Generalizability of Tau and Amyloid Plasma Biomarkers in Alzheimer's Disease Cohorts of Diverse Genetic Ancestries.

Introduction: Plasma phosphorylated threonine-181 of Tau and amyloid beta are biomarkers for differential diagnosis and preclinical detection of Alzheimer disease (AD). Given differences in AD risk across diverse populations, generalizability of existing biomarker data is not assured. Methods: In 2,086 individuals of diverse genetic ancestries (African American, Caribbean Hispanic, and Peruvians) we measured plasma pTau-181 and Aß42/Aß40. Differences in biomarkers between cohorts and clinical diagnosis groups and the potential discriminative performance of the two biomarkers were assessed. Results: pTau-181 and Aß42/Aß40 were consistent across cohorts. Higher levels of pTau181 were associated with AD while Aß42/Aß40 had minimal differences. Correspondingly, pTau-181 had greater predictive value than Aß42/Aß40, however, the area under the curve differed between cohorts. Discussion: pTau-181 as a plasma biomarker for clinical AD is generalizable across genetic ancestries, but predictive value may differ. Combining genomic and biomarker data from diverse individuals will increase understanding of genetic risk and refine clinical diagnoses.

Absence of both MGME1 and POLG EXO abolishes mtDNA whereas absence of either creates unique mtDNA duplications.

Both POLG and MGME1 are needed for mitochondrial DNA (mtDNA) maintenance in animal cells. POLG, the primary replicative polymerase of the mitochondria, has an exonuclease activity (3'→5') that corrects for the misincorporation of bases. MGME1 serves as an exonuclease (5'→3'), producing ligatable DNA ends. Although both have a critical role in mtDNA replication and elimination of linear fragments, these mechanisms are still not fully understood. Using digital PCR to evaluate and compare mtDNA integrity, we show that Mgme1 knock out (Mgme1 KK) tissue mtDNA is more fragmented than POLG exonuclease-deficient "Mutator" (Polg MM) or WT tissue. In addition, next generation sequencing of mutant hearts showed abundant duplications in/nearby the D-loop region and unique 100 bp duplications evenly spaced throughout the genome only in Mgme1 KK hearts. However, despite these unique mtDNA features at steady-state, we observed a similar delay in the degradation of mtDNA after an induced double strand DNA break in both Mgme1 KK and Polg MM models. Lastly, we characterized double mutant (Polg MM/Mgme1 KK) cells and show that mtDNA cannot be maintained without at least one of these enzymatic activities. We propose a model for the generation of these genomic abnormalities which suggests a role for MGME1 outside of nascent mtDNA end ligation. Our results highlight the role of MGME1 in and outside of the D-loop region during replication, support the involvement of MGME1 in dsDNA degradation, and demonstrate that POLG EXO and MGME1 can partially compensate for each other in maintaining mtDNA.

Utilizing RNA sequencing to identify gene expression markers of stroke-causing thrombi origin: A pilot study.

INTRODUCTION: Stroke embolic source have an unknown origin in 30-40% of cases. Mechanical thrombectomy for acute large vessel occlusion stroke has provided us with a method to directly retrieve the thrombi from patients for analysis. By collecting stroke-causing thrombi from known sources, we can then use high-throughput RNA sequencing (RNAseq) technology to directly measure the gene expression signatures of these clots. This may allow us to identify genetic markers to predict the cause of cryptogenic embolism. METHODS: This is a prospective study in which RNAseq was used to analyze cerebral thrombi retrieved by mechanical thrombectomy devices in acute ischemic stroke patients. Samples were separated into two groups based on known stroke thrombus etiology, including Carotid group (patients with ipsilateral >70% carotid stenosis) and Atrial fibrillation (AF) group (patients with atrial fibrillation). Gene expression was compared by RNAseq analysis between the groups. RESULTS: From October 2016 to September 2017, 8 thrombi (4 in Carotid group, 4 in Afib group) were included in this study. There were 131 genes that were significantly up- or down-regulated between the two groups defined as a false discovery rate ≤ 0.05 and a fold change ≥ 2. Twenty-six genes were selected as candidate gene biomarkers based on the criteria in the methods section. Candidate genes HSPA1B, which encodes a heatshock protein, and GPRC5B, which encodes a G-protein, showed the greatest fold differences in expression between the two groups. CONCLUSION: This study has shown that RNA sequencing of acute ischemic stroke thrombi is feasible and indentified potential novel biomarkers for identifying stroke-causing thrombi origin, especially in cryptogenic stroke.

mitoTALEN reduces the mutant mtDNA load in neurons.

