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O5‐01‐05: Longevity Gene KLOTHO Alters APOE4 ‐Related Cortical Thinning: Findings from the Wisconsin Registry for Alzheimer’s Prevention
Author(s) -
Schultz Stephanie A.,
Boots Elizabeth A.,
Oh Jennifer M.,
Darst Burcu F.,
Koscik Rebecca L.,
Gallagher Catherine L.,
Carlsson Cynthia M.,
Rowley Howard A.,
Bendlin Barbara B.,
Asthana Sanjay,
Sager Mark A.,
Hogan Kirk J.,
Hermann Bruce P.,
Engelman Corinne D.,
Johnson Sterling C.,
Dubal Dena B.,
Okonkwo Ozioma C.
Publication year - 2016
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2016.06.708
Subject(s) - heterozygote advantage , klotho , apolipoprotein e , entorhinal cortex , allele , alzheimer's disease neuroimaging initiative , medicine , dementia , endocrinology , psychology , oncology , biology , disease , hippocampal formation , genetics , gene , kidney
whole cerebellum and pons, respectively, yielding SUVR values. We ran step-wise linear regressions with amyloid SUVR as the outcome variable and 27 AD risk variants discovered and validated in GWAS studies as predictors while controlling for age, gender, and APOE4 status in the pooled sample and in each diagnostic group in SAS. We reproduced the final step-wise regression model using voxel-wise whole brain analysis in SPM8 with cluster and significance thresholds at 50 voxels and uncorrected p<0.01. The SPM8 regression analyses were repeated using FDG PET and MRI data. Results:The Table lists the demographic characteristics and % minor allele carriers for variants that showed significant associations with mean SUVR in our sample. The major genetic effects on each of the three imaging modalities can be seen in Figure. ABCA7 rs3752246 showed associations with brain amyloidosis across all disease stages while CLU showed an effect in the pooled sample only. The association of ABCA7 rs3764650, FERMT2, EPHA1 and SORL1 were driven by the MCI group. ZCWPW1 showed significant associations with amyloid burden in NC only. The effect of MEF2C and DSG2 were restricted to the AD stage. Some of these genes showed even stronger associations with neurodegeneration ABCA7 rs3764650, CLU, MEF2C with brain atrophy; and EPHA1rs177145 and MEF2C with brain metabolismsuggesting a primary effect on neurodegeneration. Conclusions: Our analyses suggest that the genetic influences on AD pathology are complex. Even though candidate genes were selected based on their association with brain amyloidosis, some showed even stronger effects on neurodegeneration. Importantly our data also suggest that AD biomarkers might differentially regulate across the disease stages.