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: Presenilin 2 (PSEN2) is one of three deterministic risk genes that increases the risk of early-onset Alzheimer's Disease. People with PSEN2 variants have increased risk of unprovoked seizures versus age-matched unaffected individuals yet few studies have interrogated the contributions of PSEN2 on seizure susceptibility. Critically, PSEN proteolytic capacity may be a novel regulator of hippocampal kainate-type glutamate receptors (KARs), with PSEN deletion reducing KAR availability and synaptic transmission in vitro (Barthet et al 2022).

Basic Science and Pathogenesis.

Background: The SORL1 gene (SORLA) is strongly associated with risk of developing Alzheimer's disease (AD). SORLA is a regulator of endosomal trafficking in neurons and interacts with retromer, a complex that is a "master conductor" of endosomal trafficking. Because of its size, SORLA is difficult to target therapeutically.

Basic Science and Pathogenesis.

Background: P-tau217 has emerged as a compelling alternative to long-established p-tau181 to accurately measure tau modifications in biofluids in response to brain Abeta and tau deposition in Alzheimer's disease (AD). Understanding the specificity and significance of p-tau217 changes over AD stages is critical to interpret its potential response to treatments against Abeta and tau aggregation.

Methods: We measured p-tau217 phosphorylation by mass spectrometry.

Basic Science and Pathogenesis.

Background: The long-term goal of Health & Aging Brain Study - Health Disparities (HABS-HD) is to establish population-specific informed precision medicine for novel treatment and prevention strategies as has been done in other fields. Genomic studies are integral to these efforts and contribute vital data regarding genetic ancestry of the HABS-HD participants, as well as whole genome sequence data, genome-wide genotype (Illumina Global Screening array version 3.0) and epigenetic data (Illumina EPIC DNA methylation array).

Basic Science and Pathogenesis.

Background: The cerebrovasculature is an essential component of brain homeostasis. Cerebrovascular disorders are associated with an increased risk for neurodegenerative diseases, including Alzheimer's disease (AD). However, the mechanisms by which cerebrovascular dysfunction contributes to neurodegeneration are poorly understood.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) is the leading cause of dementia and one of the most devastating neurodegenerative diseases. In the last decades, a large proportion of AD patients have been described as having aberrant accumulation of TDP-43 protein, a well-established driver of neurodegeneration. This TDP-43 proteinopathy in AD can co-occur in neurons with the main hallmarks of the disease, toxic amyloid oligomers and neurofibrillary tangles containing hyperphosphorylated Tau, and correlates with rapid progression and worse prognosis.

Basic Science and Pathogenesis.

Background: Sleep disturbances are associated with the pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD) and primary tauopathies. We have previously shown that APOE4, the strongest genetic risk factor for AD, directly influences the severity of key pathological hallmarks of neurodegeneration including tau deposition, microglial reactivity and brain atrophy. Sleep loss influences tau accumulation and microglial reactivity in both mice and humans, suggesting that sleep loss may contribute to neurodegeneration not only by influencing protein aggregation, but also through an immune mechanism.

Basic Science and Pathogenesis.

Background: Late onset Alzheimer disease is a complex syndrome, genetically, clinically and pathogenetically heterogeneous. Genome Wide association studies have identified risk alleles for AD harboring genes in the endolysosomal network (ELN). We hypothesize that aggregate burden of these endolysosomal risk alleles impacts cell type specific ELN function, thus contributing to LOAD pathogenesis.

Basic Science and Pathogenesis.

Background: Genetic variation of lysosomal protein, transmembrane protein 106B (TMEM106B) has long been known as a risk factor for a diverse range of neurodegenerative disorders, especially FTLD with progranulin (GRN) haplo-insufficiency, though the mechanisms involved are not yet understood. Recently, through advances in cryo-electron microscopy (cryo-EM), aggregates of the C-Terminal domain of TMEM106B (TMEM CT) were shown to make up previously unidentifiable protein aggregates in the brains of human FTLD, AD, progressive supranuclear palsy (PSP), and dementia with Lewy Bodies (DLB) patients.

Methods: To determine the TMEM CT aggregation propensity and neurodegenerative potential, we generated a new transgenic C.

Basic Science and Pathogenesis.

Background: Recent evidence suggests both the innate and adaptive immune system are involved in the pathogenesis of Alzheimer's disease. We recently showed that the number of T cells, especially cytotoxic T cells, are increased in areas of tauopathy both in an animal model of tau-mediated neurodegeneration as well as in the AD brain. We also found that depletion of T cells as well as microglia were both strongly neuroprotective in P301S tau transgenic mice (PMID: 36890231).

Basic Science and Pathogenesis.

