimer’s | Science & Tech | EL PAÍS English (elpais.com)


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