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: 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: 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.

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: Small, soluble oligomers, rather than mature fibrils, are the major neurotoxic agents in Alzheimer's disease (AD). In the last few years, Aprile and co-workers designed and purified a single-domain antibody (sdAb), called DesAb-O, with high specificity for Aβ oligomeric conformers. Recently, Cascella and co-workers showed that DesAb-O can selectively detect synthetic Aβ oligomers both in vitro and in cultured cells, neutralizing their associated neuronal dysfunction.

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: Accumulating evidence highlights impairment of autophagy as a key pathological feature of neurodegenerative diseases including Alzheimer's disease (AD). Autophagy is a highly dynamic, lysosome-based degradation process that promotes the clearance of degenerative factors to maintain cellular functions, preserve metabolic integrity, and ensure survival. Impaired autophagic function leads to the abnormal accumulation of autophagic vesicles (i.

Drug Development.

Background: Diabetic conditions are associated with alterations in brain functions like memory deficits through processes like synaptic dysfunction in the hippocampus. Administering a combination of silver nanonaringenin and vitamin E appears promising since they are known to prevent diabetes and memory deficits in previous studies, and nanoformulation of naringenin may be one way to improve delivery and bioavailability of naringenin in the brain. This study investigated the effects of co-administering silver nanonaringenin and vitamin E against memory deficits and synaptic dysfunction in the hippocampus of a mice model of high-fat diet and streptozotocin (HS).

Drug Development.

Background: Alzheimer's disease (AD) is the most common cause of age-related dementia, and the presence of amyloid-β (Aβ) plaques and tau-containing neurofibrillary tangles is associated with the neurodegeneration and cognitive impairment in this incurable disease. Growing evidence shows that epigenetic dysregulation through histone deacetylases (HDACs) plays a critical role in synaptic dysfunction and memory loss in AD, and HDACs have been highlighted as a novel class of anti-Alzheimer targets. Moreover, restoring Wnt/β-catenin signaling, which is greatly suppressed in AD brains, is a promising therapeutic strategy for AD.

Drug Development.

Background: Neurofibrillary tangles (NFTs), along with amyloid beta plaque, are neuropathological aggregates of Alzheimer's Disease (AD). Hyperphosphorylated tau is responsible for the NFTs formation and further neurodegeneration in AD. The hippocampal region and the entorhinal cortex (EC) have been a major focus of AD research because the deposits of hyperphosphorylated tau protein and NFT in these regions are correlated with memory deficits.

Drug Development.

Background: The effect of high consumption of psychoactive substances of codeine (CDE), tramadol (TMD), and Cannabis sativa (CNB) as concoction has been associated with altered brain cognitive and neurochemical functions. However, the understanding of the complex mechanism behind the intake of Cannabis sativa co-administration with tramadol and codeine on both cardiac and brain function, neurotransmitters, purinergic, and antioxidant enzymes activities in the brain and heart of rats remains unreported.

Method: The measure of cognition using morris water maze (MWM) and Y-maze tests, hemodynamic parameters namely systolic blood pressure (SBP) and heart rate (HR), acetylcholinesterase (AChE), butyl-cholinesterase (BCHE), adenosine deaminase (ADA), arginase, catalase (CAT), superoxide dismutase (SOD) enzymes' activities, reduced glutathione (GSH) and malondialdehyde (MDA), nitric oxide (NO) levels, in the brain and heart of CNB, TMD, and CDE exposed rats was done.

Drug Development.

Background: Recent preclinical studies have revealed a significant reduction in amyloid-β plaques and pro-inflammatory cytokines in Alzheimer's disease (AD) mouse models following low-dose radiation therapy (LDRT). This phase II, multicenter, prospective, single-blinded, randomized controlled trial (NCT05635968, funding from Korea Hydro & Nuclear Power: Grant No. A21IP11) aims to investigate the efficacy and safety of whole-brain LDRT in patients with AD.

Drug Development.

Real-World data platforms for Alzheimer's Disease (AD) offer a unique opportunity to improve health equity through better understanding of health disparities and inclusivity in research, which is critical to translatability of research findings. AD research in the US and globally remains largely inaccessible to many individuals due to individual-level, study-level, investigator-level and larger systemic barriers. ALZ-NET, a US-based registry to evaluate longitudinal outcomes of patients being evaluated for or treated with novel FDA-approved AD therapy, and New IDEAS, an observational US-based longitudinal study of amyloid PET clinical utility, both offer opportunities for examining care, inclusivity, and disparities.

Drug Development.

Background: Recent anti-amyloid mAb trial results demonstrate slowing of Alzheimer's disease progression, but to date do not fully halt or reverse this progression. Optimization of anti-amyloid therapy (timing and duration of intervention, modality, combinations, biomarker guidance) is limited by incomplete understanding of the disease, such as relationship between amyloid and tau pathways. Mechanistic Alzheimer's progression modeling investigated how amyloid and tau pathologies are connected in driving progression.

Drug Development.

