Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) is a common form of dementia characterized by the accumulation of amyloid beta (Aβ) and phosphorylated tau proteins in the brain. While clinical observations are typically used for AD diagnosis, postmortem studies have revealed individuals without dementia symptoms but with high AD pathology, known as resilient individuals. Calcium permeable AMPA receptors (CP-AMPARs) have been implicated in the calcium dyshomeostasis of AD, but it is unclear whether they are found or behave differently at the electrophysiological level in resilient and control individuals compared to AD patients.

Basic Science and Pathogenesis.

Background: Structural variants (SVs), genomic alterations exceeding 50 base-pairs, are known for their significant impact on disease pathology. However, the role of SVs in Alzheimer's Disease (AD) remains unclear. Using a novel high-accuracy SV calling pipeline, we analyzed a diverse sample from the Alzheimer's Disease Sequencing Project (ADSP).

Basic Science and Pathogenesis.

Background: Lewy bodies (LBs), characterized by intraneuronal inclusions of misfolded alpha-synuclein (α-syn) protein, are the pathological hallmark of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Because this protein is phosphorylated at serine-129 in 90% of LBs, its phosphorylation is considered a crucial pathogenic event in LB formation and disease development. Here, we present a unique brain autopsy case of a DLB patient with widespread LBs that were negative for phosphorylated-α-syn, challenging traditional diagnostic criteria.

Basic Science and Pathogenesis.

Background: The prion model of tau propagation in Alzheimer's Disease predicts that tau seeds are released from cells and taken up by neighboring cells, resulting in spreading of the disease. Our previous work revealed that tau aggregates bind to heparan sulfate proteoglycans (HSPGs) on the cell surface, followed by cellular uptake via macropinocytosis. HSPGs are glycoproteins, consisting of a protein core and decorated with linear glycosaminoglycan (GAG) chains called heparan sulfate (HS) with highly variable sulfation patterns.

Basic Science and Pathogenesis.

Background: Traumatic brain injury (TBI) is a serious societal concern and is considered a major risk factor for the development of Alzheimer's disease (AD) and related dementias. Identifying shared pathological mediators that contribute to the progression of AD following TBI may allow therapeutic targeting to reduce the likelihood of developing AD following TBI. Cerebrovascular dysfunction is present in both AD and TBI, and thrombin has been implicated as a mediator of cerebrovascular dysfunction and inflammation.

Basic Science and Pathogenesis.

Background: Positron emission tomography (PET) tau tracer PI-2620 frequently shows off-target meningeal binding (Figure 1). Of standard regions of interest, only lateral parietal (LP) is contaminated by this. We compare the standardized uptake value ratio (SUVR) in the LP before and after eroding the LP mask to remove meningeal contamination.

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: Oral and gut microbiomes have been associated with Alzheimer's disease and related dementias (ADRD). Although the role of the gut microbiome and gut dysbiosis in ADRD has been extensively studied, research on the oral microbiome is lacking. Moreover, the synergetic contribution of oral and gut microbiomes to ADRD is unexplored.

Basic Science and Pathogenesis.

Background: Glycosylation is the most common post-translational modification in the brain. Aberrant glycosylation patterns are present in cerebrospinal fluid and brain tissue from Alzheimer's disease (AD) patients. Specifically, dysregulation of a particular form of terminal glycoconjugate modification, sialylation, has been identified in AD.

Basic Science and Pathogenesis.

Background: In Alzheimer's disease (AD), changes in the brain transcriptome are hypothesized to mediate the impact of neuropathology on cognition. Gene expression profiling from postmortem brain tissue is a promising approach to identify causal pathways; however, there are challenges to definitively resolve the upstream pathologic triggers along with the downstream consequences for AD clinical manifestations.

Method: We have functionally dissected 30 AD-associated gene coexpression modules using a cross-species strategy in Drosophila melanogaster models.

Basic Science and Pathogenesis.

Background: Pathological tau aggregates cause cognitive decline in neurodegenerative tauopathies, including Alzheimer's disease (AD), and more abundant in intracellular vs. extracellular compartments. However, current immunotherapies are slow and ineffective at clearing intracellular tau aggregates.

Basic Science and Pathogenesis.

