Long COVID in People With Multiple Sclerosis and Related Disorders: A Multicenter Cross-Sectional Study.

Background: Managing long COVID in people with multiple sclerosis and related disorders (pwMSRD) is complex due to overlapping symptoms. To address evidence gaps, we evaluated long COVID susceptibility in pwMSRD versus controls and its associations with multi-domain function and disability.

Methods: In this multicenter cross-sectional study, participants completed a survey covering 71 post-infection symptoms, distinguishing new-onset from worsening symptoms.

Characterizing Post-Mortem Brain Molecular Taxonomy of Cognitive Resilience and Translating it to Living Humans.

Here, we define cognitive resilience as slower or faster cognitive decline after we regress out the effects of common brain neuropathologies. Its understanding could provide important insights into the biology underlying cognitive health, enabling the development of more effective strategies to prevent cognitive decline and dementia. However, this requires the development of a practical method to quantify resilience and measure it in living individuals, as well as identifying heterogenous pathways associated with resilience in different individuals.

Cortical Gray Matter Proteins Associated With Cerebral Amyloid Angiopathy in Community-Dwelling Older Adults: An Autopsy Study.

Background And Objectives: Cerebral amyloid angiopathy (CAA) is the accumulation of β-amyloid (Aβ) in the walls of small vessels in the leptomeninges and cortex and is a risk factor of intracerebral hemorrhage and dementia, but its underlying mechanism is unknown. We examined cortical proteins in relation to CAA to elucidate the molecular mechanisms underlying CAA.

Methods: Data were collected from participants of 5 community-based cohorts of older adults.

Sleep chart of biological aging clocks across organs and omics.

Optimal sleep plays a vital role in promoting healthy aging and enhancing longevity. This study proposes a Sleep Chart to assess the relationship between sleep duration and 23 biological aging clocks across 17 organ systems or tissues and 3 omics data types (imaging, proteomics, and metabolomics). First, a systemic, U-shaped pattern shows that both short (<6 hours) and long (>8 hours) sleep duration are linked to elevated biological age gaps (BAGs) across 9 brain and body systems and 3 omics types, with optimal sleep time varying by organ and sex ([6.

fSuSiE enables fine-mapping of QTLs from genome-scale molecular profiles.

Molecular quantitative trait locus (QTL) studies seek to identify the causal variants affecting molecular traits like DNA methylation and histone modifications. However, existing fine-mapping tools are not well suited to molecular traits, and so molecular QTL analyses typically proceed by considering each variant and each molecular measurement independently, ignoring the LD among variants and the spatial correlation in effects between nearby sites. This severely limits accuracy in identifying causal variants and quantifying their molecular trait effects.

TPClust: Temporal Profile-Guided Subtyping Using High-Dimensional Omics Data.

Clustering is widely used to identify subtypes in heterogeneous populations, yet most approaches rarely integrate longitudinal phenotypic trajectories with high-dimensional molecular profiles, limiting their ability to resolve biologically and clinically meaningful heterogeneity in progressive diseases. We developed TPClust, a supervised, semi-parametric clustering method that integrates high-dimensional omics data with longitudinal phenotypes including outcomes and covariates for outcome-guided subtyping. TPClust jointly models latent subtype membership and longitudinal outcome trajectories using multinomial logistic regression informed by molecular features selected via structured regularization, along with spline-based regression to capture subtype-specific, time-varying covariate effects.

Genotyping TOMM40'523 poly-T polymorphisms using whole-genome sequencing.

The TOMM40'523 poly-T repeat polymorphism (rs10524523) has been associated with cognitive decline and Alzheimer's disease (AD) progression. Challenges in processing whole-genome sequencing (WGS) data traditionally require additional PCR and targeted sequencing assays to genotype these polymorphisms. We introduce a computational pipeline that integrates multiple short tandem repeat (STR) detection tools in an ensemble machine learning model using XGBoost.

CD33 and clusterin interact biophysically and genetically to modulate Alzheimer risk.

We report the results of structural, functional and genetic studies on the CD33 sialic acid- binding receptor that reveal how non-coding variants in CD33 alter risk for Alzheimer's disease (AD). The full-length CD33 isoform, whose expression is upregulated by non-coding AD-risk alleles, preferentially forms dimers at the cell surface, where they interact with AD-related proteins (clusterin and Aβ). This interaction induces CD33 inhibitory signalling and downregulates protective microglial functions including phagocytic removal of amyloid plaques.

