Head-to-Head Comparison of Aptamer- and Antibody-Based Proteomic Platforms in Human Cerebrospinal Fluid Samples from a Real-World Memory Clinic Cohort.

High-throughput proteomic platforms are crucial to identify novel Alzheimer's disease (AD) biomarkers and pathways. In this study, we evaluated the reproducibility and reliability of aptamer-based (SomaScan 7k) and antibody-based (Olink Explore 3k) proteomic platforms in cerebrospinal fluid (CSF) samples from the Ace Alzheimer Center Barcelona real-world cohort. Intra- and inter-platform reproducibility were evaluated through correlations between two independent SomaScan assays analyzing the same samples, and between SomaScan and Olink results.

Patient stratification by genetic risk in Alzheimer's disease is only effective in the presence of phenotypic heterogeneity.

Case-only designs in longitudinal cohorts are a valuable resource for identifying disease-relevant genes, pathways, and novel targets influencing disease progression. This is particularly relevant in Alzheimer's disease (AD), where longitudinal cohorts measure disease "progression," defined by rate of cognitive decline. Few of the identified drug targets for AD have been clinically tractable, and phenotypic heterogeneity is an obstacle to both clinical research and basic science.

BioMedGraphica: An All-in-One Platform for Biomedical Prior Knowledge and Omic Signaling Graph Generation.

Artificial intelligence (AI) is revolutionizing scientific discovery because of its super capability, following the neural scaling laws, to integrate and analyze large-scale datasets to mine knowledge. Foundation models, large language models (LLMs) and large vision models (LVMs), are among the most important foundations paving the way for general AI by pre-training on massive domain-specific datasets. Different from the well annotated, formatted and integrated large textual and image datasets for LLMs and LVMs, biomedical knowledge and datasets are fragmented with data scattered across publications and inconsistent databases that often use diverse nomenclature systems in the field of AI for Precision Health and Medicine (AI4PHM).

Benchmarking of a multi-biomarker low-volume panel for Alzheimer's disease and related dementia research.

Introduction: In the research setting, obtaining accurate established biomarker measurements and maximizing use of the precious samples is key. Accurate technologies are available for Alzheimer's disease (AD), but no platform can measure all the established and emerging biomarkers in one run. The NUcleic acid Linked Immuno-Sandwich Assay (NULISA) is a technology that requires 15 µL of sample to measure more than 100 analytes.

Circulating blood circular RNA in Parkinson's Disease; from involvement in pathology to diagnostic tools in at-risk individuals.

To identify circRNAs associated with Parkinson's disease (PD) we leveraged two of the largest publicly available studies with longitudinal clinical and blood transcriptomic data. We performed a cross-sectional study utilizing the last visit of each participant (N = 1848), and a longitudinal analysis that included 1166 participants with at least two time points. We identified 192 differentially expressed circRNAs, with effects that were sustained during disease, in mutation carriers, and diverse ancestry.

Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and implicates causal proteins for Alzheimer's disease.

The integration of quantitative trait loci (QTLs) with disease genome-wide association studies (GWASs) has proven successful in prioritizing candidate genes at disease-associated loci. QTL mapping has been focused on multi-tissue expression QTLs or plasma protein QTLs (pQTLs). We generated a cerebrospinal fluid (CSF) pQTL atlas by measuring 6,361 proteins in 3,506 samples.

mosGraphGen: a novel tool to generate multi-omics signaling graphs to facilitate integrative and interpretable graph AI model development.

Motivation: Multi-omics data, i.e. genomics, epigenomics, transcriptomics, proteomics, characterize cellular complex signaling systems from multi-level and multi-view and provide a holistic view of complex cellular signaling pathways.

Polygenic proxies of age-related plasma protein levels reveal TIMP2 role in cognitive performance.

Background: While numerous studies have identified blood proteins that modulate brain aging in mice, the direct translation of these findings to human health remains a substantial challenge. Bridging this gap is critical for developing interventions that can effectively target human brain aging and associated diseases.

Methods: We first identified 12 proteins with aging or rejuvenating properties in murine brains through a systematic review.

A comprehensive head-to-head comparison of key plasma phosphorylated tau 217 biomarker tests.

Plasma phosphorylated-tau 217 (p-tau217) is currently the most promising biomarker for reliable detection of Alzheimer's disease (AD) pathology. Various p-tau217 assays have been developed, but their relative performance is unclear. We compared key plasma p-tau217 tests using cross-sectional and longitudinal measures of amyloid-β (Aβ)-PET, tau-PET, and cognition as outcomes, and benchmarked them against cerebrospinal fluid (CSF) biomarker tests.

CSF proteomics identifies early changes in autosomal dominant Alzheimer's disease.