Mutations within mtDNA frequently give rise to severe encephalopathies. Given that a majority of these mtDNA defects exist in a heteroplasmic state, we harnessed the precision of mitochondrial-targeted TALEN (mitoTALEN) to selectively eliminate mutant mtDNA within the CNS of a murine model harboring a heteroplasmic mutation in the mitochondrial tRNA alanine gene (m.5024C>T). This targeted approach was accomplished by the use of AAV-PHP.eB and a neuron-specific synapsin promoter for effective neuronal delivery and expression of mitoTALEN. We found that most CNS regions were effectively transduced and showed a significant reduction in mutant mtDNA. This reduction was accompanied by an increase in mitochondrial tRNA alanine levels, which are drastically reduced by the m.5024C>T mutation. These results showed that mitochondrial-targeted gene editing can be effective in reducing CNS-mutant mtDNA in vivo, paving the way for clinical trials in patients with mitochondrial encephalopathies.

African Ancestry Individuals with Higher Educational Attainment Are Resilient to Alzheimer's Disease Measured by pTau181.

Background: Cognitive and functional abilities in individuals with Alzheimer's disease (AD) pathology (ADP) are highly variable. Factors contributing to this variability are not well understood. Previous research indicates that higher educational attainment (EA) correlates with reduced cognitive impairments among those with ADP. While cognitive and functional impairments are correlated, they are distinguishable in their manifestations. Objective: To investigate whether levels of education are associated with functional impairments among those with ADP. Methods: This research involved 410 African American (AA) individuals (Institutional Review Boards 20070307, 01/27/2023) to ascertain whether EA correlates with functional resilience and if this effect varies between APOE ɛ4 carriers and non-carriers. Utilizing EA as a cognitive reserve proxy, CDR-FUNC as a functional difficulties measure, and blood pTau181 as an ADP proxy, the non-parametric Mann-Whitney U test assessed the relationship between EA and CDR-FUNC in individuals with advanced pTau181 levels. Results: The results showed that EA correlated with functional difficulties in AA individuals with high levels of pTau181, such that individuals with high EA are more likely to have better functional ability compared to those with lower EA (W = 730.5, p = 0.0007). Additionally, we found that the effect of high EA on functional resilience was stronger in ɛ4 non-carriers compared to ɛ4 carriers (W = 555.5, p = 0.022). Conclusion: This study extends the role of cognitive reserve and EA to functional performance showing that cognitive reserve influences the association between ADP burden and functional difficulties. Interestingly, this protective effect seems less pronounced in carriers of the strong genetic risk allele ɛ4.

Report of the APOE4 National Institute on Aging/Alzheimer Disease Sequencing Project Consortium Working Group: Reducing APOE4 in Carriers is a Therapeutic Goal for Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder and one of the leading causes of disability worldwide. The apolipoprotein E4 gene (APOE4) is the strongest genetic risk factor for AD. In 2023, the APOE4 National Institute on Aging/Alzheimer's Disease Sequencing Project working group came together to gather data and discuss the question of whether to reduce or increase APOE4 as a therapeutic intervention for AD. It was the unanimous consensus that cumulative data from multiple studies in humans and animal models support that lowering APOE4 should be a target for therapeutic approaches for APOE4 carriers. ANN NEUROL 2024;95:625-634.

Gatad2b, associated with the neurodevelopmental syndrome GAND, plays a critical role in neurodevelopment and cortical patterning.

