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The impact of apolipoprotein E ε4 (APOE4), the strongest genetic risk factor for Alzheimer's disease (AD), on human brain cellular function remains unclear. Here, we investigated the effects of APOE4 on brain cell types derived from population and isogenic human induced pluripotent stem cells, post-mortem brain, and APOE targeted replacement mice. Population and isogenic models demonstrate that APOE4 local haplotype, rather than a single risk allele, contributes to risk. Global transcriptomic analyses reveal human-specific, APOE4-driven lipid metabolic dysregulation in astrocytes and microglia. APOE4 enhances de novo cholesterol synthesis despite elevated intracellular cholesterol due to lysosomal cholesterol sequestration in astrocytes. Further, matrisome dysregulation is associated with upregulated chemotaxis, glial activation, and lipid biosynthesis in astrocytes co-cultured with neurons, which recapitulates altered astrocyte matrisome signaling in human brain. Thus, APOE4 initiates glia-specific cell and non-cell autonomous dysregulation that may contribute to increased AD risk.

The hemizygous R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), a microglia-specific gene in the brain, increases risk for late-onset Alzheimer’s disease (AD). Using transcriptomic analysis of single nuclei from brain tissues of patients with AD carrying the R47H mutation or the common variant (CV)–TREM2, we found that R47H-associated microglial subpopulations had enhanced inflammatory signatures reminiscent of previously identified disease-associated microglia (DAM) and hyperactivation of AKT, one of the signaling pathways downstream of TREM2. We established a tauopathy mouse model with heterozygous knock-in of the human TREM2 with the R47H mutation or CV and found that R47H induced and exacerbated TAU-mediated spatial memory deficits in female mice. Single-cell transcriptomic analysis of microglia from these mice also revealed transcriptomic changes induced by R47H that had substantial overlaps with R47H microglia in human AD brains, including robust increases in proinflammatory cytokines, activation of AKT signaling, and elevation of a subset of DAM signatures. Pharmacological AKT inhibition with MK-2206 largely reversed the enhanced inflammatory signatures in primary R47H microglia treated with TAU fibrils. In R47H heterozygous tauopathy mice, MK-2206 treatment abolished a tauopathy-dependent microglial subcluster and rescued tauopathy-induced synapse loss. By uncovering disease-enhancing mechanisms of the R47H mutation conserved in human and mouse, our study supports inhibitors of AKT signaling as a microglial modulating strategy to treat AD.

Alzheimer's disease (AD) is the most common neurodegenerative disease in the United States (US). Animal models, specifically mouse models have been developed to better elucidate disease mechanisms and test therapeutic strategies for AD. A large portion of effort in the field was focused on developing transgenic (Tg) mouse models through over-expression of genetic mutations associated with familial AD (FAD) patients. Newer generations of mouse models through knock-in (KI)/knock-out (KO) or CRISPR gene editing technologies, have been developed for both familial and sporadic AD risk genes with the hope to more accurately model proteinopathies without over-expression of human AD genes in mouse brains. In this review, we summarized the phenotypes of a few commonly used as well as newly developed mouse models in translational research laboratories including the presence or absence of key pathological features of AD such as amyloid and tau pathology, synaptic and neuronal degeneration as well as cognitive and behavior deficits. In addition, advantages and limitations of these AD mouse models have been elaborated along with discussions of any sex-specific features. More importantly, the omics data from available AD mouse models have been analyzed to categorize molecular signatures of each model reminiscent of human AD brain changes, with the hope to guide future selection of most suitable models for specific research questions to be addressed in the AD field. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common form of dementia worldwide, with a projection of 151 million cases by 2050. Previous genetic studies have identified three main genes associated with early-onset familial Alzheimer's disease, however this subtype accounts for less than 5% of total cases. Next-generation sequencing has been well established and holds great promise to assist in the development of novel therapeutics as well as biomarkers to prevent or slow the progression of this devastating disease. Here we present a public resource of functional genomic data from the parahippocampal gyrus of 201 postmortem control, mild cognitively impaired (MCI) and AD individuals from the Mount Sinai brain bank, of which whole-genome sequencing (WGS), and bulk RNA sequencing (RNA-seq) were previously published. The genomic data include bulk proteomics and DNA methylation, as well as cell-type-specific RNA-seq and assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) data. We have performed extensive preprocessing and quality control, allowing the research community to access and utilize this public resource available on the Synapse platform at https://doi.org/10.7303/syn51180043.2. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Recent studies revealed the association of abnormal methylomic changes with Alzheimer's disease (AD) but there is a lack of systematic study of the impact of methylomic alterations over the molecular networks underlying AD. METHODS: We profiled genome‐wide methylomic variations in the parahippocampal gyrus from 201 post mortem control, mild cognitive impaired, and AD brains. RESULTS: We identified 270 distinct differentially methylated regions (DMRs) associated with AD. We quantified the impact of these DMRs on each gene and each protein as well as gene and protein co‐expression networks. DNA methylation had a profound impact on both AD‐associated gene/protein modules and their key regulators. We further integrated the matched multi‐omics data to show the impact of DNA methylation on chromatin accessibility, which further modulates gene and protein expression. DISCUSSION: The quantified impact of DNA methylation on gene and protein networks underlying AD identified potential upstream epigenetic regulators of AD. Highlights: A cohort of DNA methylation data in the parahippocampal gyrus was developed from 201 post mortem control, mild cognitive impaired, and Alzheimer's disease (AD) brains.Two hundred seventy distinct differentially methylated regions (DMRs) were found to be associated with AD compared to normal control.A metric was developed to quantify methylation impact on each gene and each protein.DNA methylation was found to have a profound impact on not only the AD‐associated gene modules but also key regulators of the gene and protein networks.Key findings were validated in an independent multi‐omics cohort in AD.The impact of DNA methylation on chromatin accessibility was also investigated by integrating the matched methylomic, epigenomic, transcriptomic, and proteomic data. [ABSTRACT FROM AUTHOR]

