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Selective vulnerability of different brain regions is seen in many neurodegenerative disorders. The hippocampus and cortex are selectively vulnerable in Alzheimer’s disease (AD), however the degree of involvement of the different brain regions differs among patients. We classified corticolimbic patterns of neurofibrillary tangles in postmortem tissue to capture extreme and representative phenotypes. We combined bulk RNA sequencing with digital pathology to examine hippocampal vulnerability in AD. We identified hippocampal gene expression changes associated with hippocampal vulnerability and used machine learning to identify genes that were associated with AD neuropathology, including SERPINA5 , RYBP , SLC38A2 , FEM1B , and PYDC1 . Further histologic and biochemical analyses suggested SERPINA5 expression is associated with tau expression in the brain. Our study highlights the importance of embracing heterogeneity of the human brain in disease to identify disease-relevant gene expression. Alzheimer’s disease (AD) is typically associated with hippocampal and cortical pathology, although hippocampal sparing and limbic predominant forms exist. The authors use transcriptomic analysis and neuropathology to identify genes associated with selective hippocampal vulnerability in AD.

Insects with restricted diets rely on symbiotic bacteria to provide essential metabolites missing in their diet. The blood-sucking lice are obligate, host-specific parasites of mammals and are themselves host to symbiotic bacteria. In human lice, these bacterial symbionts supply the lice with B-vitamins. Here, we sequenced the genomes of symbiotic and heritable bacterial of human, chimpanzee, gorilla, and monkey lice and used phylogenomics to investigate their evolutionary relationships. We find that these symbionts have a phylogenetic history reflecting the louse phylogeny, a finding contrary to previous reports of symbiont replacement. Examination of the highly reduced symbiont genomes (0.53–0.57 Mb) reveals much of the genomes are dedicated to vitamin synthesis. This is unchanged in the smallest symbiont genome and one that appears to have been reorganized. Specifically, symbionts from human lice, chimpanzee lice, and gorilla lice carry a small plasmid that encodes synthesis of vitamin B5, a vitamin critical to the bacteria-louse symbiosis. This plasmid is absent in an old world monkey louse symbiont, where this pathway is on its primary chromosome. This suggests the unique genomic configuration brought about by the plasmid is not essential for symbiosis, but once obtained, it has persisted for up to 25 My. We also find evidence that human, chimpanzee, and gorilla louse endosymbionts have lost a pathway for synthesis of vitamin B1, whereas the monkey louse symbiont has retained this pathway. It is unclear whether these changes are adaptive, but they may point to evolutionary responses of louse symbionts to shifts in primate biology.

Progressive supranuclear palsy (PSP) is a neurodegenerative parkinsonian disorder characterized by cell-type-specific tau lesions in neurons and glia. Prior work uncovered transcriptome changes in human PSP brains, although their cell-specificity is unknown. Further, systematic data integration and experimental validation platforms to prioritize brain transcriptional perturbations as therapeutic targets in PSP are currently lacking. In this study, we combine bulk tissue ( n  = 408) and single nucleus RNAseq ( n  = 34) data from PSP and control brains with transcriptome data from a mouse tauopathy and experimental validations in Drosophila tau models for systematic discovery of high-confidence expression changes in PSP with therapeutic potential. We discover, replicate, and annotate thousands of differentially expressed genes in PSP, many of which reside in glia-enriched co-expression modules and cells. We prioritize DDR2, STOM , and KANK2 as promising therapeutic targets in PSP with striking cross-species validations. We share our findings and data via our interactive application tool PSP RNAseq Atlas ( https://rtools.mayo.edu/PSP_RNAseq_Atlas/ ). Our findings reveal robust glial transcriptome changes in PSP, provide a cross-species systems biology approach, and a tool for therapeutic target discoveries in PSP with potential application in other neurodegenerative diseases. Progressive supranuclear palsy is a devastating neurological disorder without treatment. Here, the authors leveraged omics data and model organisms to nominate, prioritize, and validate high-confidence candidate genes as therapeutic targets.

