4,729,821 results match your criteria: "PA; University of Adelaide[Affiliation]"

Background: Progranulin (PGRN) haploinsufficiency is a major risk factor for frontotemporal lobar degeneration with TDP-43 pathology (FTLD-GRN). Multiple therapeutic strategies are in clinical development to restore PGRN levels in the CNS, including gene therapy. However, a limitation of current gene therapy approaches aimed to alleviate FTLD-associated pathologies may be their inefficient brain exposure and biodistribution.

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Basic Science and Pathogenesis.

Alzheimers Dement

December 2024

Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.

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.

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Background: The limited treatment options for Alzheimer's emphasizes the need to explore novel drug targets and bring new therapeutics to market. Drug repurposing is an efficient route to bring a safe and effective treatment to the clinic. Agomelatine (AGO) was identified by a high-throughput drug screening algorithm as having mechanistic potential to treat Alzheimer's.

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Basic Science and Pathogenesis.

Alzheimers Dement

December 2024

Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Background: Microglia undergo varying regional dependent functional changes, which can exacerbate cognitive decline in Alzheimer's disease, but the full clinical relevance remains unclear. Ramified microglia survey the micro-environment and inert/amoeboid microglia engulf debris. A third morphological type; rod microglia, have been observed in a number of pathological conditions, but are relatively understudied.

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Background: The misfolding and aggregation of the tau protein into neurofibrillary tangles constitute a central feature of tauopathies. Traumatic brain injury (TBI) has emerged as a potential risk factor, triggering the onset and progression of tauopathies. Our previous research revealed distinct polymorphisms in soluble tau oligomers originating from single versus repetitive mild TBIs.

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Basic Science and Pathogenesis.

Alzheimers Dement

December 2024

Boston University Alzheimer's Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.

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.

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Background: The Accelerating Medicines Partnership in Alzheimer's Disease (AMP-AD) is a public-private partnership linking NIH, the FDA, pharmaceutical companies, and nonprofit organizations in an interactive, collaborative program utilizing transcriptomics, genomics, metagenomics, proteomics, and metabolomics to provide data for computational analysis, that, in turn, enables promising targets to be ranked by a combination of omic scores and druggability. This ranking informs the selection of targets for validation.

Method: Human postmortem samples were obtained from Mount Sinai, ROSMAP (Religious Orders Study and Rush Memory and Aging Project), Mayo Clinic (Florida), and Columbia University.

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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.

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Background: Non-coding RNA species, such as microRNA (miRNA), regulate multiple biological and pathological processes by binding to target mRNAs and facilitating alteration of translation levels via complexes such as RNA-induced silencing complex (RISC). Disrupting this process could contribute to AD pathogenesis by fostering aggregation of hyperphosphorylated microtubule-associated protein tau and amyloid-β (Aβ) peptides, and neuroinflammation. Understanding how these pathological changes are regulated remains our research focus.

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Background: Alzheimer's disease (AD) has a complex etiology where insults in multiple pathways conspire to disrupt neuronal function, yet molecular changes underlying AD remain poorly understood. Previously, we performed mass-spectrometry on post-mortem human brain tissue to identify >40 protein co-expression modules correlated to AD pathological and clinical traits. Module 42 has the strongest correlation to AD pathology and consists of 32 proteins including SMOC1, a predicted driver of network behavior and potential biomarker for AD.

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Basic Science and Pathogenesis.

Alzheimers Dement

December 2024

Department of Cell Biology and Pathology, New York, NY, USA.

Background: Possession of the APOE4 allele is the strongest genetic risk factor for developing the sporadic form of Alzheimer's disease (AD). Studies investigating APOE4's associated AD risk have largely centered on APOE4's propensity to regulate the deposition of extracellular amyloid beta plaques. More recent attempts to characterize APOE4's role in AD have brought into question the role APOE4 may possess in modulating the pathogenesis of intracellular tau tangles.

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Background: The common APOE2/E3/E4 polymorphism, the strongest risk factor for Alzheimer's disease (AD), is determined by two-site haplotypes at codons 112 (Cys>Arg) and 158 (Arg>Cys), resulting into six genotypes. Due to strong linkage disequilibrium between the two sites, 3 of the 4 expected haplotypes (E2, E3, E4) have been observed and extensively studied in relation to AD risk. Compared to the most common haplotype of E3 (Cys112 - Arg158), E4 (Arg112 - Arg 158) and E2 (Cys112 - Cys158) haplotypes are determined by a single-point mutation at codons 112 and 158, respectively.