Introduction: The inositol polyphosphate‐5‐phosphatase D (INPP5D) gene encodes a dual‐specificity phosphatase that can dephosphorylate both phospholipids and phosphoproteins. Single nucleotide polymorphisms in INPP5D impact risk for developing late onset sporadic Alzheimer's disease (LOAD). Methods: To assess the consequences of inducible Inpp5d knockdown in microglia of APPKM670/671NL/PSEN1Δexon9 (PSAPP) mice, we injected 3‐month‐old Inpp5dfl/fl/Cx3cr1CreER/+ and PSAPP/Inpp5dfl/fl/Cx3cr1CreER/+ mice with either tamoxifen (TAM) or corn oil (CO) to induce recombination. Results: At age 6 months, we found that the percent area of 6E10+ deposits and plaque‐associated microglia in Inpp5d knockdown mice were increased compared to controls. Spatial transcriptomics identified a plaque‐specific expression profile that was extensively altered by Inpp5d knockdown. Discussion: These results demonstrate that conditional Inpp5d downregulation in the PSAPP mouse increases plaque burden and recruitment of microglia to plaques. Spatial transcriptomics highlighted an extended gene expression signature associated with plaques and identified CST7 (cystatin F) as a novel marker of plaques. Highlights: Inpp5d knockdown increases plaque burden and plaque‐associated microglia number.Spatial transcriptomics identifies an expanded plaque‐specific gene expression profile.Plaque‐induced gene expression is altered by Inpp5d knockdown in microglia.Our plaque‐associated gene signature overlaps with human Alzheimer's disease gene networks. [ABSTRACT FROM AUTHOR]

Aims: Selective neuronal vulnerability of hippocampal Cornu Ammonis (CA)‐1 neurons is a pathological hallmark of Alzheimer's disease (AD) with an unknown underlying mechanism. We interrogated the expression of tuberous sclerosis complex‐1 (TSC1; hamartin) and mTOR‐related proteins in hippocampal CA1 and CA3 subfields. Methods: A human post‐mortem cohort of mild (n = 7) and severe (n = 10) AD and non‐neurological controls (n = 9) was used for quantitative and semi‐quantitative analyses. We also developed an in vitro TSC1 knockdown model in rat hippocampal neurons, and transcriptomic analyses of TSC1 knockdown neuronal cultures were performed. Results: We found a selective increase of TSC1 cytoplasmic inclusions in human AD CA1 neurons with hyperactivation of one of TSC1's downstream targets, the mammalian target of rapamycin complex‐1 (mTORC1), suggesting that TSC1 is no longer active in AD. TSC1 knockdown experiments showed accelerated cell death independent of amyloid‐beta toxicity. Transcriptomic analyses of TSC1 knockdown neuronal cultures revealed signatures that were significantly enriched for AD‐related pathways. Conclusions: Our combined data point to TSC1 dysregulation as a key driver of selective neuronal vulnerability in the AD hippocampus. Future work aimed at identifying targets amenable to therapeutic manipulation is urgently needed to halt selective neurodegeneration, and by extension, debilitating cognitive impairment characteristic of AD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a chronic neurodegenerative disease, with the characteristics of neurofibrillary tangle (NFT) and senile plaque (SP) formation. Although great progresses have been made in clinical trials based on relevant hypotheses, these studies are also accompanied by the emergence of toxic and side effects, and it is an urgent task to explore the underlying mechanisms for the benefits to prevent and treat AD. Herein, based on animal experiments and a few clinical trials, neuroinflammation in AD is characterized by long-term activation of pro-inflammatory microglia and the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasomes. Damaged signals from the periphery and within the brain continuously activate microglia, thus resulting in a constant source of inflammatory responses. The long-term chronic inflammatory response also exacerbates endoplasmic reticulum oxidative stress in microglia, which triggers microglia-dependent immune responses, ultimately leading to the occurrence and deterioration of AD. In this review, we systematically summarized and sorted out that exercise ameliorates AD by directly and indirectly regulating immune response of the central nervous system and promoting hippocampal neurogenesis to provide a new direction for exploring the neuroinflammation activity in AD. [ABSTRACT FROM AUTHOR]

