African origin haplotype protective for Alzheimer's disease in APOE ε4 carriers: exploring potential mechanisms.

APOE ε4 is the strongest genetic risk factor for Alzheimer's disease (AD) with approximately 50% of AD patients carrying at least one APOE ε4 allele. Our group identified a protective interaction between APOE ε4 with the African-specific A allele of rs10423769, which reduces the AD risk effect of APOE ε4 homozygotes by approximately 75%. The protective variant lies 2Mb from APOE in a region of segmental duplications (SD) of chromosome 19 containing a cluster of pregnancy specific beta-1 glycoprotein genes ( PSGs ) and a long non-coding RNA. Using both short and long read sequencing, we demonstrate that rs10423769_A allele lies within a unique single haplotype inside this region of segmental duplication. We identified the protective haplotype in all African ancestry populations studied, including both West and East Africans, suggesting the variant has an old origin. Long-read sequencing identified both structural and DNA methylation differences between the protective rs10423769_A allele and non-protective haplotypes. An expanded variable number tandem repeat (VNTR) containing multiple MEF2 family transcription factor binding motifs was found associated with the protective haplotype (p-value = 2.9e-10). These findings provide novel insights into the mechanisms of this African-origin protective variant for AD in APOE ε4 carriers and supports the importance of including all ancestries in AD research.

Validation of a Simplified Tissue-to-Reference Ratio Measurement Using SUVR to Assess Synaptic Density Alterations in Alzheimer Disease with [11C]UCB-J PET.

Simplified methods of acquisition and quantification would facilitate the use of synaptic density imaging in multicenter and longitudinal studies of Alzheimer disease (AD). We validated a simplified tissue-to-reference ratio method using SUV ratios (SUVRs) for estimating synaptic density with [11C]UCB-J PET. Methods: Participants included 31 older adults with AD and 16 with normal cognition. The distribution volume ratio (DVR) using simplified reference tissue model 2 was compared with SUVR at short scan windows using a whole-cerebellum reference region. Results: Synaptic density was reduced in AD participants using DVR or SUVR. SUVR using later scan windows (60-90 or 70-90 min) was minimally biased, with the strongest correlation with DVR. Effect sizes using SUVR at these late time windows were minimally reduced compared with effect sizes with DVR. Conclusion: A simplified tissue-to-reference method may be useful for multicenter and longitudinal studies seeking to measure synaptic density in AD.

MIAMI-AD (Methylation in Aging and Methylation in AD): an integrative knowledgebase that facilitates explorations of DNA methylation across sex, aging, and Alzheimer's disease.

Alzheimer's disease (AD) is a common neurodegenerative disorder with a significant impact on aging populations. DNA methylation (DNAm) alterations have been implicated in both the aging processes and the development of AD. Given that AD affects more women than men, it is also important to explore DNAm changes that occur specifically in each sex. We created MIAMI-AD, a comprehensive knowledgebase containing manually curated summary statistics from 98 published tables in 38 studies, all of which included at least 100 participants. MIAMI-AD enables easy browsing, querying, and downloading DNAm associations at multiple levels-at individual CpG, gene, genomic regions, or genome-wide, in one or multiple studies. Moreover, it also offers tools to perform integrative analyses, such as comparing DNAm associations across different phenotypes or tissues, as well as interactive visualizations. Using several use case examples, we demonstrated that MIAMI-AD facilitates our understanding of age-associated CpGs in AD and the sex-specific roles of DNAm in AD. This open-access resource is freely available to the research community, and all the underlying data can be downloaded. MIAMI-AD facilitates integrative explorations to better understand the interplay between DNAm across aging, sex, and AD. Database URL: https://miami-ad.org/.

Critical evaluation of the reliability of DNA methylation probes on the Illumina MethylationEPIC v1.0 BeadChip microarrays.