CD33-CD45 Interaction Reveals a Mechanistic Link to Alzheimer's Disease Susceptibility.

The innate immune gene 33, encoding a myeloid inhibitory sialic acid-binding receptor, is associated with Alzheimer's disease (AD) susceptibility. The AD-associated risk variant reduces splicing of the sialic acid-binding domain and increases expression of the full-length (sialic acid-binding) CD33 isoform seven-fold compared to the protective genotype. Here we identify CD45 as an immune cell-specific sialic acid-dependent CD33 binding partner, whose phosphatase activity is inhibited by CD33.

Single-cell transcriptomic landscape of the neuroimmune compartment in amyotrophic lateral sclerosis brain and spinal cord.

Development of therapeutic approaches that target specific microglia responses in amyotrophic lateral sclerosis (ALS) is crucial due to the involvement of microglia in ALS progression. Our study identifies the predominant microglia subset in human ALS primary motor cortex and spinal cord as an undifferentiated phenotype with dysregulated respiratory electron transport. Moreover, we find that the interferon response microglia subset is enriched in donors with aggressive disease progression, while a previously described potentially protective microglia phenotype is depleted in ALS.

The Association Between Age of Menopause and Hysterectomy Status and Alzheimer's Disease Risk in a Cohort of Older White and Black Women.

To determine whether age at menopause and premenopausal hysterectomy status are associated with incident Alzheimer's disease (AD) dementia in a group of older community-dwelling women. Participants from the Rush Memory and Aging Project, the Religious Orders Study, and the Minority Aging Research Study were included ( = 2,862, baseline age 77.1 ± 7.

Polygenic prediction of body mass index and obesity through the life course and across ancestries.

Polygenic scores (PGSs) for body mass index (BMI) may guide early prevention and targeted treatment of obesity. Using genetic data from up to 5.1 million people (4.

A Radiomic Approach to Clinical MRI Refines the Thalamus-Cognition Link in Multiple Sclerosis.

Background And Purpose: Radiomics extracts imaging features that may not be detectable through conventional volumetric analyses. Given their role in multiple sclerosis (MS), we applied radiomics to thalamic nuclei and examined their associations with cognitive performance.

Methods: A total of 601 individuals were included (342 people with MS [PwMS] from two cohorts and 259 healthy controls [HC]).

Accelerating biomedical discoveries in brain health through transformative neuropathology of aging and neurodegeneration.

Transformative neuropathology is redefining human brain research by integrating foundational descriptive pathology with advanced methodologies. These approaches, spanning multi-omics studies and machine learning applications, will drive discovery for the identification of biomarkers, therapeutic targets, and complex disease patterns through comprehensive analyses of postmortem human brain tissue. Yet critical challenges remain, including the sustainability of brain banks, expanding donor participation, strengthening training pipelines, enabling rapid autopsies, supporting collaborative platforms, and integrating data across modalities.

Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies known and novel cross-population and ancestry-specific associations as novel risk loci for Alzheimer's disease.

Background: Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in ancestry groups of predominantly non-European ancestral background in genome-wide association studies (GWAS). We construct and analyze a multi-ancestry GWAS dataset in the Alzheimer's Disease Genetics Consortium (ADGC) to test for novel shared and population-specific late-onset Alzheimer's disease (LOAD) susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6728 African American, 8899 Hispanic (HIS), and 3232 East Asian individuals, performing within ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis.

Results: We identify 13 loci with cross-population associations including known loci at/near CR1, BIN1, TREM2, CD2AP, PTK2B, CLU, SHARPIN, MS4A6A, PICALM, ABCA7, APOE, and two novel loci not previously reported at 11p12 (LRRC4C) and 12q24.

Genetic insights into the association between inflammatory bowel disease and Alzheimer's disease.

Myeloid cells, including monocytes, macrophages, and microglia, play major roles in innate and adaptive immune responses. Alzheimer's disease (AD) and inflammatory bowel disease (IBD) susceptibility loci are both enriched for genes expressed in myeloid cells, so we assessed whether these myeloid pathways may be shared. Leveraging genome-wide association study results, we investigated the causal effect of IBD (including ulcerative colitis and Crohn's disease) variants on AD and its endophenotypes.

Phosphoproteomics unveils the signaling dynamics in neuronal cells stimulated with insulin and insulin-like growth factors.

