Whole-genome sequencing suggests a chemokine gene cluster that modifies age at onset in familial Alzheimer's disease

Abstract

We have sequenced the complete genomes of 72 individuals affected with early-onset familial Alzheimer's disease caused by an autosomal dominant, highly penetrant mutation in the presenilin-1 (PSEN1) gene, and performed genome-wide association testing to identify variants that modify age at onset (AAO) of Alzheimer's disease. Our analysis identified a haplotype of single-nucleotide polymorphisms (SNPs) on chromosome 17 within a chemokine gene cluster associated with delayed onset of mild-cognitive impairment and dementia. Individuals carrying this haplotype had a mean AAO of mild-cognitive impairment at 51.0±5.2 years compared with 41.1±7.4 years for those without these SNPs. This haplotype thus appears to modify Alzheimer's AAO, conferring a large (~10 years) protective effect. The associated locus harbors several chemokines including eotaxin-1 encoded by CCL11, and the haplotype includes a missense polymorphism in this gene. Validating this association, we found plasma eotaxin-1 levels were correlated with disease AAO in an independent cohort from the University of California San Francisco Memory and Aging Center. In this second cohort, the associated haplotype disrupted the typical age-associated increase of eotaxin-1 levels, suggesting a complex regulatory role for this haplotype in the general population. Altogether, these results suggest eotaxin-1 as a novel modifier of Alzheimer's disease AAO and open potential avenues for therapy.

Molecular genetics of early‐onset Alzheimer's disease revisited

“…The role of rare variants in EOAD has been less investigated nonetheless a few examples are available like the rare protective variant detected in APP [51] and the variant in CCL11 (eotaxin-1) [74]. This last example is of particular relevance, as it demonstrated an involvement of the immune pathway in modulating the disease onset in presence of a highly penetrant mutation in PSEN1.…”

“…Genome-wide searches in the Volga German families (PSEN2 p.N141I) identified at least three additional genetic loci (1q23.3, 17p13.2, and 7q33) [91], which could harbor modifier genes. Furthermore, a whole genome-sequencing approach of a large Colombian kindred (PSEN1 p.E280A), detected a protective variant (p.A23T, rs1129844) in the gene CCL11 encoding eotaxin-1 that delayed onset age of AD by a decade [74]. Autosomal dominant families, segregating mutations in one of the 3 causal EOAD genes, show often variability in clinical presentation, even in the presence of the same mutation.…”

Ageing, neurodegeneration and brain rejuvenation

“…A role for inflammatory factors in autosomal dominant forms of neurodegeneration was suggested by the observation that numerous SNPs in the chemokine cluster that contains the gene CCL11 were linked to a 10-year difference in the age of onset of clinical AD symptoms in 72 people carrying a highly penetrant presenilin 1 mutation 61 . Indeed, inflammation has long been associated with neurodegeneration 62, 63 , and the use of non-steroidal anti-inflammatory drugs for several years before the onset of clinical symptoms is associated with a reduced risk of AD 64-66 .…”

Clinical, imaging, pathological, and biochemical characterization of a novel presenilin 1 mutation (N135Y) causing Alzheimer's disease

“…The cases we identified developed AD in their 30s–40s associated with spasticity, hippocampal hyperexcitability, and epileptiform discharges. Differences in age at onset of 10 years among individuals with the same mutation are not common, but do occur (Ryman et al, 2014), and may result from the contribution of other genes to overall dementia risk (Lalli et al, 2015). Due to the limited pedigree and the proband's co-morbidities, it is not possible to say with certainty which of her clinical and imaging features are due to a direct effect of the mutation.…”