DNA methylation (DNAm) plays a crucial role in a number of complex diseases. However, the reliability of DNAm levels measured using Illumina arrays varies across different probes. Previous research primarily assessed probe reliability by comparing duplicate samples between the 450k-450k or 450k-EPIC platforms, with limited investigations on Illumina EPIC v1.0 arrays. We conducted a comprehensive assessment of the EPIC v1.0 array probe reliability using 69 blood DNA samples, each measured twice, generated by the Alzheimer's Disease Neuroimaging Initiative study. We observed higher reliability in probes with average methylation beta values of 0.2 to 0.8, and lower reliability in type I probes or those within the promoter and CpG island regions. Importantly, we found that probe reliability has significant implications in the analyses of Epigenome-wide Association Studies (EWAS). Higher reliability is associated with more consistent effect sizes in different studies, the identification of differentially methylated regions (DMRs) and methylation quantitative trait locus (mQTLs), and significant correlations with downstream gene expression. Moreover, blood DNAm measurements obtained from probes with higher reliability are more likely to show concordance with brain DNAm measurements. Our findings, which provide crucial reliability information for probes on the EPIC v1.0 array, will serve as a valuable resource for future DNAm studies.

IL-1 receptor 1 signaling shapes the development of viral antigen-specific CD4+ T cell responses following COVID-19 mRNA vaccination.

BACKGROUND: The innate immune cytokine interleukin (IL)-1 can affect T cell immunity, a critical factor in host defense. In a previous study, we identified a subset of human CD4+ T cells which express IL-1 receptor 1 (IL-1R1). However, the expression of such receptor by viral antigen-specific CD4+ T cells and its biological implication remain largely unexplored. This led us to investigate the implication of IL-1R1 in the development of viral antigen-specific CD4+ T cell responses in humans, including healthy individuals and patients with primary antibody deficiency (PAD), and animals. METHODS: We characterized CD4+ T cells specific for SARS-CoV-2 spike (S) protein, influenza virus, and cytomegalovirus utilizing multiplexed single cell RNA-seq, mass cytometry and flow cytometry followed by an animal study. FINDINGS: In healthy individuals, CD4+ T cells specific for viral antigens, including S protein, highly expressed IL-1R1. IL-1ß promoted interferon (IFN)-γ expression by S protein-stimulated CD4+ T cells, supporting the functional implication of IL-1R1. Following the 2nd dose of COVID-19 mRNA vaccines, S protein-specific CD4+ T cells with high levels of IL-1R1 increased, likely reflecting repetitive antigenic stimulation. The expression levels of IL-1R1 by such cells correlated with the development of serum anti-S protein IgG antibody. A similar finding of increased expression of IL-1R1 by S protein-specific CD4+ T cells was also observed in patients with PAD following COVID-19 mRNA vaccination although the expression levels of IL-1R1 by such cells did not correlate with the levels of serum anti-S protein IgG antibody. In mice immunized with COVID-19 mRNA vaccine, neutralizing IL-1R1 decreased IFN-γ expression by S protein-specific CD4+ T cells and the development of anti-S protein IgG antibody. INTERPRETATION: Our results demonstrate the significance of IL-1R1 expression in CD4+ T cells for the development of viral antigen-specific CD4+ T cell responses, contributing to humoral immunity. This provides an insight into the regulation of adaptive immune responses to viruses via the IL-1 and IL-1R1 interface. FUNDING: Moderna to HJP, National Institutes of Health (NIH) 1R01AG056728 and R01AG055362 to IK and KL2 TR001862 to JJS, Quest Diagnostics to IK and RB, and the Mathers Foundation to RB.

SORD-deficient rats develop a motor-predominant peripheral neuropathy unveiling novel pathophysiological insights.

Biallelic SORD mutations cause one of the most frequent forms of recessive hereditary neuropathy, estimated to affect ∼10 000 patients in North America and Europe alone. Pathogenic SORD loss-of-function changes in the encoded enzyme sorbitol dehydrogenase result in abnormally high sorbitol levels in cells and serum. How sorbitol accumulation leads to peripheral neuropathy remains to be elucidated. A reproducible animal model for SORD neuropathy is essential to illuminate the pathogenesis of SORD deficiency and for preclinical studies of potential therapies. Therefore, we have generated a Sord knockout (KO), Sord-/-, Sprague Dawley rat, to model the human disease and to investigate the pathophysiology underlying SORD deficiency. We have characterized the phenotype in these rats with a battery of behavioural tests as well as biochemical, physiological and comprehensive histological examinations. Sord-/- rats had remarkably increased levels of sorbitol in serum, CSF and peripheral nerve. Moreover, serum from Sord-/- rats contained significantly increased levels of neurofilament light chain, an established biomarker for axonal degeneration. Motor performance significantly declined in Sord-/- animals starting at ∼7 months of age. Gait analysis evaluated with video motion-tracking confirmed abnormal gait patterns in the hindlimbs. Motor nerve conduction velocities of the tibial nerves were slowed. Light and electron microscopy of the peripheral nervous system revealed degenerating myelinated axons, de- and remyelinated axons, and a likely pathognomonic finding-enlarged 'ballooned' myelin sheaths. These findings mainly affected myelinated motor axons; myelinated sensory axons were largely spared. In summary, Sord-/- rats develop a motor-predominant neuropathy that closely resembles the human phenotype. Our studies revealed novel significant aspects of SORD deficiency, and this model will lead to an improved understanding of the pathophysiology and the therapeutic options for SORD neuropathy.

