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.

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.

Frequency of Microvascular Pathology and Hippocampal Atrophy on Magnetic Resonance Imaging in a Community Study of Alzheimer's Disease with Blood-Based Biomarkers.

Objective: Blood-based biomarkers for Alzheimer's disease (AD), representing antemortem indicators of AD pathophysiology, have greatly improved the accuracy of diagnosis. However, these biomarkers may not capture a frequent coincident pathology, such as cerebrovascular disease.

Methods: We measured plasma amyloid-β40, amyloid-β42, total tau, tau phosphorylated at threonine 181, tau phosphorylated at threonine 217, glial fibrillary acidic protein, and neurofilament light chain in 685 multiancestral individuals who had clinical assessments and brain magnetic resonance imaging.

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.

Single-nucleus multiomics in brains from Hispanic individuals reveal -driven disruption of focal adhesion signaling in the presence of cerebrovascular pathology.

The apolipoprotein E ε4 allele ( ) is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), yet its molecular impact on cerebrovascular biology remains inconclusive, particularly in underrepresented populations with elevated vascular burden. Individuals from Hispanic ancestry experience disproportionately high rates of cerebrovascular pathology, offering a unique opportunity to investigate the mechanisms of cerebrovascular pathology in AD. Here, we performed single-nucleus RNA sequencing (snSeq) on 413,175 nuclei from 52 postmortem Hispanic brains to determine -associated cell type specific transcriptomic changes in a population with elevated cerebrovascular risk.

Identification and Validation of New Molecular Subtypes within the Early and Late Mild Cognitive Impairment Stages of Alzheimer's Disease.

Alzheimer's disease (AD) is a heterogeneous neurodegenerative condition. This study identifies clinically relevant new molecular subtypes of the early and late mild cognitive impairment (EMCI and LMCI) stages of AD from 401 patients in the ADNI consortium. Metabolomics and peripheral blood mononuclear cell (PBMC) transcriptomics data are integrated using Similarity Network Fusion (SNF), resulting in two molecular subtypes within EMCI (EMCI-1 and EMCI-2) and LMCI (LMCI-1 and LMCI-2), respectively.

A factor-based analysis of individual human microglia uncovers regulators of an Alzheimer-related transcriptional signature.

Human microglial heterogeneity is only beginning to be appreciated at the molecular level. Here, we present a large, single-cell atlas of expression signatures from 441,088 live microglia broadly sampled across a diverse set of brain regions and neurodegenerative and neuroinflammatory diseases obtained from 161 donors sampled at autopsy or during a neurosurgical procedure. Using single-cell hierarchical Poisson factorization (scHPF), we derived a 23-factor model for continuous gene expression signatures across microglia which capture specific biological processes (e.

Association of dietary fatty acids with longitudinal change in plasma-based biomarkers of Alzheimer's disease.

Background: Elevated intake of omega-3 polyunsaturated fatty acids is linked to a reduced risk of dementia in some prospective studies. However, few studies have examined the relationship between nutrient intake and plasma biomarkers of Alzheimer's disease.

Objectives: We explored whether omega-3, omega-6, and monounsaturated fat intakes were associated with changes in plasma biomarkers of Alzheimer's disease over time.

Genetic Regulation of the Metabolome Differs by Sex, Alzheimer's Disease Stage, and Plasma Biomarker Status.

We investigated genetic regulators of circulating plasma metabolites to identify pathways underlying biochemical changes in clinical and biomarker-assisted diagnosis of Alzheimer's disease (AD). We computed metabolite quantitative trait loci by using whole genome sequencing and small molecule plasma metabolites from 229 older adults with clinical AD and 322 age-matched healthy controls. Unbiased associations between 6,881 metabolites and 332,772 common genetic variants were tested, adjusted for age, sex, and both metabolomic and genomic principal components.

ε4-induced Fibronectin at the blood-brain barrier is a conserved pathological mediator of disrupted astrocyte-endothelia interaction in Alzheimer's disease.

Unlabelled: Blood-brain barrier (BBB) dysfunction is a key feature of Alzheimer's disease (AD), particularly in individuals carrying the allele. This dysfunction worsens neuroinflammation and hinders the removal of toxic proteins, such as amyloid-beta (Aβ42), from the brain. In post-mortem brain tissues and in animal models, we previously reported that fibronectin accumulates at the BBB predominantly in carriers.

Pathologic subtyping of Alzheimer's disease brain tissue reveals disease heterogeneity.

In recent years, multiple groups have shown that what is currently thought of as "Alzheimer's Disease" (AD) may be usefully viewed as several related disease subtypes. As these efforts have continued, a related issue is how common co-pathologies and ethnicity intersect with AD subtypes. The goal of this study was to use a dataset constituting 153 pathologic variables recorded on 666 AD brain autopsies to better define how co-pathologies and ethnicity relate to established AD subtypes.

A cross-disease resource of living human microglia identifies disease-enriched subsets and tool compounds recapitulating microglial states.

Human microglia play a pivotal role in neurological diseases, but we still have an incomplete understanding of microglial heterogeneity, which limits the development of targeted therapies directly modulating their state or function. Here, we use single-cell RNA sequencing to profile 215,680 live human microglia from 74 donors across diverse neurological diseases and CNS regions. We observe a central divide between oxidative and heterocyclic metabolism and identify microglial subsets associated with antigen presentation, motility and proliferation.