In this high-throughput proteomic study of autosomal dominant Alzheimer's disease (ADAD), we sought to identify early biomarkers in cerebrospinal fluid (CSF) for disease monitoring and treatment strategies. We examined CSF proteins in 286 mutation carriers (MCs) and 177 non-carriers (NCs). The developed multi-layer regression model distinguished proteins with different pseudo-trajectories between these groups.

Sex-Stratified Genome-Wide Association Study in the Spanish Population Identifies a Novel Locus for Lacunar Stroke.

Background: Ischemic stroke (IS) represents a significant health burden globally, necessitating a better understanding of its genetic underpinnings to improve prevention and treatment strategies. Despite advances in IS genetics, studies focusing on the Spanish population and sex-stratified analyses are lacking.

Methods: A case-control genome-wide association study was conducted with 9081 individuals (3493 IS cases and 5588 healthy controls).

Missense and loss-of-function variants at GWAS loci in familial Alzheimer's disease.

Background: Few rare variants have been identified in genetic loci from genome-wide association studies (GWAS) of Alzheimer's disease (AD), limiting understanding of mechanisms, risk assessment, and genetic counseling.

Methods: Using genome sequencing data from 197 families in the National Institute on Aging Alzheimer's Disease Family Based Study and 214 Caribbean Hispanic families, we searched for rare coding variants within known GWAS loci from the largest published study.

Results: Eighty-six rare missense or loss-of-function (LoF) variants completely segregated in 17.

Polygenic proxies of age-related plasma protein levels reveal TIMP2 role in cognitive performance.

Several studies have identified blood proteins that influence brain aging performance in mice, yet translating these findings to humans remains challenging. Here we found that higher predicted plasma levels of Tissue Inhibitor of Metalloproteinases 2 (TIMP2) were significantly associated with improved global cognition and memory performance in humans. We first identified 12 proteins with aging or rejuvenating effects on murine brains through a systematic review.

15 Years of Longitudinal Genetic, Clinical, Cognitive, Imaging, and Biochemical Measures in DIAN.

This manuscript describes and summarizes the Dominantly Inherited Alzheimer Network Observational Study (DIAN Obs), highlighting the wealth of longitudinal data, samples, and results from this human cohort study of brain aging and a rare monogenic form of Alzheimer's disease (AD). DIAN Obs is an international collaborative longitudinal study initiated in 2008 with support from the National Institute on Aging (NIA), designed to obtain comprehensive and uniform data on brain biology and function in individuals at risk for autosomal dominant AD (ADAD). ADAD gene mutations in the amyloid protein precursor (), presenilin 1 (), or presenilin 2 () genes are deterministic causes of ADAD, with virtually full penetrance, and a predictable age at symptomatic onset.

The CentiMarker Project: Standardizing Quantitative Alzheimer's disease Fluid Biomarkers for Biologic Interpretation.

Introduction: Biomarkers have been essential to understanding Alzheimer's disease (AD) pathogenesis, pathophysiology, progression, and treatment effects. However, each biomarker measure is a representation of the biological target, the assay used to measure it, and the variance of the assay. Thus, biomarker measures are difficult to compare without standardization, and the units and magnitude of effect relative to the disease are difficult to appreciate, even for experts.

European and African-specific plasma protein-QTL and metabolite-QTL analyses identify ancestry-specific T2D effector proteins and metabolites.

Initially focused on the European population, multiple genome-wide association studies (GWAS) of complex diseases, such as type-2 diabetes (T2D), have now extended to other populations. However, to date, few ancestry-matched omics datasets have been generated or further integrated with the disease GWAS to nominate the key genes and/or molecular traits underlying the disease risk loci. In this study, we generated and integrated plasma proteomics and metabolomics with array-based genotype datasets of European (EUR) and African (AFR) ancestries to identify ancestry-specific muti-omics quantitative trait loci (QTLs).

Ubiquitin-Proteasome System in the Different Stages of Dominantly Inherited Alzheimer's Disease.

This study explored the role of the ubiquitin-proteasome system (UPS) in dominantly inherited Alzheimer's disease (DIAD) by examining changes in cerebrospinal fluid (CSF) levels of UPS proteins along with disease progression, AD imaging biomarkers (PiB PET, tau PET), neurodegeneration imaging measures (MRI, FDG PET), and Clinical Dementia Rating (CDR). Using the SOMAscan assay, we detected subtle increases in specific ubiquitin enzymes associated with proteostasis in mutation carriers (MCs) up to two decades before the estimated symptom onset. This was followed by more pronounced elevations of UPS-activating enzymes, including E2 and E3 proteins, and ubiquitin-related modifiers.