Basic Science and Pathogenesis.

Background: Activation of the mTOR pathway is pivotal for microglia to induce and sustain neuroprotective functions (Ulland et al., 2017; Wang et al., 2022).

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) is a degenerative condition characterized by a progressive decline in cognitive function, predominantly affecting older individuals. AD is associated with a range of histopathological alterations, including the gradual demise of neuronal cells, the accumulation of amyloid plaques, and the formation of neurofibrillary tangles. Furthermore, research suggests that the brain tissue of AD patients is subject to oxidative stress, which manifests as the oxidation of proteins, lipids, DNA, and the process of glycoxidation, throughout the disease progression.

Basic Science and Pathogenesis.

Background: APOEε4 significantly increases the risk of developing Alzheimer's disease (AD). Cognitively healthy APOEε4-carriers exist, suggesting potential protective mechanisms against APOEε4. We hypothesized that some APOEε4-carriers may have genetic variations protecting them from developing APOEε4-mediated AD pathology.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) is characterized by progressive, irreversible neurodegeneration, leading to memory loss and cognitive decline. In mouse models of AD, global decreases in cerebral blood flow (CBF) are brought on by the plugging of capillaries by arrested neutrophils, and the administration of the neutrophil-specific antibody against Ly6G (anti-Ly6G) reduces these capillary stalls in minutes and improves cognitive function within hours. This suggests that at least some aspects of neural activity impairment are reversible, but the mechanism of this recovery - and what specific neural activity is normalized - is not yet known.

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.

Emotional well-being (EWB) is considered to play an important role in the health of individuals over their lifespan. Clinical studies suggest an association between EWB and the risk or progression of AD. However, the mechanistic link and causal relationship between EWB and AD remain unknown, due to limited experimental access and control of the underlying brain processes in human.

Basic Science and Pathogenesis.

Background: The immunoproteasome (IP) is the inducible form of the constitutive 20S proteasome upregulated in immune cells. The IP consists of 3 inducible β subunits (β1i - LMP2, β2i - MECL1, and β5i - LMP7), which generate MHC-I compatible peptides. IPs are induced by pro-inflammatory cytokine signaling, as well as oxidative stress signaling.

Basic Science and Pathogenesis.

Background: Integrating clinical and genetic risk factors for dementia in a precision medicine framework can play a crucial role in primary prevention. Here, we ascertained the proportion of individuals who are at heightened risk of developing dementia based on their family history, genetic, and clinical risk factors and evaluated how the additive burden of these risk indicators is associated with incident dementia.

Method: We analyzed longitudinal data from 3,395 diverse older adults, dementia-free at baseline with follow-up and whole genome sequencing, enrolled in the National Alzheimer's Co-coordinating Center and the Alzheimer's Disease Neuroimaging Initiative (Table 1).

Basic Science and Pathogenesis.

The view of microglial role in the pathogenesis of Alzheimer's disease (AD) has been shaped by two major breakthroughs in the past decade: the discovery that many of the AD susceptibility genes are preferentially expressed in microglia, and the finding that microglia exist in a variety of previously not described functional phenotypes in the aged human central nervous system. As much as these discoveries brought paradigm shifts to the field, they also revealed major gaps in our understanding of the functional consequences of both the expression of AD susceptibility genes and microglia phenotypic heterogeneity. While there is progress being made in understanding the role of individual AD susceptibility genes in microglia function and what role the different microglia phenotypes might play in disease pathogenesis in AD, the connection between these two determining factors has not been established yet.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) missing heritability remains extensive despite numerous genetic risk loci identified by genome-wide association or sequencing studies. This has been attributed, at least partially, to mechanisms not currently investigated by traditional single-marker/gene approaches. Polygenic Risk Scores (PRS) aggregate sparse genetic information across the genome to identify individual genetic risk profiles for disease prediction and patient risk stratification.

Basic Science and Pathogenesis.

Background: Neuropsychiatric Symptoms (NPS) (e.g., aggression, psychosis, anxiety, apathy, depression, agitation, sleep disturbances, repetitive behaviors) occur in 85% of AD patients, and are associated with accelerated decline, out-of-home placement, increased costs, and greatly increased suffering of patients and families.

