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. 

According to a more recent study, the double copy of APOE4 should be recognized not only as a risk factor but also as a cause for distinct genetic form of Alzheimer’s. It affects between 2% and 3% of the entire Caucasian population. Besides APOE genes (that could be fixed by gene therapy), the protective effect against Alzheimer's disease concentrated on the alleles in/near ANKH, GRN, TMEM106B, SORT1, PLCG2, and RIN3 genes that provided up to >5-fold lower polygenic risk score in centenarians compared to AD cases (P = 7.69 × 10-71), and 2-fold lower compared to age-matched controls (P = 5.83 × 10-17).

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.


REFERENCES

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)

Tesi N, van der Lee S, Hulsman M, van Schoor NM, Huisman M, Pijnenburg Y, van der Flier WM, Reinders M, Holstege H. Cognitively healthy centenarians are genetically protected against Alzheimer's disease. Alzheimers Dement. 2024 Apr 18. doi: 10.1002/alz.13810. Epub ahead of print. PMID: 38634500.

Comments

Post a Comment

Popular posts from this blog

Precision Nutrigeroscience: Nutrition for Longevity and Brain Health

Image
The pursuit of extended lifespan and improved health requires a deep understanding of the complex interplay between our diet and unique biological factors.  This is where precision nutrigeroscience emerges as a transformative approach, leveraging the power of biomarker identification and analysis to tailor dietary interventions. It embraces the diversity of human physiology, acknowledging that what works for one may not work for another, especially when it comes to nutrition. The varying impact of carbohydrates and fats on mortality is a testament to this complexity. Meat intake is linked to higher life expectancies, but the impact of carbohydrates and fats varies among individuals. While some thrive on higher carbohydrate diets, others may benefit from reduced carb intake. Similarly, the type of fats consumed (animal vs. plant-based) plays a significant role in health outcomes. The goal of precision nutrigeroscience is to decipher these individual needs and craft dietary recommendatio
Read more

HippoCamera for Aging Brain

Image
Memory decline is common in aging and significantly worsens quality of life, but there are few, if any, effective interventions to improve episodic memory recall in older adults. And there are no effective interventions specifically targeting autobiographical episodic memory. A smartphone app called HippoCamera allows users to create memory cues of specific events that they personally value and hope to remember. These cues consist of a short verbal description and a short video recording of the event. The approach was shown to be effective tool for improving the recall of episodic memories in older adults. Seniors were able to improve their ability to recall episodic memories, increase the differentiation of hippocampal activity, and better remember the personal past. These findings suggest that using mobile phone technologies to record and replay episodic memories may be a feasible, low- cost, and effective way to improve memory recall in older adults (Adapted from SpinnerChef:  Spinn
Read more

Brain vs RTX and LLMs: A Computational Showdown

Image
In the age of rapidly advancing technology, comparing the human brain to building blocks of a computer opens up an intriguing conversation. Both systems represent incredible feats of engineering—one through billions of years of evolution, the other through decades of technological innovation.  This image  that I came across on reddit  illustrates features of the brain vs a powerful graphics card like the NVIDIA RTX 4090. As of September 2024, the NVIDIA GeForce RTX 4090 remains one of the most powerful consumer GPUs available, especially for gaming and productivity tasks like rendering and AI workloads. It excels in 4K gaming and can handle even the most graphically demanding games, with exceptional performance in ray tracing and DLSS 3 technology, delivering up to 3-4x the performance of previous-generation GPUs like the RTX 3090 Ti. NVIDIA GeForce RTX 4090 is rumored to be  discontinued in October in preparation For Next-Gen RTX 5090 & 5090D GPUs, which could be up to 70% faster
Read more