Recent multiscale network analyses of banked brains from subjects who died of late-onset sporadic Alzheimer's disease converged on VGF (non-acronymic) as a key hub or driver. Within this computational VGF network, we identified the dual-specificity protein phosphatase 4 (DUSP4) [also known as mitogen-activated protein kinase (MAPK) phosphatase 2] as an important node. Importantly, DUSP4 gene expression, like that of VGF, is downregulated in postmortem Alzheimer's disease (AD) brains. We investigated the roles that this VGF/DUSP4 network plays in the development of learning behavior impairment and neuropathology in the 5xFAD amyloidopathy mouse model. We found reductions in DUSP4 expression in the hippocampi of male AD subjects, correlating with increased CDR scores, and in 4-month-old female and 12–18-month-old male 5xFAD hippocampi. Adeno-associated virus (AAV5)-mediated overexpression of DUSP4 in 5xFAD mouse dorsal hippocampi (dHc) rescued impaired Barnes maze performance in females but not in males, while amyloid loads were reduced in both females and males. Bulk RNA sequencing of the dHc from 5-month-old mice overexpressing DUSP4, and Ingenuity Pathway and Enrichr analyses of differentially expressed genes (DEGs), revealed that DUSP4 reduced gene expression in female 5xFAD mice in neuroinflammatory, interferon-gamma (IFNγ), programmed cell death protein-ligand 1/programmed cell death protein 1 (PD-L1/PD-1), and extracellular signal-regulated kinase (ERK)/MAPK pathways, via which DUSP4 may modulate AD phenotype with gender-specificity. [ABSTRACT FROM AUTHOR]

Introduction: A few copy number variations (CNVs) have been reported for Alzheimer's disease (AD). However, there is a lack of a systematic investigation of CNVs in AD based on whole genome sequencing (WGS) data. Methods: We used four methods to identify consensus CNVs from the WGS data of 1,411 individuals and further investigated their functional roles in AD using the matched transcriptomic and clinicopathological data. Results: We identified 3,012 rare AD‐specific CNVs whose residing genes are enriched for cellular glucuronidation and neuron projection pathways. Genes whose mRNA expressions are significantly correlated with common CNVs are involved in major histocompatibility complex class II receptor activity. Integration of CNVs, gene expression, and clinical and pathological traits further pinpoints a key CNV that potentially regulates immune response in AD. Discussion: We identify CNVs as potential genetic regulators of immune response in AD. The identified CNVs and their downstream gene networks reveal novel pathways and targets for AD. [ABSTRACT FROM AUTHOR]

Metabolites, the biochemical products of the cellular process, can be used to measure alterations in biochemical pathways related to the pathogenesis of Alzheimer's disease (AD). However, the relationships between systemic abnormalities in metabolism and the pathogenesis of AD are poorly understood. In this study, we aim to identify AD‐specific metabolomic changes and their potential upstream genetic and transcriptional regulators through an integrative systems biology framework for analyzing genetic, transcriptomic, metabolomic, and proteomic data in AD. Metabolite co‐expression network analysis of the blood metabolomic data in the Alzheimer's Disease Neuroimaging Initiative (ADNI) shows short‐chain acylcarnitines/amino acids and medium/long‐chain acylcarnitines are most associated with AD clinical outcomes, including episodic memory scores and disease severity. Integration of the gene expression data in both the blood from the ADNI and the brain from the Accelerating Medicines Partnership Alzheimer's Disease (AMP‐AD) program reveals ABCA1 and CPT1A are involved in the regulation of acylcarnitines and amino acids in AD. Gene co‐expression network analysis of the AMP‐AD brain RNA‐seq data suggests the CPT1A‐ and ABCA1‐centered subnetworks are associated with neuronal system and immune response, respectively. Increased ABCA1 gene expression and adiponectin protein, a regulator of ABCA1, correspond to decreased short‐chain acylcarnitines and amines in AD in the ADNI. In summary, our integrated analysis of large‐scale multiomics data in AD systematically identifies novel metabolites and their potential regulators in AD and the findings pave a way for not only developing sensitive and specific diagnostic biomarkers for AD but also identifying novel molecular mechanisms of AD pathogenesis. [ABSTRACT FROM AUTHOR]