Large-scale brain bulk-RNAseq studies identified molecular pathways implicated in Alzheimer’s disease (AD), however these findings can be confounded by cellular composition changes in bulk-tissue. To identify cell intrinsic gene expression alterations of individual cell types, we designed a bioinformatics pipeline and analyzed three AD and control bulk-RNAseq datasets of temporal and dorsolateral prefrontal cortex from 685 brain samples. We detected cell-proportion changes in AD brains that are robustly replicable across the three independently assessed cohorts. We applied three different algorithms including our in-house algorithm to identify cell intrinsic differentially expressed genes in individual cell types (CI-DEGs). We assessed the performance of all algorithms by comparison to single nucleus RNAseq data. We identified consensus CI-DEGs that are common to multiple brain regions. Despite significant overlap between consensus CI-DEGs and bulk-DEGs, many CI-DEGs were absent from bulk-DEGs. Consensus CI-DEGs and their enriched GO terms include genes and pathways previously implicated in AD or neurodegeneration, as well as novel ones. We demonstrated that the detection of CI-DEGs through computational deconvolution methods is promising and highlight remaining challenges. These findings provide novel insights into cell-intrinsic transcriptional changes of individual cell types in AD and may refine discovery and modeling of molecular targets that drive this complex disease.

Cerebral amyloid angiopathy (CAA) contributes to accelerated cognitive decline in Alzheimer’s disease (AD) dementia and is a common finding at autopsy. The APOE ε4 allele and male sex have previously been reported to associate with increased CAA in AD. To inform biomarker and therapeutic target discovery, we aimed to identify additional genetic risk factors and biological pathways involved in this vascular component of AD etiology. We present a genome-wide association study of CAA pathology in AD cases and report sex- and APOE -stratified assessment of this phenotype. Genome-wide genotypes were collected from 853 neuropathology-confirmed AD cases scored for CAA across five brain regions, and imputed to the Haplotype Reference Consortium panel. Key variables and genome-wide genotypes were tested for association with CAA in all individuals and in sex and APOE ε4 stratified subsets. Pathway enrichment was run for each of the genetic analyses. Implicated loci were further investigated for functional consequences using brain transcriptome data from 1,186 samples representing seven brain regions profiled as part of the AMP-AD consortium. We confirmed association of male sex, AD neuropathology and APOE ε4 with increased CAA, and identified a novel locus, LINC-PINT, associated with lower CAA amongst APO Eε4-negative individuals (rs10234094-C, beta = −3.70 [95% CI −0.49—−0.24]; p = 1.63E-08). Transcriptome profiling revealed higher LINC-PINT expression levels in AD cases, and association of rs10234094-C with altered LINC-PINT splicing. Pathway analysis indicates variation in genes involved in neuronal health and function are linked to CAA in AD patients. Further studies in additional and diverse cohorts are needed to assess broader translation of our findings.

An amendment to this paper has been published and can be accessed via the original article.

The ε4 allele of the apolipoprotein E (APOE) gene, a genetic risk factor for Alzheimer’s disease, is abundantly expressed in both the brain and periphery. Here, we present evidence that peripheral apoE isoforms, separated from those in the brain by the blood–brain barrier, differentially impact Alzheimer’s disease pathogenesis and cognition. To evaluate the function of peripheral apoE, we developed conditional mouse models expressing human APOE3 or APOE4 in the liver with no detectable apoE in the brain. Liver-expressed apoE4 compromised synaptic plasticity and cognition by impairing cerebrovascular functions. Plasma proteome profiling revealed apoE isoform-dependent functional pathways highlighting cell adhesion, lipoprotein metabolism and complement activation. ApoE3 plasma from young mice improved cognition and reduced vessel-associated gliosis when transfused into aged mice, whereas apoE4 compromised the beneficial effects of young plasma. A human induced pluripotent stem cell-derived endothelial cell model recapitulated the plasma apoE isoform-specific effect on endothelial integrity, further supporting a vascular-related mechanism. Upon breeding with amyloid model mice, liver-expressed apoE4 exacerbated brain amyloid pathology, whereas apoE3 reduced it. Our findings demonstrate pathogenic effects of peripheral apoE4, providing a strong rationale for targeting peripheral apoE to treat Alzheimer’s disease.Mouse models expressing liver apoE in the absence of brain apoE reveal detrimental effects of peripheral apoE4 associated with Alzheimer’s risk on cognition and amyloid pathology through compromising vascular integrity and function.

