Drug Development.

Background: The first disease-modifying treatments (DMTs) for Alzheimer's disease (AD) have been approved in the USA, marking profound changes in AD-diagnosis and treatment. This will bring new challenges in terms of clinician-patient communication. We aimed to collect the perspectives of memory clinic professionals regarding the most important topics to address and what (tools) would support professionals and their patients and care partners to engage in a meaningful conversation on whether (or not) to initiate treatment.

Drug Development.

Background: Human pluripotent stem cell (hPSC)-derived brain organoids patterned towards the cerebral cortex are valuable models of interactions occurring in vivo in cortical tissue. We and others have used these cortical organoids to model dominantly inherited FTD-tau. While these studies have provided essential insights, cortical organoid models have yet to reach their full potential.

Drug Development.

Background: Recent growth in the functionality and use of technology has prompted an increased interest in the potential for remote or decentralised clinical trials in dementia. There are many potential benefits associated with decentralised medication trials, but the field is currently lacking specific recommendations for their delivery in the dementia field.

Method: A modified Delphi method engaged a panel with substantial expertise in dementia trial design and delivery and backgrounds that included neurology, psychiatry, pharmacology and psychology, to develop recommendations for the conduct of decentralised medication trials in dementia prevention.

Drug Development.

Background: The TaRget Enablement to Accelerate Therapy Development of Alzheimer's Disease (TREAT-AD) Centers are dedicated to identifying and validating targets from the NIH Accelerating Medicines Partnership for Alzheimer's Disease (AMP-AD). The centers develop Target Enabling Packages (TEPs) to explore new therapeutic target hypotheses, moving beyond the traditional focus on amyloid or tau pathologies. In accordance with open science principles, data, methods, and tools are freely shared with the research community via an open-access platform, the AD Knowledge Portal.

Drug Development.

Background: Pivotal Alzheimer's Disease (AD) trials typically require thousands of participants, resulting in long enrollment timelines and substantial costs. We leverage deep learning predictive models to create prognostic scores (forecasted control outcome) of trial participants and in combination with a linear statistical model to increase statistical power in randomized clinical trials (RCT). This is a straightforward extension of the traditional RCT analysis, allowing for ease of use in any clinical program.

Drug Development.

Background: Our limited understanding of the mechanisms that trigger the emergence of Alzheimer's disease (AD) has contributed to the lack of interventions that stop, prevent, or fully treat this disease. We believe that developing a nonhuman primate model of AD will be an essential step toward overcoming the limitations of other model systems and is crucial for investigating primate-specific mechanisms underlying the cellular and molecular root causes of the pathogenesis and progression of AD.

Method: The consortium successfully generated viable founders carrying PSEN1 mutations.

Drug Development.

The Alzheimer's Disease Neuroimaging Initiative (ADNI) has made many important contributions to the development of Alzheimer's Disease (AD) disease modifying treatments and diagnostic biomarkers. Since its funding in 2004 by the National Institutes of Aging, the goal of ADNI has been the validation of biomarkers for AD treatment trials. ADNI has enrolled over 2,400 participants in the USA and Canada for longitudinal clinical, cognitive, and biomarker studies.

Drug Development.

Background: Positive findings from testing therapeutics in AD animal models are often not translated to effective treatments due to the poor methodological rigor and inadequate reporting practices of therapeutic efficacy studies. The Alzheimer's Disease Preclinical Efficacy Database (AlzPED), developed by the NIA, is a searchable and publicly available knowledgebase that prioritizes and promotes the use of rigorous methodology to ameliorate this translation gap. Through a checklist of experimental design elements - the Rigor Report Card - AlzPED highlights reporting recommendations and standards while providing a practical tool to help plan rigorous therapeutic studies in animals.

Drug Development.

Background: The goal of the TREAT-AD Center is to enable drug discovery by developing assays and providing tool compounds for novel and emerging targets. The role of microglia in neuroinflammation has been implicated in the pathogenesis of Alzheimer's disease (AD). Genome-wide association studies, whole genome sequencing, and gene-expression network analyses comparing normal to AD brain have identified risk and protective variants in genes essential to microglial function.

Drug Development.

Background: We identified small molecule tricyclic pyrone compound CP2 as a mild mitochondrial complex I (MCI) inhibitor that induces neuroprotection in multiple mouse models of AD. One of the major concerns while targeting mitochondria is the production of reactive oxygen species (ROS). CP2 consists of two diastereoisomers, D1 and D2, with distinct activity and toxicity profiles.

Drug Development.

Background: The Mini-Mental State Examination (MMSE) is a common screening tool in Alzheimer's disease (AD) clinical trials. MMSE score inflation at inclusionary visits poses challenges by potentially amplifying placebo responses and complicating the detection of treatment effects. Despite these concerns, prior research (e.

Drug Development.

Background: Lyn kinase, a member of the Src family of tyrosine kinases, predominantly phosphorylates ITIM and ITAM motifs linked to immune receptors and adaptor proteins, and is emerging as a target for Alzheimer's disease (AD). The role of Lyn in TREM2-mediated microglial activation and phagocytosis, a critical pathway for clearing Aβ plaques, remains unclear and potent, selective, and brain penetrant Lyn inhibitors are unavailable. In this study, we report the characterization of Lyn kinase inhibitors from the literature as well as the establishment of an advanced virtual screening platform at the IUSM-Purdue-TREAT-AD center to identify new type II Lyn inhibitors suitable as molecular probes.