Recent advances in biomarkers, enabling the in vivo detection of pathological aggregates of alpha-synuclein (asyn), allow a shift from a clinical to a biological definition of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). The newly proposed "Neuronal alpha-Synuclein Disease (NSD)" is defined by the presence of pathologic neuronal (n-asyn) species detected in vivo (S), irrespective of any specific clinical syndrome. Additional biological anchors include dopaminergic neuronal dysfunction (D).

Drug Development.

Background: Benfotiamine, a prodrug of thiamine, raises blood levels by 50-100 times to achieve pharmacologic effects. It provides a novel therapeutic direction addressing a well-characterized brain tissue thiamine deficiency and related changes in glucose metabolism in AD. BenfoTeam is a seamless phase 2A-2B "proof of concept" (POC), double-blind, placebo-controlled RCT investigating tolerability, safety, and efficacy of benfotiamine, as a first-in-class small molecule treatment for early AD.

Drug Development.

Background: In a 16-week, 91-patient placebo-controlled clinical study in DLB ("AscenD-LB";NCT04001517), neflamapimod improved outcomes on the CDR Sum-of-Boxes (p = 0.023 vs. placebo) and Timed Up and Go test (p = 0.

Drug Development.

Background: A new era of Alzheimer's disease (AD) research is beginning now that multiple monoclonal antibodies (mABs) are on the market. Their use may not be widespread initially but will be more common in clinical sites likely to participate in clinical trials and will continue to grow. Many AD investigational treatments have been studied as add-on to acetylcholinesterase inhibitors; however, putative disease-modifying therapies (DMTs) like mABs are expected to alter the underlying rate of progression, potentially reducing our ability to detect effects of other DMTs on top of mABs.

Drug Development.

Background: Cognitive decline associated with Alzheimer's disease (AD) correlates with hyperphosphorylated tau (pTau) propagating between neurons along networks connected by synapses. It has been hypothesized this transcellular transmission occurs partially by extracellular vesicles (EVs). Both genetic and pharmacological inhibition of nSMase2 has been found to inhibit EV biogenesis and pTau propagation.

Drug Development.

Background: There are no approved oral disease-modifying treatments for Alzheimer disease (AD). This study was intended to assess efficacy and safety of blarcamesine (ANAVEX2-73), an orally available small-molecule activator of the sigma-1 receptor (SIGMAR1) designed to exert neuroprotection through restoration of cellular homeostasis including autophagy enhancement.

Method: ANAVEX2-73-AD-004 is a multicenter (52 medical research centers/hospitals in 5 countries), randomized, double-blind, placebo-controlled, 48-week phase 2b/3 trial that enrolled 508 participants with early AD (mild cognitive impairment/mild dementia) from July 2018 to June 2021 (last patient visit in June 2022).

Drug Development.

A 10 mg/kg every 2 week (Q2W) dose of the humanized IgG1 monoclonal antibody lecanemab was approved after demonstrating significant clinical benefit in slowing cognitive decline in early Alzheimer's disease (AD) in two clinical studies (the phase 2 Study 201 and phase 3 Clarity AD). A less frequent every 4 weeks lecanemab 10 mg/kg maintenance dosing (Q4W) has been proposed after a sufficient initial Q2W treatment. To further understand long-term benefit of continued Q4W lecanemab treatment, a quantitative systems pharmacology (QSP) model was developed which mechanistically describes AD pathophysiology using multivariate data from clinical studies.

Dementia Care Research and Psychosocial Factors.

Background: The progressive nature of dementia and the complex needs means that people living with dementia require tailored approaches to address their changing care needs over time. These include physical multimorbidity, psychological, behavioural, and cognitive symptoms and possible risks arising from these and helping family caregivers. However, provision of these interventions is highly variable between and within countries, partly due to uncertainty about their efficacy and scarce resources.

Dementia Care Research and Psychosocial Factors.

Background: People with dementia and their care givers are provided limited guidance in medication management, potentially contributing to medication-related harm. Importantly, there are no resources that provide comprehensive medication management guidance across care settings. To ensure that resources are co-designed, genuine involvement of people with dementia, their care givers and the community in identifying the priorities for medication management guidance resources is needed.

Dementia Care Research and Psychosocial Factors.

Background: We have co-produced with carers of people with dementia (hereafter carers) a culturally tailored iSupport Virtual Assistant (VA), namely e-DiVA, to support English-, Bahasa- and Vietnamese-speaking carers in Australia, Indonesia, New Zealand and Vietnam. The presented research reports qualitative findings from the e-DiVA user-testing study.

Method: Family carers and healthcare professionals working in the field of dementia care were given the e-DiVA to use on their smartphone or handheld device for 1-2 weeks.

Dementia Care Research and Psychosocial Factors.

Background: People with dementia of all ages have a human right to equal access to quality health care. Despite evidence regarding its effectiveness, many people living with dementia lack access to evidence-based rehabilitation for promoting function and quality of life. The aims of this study were to 1) explore barriers to access to dementia rehabilitation; and 2) identify solutions which improve access to rehabilitation.