Basic Science and Pathogenesis.

Background: MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression, but we have limited insight into their role in age-related cerebral pathologies. Here, we investigated the association between miRNAs and nine age-related cerebral pathologies in participants of the ROS/MAP cohorts.

Method: MiRNA sequencing was performed on samples from the dorsolateral prefrontal cortex of 617 brain donors from participants of the ROS/MAP cohorts.

Basic Science and Pathogenesis.

Background: Genome-wide association studies (GWAS) in Alzheimer's disease (AD) leveraging endophenotypes beyond case/control diagnosis, such as brain amyloid β pathology, have shown promise in identifying novel variants and understanding their potential functional impact. In this study, we leverage two brain amyloid β pathology measurement modalities, PET imaging and neuropathology, to address sample size limitations and to discover novel genetic drivers of disease.

Method: We conducted a meta-analysis on an amyloid PET imaging GWAS (N = 7,036, 35% amyloid positive, 53.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) has both genetic and environmental risk factors. Gene-environment interaction may help explain some missing heritability. There is strong evidence for cigarette smoking as a risk factor for AD.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) is a devastating neurodegenerative disorder with few therapies to treat, mitigate or prevent its onset. Understanding of this disease is predominantly based on research in non-Hispanic Whites (NHW) although AD disproportionately affects African Americans (AA) and Latin Americans (LA), underrepresented in AD research. To address this knowledge gap, the Accelerating Medicine Partnership for Alzheimer's Disease (AMP-AD) Diversity Working Group was launched to generate multi-omics data from post-mortem brain tissue from donors of predominantly AA and LA descent.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) is highly comorbid with Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC), and the combined AD+LATE-NC is more common than either pathology alone. However, the topographic relationship between tau and TDP-43 in AD+LATE-NC remains unclear.

Method: We analyzed the data from the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP) participants.

Basic Science and Pathogenesis.

Background: The Apolipoprotein E ε4 (APOE-ε4) allele is common in the population, but acts as the strongest genetic risk factor for late-onset Alzheimer's disease (AD). Despite the strength of the association, there is notable heterogeneity in the population including a strong modifying effect of genetic ancestry, with the APOE-ε4 allele showing a stronger association among individuals of European ancestry (EUR) compared to individuals of African ancestry (AFR). Given this heterogeneity, we sought to identify genetic modifiers of APOE-ε4 related to cognitive decline leveraging APOE-ε4 stratified and interaction genome-wide association analyses (GWAS).

Basic Science and Pathogenesis.

Background: To identify discrete and continuous cell type signatures in brain tissue from donors with minimal cognitive decline despite harboring substantial proteinopathies associated with Alzheimer's Disease and Alzheimer's Disease-related dementias.

Method: Three large-scale single-nucleus RNA-seq studies on Alzheimer's Disease post-mortem human tissue were re-annotated and integrated to identify cell type composition associations with cognitive resilience to various neuropathologies. Cell type signatures were defined in two ways: using an integrated clustering approach and using a continuous factor-based analysis.

Basic Science and Pathogenesis.

Background: Women are disproportionately affected by Alzheimer's disease (AD) and exhibit greater AD neuropathology than men. Women possess two X chromosomes, with one randomly silenced across each cell for dosage compensation. X chromosome inactivation (XCI) is not complete, and XCI-escaping genes provide a promising avenue of discovery for biological pathways driving sex-specific AD risk.

Basic Science and Pathogenesis.

Background: As high as 50% of Alzheimer's disease (AD) patients experience "sundowning", which refers to an increased severity of neuropsychiatric symptoms (NPS), including agitation, confusion, and anxiety, selectively in the evening. Although sundowning significantly influences the decision to institutionalize patients, few preclinical models of this phenomenon exist and the underlying neural mechanisms are unknown. Here, we establish a model of sundowning by phenotyping the sleep-wake cycle and anxiety and exploratory behavior at different times of day in an AD mouse model.

Basic Science and Pathogenesis.

Background: Hemoglobin A1C (A1C) is a measure of long-term glycemic control. In a previous study using a single measure of A1C, we showed that it is related to postmortem cerebrovascular pathology. Here, we use annually collected A1C data to study the relationship of A1C average and variability over time with neuropathology in a large number of older adults with and without diabetes.

Basic Science and Pathogenesis.

Background: A significant proportion of individuals preserve cognitive function despite meeting neuropathological criteria for Alzheimer's disease (AD) at autopsy, known as cognitive resilience. We aimed to define the molecular and cellular signatures of cognitive resilience against AD.

Method: We integrated multi-modal data from the Religious Order Study and Memory and Aging Project (ROSMAP), including bulk (n = 631) and multi-regional single nucleus (n = 48) RNA sequencing.

Basic Science and Pathogenesis.

Background: Aging is a time-dependent deterioration of physiological functions that occurs in both humans and animals. Within the brain, aging cells gradually become dysfunctional through a complex interplay of intrinsic and extrinsic factors, ultimately leading to behavioral deficits and enhanced risk of neurodegenerative diseases such as Alzheimer's disease (AD). The characteristics of normal aging are distinct from those associated with age-related diseases and it is important to understand the processes that contribute to this pathological divergence.

Basic Science and Pathogenesis.

Background: Recent advances in Alzheimer's disease (AD) therapeutics involve immunization against amyloid-β (Aβ). Post-mortem brain analysis from the first active Aβ immunotherapy trial indicated clearance of Aβ in some AD patients. Yet, the mechanisms regulating Aβ clearance following immunization remain unknown.

Basic Science and Pathogenesis.