Drug Development.

Background: Recruitment of demographically diverse participants into Alzheimer's disease (AD) clinical trials, encompassing both screening and randomization, remains a consistent and persistent challenge contributing to underrepresentation of certain groups. Despite the exciting prospects of identifying therapeutic interventions for biomarker-eligible, cognitively unimpaired individuals, these studies grapple with the inherent complexities of AD trials coupled with intricate and time-consuming screening processes. Addressing this the issue of underrepresentation necessitates concerted and intentional efforts that prioritize inclusivity and equitable access to enroll adults meeting study criteria, reflecting the demographic and social diversity of North America.

Drug Development.

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with neuroinflammation and heightened production of reactive oxygen species (ROS) in the brain from overactive NADPH Oxidase 2 (NOX2). The current study examines whether administration of a novel, brain-penetrant NOX2 inhibitor (CPP11G & CPP11H) reduces amyloid plaque load and improves AD-associated vascular dysfunction in a male APP-PS1 mouse model of AD.

Method: Intraperitoneal injections of CPP11G (n = 1) or CPP11H (n = 2) three times per week began at 9-10 months of age in the treatment APP-PS1 group (15 mg/kg).

Drug Development.

Background: Anti-amyloid immunotherapies modestly slow disease progression in early symptomatic AD; addition of other therapeutic modalities may be necessary to achieve larger treatment effects. Therapies that directly target tau can potentially produce substantial clinical benefit because the accumulation of insoluble tau protein is strongly correlated with the progression of AD. Which tau therapies are likely to be efficacious, whether or not to combine them with anti-amyloid therapies, and which individuals are most likely to benefit are important unresolved questions that would require multiple parallel design trials to answer.

Drug Development.

Background: Despite increasing knowledge of the etiology of neurodegenerative diseases, translation of these benefits into therapeutic advances for Alzheimer's Disease and related diseases (ADRD) has been slow. Drug repurposing is a promising strategy for identifying new uses for approved drugs beyond their initial indications. We developed a high-throughput drug screening platform aimed at identifying drugs capable of reducing proteotoxicity in vivo (Aß toxicity in Caenorhabditis elegans) AND inhibiting microglial inflammation (TNF-alpha IL-6), both implicated in driving AD(figure attached with sample of results in C.

Drug Development.

Background: Recruiting and retaining older adults for clinical trials is challenging, especially in low-resource settings. Such challenges led to a systematic exclusion of such participants from clinical trials, compromising the generalizability of the results obtained in high income countries.

Objective: Here we describe the strategies we used in the PROAME study for recruiting and retaining illiterate older adults from low socioeconomical levels in a non-pharmacological trial.

Drug Development.

Background: Agitation is a common and disabling symptom of Alzheimer's dementia (AD). Pharmacological treatments are recommended if agitation is not responsive to psychosocial intervention. Citalopram was effective in treating agitation in AD but was associated with cognitive and cardiac risks linked to its R- but not S-enantiomer.

Drug Development.

Background: Findings regarding the protective effect of Angiotensin II receptor blockers (ARBs) against Alzheimer's disease and related dementias (ADRD) and cognitive decline have been inconclusive.

Method: A total of 6,390,826 hypertensive individuals were included in this study from Optum's de-identified Clinformatics® Data Mart. We identified antihypertensive medication (AHM) drug classes and subclassified ARBs by blood-brain barrier (BBB) permeability.

Drug Development.

Background: Early-onset Alzheimer's disease (EOAD) associated with amyloid precursor protein (APP) duplications or presenilin (PSEN) variants increases risk of seizures. Targeting epileptiform activity with antiseizure medicine (ASM) administration to AD patients may beneficially attenuate cognitive decline (Vossel et al, JAMA Neurology 2021). However, whether mechanistically distinct ASMs differentially suppress seizures in discrete EOAD models is understudied (Lehmann et al, Neurochem Res 2021).

Drug Development.

Background: Global epidemiological studies involving over nine million participants have shown a 35% lower incidence of Alzheimer's Disease (AD) in older cancer survivors compared to those without a history of cancer. This inverse relationship, consistent across recent studies with methodological controls, suggests that cancer itself, rather than cancer treatments, may offer protective factors against AD. This insight opens avenues for novel therapeutic strategies targeting early AD by harnessing cancer-associated protective factors.

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.

Introduction: The United States is undergoing a demographic shift with increasing proportions of older adults. Currently, one in three older adults pass away with a form of Alzheimer's disease or related dementias (ADRD). This figure is higher in underrepresented and underserved groups including older adults in rural Appalachian communities.

Drug Development.

Background: Pyroptosis is a type of inflammasome-dependent cell death, in which gasdermin D (GSDMD) plays key roles as the executor. Neuroinflammation and pyroptosis have been indicated critical roles in neurodegenerative disorders including Alzheimer's disease (AD). Therefore, novel GSDMD inhibitors represent valuable probes to understand and validate GSDMD as a viable drug target for AD.

Drug Development.

Background: Accumulating evidence suggests that the presynaptic protein α-synuclein (α-syn), is involved in the pathophysiology of AD and elevated in the cerebrospinal fluid (CSF). The role of Natural Killer (NK) cells of the innate immune system in AD has largely been overlooked. In a murine model, depletion of NK cells augmented the accumulation of pathological α-syn.