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.

Basic Science and Pathogenesis.

Background: Hippocampal neuronal loss (HNL), LATE neuropathologic changes (LATE-NC), and Alzheimer's disease (AD) are common neuropathological findings in older persons. However, the inter-relationship between AD, LATE-NC, HNL, and cognition is not well understood.

Method: Participants without known dementia (n = 420; mean age-at-death = 92 years, women = 72%) enrolled, in the Rush community-based cohorts and underwent annual cognitive testing and autopsy.

Basic Science and Pathogenesis.

Background: Abnormal brain insulin signaling has been associated with Alzheimer's disease pathology and a faster rate of late-life cognitive decline. However, the underlying mechanisms remain unclear. In this study, we examined whether AD-related cortical proteins identified using targeted-proteomics play a role in the association of brain insulin signaling and cognitive decline.

Basic Science and Pathogenesis.

Background: Intracranial atherosclerosis is a common age-related neuropathology that has been linked to cognitive decline and dementia and often mixed with Alzheimer's and other neuropathologies. But the association of atherosclerosis with brain morphometric abnormalities has not been explored. This work combined Deformation-based morphometry on ex-vivo MRI with detailed neuropathological examination in a large number of community-based older adults to investigate the association.

Basic Science and Pathogenesis.

Background: Much attention has been paid to the role of the perenchymal brain immune response in Alzheimer's disease (AD). Yet, the peripheral immune system in AD has not been thoroughly studied with modern sequencing methods.

Method: Here, we used a combination of single-cell sequencing strategies, including assay for transposase-accessible chromatin and RNA sequencing, to investigate the epigenetic and transcriptional alterations to the AD peripheral immune system.

Basic Science and Pathogenesis.

Background: This study identifies and quantifies diverse pathological tau forms in the retina at both early and advanced stages of Alzheimer's disease (AD) and assesses their correlation with disease status. In the pathogenesis of AD, the tau protein undergoes post-translational modifications, including hyperphosphorylation (p-tau). As the disease progresses, pathological tau can propagate as oligomers, aggregate into fibrils, and paired helical filaments (PHF), and ultimately form intraneuronal neurofibrillary tangles (NFTs).

Basic Science and Pathogenesis.

Background: Autosomal dominant progranulin (GRN) mutations are a common genetic cause of frontotemporal lobar degeneration. Though clinical trials for GRN-related therapies are underway, there is an unmet need for biomarkers that can predict symptom onset and track disease progression. We previously showed that presymptomatic GRN carriers exhibit thalamocortical hyperconnectivity that increases with age when they are presumably closer to symptom onset.

Basic Science and Pathogenesis.

Background: The aging and dementia field has long been interested in understanding disease heterogeneity, subtypes, and progression. Work has progressed from clinical, to neuroimaging to biomedical devices to neuropathological data, and now brain and blood omic data.

Method: The AMP-AD consortium generated and/or annotated genomic, epigenomic, transcriptomic, proteomic, and metabolomic data from brain and/or blood from thousands of study participants and patients across the 8 teams.

Basic Science and Pathogenesis.

Background: microRNAs (miRNAs) are small RNAs involved in regulating gene expression by repressing target protein-coding genes. Hundreds of miRNAs are expressed in human brain, but our understanding of their role in Alzheimer's disease (AD) and cognitive decline is limited.

Method: We performed miRNA differential expression analysis using small RNA sequencing data generated from dorsolateral prefrontal cortex samples from 641 participants of the Religious Orders Study (ROS) and Memory and Aging Project (MAP).

Basic Science and Pathogenesis.

Background: Brain arteriolosclerosis is characterized by the thickening of vessel walls and arteriolar stenosis and is one of the primary pathologies of cerebral small vessel disease. Arteriolosclerosis is linked to lower cognitive and motor function, as well as an elevated risk of dementia. This study aimed to investigate the association of brain arteriolosclerosis with regional gray matter volumes in a large number of community-based older adults.

Basic Science and Pathogenesis.

Background: Elevated iron in brain is a source of free radicals that causes oxidative stress which has been linked to neuropathologies and cognitive impairment among older adults. The aim of this study was to investigate the association of iron levels with transverse relaxation rate, R, and white matter hyperintensities (WMH), independent of the effects of other metals and age-related neuropathologies.

Method: Cerebral hemispheres from 437 older adults participating in the Rush Memory and Aging Project study (Table 1) were imaged ex-vivo using 3T MRI scanners.

Basic Science and Pathogenesis.

