Authors: Courtney Johnson
Genome-wide association testing, carried out by researchers at the University of California Santa Barbara (CA, USA), has identified a novel haplotype of single-nucleotide polymorphisms (SNPs) in a gene cluster believed to be linked to neuroinflammation. In individuals with early-onset Alzheimer’s, the haplotype was associated with a relatively delayed onset of Alzheimer’s disease (AD), retarding the age of onset (AOO) by up to 10 years. The findings were published recently in Molecular Psychiatry.
AD is currently ranked among the top ten causes of death in the world with the risk of disease development being amplified exponentially with age after 65. The AOO of AD is highly heritable and the genetic contribution is predicted to be up to 78% in sporadic late-onset AD and >90% in monogenic familial early-onset AD.
Researchers sequenced the entire genome of 72 individuals within a Colombian cohort of subjects with early-onset familial AD caused by a highly penetrant autosomal dominant mutation (E280A) in the PSEN1 gene. Amongst the cohort, a selection of individuals with a delayed AOO (51 ± 5.2 years vs 41.1 ± 7.4 years) were determined to have a specific haplotype, located on a chromosome 17 gene cluster. The gene cluster contained several chemokine genes, including CCL11, encoding the chemokine protein eotaxin-1.
Subjects with delayed AOO exhibited an A23T missense polymorphism in the CCL11 gene. Previous studies have indicated a role for increased levels of the chemokine protein eotaxin-1 – which accumulates with age – in heightening the risk of developing AD. The current study indicates that eotaxin-1 may also be a novel modulator of AAO.
These results were then reinforced via a collaborative study carried out at the University of California San Francisco (CA, USA), in which the blood eotaxin levels of subjects with either mild-cognitive impairment or dementia due to AD were measured and their DNA examined to determine if it contained the same genetic variant as the first cohort. The results of the second study corroborated those of the first, insomuch as those subjects observed to possess the CCL11 mutation had eotaxin levels that did not increase with age and also exhibited a modest delay in AD onset.
Given that neuroinflammation is considered a common feature in AD, the presence of such a genetic mutation affecting an inflammatory modifier within subjects of late-onset disease suggests a regulatory role of eotaxin-1 in AOO. As chemokines are linked to both neuroprotection and inflammation, the authors propose a complex hormesis response in which a low to moderate level of eotaxin-1 results in a protective effect against neurodegeneration while higher levels of the chemokine may lead to the deleterious effects of cognitive decline and memory impairment. The authors predict that this particular genetic variant is present in approximately one in four individuals in the general population.
“We have an important preliminary finding,” remarked Kenneth Kosik (University of California Santa Barbara Neuroscience Research Institute). “If this is a true mechanism of Alzheimer’s progression, then we can modify the level of eotaxin in individuals to treat the disease. But our results must be replicated and proved by other laboratories – and in larger populations.”
Sources: University of California – Santa Barbara press release; Lalli MA, Bettcher BM, Arcila ML et al. Whole-genome sequencing suggests a chemokine gene cluster that modifies age at onset in familial Alzheimer’s disease. Mol. Psychiatry doi:10.1038/mp.2015.131 (2015) (Epub ahead of print).