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.

Aging gene signature of memory CD8+ T cells is associated with neurocognitive functioning in Alzheimer's disease.

BACKGROUND: Memory CD8+ T cells expand with age. We previously demonstrated an age-associated expansion of effector memory (EM) CD8+ T cells expressing low levels of IL-7 receptor alpha (IL-7Rαlow) and the presence of its gene signature (i.e., IL-7Rαlow aging genes) in peripheral blood of older adults without Alzheimer's disease (AD). Considering age as the strongest risk factor for AD and the recent finding of EM CD8+ T cell expansion, mostly IL-7Rαlow cells, in AD, we investigated whether subjects with AD have alterations in IL-7Rαlow aging gene signature, especially in relation to genes possibly associated with AD and disease severity. RESULTS: We identified a set of 29 candidate genes (i.e., putative AD genes) which could be differentially expressed in peripheral blood of patients with AD through the systematic search of publicly available datasets. Of the 29 putative AD genes, 9 genes (31%) were IL-7Rαlow aging genes (P < 0.001), suggesting the possible implication of IL-7Rαlow aging genes in AD. These findings were validated by RT-qPCR analysis of 40 genes, including 29 putative AD genes, additional 9 top IL-7R⍺low aging but not the putative AD genes, and 2 inflammatory control genes in peripheral blood of cognitively normal persons (CN, 38 subjects) and patients with AD (40 mild cognitive impairment and 43 dementia subjects). The RT-qPCR results showed 8 differentially expressed genes between AD and CN groups; five (62.5%) of which were top IL-7Rαlow aging genes (FGFBP2, GZMH, NUAK1, PRSS23, TGFBR3) not previously reported to be altered in AD. Unbiased clustering analysis revealed 3 clusters of dementia patients with distinct expression levels of the 40 analyzed genes, including IL-7Rαlow aging genes, which were associated with neurocognitive function as determined by MoCA, CDRsob and neuropsychological testing. CONCLUSIONS: We report differential expression of "normal" aging genes associated with IL-7Rαlow EM CD8+ T cells in peripheral blood of patients with AD, and the significance of such gene expression in clustering subjects with dementia due to AD into groups with different levels of cognitive functioning. These results provide a platform for studies investigating the possible implications of age-related immune changes, including those associated with CD8+ T cells, in AD.

Sord deficient rats develop a motor-predominant peripheral neuropathy unveiling novel pathophysiological insights.

Biallelic SORD mutations cause one of the most frequent forms of recessive hereditary neuropathy, estimated to affect approximately 10,000 patients in North America and Europe alone. Pathogenic SORD loss-of-function changes in the encoded enzyme sorbitol dehydrogenase result in abnormally high sorbitol levels in cells and serum. How sorbitol accumulation leads to peripheral neuropathy remains to be elucidated. A reproducible animal model for SORD neuropathy is essential to illuminate the pathogenesis of SORD deficiency and for preclinical studies of potential therapies. Therefore, we have generated a Sord knockout (KO), Sord -/- , Sprague Dawley rat, to model the human disease and to investigate the pathophysiology underlying SORD deficiency. We have characterized the phenotype in these rats with a battery of behavioral tests as well as biochemical, physiological, and comprehensive histological examinations. Sord -/- rats had remarkably increased levels of sorbitol in serum, cerebral spinal fluid (CSF), and peripheral nerve. Moreover, serum from Sord -/- rats contained significantly increased levels of neurofilament light chain, NfL, an established biomarker for axonal degeneration. Motor performance significantly declined in Sord -/- animals starting at ∼7 months of age. Gait analysis evaluated with video motion tracking confirmed abnormal gait patterns in the hindlimbs. Motor nerve conduction velocities of the tibial nerves were slowed. Light and electron microscopy of the peripheral nervous system revealed degenerating myelinated axons, de- and remyelinated axons, and a likely pathognomonic finding - enlarged "ballooned" myelin sheaths. These findings mainly affected myelinated motor axons; myelinated sensory axons were largely spared. In summary, Sord -/- rats develop a motor-predominant neuropathy that closely resembles the human phenotype. Our studies revealed novel significant aspects of SORD deficiency, and this model will lead to an improved understanding of the pathophysiology and the therapeutic options for SORD neuropathy.

