Some individuals have a genetic tendency to develop Alzheimer’s before they reach the age of 65. Researchers at Mass General Brigham have identified a genetic variation that may protect those whose other gene variant predisposes them to early-onset Alzheimer’s. This discovery could lead to new treatment targets for early-onset disease.
Although Alzheimer’s typically occurs after 65, it can manifest as early as the 30s. Early-onset Alzheimer’s is the term used to describe Alzheimer’s disease that develops before the age of 65.
According to researchers, genetic factors, including three rare gene variants: amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2), are responsible for most of the early-onset Alzheimer’s cases [1].
Recently, Mass General Brigham researchers found a genetic variation that appears to help shield individuals genetically prone to early-onset Alzheimer’s, which may lead to the discovery of novel treatment targets. The New England Journal of Medicine published the findings [2].
Two Specific Genetic Variations
Researchers investigated two specific genetic mutations in this study.
The first is the Paisa mutation (Presenilin-1 E280A), which occurs in an extensive Colombian family. According to earlier studies, those who carry this mutation have a higher chance of getting Alzheimer’s disease, with symptoms potentially appearing as early as their 40s [3].
The second genetic variant the team investigated was the APOE3 gene, known as Christchurch (APOE3Ch) [4]. The APOE gene carries the instructions required to produce the apolipoprotein E protein. Various APOE gene variants influence the onset of Alzheimer’s.
Researchers from Mass General Brigham presented a study in 2019 that included a person who had two copies of the Christchurch variant and a very high genetic risk for Alzheimer’s but who did not experience cognitive impairment until she was in her late 70s [5].
The Christchurch mutation may help protect the brain from clumps created by high levels of tau protein, which are thought to be a characteristic of the disease, according to a different study published in January 2024 [6].
The Findings: One Copy of the Gene Variant Delays Early-Onset Alzheimer’s.
Researchers examined genetic data from 1,077 members of the Paisa-mutant Colombian family. They found that 27 family members had one copy of the Christchurch variant and one copy of the Paisa mutation. On average, these family members did not display evidence of cognitive impairment before age 52, whereas those who did not inherit the Christchurch variant developed symptoms at age 47.
Researchers also found that family members with at least one copy of the Christchurch variant developed dementia four years later than those who did not inherit the variant.
The findings were encouraging for the researchers since they indicate the possibility of postponing cognitive decline and dementia in older people.
Yakeel T. Quiroz, PhD, a clinical neuropsychologist and neuroimaging researcher at Massachusetts General Hospital and the study’s first co-author, stated they must use this new knowledge to build effective dementia prevention treatments. He was excited about the results as a neuroscientist because they highlight the intricate connection between APOE and a deterministic mutation that causes Alzheimer’s disease, possibly opening the door for novel therapeutic strategies that target APOE-related pathways [7].
What’s Next?
As a next step, the researchers are concentrating on deepening their knowledge of brain resilience in the surviving family members who have one copy of the Christchurch variant. It includes performing structural and functional MRI scans, cognitive evaluations, and analyzing blood samples to determine protein and biomarker profiles.
Quiroz added that the continuous commitment to research demonstrated by their Colombian patients with autosomal dominant Alzheimer’s and their families was critical in enabling this study and allowing them to continue working toward treatments for this devastating disease.
Alzheimer’s Research Association is a non-profit organization dedicated to helping caregivers of Alzheimer’s disease and dementia. We provide the latest information and news about the illness and helpful tips to help caregivers cope with their daily caregiving challenges. We realize the most important thing that a caregiver needs is financial assistance. Therefore, we provide grants to caregivers to ease their financial burden. Caregivers can apply for grants here: Alzheimer’s Grant Application.
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References
- Dai, M.H., Zheng, H., Zeng, L.D. and Zhang, Y., 2018. The genes associated with early-onset Alzheimer’s disease. Oncotarget, 9(19), p.15132.
- Quiroz, Y.T., Aguillon, D., Aguirre-Acevedo, D.C., Vasquez, D., Zuluaga, Y., Baena, A.Y., Madrigal, L., Hincapié, L., Sanchez, J.S., Langella, S. and Posada-Duque, R., 2024. APOE3 Christchurch Heterozygosity and Autosomal Dominant Alzheimer’s Disease. New England Journal of Medicine, 390(23), pp.2156-2164.
- Fuller, J.T., Cronin-Golomb, A., Gatchel, J.R., Norton, D.J., Guzmán-Vélez, E., Jacobs, H.I., Hanseeuw, B., Pardilla-Delgado, E., Artola, A., Baena, A. and Bocanegra, Y., 2019. Biological and cognitive markers of presenilin1 E280A autosomal dominant Alzheimer’s disease: A comprehensive review of the Colombian kindred. The journal of prevention of Alzheimer’s disease, 6, pp.112-120.
- Xiao, B., Kuruvilla, J. and Tan, E.K., 2024. Resilience conferred by APOE-R136S: a defense bestowed by nature to combat Alzheimer’s disease. Signal Transduction and Targeted Therapy, 9(1), p.52.
- Arboleda-Velasquez, J.F., Lopera, F., O’Hare, M., Delgado-Tirado, S., Marino, C., Chmielewska, N., Saez-Torres, K.L., Amarnani, D., Schultz, A.P., Sperling, R.A. and Leyton-Cifuentes, D., 2019. Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report. Nature medicine, 25(11), pp.1680-1683.
- Chen, Y., Song, S., Parhizkar, S., Lord, J., Zhu, Y., Strickland, M.R., Wang, C., Park, J., Tabor, G.T., Jiang, H. and Li, K., 2024. APOE3ch alters microglial response and suppresses Aβ-induced tau seeding and spread. Cell, 187(2), pp.428-445.
- A genetic trait may help delay early onset Alzheimer’s. Medical News Today. https://www.medicalnewstoday.com/articles/could-a-genetic-trait-delay-alzheimers. Published Online: 25th June. 2024. Accessed: 12th July, 2024.
- Alltucker, K. Could a genetic trait delay Alzheimer’s?. USA Today. https://www.usatoday.com/story/news/health/2024/06/19/alzheimers-gene-discovery-delays-disease-study/74125939007/. Published Online: 20th June, 2024. Accessed: 12th July, 2024.