Background: Protein homeostasis (proteostasis) mechanisms fail with aging and disease, promoting toxic protein accumulation. Neurons are particularly vulnerable to proteostatic disruption leading to aging related neurodegeneration. Abnormal activation of the endoplasmic reticulum unfolded protein response (UPR) is implicated in tauopathies, a group of neurodegenerative diseases characterized by pathological accumulation of the microtubule-associated protein tau.

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 BRAIN Initiative has stimulated development of novel single cell and spatial molecular approaches to understand human brain structure and function. However, traditional methods for human brain specimen collection, including retrospective archival tissues, have not been optimized for these latest methods. A modernized approach that optimizes tissue quality, anatomical precision, and comprehensive, quantitative neuropathological assessments is needed to maximize the impact of the tremendous investment and remarkable technological advances in human neuroscience research.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) risk is markedly increased among APOE ε4/ε4 homozygotes. Previous studies of APOE genotype disclosure impact have included few ethnic minorities. This study addresses this gap by investigating the immediate impact of disclosing an APOE ε4/ε4 genotype in the Información de la Enfermedad de Alzheimer para Latinos (IDEAL) study, a Latino community-based study.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD), the most common aging-associated neurodegenerative dementia disorder, is defined by the presence of amyloid beta (Aβ) and tau aggregates in the brain. However, more than half of patients also exhibit aggregates of the protein TDP-43 as a secondary pathology. Clinically, AD patients with secondary TDP-43 pathology have more severe cognitive impairment, more rapid cognitive decline, worse brain atrophy, and a shorter disease course.

Basic Science and Pathogenesis.

Background: Several studies have indicated sex-specific genetic risk for Alzheimer's disease (AD), but these were centered on non-Hispanic White individuals of European ancestry. We sought to identify sex-specific genetic variants for AD in non-Hispanic and Hispanic subjects of admixed African ancestry.

Method: Participants were ages 60+, of African ancestry (≥25%), and diagnosed as cases or controls.

Basic Science and Pathogenesis.

Background: Blood-based biomarkers may aid in the diagnosis of Alzheimer's Disease (AD), but their contribution may be confounded by the presence of multiple chronic conditions and have not been well-tested in community populations. In the current study, we aimed to determine whether blood-based biomarkers can aid in refining a multi-ethnic, urban clinically diagnosed AD community-based cohort.

Method: We included 546 individuals in the Washington Heights, Hamilton Heights, and Inwood Columbia Aging Project (WHICAP) study in this cross-sectional study.

Basic Science and Pathogenesis.

Background: The integration of quantitative trait loci (QTLs) with disease genome-wide association studies (GWAS) has proven successful at prioritizing candidate genes at disease-associated loci. Most of QTL studies are focusing on expression QTLs in plasma and brain and cis-signals.

Method: Here we analyzed a large proteomic (Somalogic 7K) and metabolomic (Metabolon HD4) CSF (n = 3, 000) and plasma (African (AFR, N = 400) and European (EUR, N = 2,300) ancestry, respectively) to identify novel QTLs.

Basic Science and Pathogenesis.

Background: A multitude of high-quality imaging modalities exist that provide structural data at unprecedented levels of detail. Tissue ultrastructure greatly influences the rate of transport of proteins and other molecules that contribute to neurodegeneration. However, our ability to model flow and diffusion processes in the brain lags behind the quality of the neuroimaging data.

Basic Science and Pathogenesis.

Background: Amyloid PET imaging is a promising biomarker to track the accumulation of parenchymal amyloid beta (Aβ) deposits in the brain. Recent large-scale genome-wide association studies (GWAS) reported common risk factors associated with amyloidosis, suggesting that this endophenotype is driven by genetic variants. We hypothesized that genes with multiple variants with deleterious effect are associated with Aβ accumulation.

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: Human Apolipoprotein (APOE) has three isoforms, ε2, ε3, and ε4 among which ε4 (APOE4) confers the highest risk for late-onset Alzheimer's disease (AD). APOE4 is also the most prone to aggregate among APOE isoforms. Current evidence strongly suggests that APOE aggregation leads to neuronal dysfunction and eventually to AD.

Basic Science and Pathogenesis.

Background: We recently reported genetic associations with dementia-related proteinopathies. Using multidimensional generalized partial credit modeling, we constructed three continuous latent variables, corresponding to TDP-43, Aβ/Tau, and a-synuclein related neuropathology endophenotype scores.

Method: Participant data were drawn from the National Alzheimer's Coordinating Center (NACC) neuropathology (NP) data (from the September 2023 data freeze) linked to Alzheimer's Disease Genetics Consortium (ADGC) genotype data.

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.