Drug Development.

Background: Alzheimer's disease neuropathology involves the deposition in brain of aggregates enriched with microtubule-binding-region (MTBR) of tau adopting an abnormal conformation between residues 306-378 in the core of aggregates. Anti-tau drugs targeting around this domain have the potential to interfere with the cell-to-cell propagation of pathological tau. Bepranemab is a humanized monoclonal Ig4 antibody binding to tau residues 235-250.

Drug Development.

Background: Impaired Aβ clearance plays a key role in the common, late-onset AD. Anti-Aβ immunotherapies are controversial, in part because of high rates of serious side effects including edema, microhemorrhages, and siderosis, highlighting the importance of the development of alternative Aβ clearance strategy. Here, we introduce a bioinspired nanoparticle named MG-PE3 crossing the human blood-brain barrier (BBB) and clearing Aβ with no adverse effect.

Drug Development.

Background: Convergent evidence indicates that deficits in the endosomal recycling pathway underlies pathogenesis of Alzheimer's disease (AD). SORL1 encodes the retromer-associated receptor SORLA that plays an essential role in recycling of AD-associated cargos such as the amyloid precursor protein and the glutamatergic AMPA receptor. Importantly, loss of function pathogenic SORL1 variants are associated with AD.

Drug Development.

Background: The hyperphosphorylation, mislocalization, and aggregation of the microtubule associated protein Tau (MAPT) is a driving force in tauopathies, a group of progressive, neurodegenerative disorders. These pathogenic intracellular aggregates, known as neurofibrillary tangles (NFTs), are a hallmark in several diseases such as frontotemporal dementia, progressive supranuclear palsy, and Alzheimer's Disease. While anti-Tau immunotherapies emphasize the clearance of extracellular Tau aggregates, they do not address the intracellular accumulation of NFTs.

Drug Development.

Background: Rater change is inevitable in often lengthy clinical trials in Alzheimer's disease. Other groups have previously assessed the impact of rater change on data variability. Their conclusions varied, possibly due to differing methodologies (e.

Drug Development.

Background: The ability to monitor cognitive trajectories over the course of trials can provide valuable insights into treatment efficacy. However, existing trial methods are limited in monitoring cognition in real-time and at high frequencies. Gameplay-based assessments hold promise as complementary cognitive tools.

Drug Development.

Background: Only about 50% of the variance in cognitive decline occurring during Alzheimer's pathogenesis is attributable to standard AD biomarkers (cerebrocortical Aβ, pathological tau, and atrophy) (Tosun et al., Alzheimer's Dement. 18: 1370, 2022).

Drug Development.

Background: We have previously reported the neuroprotective effects of fosgonimeton in amyloid-β (Aβ)-driven preclinical models of Alzheimer's disease (AD). Fosgonimeton is an investigational small-molecule positive modulator of the neurotrophic hepatocyte growth factor (HGF) system, currently under investigation for mild-to-moderate AD (LIFT-AD; NCT04488419). Given the recent approvals of Aβ-targeting monoclonal antibodies (Aβ-mAbs) for the treatment of AD, and growing recognition that combination therapies may improve treatment outcomes, we sought to investigate the preclinical activity of fosgonimeton in the presence of Aβ-mAbs.

Drug Development.

Background: Alzheimer's Disease (AD) is the leading form of senile dementia, affecting ∼6 million Americans and having a national economic impact of $321 billion, numbers expected to double by 2050. The major pathological hallmarks of AD include Amyloid Beta (Aβ) plaques and Tau neurofibrillary tangles (NFT). The first goal of this research was to develop novel forms of carbon dots (CD) using various precursors.

Drug Development.

Background: Although investment in biomedical and pharmaceutical research has increased significantly over the past two decades, there are no oral disease-modifying treatments for Alzheimer's disease (AD).

Method: We performed comprehensive human genetic and multi-omics data analyses to test likely causal relationship between EPHX2 (encoding soluble epoxide hydrolase [sEH]) and risk of AD. Next, we tested the effect of the oral administration of EC5026 (a first-in-class, picomolar sEH inhibitor) in a transgenic mouse model of AD-5xFAD and mechanistic pathways of EC5026 in patient induced Pluripotent Stem Cells (iPSC) derived neurons.

Drug Development.

Background: Epidemiological studies report an elevated risk of neurodegenerative disorders, particularly Parkinson's disease (PD), in patients with type 2 diabetes mellitus (T2DM) that is mitigated in those prescribed incretin mimetics or dipeptidyl peptidase 4 inhibitors (DPP-4Is). Incretin mimetic repurposing appears promising in human PD and Alzheimer's disease (AD) clinical trials. DPP-4Is are yet to be evaluated in PD or AD human studies.

Drug Development.

Background: DYRK1A overexpression, common in neurodegenerative diseases like Alzheimer's (AD), contributes to neurofibrillary tangles via Tau protein hyperphosphorylation and amyloid plaque formation, key AD hallmarks. Therefore, DYRK1A has been regarded as a novel target for neurodegenerative diseases. However, developing DYRK1A selective inhibitors has been a difficult challenge due to the highly conserved ATP-binding site of protein kinases, particularly among the CMGC family.

