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.
Association of a novel locus on chromosome 17 modifying Alzheimer’s AAO
Association analysis revealed a cluster of single-nucleotide variants comprising a haplotype on chromosome 17 approaching genome-wide significance for association with AAO of MCI (best P-value 6.43E−08). This P-value is genome-wide significant at the empirical threshold for European populations29 and was well supported by association of multiple variants in the region (Figure 1 and Supplementary Table 1). Adjusted for APOE status, the regression model identified the same peak at chromosome 17 and improved the best P to a genome-wide significant 4.85E−08. APOE ε4 was not significant in this model. Permutation testing empirically supported the chromosome 17 peak as the top associated locus in our study (P=1E−06, the lowest achievable P-value; Supplementary Table 2). The regression model using AAO of dementia as the trait of interest also indicated this same region as the top hit, although the overall P-value was increased as a result of the diminished sample size for this variable (Supplementary Table 3). The Mendel software program, accounting for relatedness among the samples, identified the same locus as the top associated region in this study and achieved genome-wide significance (P=2.86E−08; Supplementary Table 4). Remarkably, the effect size of this haplotype was almost 10 years of delayed onset in carriers. Average AAO of MCI in carriers of the protective haplotype was 51.0±5.2 years compared with non-carriers age at MCI 41.1±7 years (mean±s.d.) (Figure 2).
Examination of the regional association plot on chromosome 17 revealed that the associated haplotype spans several chemokines, including some proinflammatory factors reported to be elevated in AD (Figure 3).37 One chemokine subfamily, the monocyte chemoattractant proteins (MCPs), is implicated in neuronal death during sustained inflammation.38 Four major MCPs reside within the genomic neighborhood associated in this study—MCP1 encoded by the CCL2 gene, MCP2 encoded by CCL7 gene, MCP3 encoded by CCL8 gene and MCP4 encoded by CCL13gene. Two additional genes in this locus include CCL1, encoding a well-characterized proinflammatory chemokine,39 and CCL11, which encodes eotaxin-1, a chemokine whose serum and cerebrospinal fluid levels increase with age and correlate with reduced neurogenesis,40 making it a promising candidate for modifying Alzheimer’s AAO.