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- Seto, Mabel, et al.
(författare)
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Exploring common genetic contributors to neuroprotection from amyloid pathology.
- 2022
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Ingår i: Brain communications. - : Oxford University Press (OUP). - 2632-1297. ; 4:2
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Tidskriftsartikel (refereegranskat)abstract
- Preclinical Alzheimer's disease describes some individuals who harbour Alzheimer's pathologies but are asymptomatic. For this study, we hypothesized that genetic variation may help protect some individuals from Alzheimer's-related neurodegeneration. We therefore conducted a genome-wide association study using 5891064 common variants to assess whether genetic variation modifies the association between baseline beta-amyloid, as measured by both cerebrospinal fluid and positron emission tomography, and neurodegeneration defined using MRI measures of hippocampal volume. We combined and jointly analysed genotype, biomarker and neuroimaging data from non-Hispanic white individuals who were enrolled in four longitudinal ageing studies (n=1065). Using regression models, we examined the interaction between common genetic variants (Minor Allele Frequency >0.01), including APOE-ɛ4 and APOE-ɛ2, and baseline cerebrospinal levels of amyloid (CSF Aβ42) on baseline hippocampal volume and the longitudinal rate of hippocampal atrophy. For targeted replication of top findings, we analysed an independent dataset (n=808) where amyloid burden was assessed by Pittsburgh Compound B ([11C]-PiB) positron emission tomography. In this study, we found that APOE-ɛ4 modified the association between baseline CSF Aβ42 and hippocampal volume such that APOE-ɛ4 carriers showed more rapid atrophy, particularly in the presence of enhanced amyloidosis. We also identified a novel locus on chromosome 3 that interacted with baseline CSF Aβ42. Minor allele carriers of rs62263260, an expression quantitative trait locus for the SEMA5B gene (P=1.46×10-8; 3:122675327) had more rapid neurodegeneration when amyloid burden was high and slower neurodegeneration when amyloid was low. The rs62263260×amyloid interaction on longitudinal change in hippocampal volume was replicated in an independent dataset (P=0.0112) where amyloid burden was assessed by positron emission tomography. In addition to supporting the established interaction between APOE and amyloid on neurodegeneration, our study identifies a novel locus that modifies the association between beta-amyloid and hippocampal atrophy. Annotation results may implicate SEMA5B, a gene involved in synaptic pruning and axonal guidance, as a high-quality candidate for functional confirmation and future mechanistic analysis.
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| 2. |
- Winfree, Rebecca L., et al.
(författare)
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Variants in the MS4A cluster interact with soluble TREM2 expression on biomarkers of neuropathology
- 2024
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Ingår i: MOLECULAR NEURODEGENERATION. - 1750-1326. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- Recent evidence suggests that Alzheimer's disease (AD) genetic risk variants (rs1582763 and rs6591561) of the MS4A locus are genome-wide significant regulators of soluble TREM2 levels such that the minor allele of the protective variant (rs1582763) is associated with higher sTREM2 and lower AD risk while the minor allele of (rs6591561) relates to lower sTREM2 and higher AD risk. Our group previously found that higher sTREM2 relates to higher A beta(40), worse blood-brain barrier (BBB) integrity (measured with the CSF/plasma albumin ratio), and higher CSF tau, suggesting strong associations with amyloid abundance and both BBB and neurodegeneration complicate interpretation. We expand on this work by leveraging these common variants as genetic tools to tune the interpretation of high CSF sTREM2, and by exploring the potential modifying role of these variants on the well-established associations between CSF sTREM2 as well as TREM2 transcript levels in the brain with AD neuropathology. Biomarker analyses leveraged data from the Vanderbilt Memory & Aging Project (n = 127, age = 72 +/- 6.43) and were replicated in the Alzheimer's Disease Neuroimaging Initiative (n = 399, age = 73 +/- 7.39). Autopsy analyses were performed leveraging data from the Religious Orders Study and Rush Memory and Aging Project (n = 577, age = 89 +/- 6.46). We found that the protective variant rs1582763 attenuated the association between CSF sTREM2 and A beta(40) (beta = -0.44, p-value = 0.017) and replicated this interaction in ADNI (beta = -0.27, p = 0.017). We did not observe this same interaction effect between TREM2 mRNA levels and A beta peptides in brain (A beta total beta = -0.14, p = 0.629; A beta(1-38), beta = 0.11, p = 0.200). In contrast to the effects on A beta, the minor allele of this same variant seemed to enhance the association with blood-brain barrier dysfunction (beta = 7.0e-4, p = 0.009), suggesting that elevated sTREM2 may carry a much different interpretation in carriers vs. non-carriers of this allele. When evaluating the risk variant (rs6591561) across datasets, we did not observe a statistically significant interaction against any outcome in VMAP and observed opposing directions of associations in ADNI and ROS/MAP on A beta levels. Together, our results suggest that the protective effect of rs1582763 may act by decoupling the associations between sTREM2 and amyloid abundance, providing important mechanistic insight into sTREM2 changes and highlighting the need to incorporate genetic context into the analysis of sTREM2 levels, particularly if leveraged as a clinical biomarker of disease in the future.
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