Drug Development.

Background: The well-accepted statistical efficacy inference approach for Alzheimer's disease (AD) clinical trials compares the absolute difference in change from baseline at the last study visit using MMRM (henceforth referred to as MMRM-Last-Visit). Recent AD clinical trials have shown that treatment effects may be manifested prior to 18 months. The objective is to evaluate models estimating an overall treatment effect across all post-baseline visits that may characterize disease modifying effects in contemporary early AD clinical trials.

Drug Development.

Dementia patients often received one clinical diagnosis, yet most of these cases present multiple underlying pathologies. Bringing the transition from clinical-based to biological-based diagnosis holds promise with the diagnostic criteria proposed by the Alzheimer's Association (AA) Revised Criteria for Diagnosis and Staging of Alzheimer's Disease and the Neuronal Synuclein Disease Integrated Staging System (NSD-ISS). This session aims to explore the practical implications of the AA revised criteria for diagnosing and designing clinical trials in Lewy body disease (LBD).

Drug Development.

Background: In preparation for therapeutic trails involving patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI), there is a need for valid, disease-specific caregiver-reported outcome (CRO) measures capable of tracking symptomatic burden in response to therapy over time. CROs are useful tools in clinical trials for individuals with AD, MCI, and dementia who are unable to self-report. In addition, CROs are accepted by the United States Food and Drug Administration to support regulatory claims.

Drug Development.

Background: TREM2 is a lipid-sensing receptor expressed by microglial sub-populations within neuropathological microenvironments, whose downstream signaling promotes microglial survival, plasticity, and migration. Multiple loss-of-function variants strongly implicate TREM2 as a key regulator of Alzheimer's disease (AD) risk. Accordingly, TREM2 antibodies are currently in development to evaluate the therapeutic potential of TREM2 agonism in neurodegenerative diseases.

Drug Development.

Background: Progranulin (GRN) plays a critical role in familial frontotemporal dementia (fFTD), where GRN haploinsufficiency leads to reduction in PGRN levels in the brain, resulting in degeneration of neurons in the frontal lobe of brain responsible for personality, language, and behavior. FTD is the most common dementia in people under 60. Sortilin (Sort1), expressed by neurons, endocytoses, and delivers PGRN rapidly to lysosomes for degradation.

Drug Development.

Background: Participant retention is a key determinant for a successful clinical trial. In Alzheimer's disease (AD) trials, participants are typically required to enroll with a study partner, which adds barriers to retention. Previous analyses of North American trial data found that most study partners were spouses and that such dyads had higher study completion rates than other study partner types.

Drug Development.

Background: Some types of cancer have been associated with reduced risk of clinical dementia diagnosis. Whether cancer history may be associated with neuropathological features of neurodegeneration or cerebrovascular disease is not well understood. We investigated the relation between cancer diagnosis and brain pathology in a sample of community-based research volunteers enrolled in an Alzheimer's Disease Research Center (ADRC) cohort.

Drug Development.

Background: Recruitment registries are tools to decrease the time and cost required to identify and enroll eligible participants into clinical research. Despite their potential to increase the efficiency of accrual, few analyses have assessed registry effectiveness. We investigated the outcomes of study referrals from the Consent-to-Contact (C2C) registry, a recruitment registry at the University of California, Irvine.

Drug Development.

Background: Brain organoid models were generated from healthy control or Alzheimer's disease patient iPSCs to facilitate our understanding of AD pathogenesis.

Method: ApoE3 and ApoE4 iPSCs were developed into brain organoids using our recently developed brain organoid platform that allows prolonged culture of brain organoids. Human iPSCs were also differentiated into microglia, which were then co-cultured with brain organoids.

Drug Development.

Background: Efforts to genetically reverse C9orf72 pathology have been hampered by our incomplete understanding of the regulation of this complex locus.

Method: We generated five different genomic excisions at the C9orf72 locus in a patient-derived iPSC line and a WT line (11 total isogenic lines), and examined gene expression and pathological hallmarks of C9 FTD/ALS in motor neurons differentiated from these lines. Comparing the excisions in these isogenic series removed the confounding effects of different genomic backgrounds and allowed us to probe the effects of specific genomic changes.

Drug Development.

Background: Alzheimer's disease (AD) is an age-dependent neurodegenerative disorder with limited treatment options. As it progresses, synapse degeneration is the most important feature contributing to cognitive dysfunction. Mitochondria supply synapses with ATP for neurotransmitter release and vesicle recycling and buffer calcium concentrations.

Drug Development.

Background: Differences in patient characteristics across geographical regions may result in heterogeneity in clinical trial populations. evoke (NCT04777396) and evoke+ (NCT04777409) are two phase 3, multinational, randomised trials investigating semaglutide versus placebo in individuals with mild cognitive impairment or mild dementia due to Alzheimer's disease (AD) (early AD). We present baseline characteristics across the geographical regions in evoke/evoke+.

Drug Development.

Background: The TREAT-AD centers aim to improve Alzheimer's Disease (AD) research by offering free, high-quality tools and technologies. Lyn is a tyrosine kinase that belongs to the Src family kinases. The expression of Lyn and its activity have been implicated in AD.