CD33 and SHP-1/ Interaction in Alzheimer's Disease.

Large-scale genetic studies have identified numerous genetic risk factors that suggest a central role for innate immune cells in susceptibility to Alzheimer's disease (AD). CD33, an immunomodulatory transmembrane sialic acid binding protein expressed on myeloid cells, was identified as one such genetic risk factor associated with Alzheimer's disease. Several studies explored the molecular outcomes of genetic variation at the locus.

Gliovascular transcriptional perturbations in Alzheimer's disease reveal molecular mechanisms of blood brain barrier dysfunction.

To uncover molecular changes underlying blood-brain-barrier dysfunction in Alzheimer's disease, we performed single nucleus RNA sequencing in 24 Alzheimer's disease and control brains and focused on vascular and astrocyte clusters as main cell types of blood-brain-barrier gliovascular-unit. The majority of the vascular transcriptional changes were in pericytes. Of the vascular molecular targets predicted to interact with astrocytic ligands, SMAD3, upregulated in Alzheimer's disease pericytes, has the highest number of ligands including VEGFA, downregulated in Alzheimer's disease astrocytes.

ZCCHC17 Modulates Neuronal RNA Splicing and Supports Cognitive Resilience in Alzheimer's Disease.

ZCCHC17 is a putative master regulator of synaptic gene dysfunction in Alzheimer's disease (AD), and ZCCHC17 protein declines early in AD brain tissue, before significant gliosis or neuronal loss. Here, we investigate the function of ZCCHC17 and its role in AD pathogenesis using data from human autopsy tissue (consisting of males and females) and female human cell lines. Co-immunoprecipitation (co-IP) of ZCCHC17 followed by mass spectrometry analysis in human iPSC-derived neurons reveals that ZCCHC17's binding partners are enriched for RNA-splicing proteins.

Lysophosphatidylcholines are associated with P-tau181 levels in early stages of Alzheimer's Disease.

Background: We investigated systemic biochemical changes in Alzheimer's disease (AD) by investigating the relationship between circulating plasma metabolites and both clinical and biomarker-assisted diagnosis of AD.

Methods: We used an untargeted approach with liquid chromatography coupled to high-resolution mass spectrometry to measure exogenous and endogenous small molecule metabolites in plasma from 150 individuals clinically diagnosed with AD and 567 age-matched elderly without dementia of Caribbean Hispanic ancestry. Plasma biomarkers of AD were also measured including P-tau181, Aβ40, Aβ42, total tau, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP).

Reliability and Validity of Self-Reported Vascular Risk Factors: Hypertension, Diabetes, and Heart Disease, in a Multi-Ethnic Community Based Study of Aging and Dementia.

Background: Queries for the presence of cardiovascular and cerebrovascular risk factors are typically assessed through self-report. However, the reliability and validity of self-reported cardiovascular and cerebrovascular risk factors remain inconsistent in aging research.

Objective: To determine the reliability and validity of the most frequently self-reported vascular risk factors: hypertension, diabetes, and heart disease.

Reliability and Validity of self-reported Vascular Risk Factors in a Multi-Ethnic Community Based Study of Aging and Dementia.

Introduction: The reliability and validity of self-reported cardiovascular and cerebrovascular risk factors remains inconsistent in aging research.

Methods: We assessed the reliability, validity, sensitivity, specificity, and percent agreement of self-reported hypertension, diabetes, and heart disease, in comparison with direct measures of blood pressure, hemoglobin A1c (HbA1c), and medication use in 1870 participants in a multiethic study of aging and dementia.

Results: Reliability of self-reported for hypertension, diabetes, and heart disease was excellent.

Evaluation of Plasma Biomarkers for A/T/N Classification of Alzheimer Disease Among Adults of Caribbean Hispanic Ethnicity.

Importance: Cerebrospinal fluid (CSF) and plasma biomarkers can detect biological evidence of Alzheimer disease (AD), but their use in low-resource environments and among minority ethnic groups is limited.

Objective: To assess validated plasma biomarkers for AD among adults of Caribbean Hispanic ethnicity.

Design, Setting, And Participants: In this decision analytical modeling study, adults were recruited between January 1, 2018, and April 30, 2022, and underwent detailed clinical assessments and venipuncture.

ZCCHC17 modulates neuronal RNA splicing and supports cognitive resilience in Alzheimer's disease.

ZCCHC17 is a putative master regulator of synaptic gene dysfunction in Alzheimer's Disease (AD), and ZCCHC17 protein declines early in AD brain tissue, before significant gliosis or neuronal loss. Here, we investigate the function of ZCCHC17 and its role in AD pathogenesis. Co-immunoprecipitation of ZCCHC17 followed by mass spectrometry analysis in human iPSC-derived neurons reveals that ZCCHC17's binding partners are enriched for RNA splicing proteins.

Polygenic risk score penetrance & recurrence risk in familial Alzheimer disease.

Objective: To compute penetrance and recurrence risk using a genome-wide PRS (including and excluding the APOE region) in families with Alzheimer's disease.

Methods: Genotypes from the National Institute on Aging Late-Onset Alzheimer's Disease Family-Based Study and a study of familial Alzheimer's disease in Caribbean Hispanics were used to compute PRS with and without variants in the 2 MB region flanking APOE. PRS was calculated in using clumping/thresholding and Bayesian methods and was assessed for association with Alzheimer's disease and age at onset.