Genes implicated in late-onset Alzheimer's disease

11 new genetic susceptibility factors for Alzheimer’s identified

The largest international study ever conducted on Alzheimer's disease (I-GAP) has identified 11 new genetic regions that increase the risk of late-onset Alzheimer’s, plus 13 other genes yet to be validated. Genetic data came from 74,076 patients and controls from 15 countries.

Eleven genes for Alzheimer's disease have previously been identified.

Some of the newly associated genes confirm biological pathways already known to be involved, including the amyloid (SORL1, CASS4 ) and tau (CASS4 , FERMT2 ) pathways. The role of the immune response and inflammation (HLA-DRB5/DRB1 , INPP5D , MEF2C ) already implied by previous work (CR1, TREM2) is reinforced, as are the importance of cell migration (PTK2B), lipid transport and endocytosis (SORL1 ). New hypotheses have also emerged related to hippocampal synaptic function (MEF2C , PTK2B), the cytoskeleton and axonal transport (CELF1 , NME8, CASS4) as well as myeloid and microglial cell functions (INPP5D).

All this reinforces the idea that there are several paths to Alzheimer's, and no single treatment approach is likely to be successful.

http://www.eurekalert.org/pub_releases/2013-10/bumc-eng102513.php

[3586] Lambert J-C, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, Jun G, DeStefano AL, Bis JC, Beecham GW, et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nature Genetics [Internet]. 2013 ;45(12):1452 - 1458. Available from: http://www.nature.com/ng/journal/v45/n12/full/ng.2802.html

ADAM10 mutations increase risk of Alzheimer's

Mouse studies have found that two mutations in a gene called ADAM10 (which codes for an enzyme involved in processing the amyloid precursor protein) impaired the folding of the gene, resulting in an increase in toxic amyloid-beta, and reduced neurogenesis in the hippocampus. Previous research had found that either of these mutations was associated with an increased risk of Alzheimer’s in seven families with the late-onset form of the disease.

The finding suggests that increasing ADAM10 activity might be a potential therapeutic approach.

http://www.eurekalert.org/pub_releases/2013-09/mgh-sct092413.php

[3610] Suh J, Choi SH, Romano DM, Gannon MA, Lesinski AN, Kim DY, Tanzi RE. ADAM10 Missense Mutations Potentiate β-Amyloid Accumulation by Impairing Prodomain Chaperone Function. Neuron [Internet]. 2013 ;80(2):385 - 401. Available from: http://www.cell.com/article/S0896627313007940/abstract

TREM2 gene variant has dramatic effect on brain atrophy

Back in January 2013, a study (initially involving 2261 Icelanders, but then repeated on data from the U.S., Norway, the Netherlands, and Germany) reported on a rare genetic variant (TREM2) that nearly trebled Alzheimer’s risk. The variant was found in 0.46% of controls aged 85+. Carriers (aged 85-100) without Alzheimer’s also had poorer cognitive function than non-carriers.

TREM2 is thought to have an anti-inflammatory role, and so it’s thought that this rare mutation reduces its effectiveness.

In a more recent study, brain scans of 478 older adults (average age 76), of whom 100 had Alzheimer's, 221 had MCI and 157 were healthy controls, found that those carrying the TREM2 mutation lost 1.4-3.3% more of their brain tissue than non-carriers, and twice as fast. The loss appeared to be concentrated in the temporal lobe and hippocampus. Those carrying the TREM2 mutation may develop the disease three years earlier than expected.

http://www.eurekalert.org/pub_releases/2013-10/uosc-gml101513.php

[3581] Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, Bjornsson S, Huttenlocher J, Levey AI, Lah JJ, et al. Variant of TREM2 Associated with the Risk of Alzheimer's Disease. New England Journal of Medicine [Internet]. 2013 ;368(2):107 - 116. Available from: http://www.nejm.org/doi/full/10.1056/NEJMoa1211103

Rajagopalan, P., Hibar, D.P., & Thompson, P.M. (2013). TREM2 and neurodegenerative disease. The New England Journal of Medicine, 369(16), 1564-1567. Published online Oct. 16, 2013; doi:10.1056/NEJMc1306509

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