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Background: Astrocytes are a numerous and diverse glial subtype specialised to carry out distinct roles involving maintaining homeostasis and effective functioning of the nervous system. To do so effectively, they respond to and secrete various proteins. In addition, astrocytes have been linked to Alzheimer's disease (AD), where they are believed to become reactive and contribute to neuroinflammation.

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Background: Individuals with Down syndrome (DS) have an increased genetic risk of developing Alzheimer's disease (AD), with most adults developing AD neuropathology in their 40s. Despite having a low frequency of systemic vascular risk factors such as hypertension and atherosclerosis, adults with DS display cerebrovascular pathology, including microbleeds, microinfarcts, and cerebral amyloid angiopathy. This suggests that blood-brain barrier (BBB) integrity may be compromised allowing the extravasation of blood proteins in the brain parenchyma.

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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).

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Background: Alzheimer's disease (AD) is an age-related neurodegenerative disorder affecting nearly 50 million individuals worldwide. Besides aging, various comorbidities can increase the risk of AD, such as asthma. However, the molecular mechanism(s) underlying this asthma-associated AD exacerbation is unknown.

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Background: Spatial disorientation is an early symptom of Alzheimer's disease (AD). The hippocampus creates a cognitive map, wherein cells form firing fields in specific locations within an environment, termed place cells. Critically, place cells remain stable across visits to an environment, but change their firing rate or field location in a different environment.

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Basic Science and Pathogenesis.

Alzheimers Dement

December 2024

VA Boston Healthcare System, Boston, MA, USA.

Background: T-cell infiltration into the brain parenchyma is associated with hyperphosphorylated tau (p-tau) accumulation in neurodegenerative diseases. Chronic traumatic encephalopathy (CTE) is a progressive tauopathy caused by exposure to repetitive head impacts (RHI). CTE is defined by the perivascular accumulation of p-tau at the cortical sulcal depths and can be stratified into mild and severe pathological stages.

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Basic Science and Pathogenesis.

Alzheimers Dement

December 2024

Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.

Background: Vascular dysfunction, blood-brain barrier (BBB) dysregulation, and neuroinflammation are thought to participate in Alzheimer`s disease (AD) pathogenesis, though the mechanism is poorly understood. Among pathways of interest, AD pathology appears to affect vascular endothelial growth factor-A (VEGFA) signaling in a bidirectional manner. Higher VEGF levels are thought to have a protective role and slow cognitive decline.

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Basic Science and Pathogenesis.

Alzheimers Dement

December 2024

Brain Research Institute, Niigata University, Niigata, Niigata, Japan.

Background: Recent single-cell omics analyses have revealed that microglia change into reactive microglia when Aβ accumulates in the brain and exhibit Aβ phagocytosis. However, reactive microglia are less likely to be induced in TREM2 mutation carriers. This microglia-centred pathological mechanism may be considered one of the pathologies of AD.

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Background: Stress is a common modifiable risk factor for AD, which increases dementia risk 2-fold. During the stress response, the hypothalamic-pituitary adrenal (HPA) axis is activated which stimulates the release of stress hormones called glucocorticoids into the blood stream. Studies on early-life stress have shown a glucocorticoid dependent vulnerability towards late-life inflammation.

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Background: Imbalanced Fe levels can lead to oxidative stress and initiate ferroptosis, an Fe-dependent cell death that involves lipid peroxidation and can lead to neuron cell loss in neurodegenerative diseases including Alzheimer's disease (AD). While the Fe/Fe ratio has been identified as the primary determining factor for lipid peroxidation, the role of Fe redox equilibrium and dynamic in AD is not well understood, due to limited tools for visualizing Fe and Fe simultaneously. To overcome this limitation, we recently reported DNAzyme-based sensors for simultaneous imaging of Fe and Fe.

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Background: Examining the neuropathology of the oldest-old has significantly advanced our understanding of the multiple etiologies in very late life. Most studies have included exclusively White decedents with limited ethnoracial diversity. Our goal was to characterize neuropathology in a cohort of ethnically and racially diverse oldest-old decedents.

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Background: We previously discovered that Aβ accumulates in the cortical/supranuclear region of the lens in people with Alzheimer's Disease (AD) (Goldstein et al., 2003) and Down Syndrome (DS; (Moncaster et al., 2010).

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Background: Glutamatergic neurotransmission plays an essential role in learning and memory. Previous studies support a dynamic shift in excitatory signaling with Alzheimer's disease (AD) progression, contributing to negative cognitive outcomes. The majority of previous studies have relied heavily on male physiology when determining these alterations in AD mouse models.

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