Background: Alzheimer's Disease (AD) is a widespread neurodegenerative disease with Mild Cognitive Impairment (MCI) acting as an interim phase between normal cognitive state and AD. The irreversible nature of AD and the difficulty in early prediction present significant challenges for patients, caregivers, and the healthcare sector. Deep learning (DL) methods such as Recurrent Neural Networks (RNN) have been utilized to analyze Electronic Health Records (EHR) to model disease progression and predict diagnosis.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) is the memory-related neurodegenerative disorder, contributing to 70% of the cases globally. Synaptic dysfunction is a well-known early event that causes progressive cognitive decline in AD. The latest AD therapeutics on the forefront only offer a moderate symptomatic relief with significant off-target effects.

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: Older females, particularly susceptible to Alzheimer's disease (AD), may be affected by hormonal fluctuation during life. We aim to investigate the relationship between changes in brain volume and sex steroid hormones over time. We hypothesize that levels of sex hormones (17ß-estradiol, progesterone, and testosterone) relate to changes in brain volume, especially in the hippocampus (HPC) and cerebellum (CB).

Basic Science and Pathogenesis.

Background: During aging, we observe several changes in the brain that render it more vulnerable to a variety of age-related neurodegenerative diseases, including Alzheimer's Disease. Glia-neuron interactions mediate brain development and physiology via cell-surface proteins at the cell-surface interface, and dysregulation of these interactions is considered one of the hallmarks of brain aging. Due to the critical role glial cells play in neuroplasticity, immune function, and homeostasis, dysregulation of glial cell-surface proteins is hypothesized to contribute to neurodegeneration.

Basic Science and Pathogenesis.

Background: Chemotherapy-induced cognitive impairment (CICI) is a commonly reported neurotoxic side effect of chemotherapy, occurring in up to 75% cancer patients. Connections between chemo-treatment and increased risk of dementia have been reported. Mechanistically, chemotherapy treatment contributes to an accelerated aging phenotype in the brain through induction of pathogenic tau, disruption of neuronal integrity, reactive gliosis and neuroinflammation.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder leading to dementia. The existence of individuals who remain cognitively intact despite presenting histopathological signs of AD, here referred to as "Non-demented with AD neuropathology" (NDAN), suggests that some mechanisms are triggered to resist cognitive impairment. These individuals are distinguished by the presence of highly phagocytic microglia capable of clearing damaged synapses near plaques, mitigating further damage to axons and dendrites.

Basic Science and Pathogenesis.

Background: The oligomers and fibrils of tau are well known as an indicator of Alzheimer's disease (AD). Recently, other protein aggregates have been shown to be potentially involved in the development of the disease. One of these proteins is p53, involved in DNA repair.

Basic Science and Pathogenesis.

Background: APP duplications are a rare form of familial Alzheimer's disease (AD). Research has shown variability in clinical presentation with full duplications. There is limited information on those with partial duplications, especially in underrepresented minorities.

Basic Science and Pathogenesis.

Background: Consortium-wide studies of volumetric brain imaging measures with single-nucleotide polymorphisms (SNPs) have revealed numerous disease-risk SNPs and emphasized the significance of brain imaging phenotypes as preclinical markers (endophenotypes) for Alzheimer's disease (AD). Nevertheless, the bulk of these risk variants are in genomic regions that govern multiple genes, posing major challenges in fine-mapping strategies. Evolutionarily conserved transposable elements are master regulators of gene expression, and by studying these endogenous gene regulatory units in relation to AD endophenotypes, we aimed to better identify the disease-causal gene.

Basic Science and Pathogenesis.

Background: The efficacy of Calorie Restriction (CR) in enhancing cognition, promoting healthy aging, and extending lifespan is well-established. Yet, it remains unclear whether the apolipoprotein E (APOE) genotype, a known modifier for aging and age-related disorders, influences the beneficial effects of CR in countering aging.

Methods: To investigate this question, we utilized humanized APOE mouse models, which express APOE2, APOE3, or APOE4 alleles systematically (refer to as E2, E3, and E4 mice).

Basic Science and Pathogenesis.

Background: Worldwide, the actual number of 55 million people diagnosed with dementia is estimated to increase to 139 million people affected by dementia in 2050. 61% of these individuals resided in low and middle-income countries (LMIC). Genetic risk factors account for up to 80% of the attributable risk of Alzheimer's disease (AD), the leading cause of dementia.

Basic Science and Pathogenesis.

Background: Aging is a natural, irreversible process that can be successful or pathological, resulting in chronic degenerative diseases such as Alzheimer's disease. Low levels of estrogen characterize menopause. Research reveals that the lack of these hormones may be related to dementia and that vitamin D (vit D), when supplemented, has a neuroprotective and neuromodulator effect.