GATAD2B (GATA zinc finger domain containing 2B) variants are associated with the neurodevelopmental syndrome GAND, characterized by intellectual disability (ID), infantile hypotonia, apraxia of speech, epilepsy, macrocephaly and distinct facial features. GATAD2B encodes for a subunit of the Nucleosome Remodeling and Histone Deacetylase (NuRD) complex. NuRD controls transcriptional programs critical for proper neurodevelopment by coupling histone deacetylase with ATP-dependent chromatin remodeling activity. To study mechanisms of pathogenesis for GAND, we characterized a mouse model harboring an inactivating mutation in Gatad2b. Homozygous Gatad2b mutants die perinatally, while haploinsufficient Gatad2b mice exhibit behavioral abnormalities resembling the clinical features of GAND patients. We also observed abnormal cortical patterning, and cellular proportions and cell-specific alterations in the developmental transcriptome in these mice. scRNAseq of embryonic cortex indicated misexpression of genes key for corticogenesis and associated with neurodevelopmental syndromes such as Bcl11b, Nfia and H3f3b and Sox5. These data suggest a crucial role for Gatad2b in brain development.

The intricate cellular ecosystem of human peripheral veins as revealed by single-cell transcriptomic analysis.

The venous system has been historically understudied despite its critical roles in blood distribution, heart function, and systemic immunity. This study dissects the microanatomy of upper arm veins at the single cell level, and how it relates to wall structure, remodeling processes, and inflammatory responses to injury. We applied single-cell RNA sequencing to 4 non-diseased human veins (3 basilic, 1 cephalic) obtained from organ donors, followed by bioinformatic and histological analyses. Unsupervised clustering of 20,006 cells revealed a complex ecosystem of endothelial cell (EC) types, smooth muscle cell (SMCs) and pericytes, various types of fibroblasts, and immune cell populations. The venous endothelium showed significant upregulation of cell adhesion genes, with arteriovenous zonation EC phenotypes highlighting the heterogeneity of vasa vasorum (VV) microvessels. Venous SMCs had atypical contractile phenotypes and showed widespread localization in the intima and media. MYH11+DESlo SMCs were transcriptionally associated with negative regulation of contraction and pro-inflammatory gene expression. MYH11+DEShi SMCs showed significant upregulation of extracellular matrix genes and pro-migratory mediators. Venous fibroblasts ranging from secretory to myofibroblastic phenotypes were 4X more abundant than SMCs and widely distributed throughout the wall. Fibroblast-derived angiopoietin-like factors were identified as versatile signaling hubs to regulate angiogenesis and SMC proliferation. An abundant monocyte/macrophage population was detected and confirmed by histology, including pro-inflammatory and homeostatic phenotypes, with cell counts positively correlated with age. Ligand-receptor interactome networks identified the venous endothelium in the main lumen and the VV as a niche for monocyte recruitment and infiltration. This study underscores the transcriptional uniqueness of venous cells and their relevance for vascular inflammation and remodeling processes. Findings from this study may be relevant for molecular investigations of upper arm veins used for vascular access creation, where single-cell analyses of cell composition and phenotypes are currently lacking.

An Alzheimer's disease risk variant in TTC3 modifies the actin cytoskeleton organization and the PI3K-Akt signaling pathway in iPSC-derived forebrain neurons.

A missense variant in the tetratricopeptide repeat domain 3 (TTC3) gene (rs377155188, p.S1038C, NM_003316.4:c 0.3113C>G) was found to segregate with disease in a multigenerational family with late-onset Alzheimer's disease. This variant was introduced into induced pluripotent stem cells (iPSCs) derived from a cognitively intact individual using CRISPR genome editing, and the resulting isogenic pair of iPSC lines was differentiated into cortical neurons. Transcriptome analysis showed an enrichment for genes involved in axon guidance, regulation of actin cytoskeleton, and GABAergic synapse. Functional analysis showed that the TTC3 p.S1038C iPSC-derived neuronal progenitor cells had altered 3-dimensional morphology and increased migration, while the corresponding neurons had longer neurites, increased branch points, and altered expression levels of synaptic proteins. Pharmacological treatment with small molecules that target the actin cytoskeleton could revert many of these cellular phenotypes, suggesting a central role for actin in mediating the cellular phenotypes associated with the TTC3 p.S1038C variant.

