RESUMO
The precise physiologic function of many of the recently discovered Alzheimer's disease risk variants remains unknown. The downstream effects of genetic variants remain largely unexplored. We studied the relationship between the top 10 non-APOE genes with cortical and hippocampal atrophy as markers of neurodegeneration using 1.5T magnetic resonance imaging, 1-million single nucleotide polymorphism Illumina Human Omni-Quad array and Illumina Human BeadChip peripheral blood expression array data on 50 cognitively normal and 98 mild cognitive impairment subjects. After explicit matching of cortical and hippocampal morphology, we computed in 3D, the cortical thickness and hippocampal radial distance measures for each participant. Associations between the top 10 non-APOE genome-wide hits and neurodegeneration were explored using linear regression. Map-wise statistical significance was determined with permutations using threshold of p < 0.01. MS4A6A rs610932 and ABCA7 rs3764650 demonstrated significant associations with cortical and hippocampal atrophy. Exploratory MS4A6A and ABCA7 peripheral blood expression analyses revealed a similar pattern of associations with cortical neurodegeneration. To our knowledge, this is the first report of the effect of ABCA7 and MS4A6A on neurodegeneration.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Córtex Cerebral/patologia , Estudos de Associação Genética , Variação Genética/genética , Hipocampo/patologia , Proteínas de Membrana/genética , Transportadores de Cassetes de Ligação de ATP/sangue , Idoso , Idoso de 80 Anos ou mais , Apolipoproteínas E/genética , Atrofia/genética , Feminino , Humanos , Masculino , Proteínas de Membrana/sangue , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: We investigated the association between apoE protein plasma levels and brain amyloidosis and the effect of the top 10 Alzheimer disease (AD) risk genes on this association. METHODS: Our dataset consisted of 18 AD, 52 mild cognitive impairment, and 3 cognitively normal Alzheimer's Disease Neuroimaging Initiative 1 (ADNI1) participants with available [(11)C]-Pittsburgh compound B (PiB) and peripheral blood protein data. We used cortical pattern matching to study associations between plasma apoE and cortical PiB binding and the effect of carrier status for the top 10 AD risk genes. RESULTS: Low plasma apoE was significantly associated with high PiB SUVR, except in the sensorimotor and entorhinal cortex. For BIN1 rs744373, the association was observed only in minor allele carriers. For CD2AP rs9349407 and CR1 rs3818361, the association was preserved only in minor allele noncarriers. We did not find evidence for modulation by CLU, PICALM, ABCA7, BIN1, and MS4A6A. CONCLUSIONS: Our data show that BIN1 rs744373, CD2AP rs9349407, and CR1 rs3818361 genotypes modulate the association between apoE protein plasma levels and brain amyloidosis, implying a potential epigenetic/downstream interaction.
