Effect of CLU genetic variants on cerebrospinal fluid and neuroimaging markers in healthy, mild cognitive impairment and Alzheimer's disease cohorts.

The Clusterin (CLU) gene, also known as apolipoprotein J (ApoJ), is currently the third most associated late-onset Alzheimer's disease (LOAD) risk gene. However, little was known about the possible effect of CLU genetic variants on AD pathology in brain. Here, we evaluated the interaction between 7 CLU SNPs (covering 95% of genetic variations) and the role of CLU in ß-amyloid (Aß) deposition, AD-related structure atrophy, abnormal glucose metabolism on neuroimaging and CSF markers to clarify the possible approach by that CLU impacts AD. Finally, four loci (rs11136000, rs1532278, rs2279590, rs7982) showed significant associations with the Aß deposition at the baseline level while genotypes of rs9331888 (P = 0.042) increased Aß deposition. Besides, rs9331888 was significantly associated with baseline volume of left hippocampus (P = 0.014). We then further validated the association with Aß deposition in the AD, mild cognitive impairment (MCI), normal control (NC) sub-groups. The results in sub-groups confirmed the association between CLU genotypes and Aß deposition further. Our findings revealed that CLU genotypes could probably modulate the cerebral the Aß loads on imaging and volume of hippocampus. These findings raise the possibility that the biological effects of CLU may be relatively confined to neuroimaging trait and hence may offer clues to AD.

Impact of SORL1 genetic variations on MRI markers in non-demented elders.

The sorting protein-related receptor 1 (SORL1 or LR11) gene has been verified to play an important role in the pathologic process of ß-amyloid (Aß) formation and trafficking in Alzheimer's Disease (AD) by plenty of cytological and molecular biological studies. But there were few studies investigated the association of SORL1 gene and neurodegeneration features from a rather macroscopic perspective. In the present study, we explored the effect of SORL1 genotypes on AD-related brain atrophy. We recruited 812 individuals with both baseline and two-year follow-up information from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database and applied multiple linear regression models to examine the association between eight single nucleotide polymorphisms (SNPs) and neuroimaging phenotypes. Finally, four SNPs (rs11219350, rs2298813, rs3781836, rs3824968) showed trend of association with the volume of hippocampus and parahippocampal gyrus but failed to survive the false discovery rate (FDR) correction. Only rs1784933 and rs753780 showed significant association with right parahippocampal gyrus. According to our findings, SORL1 variations influence the atrophy of specific AD-related brain structures, which suggested the potential role of SORL1 in the neurodegeneration of cognitive related regions.

The impact of PICALM genetic variations on reserve capacity of posterior cingulate in AD continuum.

Phosphatidylinositolbinding clathrin assembly protein (PICALM) gene is one novel genetic player associated with late-onset Alzheimer's disease (LOAD), based on recent genome wide association studies (GWAS). However, how it affects AD occurrence is still unknown. Brain reserve hypothesis highlights the tolerant capacities of brain as a passive means to fight against neurodegenerations. Here, we took the baseline volume and/or thickness of LOAD-associated brain regions as proxies of brain reserve capacities and investigated whether PICALM genetic variations can influence the baseline reserve capacities and the longitudinal atrophy rate of these specific regions using data from Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. In mixed population, we found that brain region significantly affected by PICALM genetic variations was majorly restricted to posterior cingulate. In sub-population analysis, we found that one PICALM variation (C allele of rs642949) was associated with larger baseline thickness of posterior cingulate in health. We found seven variations in health and two variations (rs543293 and rs592297) in individuals with mild cognitive impairment were associated with slower atrophy rate of posterior cingulate. Our study provided preliminary evidences supporting that PICALM variations render protections by facilitating reserve capacities of posterior cingulate in non-demented elderly.

The Impact of UNC5C Genetic Variations on Neuroimaging in Alzheimer's Disease.

UNC5C, which is a transmembrane receptor for netrin-1 to trigger the apoptosis, has been confirmed as a new risk factor for Alzheimer's disease (AD) recently. However, there is lack of the evidence on the brain structure associated with the polymorphisms of UNC5C in AD. The objective of this study is to investigate the influence of UNC5C loci on the neuroimaging of strategic regions of AD. In 812 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset, we explored the genotypes of UNC5C loci in the volumes of the hippocampus, parahippocampal gyrus, posterior cingulate gyrus, middle temporal and precuneus, and the thickness of the entorhinal cortex which are measured by magnetic resonance imaging (MRI). We also investigated the atrophy rate of above structures influenced by UNC5C loci using the longitudinal data. UNC5C loci were associated with the volume of right middle temporal (rs34585936 Pc = 0.0031). Meanwhile, the polymorphisms of UNC5C loci could alter the atrophy rate of strategic regions especially the left hippocampus (rs72672784 Pc = 0.0090; rs13120458 Pc = 0.0434; rs34875919 Pc = 0.0434) and right precuneus (rs72672784 Pc = 0.0068; rs2001246 Pc = 0.0055; rs74690179 Pc = 0.0055). UNC5C genotypes were significantly associated with the volume of the middle temporal on MRI; meanwhile, UNC5C loci could alter the atrophy of strategic regions of AD such as the hippocampus and precuneus. And the above effects of polymorphisms of UNC5C were more obvious in the population with the impaired cognition than those with the normal cognition.

Common Variants in PLD3 and Correlation to Amyloid-Related Phenotypes in Alzheimer's Disease.

The phospholipase D3 (PLD3) gene has shown association with Alzheimer's disease (AD). However, the role of PLD3 common variants in amyloid-ß (Aß) pathology remains unclear. We examined the association of thirteen common single nucleotide polymorphisms (SNPs) with cerebrospinal fluid (CSF) Aß(1- 42) levels and florbetapir retention on florbetapir 18F amyloid positron emission tomography (AV45-PET) in a large population. We found that one SNP (rs11667768) was significantly associated with CSF Aß(1- 42) levels in the normal cognition group. We did not observe an association of any SNP with florbetapir retention. Our study predicted the potential role of PLD3 variants in Aß pathology.