Multi-omic subtypes of Alzheimer's dementia are differentially associated with psychological traits.

Importance: Psychological traits reflecting neuroticism, depressive symptoms, loneliness, and purpose in life are risk factors of AD dementia; however, the underlying biologic mechanisms of these associations remain largely unknown.

Objective: To examine whether one or more multi-omic brain molecular subtypes of AD is associated with neuroticism, depressive symptoms, loneliness, and/or purpose in life.

Design: Two cohort-based studies; Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP), both ongoing longitudinal clinical pathological studies that began enrollment in 1994 and 1997.

Structural variants linked to Alzheimer's disease and other common age-related clinical and neuropathologic traits.

Background: Alzheimer's disease (AD) is a complex neurodegenerative disorder with substantial genetic influence. While genome-wide association studies (GWAS) have identified numerous risk loci for late-onset AD (LOAD), the functional mechanisms underlying most of these associations remain unresolved. Large genomic rearrangements, known as structural variants (SVs), represent a promising avenue for elucidating such mechanisms within some of these loci.

Systems-Level Interactome Mapping Reveals Actionable Protein Network Dysregulation Across the Alzheimer's Disease Spectrum.

Alzheimer's disease (AD) progresses as a continuum, from preclinical stages to late-stage cognitive decline, yet the molecular mechanisms driving this progression remain poorly understood. Here, we provide a systems-level map of protein-protein interaction (PPI) network dysfunction across the AD spectrum and uncover epichaperomes-stable scaffolding platforms formed by chaperones and co-factors-as central drivers of this process. Using over 100 human brain specimens, mouse models, and human neurons, we show that epichaperomes emerge early, even in preclinical AD, and progressively disrupt multiple PPI networks critical for synaptic function and neuroplasticity.

Gene module-trait network analysis uncovers cell type specific systems and genes relevant to Alzheimer's Disease.

Alzheimer's Disease (AD) is marked by the accumulation of pathology, neuronal loss, and gliosis and frequently accompanied by cognitive decline. Understanding brain cell interactions is key to identifying new therapeutic targets to slow its progression. Here, we used systems biology methods to analyze single-nucleus RNA sequencing (snRNASeq) data generated from dorsolateral prefrontal cortex (DLPFC) tissues of 424 participants in the Religious Orders Study or the Rush Memory and Aging Project (ROSMAP).

Genetic Markers of Postmortem Brain Iron.

Brain iron (Fe) dyshomeostasis is implicated in neurodegenerative diseases. Genome-wide association studies (GWAS) have identified plausible loci correlated with peripheral levels of Fe. Systemic organs and the brain share several Fe regulatory proteins but there likely exist different homeostatic pathways.

Hippocampal neuronal loss and cognitive decline in LATE-NC and ADNC among community-dwelling older persons.

Introduction: This study investigates the inter-related roles of hippocampal neuronal loss (HNL), limbic-predominant age-related TAR-DNA binding protein of 43 kDa (TDP-43) encephalopathy neuropathologic changes (LATE-NC), and Alzheimer's disease neuropathologic changes (ADNC) on cognitive decline.

Methods: Participants underwent annual cognitive testing and autopsy. HNL, ADNC, LATE-NC, and other age-related pathologies were evaluated.

Evaluating the association of genotype and cognitive resilience in SuperAgers.

Importance: "SuperAgers" are oldest-old adults (ages 80+) whose memory performance resembles that of adults in their 50s to mid-60s. Factors underlying their exemplary memory are underexplored in large, racially diverse cohorts.

Objective: To determine the frequency of genotypes in non-Hispanic Black and non-Hispanic White SuperAgers compared to middle-aged (ages 50-64), old (ages 65-79), and oldest-old (ages 80+) controls and Alzheimer's disease (AD) dementia cases.

Clinical criteria for limbic-predominant age-related TDP-43 encephalopathy.

Limbic predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is highly prevalent in late life and a common co-pathology with Alzheimer's disease neuropathologic change (ADNC). LATE-NC is a slowly progressive, amnestic clinical syndrome. Alternatively, when present with ADNC, LATE-NC is associated with a more rapid course.

Sex-specific Associations of Gene Expression with Alzheimer's Disease Neuropathology and Ante-mortem Cognitive Performance.

The biological mechanisms underlying women's increased Alzheimer's disease (AD) prevalence remain undefined. Previous case/control studies have identified sex-biased molecular pathways, but sex-specific relationships between gene expression and AD endophenotypes, particularly sex chromosomes, are underexplored. With bulk transcriptomic data across 3 brain regions from 767 decedents, we investigated sex-specific associations between gene expression and post-mortem β-amyloid and tau as well as antemortem longitudinal cognition.

Astrocyte Reactivity Polygenic Risk Score May Predict Cognitive Decline in Alzheimer's Disease.

Alzheimer's disease (AD) is a polygenic disorder with a prolonged prodromal phase, complicating early diagnosis. Recent research indicates that increased astrocyte reactivity is associated with a higher risk of pathogenic tau accumulation, particularly in amyloid-positive individuals. However, few clinical tools are available to predict which individuals are likely to exhibit elevated astrocyte activation and, consequently, be susceptible to hyperphosphorylated tau-induced neurodegeneration.