Alveolar epithelial cell growth hormone releasing hormone receptor in alveolar epithelial inflammation.

Purpose: Growth hormone-releasing hormone (GHRH) is a 44-amino acid peptide that regulates growth hormone (GH) secretion. We hypothesized that GHRH receptor (GHRH-R) in alveolar type 2 (AT2) cells could modulate pro-inflammatory and possibly subsequent pro-fibrotic effects of lipopolysaccharide (LPS) or cytokines, such that AT2 cells could participate in lung inflammation and fibrosis. Methods: We used human alveolar type 2 (iAT2) epithelial cells derived from induced pluripotent stem cells (iPSC) to investigate how GHRH-R modulates gene and protein expression. We tested iAT2 cells' gene expression in response to LPS or cytokines, seeking whether these mechanisms caused endogenous production of pro-inflammatory molecules or mesenchymal markers. Quantitative real-time PCR (RT-PCR) and Western blotting were used to investigate differential expression of epithelial and mesenchymal markers. Result: Incubation of iAT2 cells with LPS increased expression of IL1-ß and TNF-α in addition to mesenchymal genes, including ACTA2, FN1 and COL1A1. Alveolar epithelial cell gene expression due to LPS was significantly inhibited by GHRH-R peptide antagonist MIA-602. Incubation of iAT2 cells with cytokines like those in fibrotic lungs similarly increased expression of genes for IL1-ß, TNF-α, TGFß-1, Wnt5a, smooth muscle actin, fibronectin and collagen. Expression of mesenchymal proteins, such as N-cadherin and vimentin, were also elevated after prolonged exposure to cytokines, confirming epithelial production of pro-inflammatory molecules as an important mechanism that might lead to subsequent fibrosis. Conclusion: iAT2 cells clearly expressed the GHRH-R. Exposure to LPS or cytokines increased iAT2 cell production of pro-inflammatory factors. GHRH-R antagonist MIA-602 inhibited pro-inflammatory gene expression, implicating iAT2 cell GHRH-R signaling in lung inflammation and potentially in fibrosis.

Cotargeting Phosphoinositide 3-Kinase and Focal Adhesion Kinase Pathways Inhibits Proliferation of NF2 Schwannoma Cells.

Neurofibromatosis Type 2 (NF2) is a tumor predisposition syndrome caused by germline inactivating mutations in the NF2 gene encoding the merlin tumor suppressor. Patients develop multiple benign tumor types in the nervous system including bilateral vestibular schwannomas (VS). Standard treatments include surgery and radiation therapy, which may lead to loss of hearing, impaired facial nerve function, and other complications. Kinase inhibitor monotherapies have been evaluated clinically for NF2 patients with limited success, and more effective nonsurgical therapies are urgently needed. Schwannoma model cells treated with PI3K inhibitors upregulate activity of the focal adhesion kinase (FAK) family as a compensatory survival pathway. We screened combinations of 13 clinically relevant PI3K and FAK inhibitors using human isogenic normal and merlin-deficient Schwann cell lines. The most efficacious combination was PI3K/mTOR inhibitor omipalisib with SRC/FAK inhibitor dasatinib. Sub-GI50 doses of the single drugs blocked phosphorylation of their major target proteins. The combination was superior to either single agent in promoting a G1 cell-cycle arrest and produced a 44% decrease in tumor growth over a 2-week period in a pilot orthotopic allograft model. Evaluation of single and combination drugs in six human primary VS cell models revealed the combination was superior to the monotherapies in 3 of 6 VS samples, highlighting inter-tumor variability between patients consistent with observations from clinical trials with other molecular targeted agents. Dasatinib alone performed as well as the combination in the remaining three samples. Preclinically validated combination therapies hold promise for NF2 patients and warrants further study in clinical trials.