Background: Evidence is accumulating that cerebral small vessel disease may contribute to neurodegeneration. Brain arteriolosclerosis, a prominent type of small vessel disease in the aging brain, is associated with cognition. Using a previously developed published automated in-vivo MRI classifier for arteriolosclerosis (ARTS), we examined cross-sectionally the associations between ARTS, cortical thinning, and cognition.

Basic Science and Pathogenesis.

Background: Cerebrovascular pathology frequently co-occurs with Alzheimer's disease (AD) pathology and the combinations of these forms of pathology may underly AD dementia. Sex hormones influence many aspects of cerebrovascular systems and may contribute to cerebrovascular pathology, but many studies of aging and AD do not measure hormones. Therefore, in this study, we explored whether a polygenic score predicting sex hormone levels relates to cerebrovascular pathology in the AD brain.

Basic Science and Pathogenesis.

Background: Previously, we developed a co-calibrated and harmonized brain pathology score (BPS) across prospective cohort studies with research brain donation that incorporates multiple forms of postmortem neuropathology, using confirmatory factor analysis. We sought to identify genetic loci associated with BPS using a systems-biology approach, combining data from participants in the Adult Changes in Thought (ACT), the Religious Orders Study, and Rush Memory and Aging Project (ROSMAP) autopsy cohorts.

Method: We used PLINK in each cohort separately for genome-wide association studies (GWAS) of BPS using HRC imputed data from European ancestry participants, adjusting for age at death, sex, and population substructure.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) is characterized by neocortical dissemination of neurofibrillary tangles (NFTs) while primary age-related tauopathy (PART) has NFTs largely confined to the hippocampus and adjacent structures. Thus, PART and AD represent two extremes of a spectrum of NFT spread. We investigated epigenetic mechanisms of interindividual variation in NFT spread.

Basic Science and Pathogenesis.

Background: Apolipoprotein E4 (E4) is the strongest genetic risk factor for sporadic Alzheimer's Disease (AD), and aging is the greatest overall risk factor for AD. Many cellular and molecular changes occur within the brain throughout aging, one of which being the increased bone morphogenetic protein 4 (BMP4) signaling. As APOE and BMPs are known to interact in non-neuronal organs, we hypothesized that enhanced BMP signaling in the brain may interact with APOE in a genotype-dependent manner to initiate or exacerbate neuropathological cascades relevant to AD.

Basic Science and Pathogenesis.

Background: The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is analyzing the genetic etiology of early onset (40-64 years) cognitive impairment, including amyloid-positive early-onset Alzheimer's disease (EOAD) and amyloid-negative early-onset Alzheimer's disease (EOnonAD). One goal of this investigation is to identify novel or under-characterized genetic variants.

Methods: Cognitively impaired (CI) LEADS participants, including amyloid-positive and amyloid-negative early-onset cases, were whole exome or genome sequenced (N = 361).

Basic Science and Pathogenesis.

Background: Although the rate of Alzheimer's disease (AD) in African-ancestry (AA) Americans is higher than that of persons from European-ancestry (EA) populations, AA participants have been underrepresented in AD neuropathological studies.

Method: Utilizing the AD Research Centers (ADRC) infrastructure, we obtained AA donor pre-frontal cortex (PFC) tissue from brain repositories of 12 ADRC and generated bulk RNA sequencing (RNA-seq) data for 179 samples that met QC and inclusion criteria. Previously generated PFC RNAseq data were obtained for 28 additional AA donors from the Columbia University ADRC.

Basic Science and Pathogenesis.

Background: Non-Hispanic White APOE4 carriers have a higher risk of developing AD compared to African American APOE4 carriers. The local ancestry (LA) surrounding the APOE region was previously shown to be the primary factor in this risk difference. APOE4 carriers of European LA (ELA) have been found to have higher APOE4 expression and chromatin accessibility compared to African LA (ALA).

Basic Science and Pathogenesis.

Background: Aging is the most significant risk factor for neurodegenerative tauopathies, including Alzheimer's disease (AD), frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), and others. However, no specific age-related molecular change in the brain has been identified that leads to disease onset and progression. We have found age-related increases in bone morphogenic protein (BMP) signaling in both human and mouse brains.

Clinical Manifestations.

Background: Cardiovascular risk factors and depressive symptoms have both been independently shown to be negatively associated with cognitive function. However, the nature of the influence of comorbid depressive symptoms and cardiovascular risk on cognitive function is unclear, and there have been inconsistent findings as to which cognitive domains may be most associated with this relationship.

Method: U.