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.

Pathologic and clinical correlates of region-specific brain GFAP in Alzheimer's disease.

Plasma glial fibrillary acidic protein (GFAP) is an emerging biomarker of Alzheimer's disease (AD), with higher blood GFAP levels linked to faster cognitive decline, particularly among individuals with high brain amyloid burden. However, few studies have examined brain GFAP expression to clarify if peripheral associations reflect brain changes. This study aimed to correlate region-specific GFAP mRNA expression (n = 917) and protein abundance (n=386) with diverse neuropathological measures at autopsy in the Religious Orders Study and Rush Memory and Aging Project (ROS/MAP) and to characterize the interaction between brain GFAP and brain amyloid burden on downstream outcomes.

Temporal Sequence of Incident Mild Cognitive Impairment, Incident Parkinsonism, and Risk of Death in Unimpaired Community-Dwelling Older Adults.

Background: Mild cognitive impairment (MCI) and parkinsonism affect many older adults. The objective of this study was to determine the sequence of their occurrence and associated risk of death.

Methods: A total of 1255 community-dwelling unimpaired participants from 2 epidemiological cohorts were examined annually.

Effects of brain microRNAs in cognitive trajectory and Alzheimer's disease.

microRNAs (miRNAs) have a broad influence on gene expression; however, we have limited insights into their contribution to rate of cognitive decline over time or Alzheimer's disease (AD). Given this, we tested associations of 528 miRNAs with cognitive trajectory, AD hallmark pathologies, and AD clinical diagnosis using small RNA sequencing from the dorsolateral prefrontal cortex of 641 community-based donors. We found 311 miRNAs differentially expressed in AD or its endophenotypes after adjusting for technical and sociodemographic variables.

Intracranial atherosclerotic disease and neurodegeneration: a narrative review and plausible mechanisms.

Introduction: Intracranial atherosclerotic disease (ICAD) of the large cerebral arteries, a leading cause of stroke worldwide, is increasingly implicated in cognitive impairment and neurodegeneration among the general population; however, the underlying pathophysiologic mechanisms in this relationship remain unknown.

Methods: In this narrative review, we aim to provide an overview of the epidemiology and pathophysiology of ICAD, the evidence that relates ICAD to neurodegeneration, putative mechanisms, and future research directions. We synthesized available evidence on PubMed up to August 2024.

A Sensitive Method for Determination 1,25-Dihydroxyvitamin D3 in Human Brain using Ultra-Pressure Liquid Chromatography Tandem Mass Spectrometry.

The hormonally active form of vitamin D, 1,25-Dihydroxyvitamin D3 [1,25(OH)D], has been associated with neuroprotective effects in the brain, but has been difficult to measure in human brain tissue because of its low concentration. The aim of this study was to develop and validate a sensitive method to quantify 1,25(OH)D in the human brain. Prior to analysis by the LC-MS/MS, the samples were derivatized with 4-phenyl-1,2,4-triazoline-3,5-dione.

Structural variants linked to Alzheimer's Disease and other common age-related clinical and neuropathologic traits.

Advances have led to a greater understanding of the genetics of Alzheimer's Disease (AD). However, the gap between the predicted and observed genetic heritability estimates when using single nucleotide polymorphisms (SNPs) and small indel data remains. Large genomic rearrangements, known as structural variants (SVs), have the potential to account for this missing genetic heritability.

Quantitative assessment of enlarged perivascular spaces via deep-learning in community-based older adults reveals independent associations with vascular neuropathologies, vascular risk factors and cognition.

Enlarged perivascular spaces (EPVS) are common in older adults, but their neuropathologic correlates are unclear mainly because most work to date has relied on visual rating scales and/or clinical cohorts. The present study first developed a deep-learning model for automatic segmentation, localization and quantification of EPVS in brain MRI, and then used this model to investigate the neuropathologic, clinical and cognitive correlates of EPVS in 817 community-based older adults that underwent autopsy. The new method exhibited high sensitivity in detecting EPVS as small as 3 mm, good segmentation accuracy and consistency.

The MIND diet, brain transcriptomic alterations, and dementia.

Introduction: Dietary patterns are associated with dementia risk, but the underlying molecular mechanisms are largely unknown.

Methods: We used RNA sequencing data from post mortem prefrontal cortex tissue and annual cognitive evaluations from 1204 participants in the Religious Orders Study and Memory and Aging Project. We identified a transcriptomic profile correlated with the MIND diet (Mediterranean-Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay) among 482 individuals who completed ante mortem food frequency questionnaires; and examined its associations with cognitive health in the remaining 722 participants.

Grey matter ageing-related tau astrogliopathy: associations with brain pathologies and cognitive decline.

Grey matter ageing-related tau astrogliopathy (ARTAG) pathology is common in aged brains and detected in multiple brain regions. However, the associations of grey matter ARTAG with Alzheimer's disease and other common age-related proteinopathies, in addition to clinical phenotypes, including Alzheimer's dementia and cognitive decline, remain unclear. We examined 442 decedents (mean age at death = 90 years, males = 32%) from three longitudinal community-based clinical-pathological studies.