Background: Given the role of metabolism in brain health and disease, investigating the role of insulin (INS) and insulin-like growth factors (IGFs) as potential therapeutic strategies for neurodegenerative diseases is currently underway. Yet, the signaling pathways associated with INS and IGFs in the brain remain elusive, particularly for the human brain. Unraveling these pathways is critical for harnessing their therapeutic potential in metabolism-associated brain disorders.

A Radiomic Approach to Clinical MRI Refines the Thalamus-Cognition Link in Multiple Sclerosis.

Background And Objectives: Radiomics extracts imaging features that may not be detectable through conventional volumetric analyses. Given their role in multiple sclerosis (MS), we applied radiomics to thalamic nuclei and examined their associations with cognitive performance.

Methods: A total of 601 individuals were included (342 people with MS-PwMS from two cohorts, and 259 healthy controls-HC).

Biological Age and Age Acceleration Predict Alzheimer's Disease Plasma Biomarker Levels.

Epigenetic clocks can predict pathological aging associated with Alzheimer's disease (AD) risk, albeit findings are mixed regarding if clocks are predictive in blood and in non-European populations. We constructed epigenetic clocks from blood methylation data in 704 older Hispanic adults and tested the association with a clinical diagnosis of AD and plasma biomarker levels. Biological age and age acceleration, the rate of biological aging, were significantly associated with sex, clinical diagnosis, and levels of eight plasma biomarkers, including P-Tau217 levels.

Sleep, pericyte subtypes and cognitive decline in adults with and without Alzheimer's disease.

Sleep fragmentation is common in older adults and is associated with cognitive impairment and dementia, as well as key histopathological correlates of dementia, including small vessel disease and cerebral infarcts. Vascular and blood-brain barrier dysfunction are thought to contribute to cognitive decline and dementia. Pericytes, a key vascular cell type, may play a key role.

Cell type-specific associations with Alzheimer's Disease conserved across racial and ethnic groups.

Genomic studies at single-cell resolution have implicated multiple cell types associated with clinical and pathological traits in Alzheimer's Disease (AD), but have not examined common features across broad, multi-ethnic populations, and across multiple regions. To bridge this gap, we performed single-nucleus RNA-seq and ATAC-seq profiling of cortical and subcortical brain regions from post-mortem samples across Non-Latin White, African American, and Latin donors (the latter of any race). Using discrete and continuous dissection of molecular programs, we elucidate cell-type-specific glial and neuronal signatures associated with AD across multiple population groups.

Proteome-wide association studies using summary pQTL data of brain, CSF, and plasma identify 30 risk genes of Alzheimer's disease dementia.

Background: A proteome-wide association study (PWAS) that integrates proteomic data with genome-wide association study (GWAS) summary data is a powerful tool for studying Alzheimer's disease (AD) dementia. Existing PWAS analyses of AD often rely on the availability of individual-level proteomic and genetic data of a reference panel. Leveraging summary protein quantitative trait loci (pQTL) reference data of multiple AD-relevant tissues is expected to improve PWAS findings of AD dementia.

Early neuronal reprogramming and cell cycle reentry shape Alzheimer's disease progression.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by hallmark pathologies, synaptic dysfunction, neuronal loss, gliosis and cognitive decline-dementia. Recent large-scale cell atlases of human AD brains exposed vulnerability of specific neuronal subtypes and highlighted early, coordinated glial responses, suggesting glial involvement in disease progression. However, the timing and nature of neuronal changes, differences between neuronal subtypes, and their coordination with glia remain unclear.

Cytokine expression profile in the human brain of older adults.

Alzheimer's disease (AD) is a complex neurodegenerative condition linked to chronic neuroinflammation. This study investigates the cytokine gene expression profile in cortical tissue samples from elderly individuals with and without AD to identify potential biomarkers and enhance our understanding of disease pathogenesis. Utilizing high-depth RNA sequencing data, we identified a set of cytokines whose expression significantly associated with different aspects of the AD phenotype, including measures of neurofibrillary tangles, amyloid-β deposition, and a person-specific rate of cognitive decline.

Cell-type-specific Transcriptomic-wide Association Studies Detected 91 Independent Risk Genes for Alzheimer's Disease Dementia.

Existing TWASs of AD dementia typically use a single statistical method to identify cell-type-specific risk genes. Here we sought to improve on existing approaches and utilized an omnibus xWAS pipeline to integrate snRNA-seq dataset (n=415) of dorsolateral prefrontal cortex (DLPFC) and the latest GWAS data of AD dementia to detect cell-type-specific risk genes. We identified 223 cell-type-specific TWAS risk genes across six major brain cell types, including 91 independent associations of which 11 are novel.