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APOE E4 - not the whole story on Alzheimer's

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It has long been known that APOE E4, is associated with Alzheimer's, but there are always questions about what other factors might push one over into the actual disease. Amyloid plaque has been associated with Alzheimer's too - and E4 carriers have a higher rate of accumulation. But now it has been found that a variant in the IL1RAP gene was associated with greater amyloid plaque accumulation over two years and had an even stronger effect than the well-known APOE e4 allele which is notorious for its association with the development of Alzheimer’s disease.


The SNP identified was rs12053868 and the risk allele was G - conveniently, you can check 23andme for your variant (mine is AA). The paper (available as full text) is quite fascinating:


GWAS of longitudinal amyloid accumulation on 18F-florbetapir PET in Alzheimer’s disease implicates microglial activation gene IL1RAP


Vijay K Ramanan, Shannon L. Risacher, Kwangsik Nho, Sungeun Kim, Li Shen, Brenna C. McDonald, Karmen K. Yoder, Gary D.Hutchins, John D. West, Eileen F. Tallman, Sujuan Gao, Tatiana M. Foroud, Martin R. Farlow, Philip L. De Jager, David A. Bennett, Paul S. Aisen, Ronald C. Petersen, Clifford R. Jack Jr., Arthur W. Toga, Robert C. Green, William J. Jagust, Michael W. Weiner, Andrew J.Saykin,

First published online: 11 August 2015

Brain amyloid deposition is thought to be a seminal event in Alzheimer’s disease. To identify genes influencing Alzheimer’s disease pathogenesis, we performed a genome-wide association study of longitudinal change in brain amyloid burden measured by 18F-florbetapir PET. A novel association with higher rates of amyloid accumulation independent from APOE (apolipoprotein E) ε4 status was identified in IL1RAP (interleukin-1 receptor accessory protein; rs12053868-G; P = 1.38 × 10−9) and was validated by deep sequencing. IL1RAP rs12053868-G carriers were more likely to progress from mild cognitive impairment to Alzheimer’s disease and exhibited greater longitudinal temporal cortex atrophy on MRI. In independent cohorts rs12053868-G was associated with accelerated cognitive decline and lower cortical11C-PBR28 PET signal, a marker of microglial activation. These results suggest a crucial role of activated microglia in limiting amyloid accumulation and nominate the IL-1/IL1RAP pathway as a potential target for modulating this process.


What I found particularly interesting was the quote below:


"A genome-wide significant association was identified on chromosome 3 for rs12053868, an intronic SNP inIL1RAP (P = 1.38 × 10−9; Fig. 3A). The rs12053868-G allele was associated with higher rates of amyloid accumulation compared to the major (A) allele (Fig. 3B). A large effect size was observed in homozygous GG participants (Cohen’s d = 1.20) equivalent to an odds ratio of 8.79 (Borenstein, 2009). Using stepwise linear regression with forward selection, this SNP explained 7.1% of the phenotypic variance in addition to, and independent from, the 3.4% explained by APOE ε4 status (Supplementary Fig. 4). This association remained genome-wide significant (P = 5.80 × 10−9) after the inclusion of APOE ε4 status, baseline diagnosis, years of education, baseline cortical amyloid PET burden (modelled as described in the ‘Materials and methods’ section), and the first three principal components from population structure analysis. No significant interactions were identified between rs12053868 and any of these factors, or age or gender. The effect of the G allele on higher rates of amyloid accumulation was present in both amyloid-negative and amyloid-positive participants as classified by the baseline PET scan (Supplementary Fig. 5). Using voxel-wise analysis to further characterize the spatial effect of this SNP in the brain, we again observed an association of rs12053868-G with higher rates of amyloid accumulation, with significant clusters for this effect observed primarily in the bilateral frontal, medial, and lateral parietal, and lateral temporal lobes, as well as throughout the posterior and anterior cingulate cortex"


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