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. 2011 Dec;32(12):2113-22.
doi: 10.1016/j.neurobiolaging.2010.01.010. Epub 2010 May 7.

Alzheimer disease pathology in cognitively healthy elderly: a genome-wide study

Patricia L Kramer  1 , Haiyan Xu, Randall L Woltjer, Shawn K Westaway, David Clark, Deniz Erten-Lyons, Jeffrey A Kaye, Kathleen A Welsh-Bohmer, Juan C Troncoso, William R Markesbery, Ronald C Petersen, R Scott Turner, Walter A Kukull, David A Bennett, Douglas Galasko, John C Morris, Jurg Ott
Affiliations

Alzheimer disease pathology in cognitively healthy elderly: a genome-wide study

Patricia L Kramer et al. Neurobiol Aging. 2011 Dec.

Abstract

Many elderly individuals remain dementia-free throughout their life. However, some of these individuals exhibit Alzheimer disease neuropathology on autopsy, evidenced by neurofibrillary tangles (NFTs) in AD-specific brain regions. We conducted a genome-wide association study to identify genetic mechanisms that distinguish non-demented elderly with a heavy NFT burden from those with a low NFT burden. The study included 299 non-demented subjects with autopsy (185 subjects with low and 114 with high NFT levels). Both a genotype test, using logistic regression, and an allele test provided consistent evidence that variants in the RELN gene are associated with neuropathology in the context of cognitive health. Immunohistochemical data for reelin expression in AD-related brain regions added support for these findings. Reelin signaling pathways modulate phosphorylation of tau, the major component of NFTs, either directly or through β-amyloid pathways that influence tau phosphorylation. Our findings suggest that up-regulation of reelin may be a compensatory response to tau-related or beta-amyloid stress associated with AD even prior to the onset of dementia.

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Figures

Figure 1
Figure 1
Q-Q plot based on nominal p-values resulting from the allelic association test
Figure 2
Figure 2
Manhattan plot showing the distribution of analyzed SNPs and their corresponding genotypic association p-values from logistic regression. The SNPs are ordered by their positions on the chromosomes, and the chromosomes (number 1 to 22 from left to right) are alternately colored. The y axis is –log10(p-value).
Figure 3
Figure 3
Reelin expression in hippocampal pyramidal neurons. Hippocampal immunohistochemistry was performed on paraffin sections of hippocampus and representative pyramidal neurons from the CA2 region are depicted in AD (upper panel) and in non-demented subjects (lower panel). Strong cytoplasmic staining was noted in pyramidal neurons in AD, especially in regions in which significant granulovacuolar degeneration (GVD) was noted. Neuritic plaques and neurofibrillary tangles (NFTs) did not stain strongly for reelin. Cytoplasmic expression of reelin in pyramidal neurons was also present in non-demented subjects with HI Braak stages as defined in the text (lower right panel), similar to that observed in AD. Expression of reelin in LO Braak stages was less conspicuous (lower left panel).
Figure 4
Figure 4
Analysis of reelin expression in hippocampus. Immunohistochemical (IHC) expression of reelin was scored in the hippocampus of OHSU cases with postmortem interval less than 24 hours. Scores are the sum of semiquantitative assessments of cytoplasmic reelin positivity of pyramidal neurons in each sector as described in the text. Cases were stratified by Braak grouping and by genotype. Two-way ANOVA showed a significant association of reelin expression with HI vs. LO Braak stage (P=0.025) but no association with genotype.
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References

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WEB References

    1. Plink, http://pngu.mgh.harvard.edu/~purcell/plink/
    1. R, http://cran.cnr.berkeley.edu/web/packages/qvalue/index.html.
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