Isolating Genes That Delay Alzheimer’s Onset

Scientists have identified a network of nine genes that play a key role in the onset of Alzheimer’s Disease.

The finding could help scientists develop new treatments to delay the onset of the disease, said lead researcher Associate Professor Mauricio Arcos-Burgos from The Australian National University (ANU).

In a study of a family of 5,000 people in Columbia, scientists identified genes that delayed the disease, and others that accelerated it, and by how much.

“If you can work out how to decelerate the disease, then you can have a profound impact,” said Associate Professor Arcos-Burgos, a medical geneticist at The John Curtin School of Medical Research (JCSMR) at ANU.

“I think it will be more successful to delay the onset of the disease than to prevent it completely. Even if we delay the onset by on average one year, that will mean nine million fewer people have the disease in 2050.”

Alzheimer’s disease affects up to 35 million people around the world and is predicted to affect one in 85 people globally by 2050.

The Columbian family are afflicted by a type of hereditary Alzheimer’s. They are a unique resource in the fight against the disease because they are such a large, close-knit family and live in a specific region in the western mountains of Columbia.

The United States National Institute of Health has put $170 million towards developing treatments for Alzheimer’s, which will be tested amongst this family.

Associate Professor Arcos-Burgos and his team took a different approach, studying the variable age of onset of dementia in this family, rather than trying to treat symptoms which develop later in life, even though changes in the brain can be observed in individuals before the age of 20.

Drawing of a brain in orange on a background with blue dna strands.
The team was able to isolate the nine genes involved in Alzheimer’s, some of which delay the onset by up to 17 years, while others advance its progress. Image is for illustrative purposes only.

With the cooperation of the family, the team were able to discount environmental factors and trace their genetic predisposition to Alzheimer’s Disease back to a founder mutation in one individual who came to the region about 500 years ago.

The team was able to isolate the nine genes involved in Alzheimer’s, some of which delay the onset by up to 17 years, while others advance its progress.

Associate Professor Arcos-Burgos is now turning closer to home, to study the genes of a group of Queanbeyan people who have been followed for the past 10 years.

About this genetics and Alzheimer’s diseaseresearch

Source: Phil Dooley – Australian National University
Image Source: The image is in the public domain
Original Research: Full open access research for “APOE*E2 allele delays age of onset in PSEN1 E280A Alzheimer’s disease” by J I Vélez, F Lopera, D Sepulveda-Falla, H R Patel, A S Johar, A Chuah, C Tobón, D Rivera, A Villegas, Y Cai, K Peng, R Arkell, F X Castellanos, S J Andrews, M F Silva Lara, P K Creagh, S Easteal, J de Leon, M L Wong, J Licinio, C A Mastronardi and M Arcos-Burgos in Molecular Psychiatry. Published online December 1 2015 doi:10.1038/mp.2015.177


Abstract

APOE*E2 allele delays age of onset in PSEN1 E280A Alzheimer’s disease

Alzheimer’s disease (AD) age of onset (ADAOO) varies greatly between individuals, with unique causal mutations suggesting the role of modifying genetic and environmental interactions. We analyzed ~50 000 common and rare functional genomic variants from 71 individuals of the ‘Paisa’ pedigree, the world’s largest pedigree segregating a severe form of early-onset AD, who were affected carriers of the fully penetrant E280A mutation in the presenilin-1 (PSEN1) gene. Affected carriers with ages at the extremes of the ADAOO distribution (30s–70s age range), and linear mixed-effects models were used to build single-locus regression models outlining the ADAOO. We identified the rs7412 (APOE*E2 allele) as a whole exome-wide ADAOO modifier that delays ADAOO by ~12 years (β=11.74, 95% confidence interval (CI): 8.07–15.41, P=6.31 × 10−8, PFDR=2.48 × 10−3). Subsequently, to evaluate comprehensively the APOE (apolipoprotein E) haplotype variants (E1/E2/E3/E4), the markers rs7412 and rs429358 were genotyped in 93 AD affected carriers of the E280A mutation. We found that the APOE*E2 allele, and not APOE*E4, modifies ADAOO in carriers of the E280A mutation (β=8.24, 95% CI: 4.45–12.01, P=3.84 × 10−5). Exploratory linear mixed-effects multilocus analysis suggested that other functional variants harbored in genes involved in cell proliferation, protein degradation, apoptotic and immune dysregulation processes (i.e., GPR20, TRIM22, FCRL5, AOAH, PINLYP, IFI16, RC3H1 and DFNA5) might interact with the APOE*E2 allele. Interestingly, suggestive evidence as an ADAOO modifier was found for one of these variants (GPR20) in a set of patients with sporadic AD from the Paisa genetic isolate. This is the first study demonstrating that the APOE*E2 allele modifies the natural history of AD typified by the age of onset in E280A mutation carriers. To the best of our knowledge, this is the largest analyzed sample of patients with a unique mutation sharing uniform environment. Formal replication of our results in other populations and in other forms of AD will be crucial for prediction, follow-up and presumably developing new therapeutic strategies for patients either at risk or affected by AD.

“APOE*E2 allele delays age of onset in PSEN1 E280A Alzheimer’s disease” by J I Vélez, F Lopera, D Sepulveda-Falla, H R Patel, A S Johar, A Chuah, C Tobón, D Rivera, A Villegas, Y Cai, K Peng, R Arkell, F X Castellanos, S J Andrews, M F Silva Lara, P K Creagh, S Easteal, J de Leon, M L Wong, J Licinio, C A Mastronardi and M Arcos-Burgos in Molecular Psychiatry. Published online December 1 2015 doi:10.1038/mp.2015.177

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