Therapeutic Perspectives for Inflammation and Senescence in Osteoarthritis Using Mesenchymal Stem Cells, Mesenchymal Stem Cell-Derived Extracellular Vesicles and Senolytic Agents.

Osteoarthritis (OA) is the most common cause of disability worldwide among the elderly. Alarmingly, the incidence of OA in individuals less than 40 years of age is rising, likely due to the increase in obesity and post-traumatic osteoarthritis (PTOA). In recent years, due to a better understanding of the underlying pathophysiology of OA, several potential therapeutic approaches targeting specific molecular pathways have been identified. In particular, the role of inflammation and the immune system has been increasingly recognized as important in a variety of musculoskeletal diseases, including OA. Similarly, higher levels of host cellular senescence, characterized by cessation of cell division and the secretion of a senescence-associated secretory phenotype (SASP) within the local tissue microenvironments, have also been linked to OA and its progression. New advances in the field, including stem cell therapies and senolytics, are emerging with the goal of slowing disease progression. Mesenchymal stem/stromal cells (MSCs) are a subset of multipotent adult stem cells that have demonstrated the potential to modulate unchecked inflammation, reverse fibrosis, attenuate pain, and potentially treat patients with OA. Numerous studies have demonstrated the potential of MSC extracellular vesicles (EVs) as cell-free treatments that comply with FDA regulations. EVs, including exosomes and microvesicles, are released by numerous cell types and are increasingly recognized as playing a critical role in cell-cell communication in age-related diseases, including OA. Treatment strategies for OA are being developed that target senescent cells and the paracrine and autocrine secretions of SASP. This article highlights the encouraging potential for MSC or MSC-derived products alone or in combination with senolytics to control patient symptoms and potentially mitigate the progression of OA. We will also explore the application of genomic principles to the study of OA and the potential for the discovery of OA phenotypes that can motivate more precise patient-driven treatments.

An Alzheimer's disease risk variant in TTC3 modifies the actin cytoskeleton organization and the PI3K-Akt signaling pathway in iPSC-derived forebrain neurons.

A missense variant in the tetratricopeptide repeat domain 3 ( TTC3 ) gene (rs377155188, p.S1038C, NM_003316.4:c.3113C>G) was found to segregate with disease in a multigenerational family with late onset Alzheimer's disease. This variant was introduced into induced pluripotent stem cells (iPSCs) derived from a cognitively intact individual using CRISPR genome editing and the resulting isogenic pair of iPSC lines were differentiated into cortical neurons. Transcriptome analysis showed an enrichment for genes involved in axon guidance, regulation of actin cytoskeleton, and GABAergic synapse. Functional analysis showed that the TTC3 p.S1038C iPSC-derived neuronal progenitor cells had altered 3D morphology and increased migration, while the corresponding neurons had longer neurites, increased branch points, and altered expression levels of synaptic proteins. Pharmacological treatment with small molecules that target the actin cytoskeleton could revert many of these cellular phenotypes, suggesting a central role for actin in mediating the cellular phenotypes associated with the TTC3 p.S1038C variant. Highlights: The AD risk variant TTC3 p.S1038C reduces the expression levels of TTC3 The variant modifies the expression of AD specific genes BACE1 , INPP5F , and UNC5C Neurons with the variant are enriched for genes in the PI3K-Akt pathwayiPSC-derived neurons with the alteration have increased neurite length and branchingThe variant interferes with actin cytoskeleton and is ameliorated by Cytochalasin D.

Ancestry-related differences in chromatin accessibility and gene expression of APOE ε4 are associated with Alzheimer's disease risk.