Microglia have fundamental roles in health and disease; however, effects of age, sex, and genetic factors on human microglia have not been fully explored. We applied bulk and single‐cell approaches to comprehensively characterize human microglia transcriptomes and their associations with age, sex, and APOE. We identified a novel microglial signature, characterized its expression in bulk tissue and single‐cell microglia transcriptomes. We discovered microglial co‐expression network modules associated with age, sex, and APOE‐ε4 that are enriched for lipid and carbohydrate metabolism genes. Integrated analyses of modules with single‐cell transcriptomes revealed significant overlap between age‐associated module genes and both pro‐inflammatory and disease‐associated microglial clusters. These modules and clusters harbor known neurodegenerative disease genes including APOE, PLCG2, and BIN1. Meta‐analyses with published bulk and single‐cell microglial datasets further supported our findings. Thus, these data represent a well‐characterized human microglial transcriptome resource and highlight age, sex, and APOE‐related microglial immunometabolism perturbations with potential relevance in neurodegeneration. Using bulk and single‐cell approaches, we identified microglial subclusters enriched for different biological functions. Activated microglia were more abundant with aging and lipid localization genes were upregulated. In APOE‐ε4 carriers, homeostatic microglia were reduced along with downregulation of carbohydrate metabolism genes, whereas cholesterol absorption genes were unregulated in macrophages and activated microglia.

INTRODUCTION Phosphorylated ubiquitin (p‐S65‐Ub) is generated during PINK1‐PRKN mitophagy as a specific marker of mitochondrial damage. Despite the widespread deposition of p‐S65‐Ub in aged and diseased human brain, the genetic contribution to its accumulation remains unclear. METHODS To identify novel mitophagy regulators, we performed a genome‐wide association study using p‐S65‐Ub level as a quantitative trait in 1012 autopsy‐confirmed Lewy body disease (LBD) samples. RESULTS We identified a significant genome‐wide association with p‐S65‐Ub for rs429358 (apolipoprotein E ε4 [APOE4]) and a suggestive association for rs6480922 (ZMIZ1). APOE4 was associated with higher p‐S65‐Ub levels and greater neuropathological burden. Functional validation in mouse and human induced pluripotent stem cell (iPSC) models confirmed APOE4‐mediated mitophagy alterations. Intriguingly, ZMIZ1 rs6480922 was associated with lower p‐S65‐Ub levels, reduced neuropathological load, and increased brain weight, indicating a potential protective role. DISCUSSION Our findings underscore the importance of mitochondrial quality control in LBD pathogenesis and nominate regulators that may contribute to disease risk or resilience. Highlights p‐S65‐Ub levels were used as a quantitative marker of mitochondrial damage. A GWAS identified two genetic variants that modify mitophagy in LBD autopsy brain. APOE4 was associated with increased p‐S65‐Ub accumulation and neuropathology. APOE4 altered mitophagy via pathology‐dependent and pathology‐independent mechanisms. ZMIZ1 was linked to reduced p‐S65‐Ub and neuropathology indicative of protection.

INTRODUCTION Multi‐omics studies in Alzheimer's disease (AD) revealed many potential disease pathways and therapeutic targets. Despite their promise of precision medicine, these studies lacked Black Americans (BA) and Latin Americans (LA), who are disproportionately affected by AD. METHODS To bridge this gap, Accelerating Medicines Partnership in Alzheimer's Disease (AMP‐AD) expanded brain multi‐omics profiling to multi‐ethnic donors. RESULTS We generated multi‐omics data and curated and harmonized phenotypic data from BA (n = 306), LA (n = 326), or BA and LA (n = 4) brain donors plus non‐Hispanic White (n = 252) and other (n = 20) ethnic groups, to establish a foundational dataset enriched for BA and LA participants. This study describes the data available to the research community, including transcriptome from three brain regions, whole genome sequence, and proteome measures. DISCUSSION The inclusion of traditionally underrepresented groups in multi‐omics studies is essential to discovering the full spectrum of precision medicine targets that will be pertinent to all populations affected with AD. Highlights Accelerating Medicines Partnership in Alzheimer's Disease Diversity Initiative led brain tissue profiling in multi‐ethnic populations. Brain multi‐omics data is generated from Black American, Latin American, and non‐Hispanic White donors. RNA, whole genome sequencing and tandem mass tag proteomicsis completed and shared. Multiple brain regions including caudate, temporal and dorsolateral prefrontal cortex were profiled.