MIAMI-AD (Methylation in Aging and Methylation in AD): an integrative knowledgebase that facilitates explorations of DNA methylation across sex, aging, and Alzheimer's disease.

Alzheimer's disease (AD) is a common neurodegenerative disorder with a significant impact on aging populations. DNA methylation (DNAm) alterations have been implicated in both the aging processes and the development of AD. Given that AD affects more women than men, it is also important to explore DNAm changes that occur specifically in each sex. We created MIAMI-AD, a comprehensive knowledge base containing manually curated summary statistics from 97 published tables in 37 studies, all of which included at least 100 participants. MIAMI-AD enables easy browsing, querying, and downloading DNAm associations at multiple levels - at individual CpG, gene, genomic regions, or genome-wide, in one or multiple studies. Moreover, it also offers tools to perform integrative analyses, such as comparing DNAm associations across different phenotypes or tissues, as well as interactive visualizations. Using several use case examples, we demonstrated that MIAMI-AD facilitates our understanding of age-associated CpGs in AD and the sex-specific roles of DNAm in AD. This open-access resource is freely available to the research community, and all the underlying data can be downloaded. MIAMI-AD (https://miami-ad.org/) facilitates integrative explorations to better understand the interplay between DNAm across aging, sex, and AD.

Critical evaluation of the reliability of DNA methylation probes on the Illumina MethylationEPIC BeadChip microarrays.

DNA methylation (DNAm) plays a crucial role in a number of complex diseases. However, the reliability of DNAm levels measured using Illumina arrays varies across different probes. Previous research primarily assessed probe reliability by comparing duplicate samples between the 450k-450k or 450k-EPIC platforms, with limited investigations on Illumina EPIC arrays. We conducted a comprehensive assessment of the EPIC array probe reliability using 138 duplicated blood DNAm samples generated by the Alzheimer's Disease Neuroimaging Initiative study. We introduced a novel statistical measure, the modified intraclass correlation, to better account for the disagreement in duplicate measurements. We observed higher reliability in probes with average methylation beta values of 0.2 to 0.8, and lower reliability in type I probes or those within the promoter and CpG island regions. Importantly, we found that probe reliability has significant implications in the analyses of Epigenome-wide Association Studies (EWAS). Higher reliability is associated with more consistent effect sizes in different studies, the identification of differentially methylated regions (DMRs) and methylation quantitative trait locus (mQTLs), and significant correlations with downstream gene expression. Moreover, blood DNAm measurements obtained from probes with higher reliability are more likely to show concordance with brain DNAm measurements. Our findings, which provide crucial reliable information for probes on the EPIC array, will serve as a valuable resource for future DNAm studies.

Aging gene signature of IL-7 receptor alpha low effector memory CD8+ T cells is associated with neurocognitive functioning in Alzheimer's disease.

CD45RA+ effector memory (EM) CD8+ T cell expansion was reported in Alzheimer's disease (AD). Such cells are IL-7 receptor alpha (IL-7Rα)low EM CD8+ T cells, which expand with age and have a unique aging gene signature (i.e., IL-7Rαlow aging genes). Here we investigated whether IL-7Rαlow aging genes and previously reported AD and memory (ADM) genes overlapped with clinical significance in AD patients. RT-qPCR analysis of 40 genes, including 29 ADM, 9 top IL-7Ralow aging and 2 control genes, showed 8 differentially expressed genes between AD and cognitively normal groups; five (62.5%) of which were top IL-7Rαlow aging genes. Over-representation analysis revealed that these genes were highly present in molecular and biological pathways associated with AD. Distinct expression levels of these genes were associated with neuropsychological testing performance in 3 subgroups of dementia participants. Our findings support the possible implication of the IL-7Rαlow aging gene signature with AD.