INTRODUCTION: European local ancestry (ELA) surrounding apolipoprotein E (APOE) ε4 confers higher risk for Alzheimer's disease (AD) compared to African local ancestry (ALA). We demonstrated significantly higher APOE ε4  expression in ELA versus ALA in AD brains from APOE ε4/ε4 carriers. Chromatin accessibility differences could contribute to these expression changes. METHODS: We performed single nuclei assays for transposase accessible chromatin sequencing from the frontal cortex of six ALA and six ELA AD brains, homozygous for local ancestry and APOE ε4. RESULTS: Our results showed an increased chromatin accessibility at the APOE ε4  promoter area in ELA versus ALA astrocytes. This increased accessibility in ELA astrocytes extended genome wide. Genes with increased accessibility in ELA in astrocytes were enriched for synapsis, cholesterol processing, and astrocyte reactivity. DISCUSSION: Our results suggest that increased chromatin accessibility of APOE ε4  in ELA astrocytes contributes to the observed elevated APOE ε4  expression, corresponding to the increased AD risk in ELA versus ALA APOE ε4/ε4 carriers.

The Transcriptomics of the Human Vein Transformation After Arteriovenous Fistula Anastomosis Uncovers Layer-Specific Remodeling and Hallmarks of Maturation Failure.

Introduction: The molecular transformation of the human preaccess vein after arteriovenous fistula (AVF) creation is poorly understood. This limits our ability to design efficacious therapies to improve maturation outcomes. Methods: Bulk RNA sequencing (RNA-seq) followed by paired bioinformatic analyses and validation assays were performed in 76 longitudinal vascular biopsies (veins and AVFs) from 38 patients with stage 5 chronic kidney disease or end-stage kidney disease undergoing surgeries for 2-stage AVF creation (19 matured, 19 failed). Results: A total of 3637 transcripts were differentially expressed between veins and AVFs independent of maturation outcomes, with 80% upregulated in fistulas. The postoperative transcriptome demonstrated transcriptional activation of basement membrane and interstitial extracellular matrix (ECM) components, including preexisting and novel collagens, proteoglycans, hemostasis factors, and angiogenesis regulators. A postoperative intramural cytokine storm involved >80 chemokines, interleukins, and growth factors. Postoperative changes in ECM expression were differentially distributed in the AVF wall, with proteoglycans and fibrillar collagens predominantly found in the intima and media, respectively. Interestingly, upregulated matrisome genes were enough to make a crude separation of AVFs that failed from those with successful maturation. We identified 102 differentially expressed genes (DEGs) in association with AVF maturation failure, including upregulation of network collagen VIII in medial smooth muscle cells (SMCs) and downregulation of endothelial-predominant transcripts and ECM regulators. Conclusion: This work delineates the molecular changes that characterize venous remodeling after AVF creation and those relevant to maturation failure. We provide an essential framework to streamline translational models and our search for antistenotic therapies.

A haptoglobin (HP) structural variant alters the effect of APOE alleles on Alzheimer's disease.

BACKGROUND: Haptoglobin (HP) is an antioxidant of apolipoprotein E (APOE), and previous reports have shown HP binds with APOE and amyloid beta (Aß) to aid its clearance. A common structural variant of the HP gene distinguishes it into two alleles: HP1 and HP2. METHODS: HP genotypes were imputed in 29 cohorts from the Alzheimer's Disease Genetics Consortium (N = 20,512). Associations between the HP polymorphism and Alzheimer's disease (AD) risk and age of onset through APOE interactions were investigated using regression models. RESULTS: The HP polymorphism significantly impacts AD risk in European-descent individuals (and in meta-analysis with African-descent individuals) by modifying both the protective effect of APOE ε2 and the detrimental effect of APOE ε4. The effect is particularly significant among APOE ε4 carriers. DISCUSSION: The effect modification of APOE by HP suggests adjustment and/or stratification by HP genotype is warranted when APOE risk is considered. Our findings also provided directions for further investigations on potential mechanisms behind this association.

Whole Exome Sequencing Identifies a Rare CFTR Mutation in Brothers With Anomalies of the Vas Deferens: A Case Study.

Congenital bilateral absence of the vas deferens (CBAVD) occurs in almost all men with cystic fibrosis. Prevailing theories on this pathophysiology relate to pathogenic mutations in the cystic fibrosis transmembrane regulator gene leading to agenesis or obliteration of vas deferens in utero. In this study, we present a case of two brothers with congenital anomalies of the vas deferens who were found to have carried a rare, heterozygous cystic fibrosis transmembrane regulator variant p.r347h without pulmonary or gastrointestinal signs or symptoms of cystic fibrosis .