RNA editing is a feature of RNA maturation resulting in the formation of transcripts whose sequence differs from the genome template. Brain RNA editing may be altered in Alzheimer's disease (AD). Here, we analyzed data from 1,865 brain samples covering 9 brain regions from 1,074 unrelated subjects on a transcriptome-wide scale to identify inter-regional differences in RNA editing. We expand the list of known brain editing events by identifying 58,761 previously unreported events. We note that only a small proportion of these editing events are found at the protein level in our proteome-wide validation effort. We also identified the occurrence of editing events associated with AD dementia, neuropathological measures and longitudinal cognitive decline in: SYT11, MCUR1, SOD2, ORAI2, HSDL2, PFKP, and GPRC5B. Thus, we present an extended reference set of brain RNA editing events, identify a subset that are found to be expressed at the protein level, and extend the narrative of transcriptomic perturbation in AD to RNA editing. Resources reporting RNA editing sites from brain tissue have been published. Here, the authors provide an atlas of RNA editing events found in the aged and Alzheimer's disease human brain tissue resulting in changes at protein level. [ABSTRACT FROM AUTHOR]

Aging is a major risk factor for late-onset Alzheimer's disease (LOAD). How aging contributes to the development of LOAD remains elusive. In this study, we examined multiple large-scale transcriptomic datasets from both normal aging and LOAD brains to understand the molecular interconnection between aging and LOAD. We found that shared gene expression changes between aging and LOAD are mostly seen in the hippocampal and several cortical regions. In the hippocampus, the expression of phosphoprotein, alternative splicing and cytoskeleton genes are commonly changed in both aging and AD, while synapse, ion transport, and synaptic vesicle genes are commonly down-regulated. Aging-specific changes are associated with acetylation and methylation, while LOAD-specific changes are more related to glycoprotein (both up- and down-regulations), inflammatory response (up-regulation), myelin sheath and lipoprotein (down-regulation). We also found that normal aging brain transcriptomes from relatively young donors (45–70 years old) clustered into several subgroups and some subgroups showed gene expression changes highly similar to those seen in LOAD brains. Using brain transcriptomic datasets from another cohort of older individuals (>70 years), we found that samples from cognitively normal older individuals clustered with the "healthy aging" subgroup while AD samples mainly clustered with the "AD similar" subgroups. This may imply that individuals in the healthy aging subgroup will likely remain cognitively normal when they become older and vice versa. In summary, our results suggest that on the transcriptome level, aging and LOAD have strong interconnections in some brain regions in a subpopulation of cognitively normal aging individuals. This supports the theory that the initiation of LOAD occurs decades earlier than the manifestation of clinical phenotype and it may be essential to closely study the "normal brain aging" to identify the very early molecular events that may lead to LOAD development. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea, characterized by sleep fragmentation and chronic intermittent hypoxia (CIH), is a risk factor for Alzheimer's disease (AD) progression. Recent epidemiological studies point to CIH as the best predictor of developing cognitive decline and AD in older adults with obstructive sleep apnea. However, the precise underlying mechanisms remain unknown. This study was undertaken to evaluate the effect of CIH on pathological human tau seeding, propagation, and accumulation; cognition; synaptic plasticity; neuronal network excitability; and gene expression profiles in a P301S human mutant tau mouse model of AD and related tauopathies. We exposed 4- to 4.5-month-old male P301S and wild-type mice to an 8-week CIH protocol (6-min cycle: 21% O 2 to 8% O 2 to 21% O 2 , 80 cycles per 8 hours during daytime) and assessed its effect on tau pathology and various AD-related phenotypic and molecular signatures. Age- and sex-matched P301S and wild-type mice were reared in normoxia (21% O 2) as experimental controls. CIH significantly enhanced pathological human tau seeding and spread across connected brain circuitry in P301S mice; it also increased phosphorylated tau load. CIH also exacerbated memory and synaptic plasticity deficits in P301S mice. However, CIH had no effect on seizure susceptibility and network hyperexcitability in these mice. Finally, CIH exacerbated AD-related pathogenic molecular signaling in P301S mice. CIH-induced increase in pathologic human tau seeding and spread and exacerbation of other AD-related impairments provide new insights into the role of CIH and obstructive sleep apnea in AD pathogenesis. [ABSTRACT FROM AUTHOR]