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: Up to 84% of patients with Alzheimer's Disease (AD) have vascular damage which precedes cognitive decline. Inflammation induces changes in blood-brain-barrier (BBB) integrity, though the link between induction of inflammation and AD is unclear. IL1β, a cytokine upregulated in patients with AD and in mouse models of the disease, is released and interacts with IL1R1 and its obligate co-receptor, IL1RAP, to induce downstream signaling.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) exhibits considerable phenotypic heterogeneity, suggesting the potential existence of subtypes. AD is under substantial genetic influence, thus identifying systematic variation in genetic risk may provide insights into disease origins. We previously identified a genetic heterogeneity across two levels.

Basic Science and Pathogenesis.

Background: DAP12 (DNAX-activation protein 12 or TYROBP) functions as a pivotal adaptor, facilitating signal transmission from surface immune receptors on microglia, including TREM2-a known risk gene for Alzheimer's disease (AD). Previous studies showed that DAP12-deficient mice exhibit resistance to tau toxicity in a tauopathy model, manifesting reduced brain inflammation and improved cognition, despite increased tau pathology. However, the precise mechanism underlying how DAP12 deficiency enhances resilience to tauopathy remains elusive.

Basic Science and Pathogenesis.

Background: The accumulation of abnormal tau protein in neurons and glia in the human brain is the defining feature of neurodegenerative diseases known as tauopathies. Progressive supranuclear palsy (PSP), the most common primary tauopathy, is typified by selective vulnerability of dopaminergic neurons and glia in the midbrain leading to an atypical parkinsonian movement disorder. To investigate candidate disease mechanisms underlying PSP, there is a critical need for model systems that more accurately recapitulate the cellular and molecular environment in the human brain.

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: In Alzheimer's disease (AD), specific brain regions become vulnerable to pathology while others remain resilient. New methods of imaging such as highly multiplexed immunofluorescence (MxIF) provide an abundance of spatial information, while analytical techniques like machine learning (ML) can address questions of cellular contributors to this regional vulnerability.

Method: We performed MxIF staining for 26 markers and compared postmortem human samples from an AD-susceptible brain area, the prefrontal cortex (PFC, Brodmann's areas 9, 10 or 46) to an AD-resilient brain area, the primary visual cortex (V1, area 17).

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: The connection between inflammasomes and Alzheimer's disease (AD) has garnered significant interest, with emerging evidence suggesting genetic associations and functional implications. Notably, studies have reported the upregulation of inflammasome components like NLRP1, NLRP3, and Caspase-1 in AD patients. Moreover, genetic polymorphisms in inflammasome-related genes are linked to increased AD risk.

Basic Science and Pathogenesis.

Background: Presenilin1 (PS1)/γ-secretase cleaves within the transmembrane domain of numerous receptor substrates. Mutations in PS1 have implications on the catalytic subunit of γ-secretase decreasing its activity and becoming a potential causative factor for Familial Alzheimer's Disease (FAD). This work studies the role of PS1/γ-secretase on the processing, angiogenic signaling, and functions of VEGFR2 and the effects of PS1 FAD mutants on the γ-secretase-mediated epsilon cleavage of VEGFR2.

Basic Science and Pathogenesis.

Background: Recent advances in Alzheimer's Disease (AD) research have emphasized the importance of recruiting from diverse populations. Notably, African-descent individuals have an almost doubled risk of developing AD compared to European-descent individuals. Transcriptome-wide association studies (TWAS) have advanced the analysis of non-coding variants by integrating gene expression with GWAS data.

Basic Science and Pathogenesis.

Background: The Cognitive Function Index (CFI) is a validated test used to assess changes in self-perceived cognitive and functional status as reported by an individual and their study partner. Previous studies have demonstrated an inverse correlation between higher amyloid-beta (Aβ) burden and CFI, with certain CFI items exhibiting stronger associations than others. However, there is limited understanding of the association between declines in cognition and function, as assessed by CFI, and Tau levels measured by PET.