Hyun-Sik Yang, United States of America
Brigham and Women's Hospital NeurologyAuthor Of 3 Presentations
GENOME-WIDE ASSOCIATION STUDY IMPLICATES APOE, GRM8, AND TYPE I INTERFERON PATHWAY IN LIMBIC-PREDOMINANT AGE-RELATED TDP-43 ENCEPHALOPATHY PATHOGENESIS
Abstract
Aims
To elucidate the genetic architecture of limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC), a common TDP-43 proteinopathy that is frequently comorbid with Alzheimer’s disease (AD) and increases dementia risk.
Methods
We studied the Religious Orders Study and the Rush Memory and Aging Project participants of European ancestry with imputed genotypes and post-mortem TDP-43 immunohistochemistry (n=1,180). TDP-43, amyloid-β (Aβ), and paired helical filament tau (PHFtau) were quantified using immunohistochemistry. LATE-NC burden was defined as a semi-quantitative six-point scale of TDP-43 burden averaged across six brain regions including amygdala, hippocampus, and neocortex. Genome-wide association study (GWAS) was performed using linear additive models controlling for age, sex, genotyping platform, and first three principal components from the genotype covariance matrix.
Results
Two distinct loci reached genome-wide significance in their association with higher LATE-NC burden: rs429358C, an allele defining the APOE ε4 haplotype (beta=0.46, p=1.2×10-12); rs17608393A within GRM8 (beta=0.68, p=4.5×10-8). There were 10 additional loci that reached pre-defined suggestive significance (p<10-6). A suggestive variant rs72701368G (beta=0.54, p=1.1×10-7) tagged a large haplotype spanning the interferon-alpha (IFNA) gene cluster, and another suggestive variant rs56902449A (beta=0.72, p=8.0×10-7) was a cis-eQTL increasing the expression of MX2, a gene encoding interferon-induced GTP-binding protein Mx2. After adjusting for Aβ and PHFtau, the association between APOE rs429358C and LATE-NC was partially attenuated (beta=0.28, p=2.6×10-5), while GRM8 and IFNA variants’ association with LATE-NC remained similar.
Conclusions
AD-related APOE locus and AD-independent GRM8 locus were associated with LATE-NC burden, and converging evidence also implicated type I interferon pathway that is regulated by TBK1 (a FTD/ALS risk gene).
LIVE DISCUSSION
DISSECTING THE COMPLEXITY OF ASTROCYTE HETEROGENEITY IN THE AGED HUMAN BRAIN
Abstract
Aims
Neuroinflammation plays a critical role in the pathophysiology of neurodegenerative disorders, and astrocyte activity impairment has been implicated in the initiation and progression of Alzheimer’s Disease (AD). However, understanding the astrocyte heterogeneity in the aged human brain and identifying the subtypes relevant to AD remain challenging due inter-individual variability. This study aims to characterize astrocyte heterogeneity among aged individuals with or without AD and investigate the association of astrocyte subtypes with AD traits at RNA and protein levels.
Methods
We used single nucleus RNASeq (snRNAseq) to characterize subtypes of astrocytes in the dorsolateral prefrontal cortex of 24 aged individuals with or without AD from the Religious Orders Study and the Rush Memory and Aging Project cohorts. Then, a marker for each cluster was selected and stained by immunohistochemistry on post-mortem brain tissue from the same 24 individuals.
Results
We identified five different astrocyte subtypes that we classified in four categories: homeostatic, reactive, fibrous-like and inflammatory. The snRNAseq data revealed an association between increased fibrous-like astrocytes and cognitive decline, especially in individuals with AD pathology. No significant association was detected between AD traits and other astrocytes subtypes. Both snRNAseq and immunohistochemistry demonstrated that not all astrocyte subtypes were detected in all 24 individuals. SOCS3, a marker for reactive-like astrocyte was only detected in few individuals at RNA and protein levels.
Conclusions
Fibrous-like astrocyte subtype was associated with cognitive decline in AD. Further, combined snRNAseq and immunohistochemistry demonstrated the complexity of astrocyte heterogeneity, that is driven by high inter-individual variability.
Presenter of 2 Presentations
LIVE DISCUSSION
GENOME-WIDE ASSOCIATION STUDY IMPLICATES APOE, GRM8, AND TYPE I INTERFERON PATHWAY IN LIMBIC-PREDOMINANT AGE-RELATED TDP-43 ENCEPHALOPATHY PATHOGENESIS
Abstract
Aims
To elucidate the genetic architecture of limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC), a common TDP-43 proteinopathy that is frequently comorbid with Alzheimer’s disease (AD) and increases dementia risk.
Methods
We studied the Religious Orders Study and the Rush Memory and Aging Project participants of European ancestry with imputed genotypes and post-mortem TDP-43 immunohistochemistry (n=1,180). TDP-43, amyloid-β (Aβ), and paired helical filament tau (PHFtau) were quantified using immunohistochemistry. LATE-NC burden was defined as a semi-quantitative six-point scale of TDP-43 burden averaged across six brain regions including amygdala, hippocampus, and neocortex. Genome-wide association study (GWAS) was performed using linear additive models controlling for age, sex, genotyping platform, and first three principal components from the genotype covariance matrix.
Results
Two distinct loci reached genome-wide significance in their association with higher LATE-NC burden: rs429358C, an allele defining the APOE ε4 haplotype (beta=0.46, p=1.2×10-12); rs17608393A within GRM8 (beta=0.68, p=4.5×10-8). There were 10 additional loci that reached pre-defined suggestive significance (p<10-6). A suggestive variant rs72701368G (beta=0.54, p=1.1×10-7) tagged a large haplotype spanning the interferon-alpha (IFNA) gene cluster, and another suggestive variant rs56902449A (beta=0.72, p=8.0×10-7) was a cis-eQTL increasing the expression of MX2, a gene encoding interferon-induced GTP-binding protein Mx2. After adjusting for Aβ and PHFtau, the association between APOE rs429358C and LATE-NC was partially attenuated (beta=0.28, p=2.6×10-5), while GRM8 and IFNA variants’ association with LATE-NC remained similar.
Conclusions
AD-related APOE locus and AD-independent GRM8 locus were associated with LATE-NC burden, and converging evidence also implicated type I interferon pathway that is regulated by TBK1 (a FTD/ALS risk gene).