Background: Cellular senescence is a hallmark of aging and has been implicated in several neurodegenerative diseases including Alzheimer's disease (AD). Senescence cells undergo changes in gene expression and metabolism and can exhibit a so-called "senescence-associated secretory phenotype" (SASP) characterized by increased secretion of pro-inflammatory molecules and factors which can damage nearby cells, contributing to AD pathology progression.

Method: In this study, we determined mechanisms of cellular senescence using human postmortem brain samples, cellular models, and APOE4 animal models.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD), an age-associated neurodegenerative disorder, is characterized by progressive neuronal loss and the accumulation of misfolded proteins such as amyloid-β and tau. While neuroinflammation, mediated by microglia and brain-resident macrophages, plays a pivotal role in AD pathogenesis, the intricate interactions among age, genes, and other risk factors remain elusive. Somatic mutations, known to accumulate with age, instigate clonal expansion across diverse cell types, impacting both cancer and non-cancerous conditions.

Basic Science and Pathogenesis.

Background: Cardio and cerebrovascular risk factors (CVRFs) increase the risk of cerebrovascular disease and clinical Alzheimer's Disease (AD), and over 70% of the patients with AD coincident cerebrovascular pathology. We previously found that FMNL2 interacts with a burden score of hypertension, diabetes, heart disease, and body mass index (BMI) by altering the normal astroglial-vascular mechanisms that underly amyloid clearance. Stroke, defined by history of a clinical stroke or brain imaging, is a moderately robust risk factor for AD and dementia.

Basic Science and Pathogenesis.

Background: Annotation of target genes of non-coding GWAS loci remains a challenge since 1) regulatory elements identified by GWAS can be metabases away from its actual target, 2) one regulatory element can target multiple genes, and 3) multiple regulatory elements can target one gene. AD GWAS in populations with different ancestries have identified different loci, suggesting ancestry-specific genetic risks. To understand the connection between associated loci (potential regulatory elements) and their target genes, we conducted Hi-C analysis in frontal cortex of African American (AA) and Non-Hispanic Whites (NHW) AD patients to map chromatin loops, which often represent enhancer-promoter (EP) interactions.

Basic Science and Pathogenesis.

Background: Angiotensin-converting enzyme (ACE) is a validated risk locus for developing late-onset Alzheimer's disease (LOAD). ACE1 controls blood pressure through the renin-angiotensin system (RAS), but it is also present and acts locally in the brain. Hypertension is associated with an increased risk for developing AD, and people taking select RAS-targeting therapeutics have reduced incidence of AD.

Basic Science and Pathogenesis.

Background: Two-thirds of Alzheimer's Disease (AD) cases are women, and our team has identified molecular factors that relate to disease in a sex-specific manner. Here, we leverage single-cell transcriptomics from dorsolateral prefrontal cortex (N = 424) from the Religious Orders Study and Memory and Aging Project (ROS/MAP; AD Knowledge Portal syn2580853) to characterize sex-specific contributors at cellular resolution.

Method: Single-nucleic RNAseq data was generated and processed as previously described.

Basic Science and Pathogenesis.

Background: "SuperAgers" are older adults (ages 80+) whose cognitive performance resembles that of adults in their 50s to mid-60s. Factors underlying their exemplary aging are underexplored in large, racially diverse cohorts. Using eight cohorts, we investigated the frequency of APOE genotypes in SuperAgers compared to middle-aged and older adults.

Basic Science and Pathogenesis.

Background: In AD, neurofibrillary tangles (NFTs) develop earliest in the limbic system before spreading to neocortical areas. When accounting for covariates of AD pathology, such as age and APOE, there remains interindividual variation in NFT spread in the brain. We therefore used a machine-learning approach to investigate whether age-independent DNA methylation (DNAm) changes in brain associate with histopathological differences in AD.

Basic Science and Pathogenesis.

Background: Currently, it is unclear to what extent late-onset Alzheimer's disease (AD) risk variants contribute to early-onset AD (EOAD). One method to clarify the contribution of late-onset AD genetic risk to EOAD is to investigate the association of AD polygenic risk scores (PRS) with EOAD. We hypothesize that in the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS), EOAD participants will have greater PRS than early-onset amyloid-negative cognitively-impaired participants (EOnonAD) and controls, and investigate the association of AD PRS with age of disease onset (AoO) and cognitive performance.

Basic Science and Pathogenesis.

Background: African Americans (AA) are disproportionally burdened by Alzheimer's disease (AD), but there is a scarcity of research focusing on understanding the neuroimmune component of AD pathogenesis in this population. It is generally accepted that microglia would be an ideal therapeutic target for AD and that genetic, lifestyle, societal and environmental factors and stressors have the potential to shape microglia phenotypes and their contribution to neurodegenerative processes. The overarching goal of the current study is to establish the population structure of microglia in older AAs and to investigate the relationship of the different microglia subsets with histopathological hallmarks of brain aging and AD in AAs.

Basic Science and Pathogenesis.

Background: Synaptic loss predicts cognitive decline in Alzheimer's disease (AD). However, the critical disease modifying molecular mechanisms of synaptic failure remain elusive. Animal studies implicate the increased activation of cytosolic phospholipase (cPLA2) activation in synaptic loss and neuroinflammation.

Basic Science and Pathogenesis.

Background: Cerebrovascular disease (CVD) is a major cause of mortality in females, while two-thirds of Alzheimer's disease (AD) patients are female. AD and CVD share many genetic risk factors, one of them being apolipoprotein E (APOE) genotype. Sex differences in APOE and AD are well-established; it is unclear if associations between APOE and CVD are sex-specific.