Distinct CSF biomarker-associated DNA methylation in Alzheimer's disease and cognitively normal subjects.

BACKGROUND: Growing evidence has demonstrated that DNA methylation (DNAm) plays an important role in Alzheimer's disease (AD) and that DNAm differences can be detected in the blood of AD subjects. Most studies have correlated blood DNAm with the clinical diagnosis of AD in living individuals. However, as the pathophysiological process of AD can begin many years before the onset of clinical symptoms, there is often disagreement between neuropathology in the brain and clinical phenotypes. Therefore, blood DNAm associated with AD neuropathology, rather than with clinical data, would provide more relevant information on AD pathogenesis. METHODS: We performed a comprehensive analysis to identify blood DNAm associated with cerebrospinal fluid (CSF) pathological biomarkers for AD. Our study included matched samples of whole blood DNA methylation, CSF Aß42, phosphorylated tau181 (pTau181), and total tau (tTau) biomarkers data, measured on the same subjects and at the same clinical visits from a total of 202 subjects (123 CN or cognitively normal, 79 AD) in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. To validate our findings, we also examined the association between premortem blood DNAm and postmortem brain neuropathology measured on a group of 69 subjects in the London dataset. RESULTS: We identified a number of novel associations between blood DNAm and CSF biomarkers, demonstrating that changes in pathological processes in the CSF are reflected in the blood epigenome. Overall, the CSF biomarker-associated DNAm is relatively distinct in CN and AD subjects, highlighting the importance of analyzing omics data measured on cognitively normal subjects (which includes preclinical AD subjects) to identify diagnostic biomarkers, and considering disease stages in the development and testing of AD treatment strategies. Moreover, our analysis revealed biological processes associated with early brain impairment relevant to AD are marked by DNAm in the blood, and blood DNAm at several CpGs in the DMR on HOXA5 gene are associated with pTau181 in the CSF, as well as tau-pathology and DNAm in the brain, nominating DNAm at this locus as a promising candidate AD biomarker. CONCLUSIONS: Our study provides a valuable resource for future mechanistic and biomarker studies of DNAm in AD.

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.

Distinct CSF biomarker-associated DNA methylation in Alzheimer's disease and cognitively normal subjects.

Background Growing evidence has demonstrated that DNA methylation (DNAm) plays an important role in Alzheimer's disease (AD) and that DNAm differences can be detected in the blood of AD subjects. Most studies have correlated blood DNAm with the clinical diagnosis of AD in living individuals. However, as the pathophysiological process of AD can begin many years before the onset of clinical symptoms, there is often disagreement between neuropathology in the brain and clinical phenotypes. Therefore, blood DNAm associated with AD neuropathology, rather than with clinical data, would provide more relevant information on AD pathogenesis. Methods We performed a comprehensive analysis to identify blood DNAm associated with cerebrospinal fluid (CSF) pathological biomarkers for AD. Our study included matched samples of whole blood DNA methylation, CSF Aß 42 , phosphorylated tau 181 (pTau 181 ), and total tau (tTau) biomarkers data, measured on the same subjects and at the same clinical visits from a total of 202 subjects (123 CN or cognitively normal, 79 AD) in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. To validate our findings, we also examined the association between premortem blood DNAm and postmortem brain neuropathology measured on a group of 69 subjects in the London dataset. Results We identified a number of novel associations between blood DNAm and CSF biomarkers, demonstrating that changes in pathological processes in the CSF are reflected in the blood epigenome. Overall, the CSF biomarker-associated DNAm is relatively distinct in CN and AD subjects, highlighting the importance of analyzing omics data measured on cognitively normal subjects (which includes preclinical AD subjects) to identify diagnostic biomarkers, and considering disease stages in the development and testing of AD treatment strategies. Moreover, our analysis revealed biological processes associated with early brain impairment relevant to AD are marked by DNAm in the blood, and blood DNAm at several CpGs in the DMR on HOXA5 gene are associated with pTau 181 in the CSF, as well as tau-pathology and DNAm in the brain, nominating DNAm at this locus as a promising candidate AD biomarker. Conclusions Our study provides a valuable resource for future mechanistic and biomarker studies of DNAm in AD.

