Late-Onset Alzheimer's Disease Genetic Variants in Posterior Cortical Atrophy and Posterior AD
Minerva M. Carrasquillo, Ph.D.1, Qurat ul Ain Khan, M.D.2, Melissa E. Murray, Ph.D.1, Siddharth Krishnan1, Jeremiah Aakre3, V. Shane Pankratz, Ph.D.3, Thuy Nguyen1, Li Ma1, Gina Bisceglio1, Ronald C. Petersen, M.D., Ph.D.4, Steven G. Younkin, M.D., Ph.D.1, Dennis W. Dickson, M.D.1, Bradley F. Boeve, M.D.4, Neill R. Graff-Radford, M.D.2, Nilüfer Ertekin-Taner, M.D., Ph.D.1,2*
1)Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL32224, USA.
2)Department of Neurology, Mayo Clinic Florida, Jacksonville, FL32224, USA.
3)Department of Biostatistics, Mayo Clinic Minnesota, Rochester, MN 555905, USA.
4)Department of Neurology, Mayo Clinic Minnesota, Rochester, MN55905, USA.
Appendix e-1 Introduction:
In an investigation of 40 subjects with posterior cortical atrophy (PCA), 9 of whom had autopsies, 7 had AD pathology and the other two had corticobasal degeneration1. In a clinicopathologic study of 100 consecutive cases with focal cortical syndromes2 7 patients had clinical PCA, all of whom had AD pathology. In the largest neuropathologic series of PCA to date3, AD pathology was reported in 16 out of 21 subjects. The remaining 24% of subjects in this study had Lewy body disease plus progressive subcortical gliosis of Neumann (n=1), corticobasal degeneration (n=2), Creutzfeldt-Jakob disease (n=1) and fatal familial insomnia (n=1).
In a comparison of 9 patients with clinical PCA vs. 9 with typical AD and 10 healthy elderly controls4, identical patterns of CSF amyloid ß (Aß) and tau, as well as 11C-PIB-PET amyloid binding were detected in PCA and AD subjects. In a study of 22 patients with clinical PCA in comparison to 160 subjects with AD and 138 patients with other dementias5 (dementia with Lewy bodies=DLB and frontotemporal dementia=FTD), 20 out of 22 PCA patients had CSF Aβ and/or tau levels consistent with an AD profile. The remaining two patients had clinical features compatible with corticobasal syndrome (CBS) in addition to PCA. Diffuse 11C-PIB-PET amyloid binding in 12 PCA patients had no regional differences in comparison to 14 AD subjects6. Despite the similarity in amyloid deposition, patients with PCA showed greater glucose hypometabolism in posterior cortical regions (inferior occipitotemporal cortex) compared to those with AD and 30 elderly cognitively normal controls, highlighting the dissociation between fibrillar amyloidosis and neurodegeneration in the clinically relevant areas in PCA. Nevertheless, a more detailed study by the same group determined higher amyloid imaging in the visual processing related regions, consistent with some neuropathologic studies that detected higher amyloid plaque counts and neurofibrillary tangles in posterior cortical areas, but contrasted with others that identified higher tangles but not plaques in these regions (reviewed7).
One genetic study of <30 PCA patients determined that APOE4 and tau haplotype frequencies in PCA are similar to those published for AD1. In contrast, in a study including 24 PCA patients in a mixed cohort of 523 subjects with typical AD, mild cognitive impairment (MCI) or focal cortical AD syndromes8, significantly lower APOE4 frequency was detected in PCA in comparison to subjects with amnestic presentation.
Appendix e-1 Results:
Observed and expected genotype counts of all 11 SNPs in the combined case-control cohort are shown in Supplementary Table e-1. The only Hardy-Weinberg disequilibrium was observed for the ABCA7 locus SNP rs3764650 in the combined cases.
We compared the effect sizes of the variants with nominal significance in the combined cases to the ORs estimated for LOAD subjects in our cohort and determined that they were not statistically different, except for BIN1, which has a stronger risk effect in PCA (OR=1.42, 95% CI=1.03-1.96) compared to estimates in our LOAD subjects (OR=1.05, 95%CI=0.91-1.21). Our power calculations based on known OR estimates from LOAD studies and minor allele frequencies in control subjects revealed the smallest effect sizes that would be detectable in our relatively modest combined sample size of 135 subjects (Table e-2). As would be predicted from these calculations, only APOE4 and CLU rs11136000 SNPs can be detected in this sample, and APOE2 and BIN1 rs744373 are slightly below 80% power for detection.
Supplemental References:
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