Preksha Dhyana Meditation Effect on the DNA Methylation Signature in College Students.

Introduction: The stress and psychological factors affect the human transcriptomic and epigenomic landscapes. Preksha Dhyana meditation (PM) was found to be effective, in novice healthy college student meditators, at the cognitive skills and transcriptomic levels. Recently published data showed that PM induced alterations at the transcriptome level in healthy and novice college students. Methods: To decipher potential mechanisms underlying the PM effect at the cellular level, array-based methylation analyses in peripheral blood were performed at baseline and 8 weeks postintervention in 34 participants. Results: Overall, 470 CpG sites were nominally differentially methylated (p ≤ 0.05 and change magnitude from ≥3% to ≤ -3%) between baseline and 8 weeks postintervention with 180 sites hypermethylated and 290 sites hypomethylated. Pathway analysis of the genes linked to the differentially methylated sites revealed the enrichment of several molecular and cellular signaling pathways, especially metabolic and brain function signaling pathways. Conclusions: Besides its beneficial effects on cognitive skills and transcriptome alterations, the current data indicate that PM meditation also affects the DNA methylation profile of novice and healthy college students 8 weeks postintervention. Clinical Trial Registration: NCT03779269.

Admixture mapping identifies novel Alzheimer's disease risk regions in African Americans.

BACKGROUND: This study used admixture mapping to prioritize the genetic regions associated with Alzheimer's disease (AD) in African American (AA) individuals, followed by ancestry-aware regression analysis to fine-map the prioritized regions. METHODS: We analyzed 10,271 individuals from 17 different AA datasets. We performed admixture mapping and meta-analyzed the results. We then used regression analysis, adjusting for local ancestry main effects and interactions with genotype, to refine the regions identified from admixture mapping. Finally, we leveraged in silico annotation and differential gene expression data to prioritize AD-related variants and genes. RESULTS: Admixture mapping identified two genome-wide significant loci on chromosomes 17p13.2 (p = 2.2 × 10-5 ) and 18q21.33 (p = 1.2 × 10-5 ). Our fine mapping of the chromosome 17p13.2 and 18q21.33 regions revealed several interesting genes such as the MINK1, KIF1C, and BCL2. DISCUSSION: Our ancestry-aware regression approach showed that AA individuals have a lower risk of AD if they inherited African ancestry admixture block at the 17p13.2 locus. HIGHLIGHTS: We identified two genome-wide significant admixture mapping signals: on chromosomes 17p13.2 and 18q21.33, which are novel in African American (AA) populations. Our ancestry-aware regression approach showed that AA individuals have a lower risk of Alzheimer's disease (AD) if they inherited African ancestry admixture block at the 17p13.2 locus. We found that the overall proportion of African ancestry does not differ between the cases and controls that suggest African genetic ancestry alone is not likely to explain the AD prevalence difference between AA and non-Hispanic White populations.

Transcriptomic analysis of isolated and pooled human postmortem cerebellar Purkinje cells in autism spectrum disorders.

At present, the neuronal mechanisms underlying the diagnosis of autism spectrum disorder (ASD) have not been established. However, studies from human postmortem ASD brains have consistently revealed disruptions in cerebellar circuitry, specifically reductions in Purkinje cell (PC) number and size. Alterations in cerebellar circuitry would have important implications for information processing within the cerebellum and affect a wide range of human motor and non-motor behaviors. Laser capture microdissection was performed to obtain pure PC populations from a cohort of postmortem control and ASD cases and transcriptional profiles were compared. The 427 differentially expressed genes were enriched for gene ontology biological processes related to developmental organization/connectivity, extracellular matrix organization, calcium ion response, immune function and PC signaling alterations. Given the complexity of PCs and their far-ranging roles in response to sensory stimuli and motor function regulation, understanding transcriptional differences in this subset of cerebellar cells in ASD may inform on convergent pathways that impact neuronal function.