Post cardiac arrest physical exercise mitigates cell death in the septal and thalamic nuclei and ameliorates contextual fear conditioning deficits in rats.

A major concern for cardiac arrest (CA) survivors is the manifestation of long-term cognitive impairments. Physical exercise (PE) is a well-established approach to improve cognitive functions under certain pathological conditions. We previously showed that PE post-CA mitigates cognitive deficits, but the underlying mechanisms remain unknown. To define neuroprotective mechanisms, we analyzed whether PE post-CA protects neurons involved in memory. We first performed a contextual fear conditioning (CFC) test to confirm that PE post-CA preserves memory in rats. We then conducted a cell-count analysis and determined the number of live cells in the hippocampus, and septal and thalamic nuclei, all areas involved in cognitive functions. Lastly, we performed RNA-seq to determine PE post-CA effect on gene expression. Following CA, exercised rats had preserved CFC memory than sham PE animals. Despite this outcome, PE post-CA did not protect hippocampal cells from dying. However, PE ameliorated cell death in septal and thalamic nuclei compared to sham PE animals, suggesting that these nuclei are crucial in mitigating cognitive decline post-CA. Interestingly, PE affected regulation of genes related to neuroinflammation, plasticity, and cell death. These findings reveal potential mechanisms whereby PE post-CA preserves cognitive functions by protecting septal and thalamic cells via gene regulation.

Implication of IL-7 receptor alpha chain expression by CD8+ T cells and its signature in defining biomarkers in aging.

CD8+ T cells play an important role in host defense against infections and malignancies as well as contribute to the development of inflammatory disorders. Alterations in the frequency of naïve and memory CD8+ T cells are one of the most significant changes in the immune system with age. As the world population rapidly ages, a better understanding of aging immune function or immunosenescence could become a basis for discovering treatments of illnesses that commonly occur in older adults. In particular, biomarkers for immune aging could be utilized to identify individuals at high risk of developing age-associated conditions and help monitor the efficacy of therapeutic interventions targeting such conditions. This review details the possible role of CD8+ T cell subsets expressing different levels of the cytokine receptor IL-7 receptor alpha chain (IL-7Rα) and the gene signature associated with IL-7Rα as potential biomarkers for immune aging given the association of CD8+ T cells in host defense, inflammation, and immunosenescence.

Distinct sex-specific DNA methylation differences in Alzheimer's disease.

BACKGROUND: Sex is increasingly recognized as a significant factor contributing to the biological and clinical heterogeneity in AD. There is also growing evidence for the prominent role of DNA methylation (DNAm) in Alzheimer's disease (AD). METHODS: We studied sex-specific DNA methylation differences in the blood samples of AD subjects compared to cognitively normal subjects, by performing sex-specific meta-analyses of two large blood-based epigenome-wide association studies (ADNI and AIBL), which included DNA methylation data for a total of 1284 whole blood samples (632 females and 652 males). Within each dataset, we used two complementary analytical strategies, a sex-stratified analysis that examined methylation to AD associations in male and female samples separately, and a methylation-by-sex interaction analysis that compared the magnitude of these associations between different sexes. After adjusting for age, estimated immune cell type proportions, batch effects, and correcting for inflation, the inverse-variance fixed-effects meta-analysis model was used to identify the most consistent DNAm differences across datasets. In addition, we also evaluated the performance of the sex-specific methylation-based risk prediction models for AD diagnosis using an independent external dataset. RESULTS: In the sex-stratified analysis, we identified 2 CpGs, mapped to the PRRC2A and RPS8 genes, significantly associated with AD in females at a 5% false discovery rate, and an additional 25 significant CpGs (21 in females, 4 in males) at P-value < 1×10-5. In methylation-by-sex interaction analysis, we identified 5 significant CpGs at P-value < 10-5. Out-of-sample validations using the AddNeuroMed dataset showed in females, the best logistic prediction model included age, estimated immune cell-type proportions, and methylation risk scores (MRS) computed from 9 of the 23 CpGs identified in AD vs. CN analysis that are also available in AddNeuroMed dataset (AUC = 0.74, 95% CI: 0.65-0.83). In males, the best logistic prediction model included only age and MRS computed from 2 of the 5 CpGs identified in methylation-by-sex interaction analysis that are also available in the AddNeuroMed dataset (AUC = 0.70, 95% CI: 0.56-0.82). CONCLUSIONS: Overall, our results show that the DNA methylation differences in AD are largely distinct between males and females. Our best-performing sex-specific methylation-based prediction model in females performed better than that for males and additionally included estimated cell-type proportions. The significant discriminatory classification of AD samples with our methylation-based prediction models demonstrates that sex-specific DNA methylation could be a predictive biomarker for AD. As sex is a strong factor underlying phenotypic variability in AD, the results of our study are particularly relevant for a better understanding of the epigenetic architecture that underlie AD and for promoting precision medicine in AD.

Cross-tissue analysis of blood and brain epigenome-wide association studies in Alzheimer's disease.

To better understand DNA methylation in Alzheimer's disease (AD) from both mechanistic and biomarker perspectives, we performed an epigenome-wide meta-analysis of blood DNA methylation in two large independent blood-based studies in AD, the ADNI and AIBL studies, and identified 5 CpGs, mapped to the SPIDR, CDH6 genes, and intergenic regions, that are significantly associated with AD diagnosis. A cross-tissue analysis that combined these blood DNA methylation datasets with four brain methylation datasets prioritized 97 CpGs and 10 genomic regions that are significantly associated with both AD neuropathology and AD diagnosis. An out-of-sample validation using the AddNeuroMed dataset showed the best performing logistic regression model includes age, sex, immune cell type proportions, and methylation risk score based on prioritized CpGs in cross-tissue analysis (AUC = 0.696, 95% CI: 0.616 - 0.770, P-value = 2.78 × 10-5). Our study offers new insights into epigenetics in AD and provides a valuable resource for future AD biomarker discovery.

A locus at 19q13.31 significantly reduces the ApoE ε4 risk for Alzheimer's Disease in African Ancestry.

African descent populations have a lower Alzheimer disease risk from ApoE ε4 compared to other populations. Ancestry analysis showed that the difference in risk between African and European populations lies in the ancestral genomic background surrounding the ApoE locus (local ancestry). Identifying the mechanism(s) of this protection could lead to greater insight into the etiology of Alzheimer disease and more personalized therapeutic intervention. Our objective is to follow up the local ancestry finding and identify the genetic variants that drive this risk difference and result in a lower risk for developing Alzheimer disease in African ancestry populations. We performed association analyses using a logistic regression model with the ApoE ε4 allele as an interaction term and adjusted for genome-wide ancestry, age, and sex. Discovery analysis included imputed SNP data of 1,850 Alzheimer disease and 4,331 cognitively intact African American individuals. We performed replication analyses on 63 whole genome sequenced Alzheimer disease and 648 cognitively intact Ibadan individuals. Additionally, we reproduced results using whole-genome sequencing of 273 Alzheimer disease and 275 cognitively intact admixed Puerto Rican individuals. A further comparison was done with SNP imputation from an additional 8,463 Alzheimer disease and 11,365 cognitively intact non-Hispanic White individuals. We identified a significant interaction between the ApoE ε4 allele and the SNP rs10423769_A allele, (ß = -0.54,SE = 0.12,p-value = 7.50x10-6) in the discovery data set, and replicated this finding in Ibadan (ß = -1.32,SE = 0.52,p-value = 1.15x10-2) and Puerto Rican (ß = -1.27,SE = 0.64,p-value = 4.91x10-2) individuals. The non-Hispanic Whites analyses showed an interaction trending in the "protective" direction but failing to pass a 0.05 significance threshold (ß = -1.51,SE = 0.84,p-value = 7.26x10-2). The presence of the rs10423769_A allele reduces the odds ratio for Alzheimer disease risk from 7.2 for ApoE ε4/ε4 carriers lacking the A allele to 2.1 for ApoE ε4/ε4 carriers with at least one A allele. This locus is located approximately 2 mB upstream of the ApoE locus, in a large cluster of pregnancy specific beta-1 glycoproteins on chromosome 19 and lies within a long noncoding RNA, ENSG00000282943. This study identified a new African-ancestry specific locus that reduces the risk effect of ApoE ε4 for developing Alzheimer disease. The mechanism of the interaction with ApoEε4 is not known but suggests a novel mechanism for reducing the risk for ε4 carriers opening the possibility for potential ancestry-specific therapeutic intervention.