Drug Development.

Background: Genetic variants in GRN, the gene encoding progranulin, are causal for or are associated with the risk of multiple neurodegenerative diseases. Modulating progranulin has been considered as a therapeutic strategy for neurodegenerative diseases including Frontotemporal Dementia (FTD) and Alzheimer's Disease (AD). Here, we integrated genetics with proteomic data to determine the causal human evidence for the therapeutic benefit of modulating progranulin in AD.

Drug Development.

Background: Availability of amyloid modifying therapies will dramatically increase the need for disclosure of Alzheimer's disease (AD) related genetic and/or biomarker test results. The 21st Century Cares Act requires the immediate return of most medical test results, including AD biomarkers. A shortage of genetic counselors and dementia specialists already exists, thus driving the need for scalable methods to responsibly communicate test results.

Drug Development.

Background: The presence of multiple comorbid pathologic features in late-onset dementia has been well documented across cohort studies that incorporate autopsy evaluation. It is likely that such mixed pathology potentially confounds the results of interventional trials that are designed to target a solitary pathophysiologic mechanism in Alzheimer's disease and related dementias (ADRD).

Method: The UK ADRC autopsy database was screened for participants who had previously engaged in therapeutic interventional trials for Alzheimer's disease, vascular cognitive impairment, dementia, and/or ADRD prevention trials from 2005 to the present.

Drug Development.

The lack of an in-vivo pathology marker for synuclein pathology has been a long standing challenge for dementia for Lewy bodies (DLB) research. This issue is critically important for phase II trials, which are often small, requiring the precise measurement of the biological effects, whether disease modifying or symptomatic. Recent advances have enabled the determination of alpha-synuclein pathology status with CSF measurements, using aggregation assays [RT-QUIC].

Drug Development.

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the formation of amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs) composed of tau aggregates. Research in animal models has generated hypotheses on the underlying mechanisms of the interaction between Aβ and tau pathology. In support of this interaction, results from clinical trials have shown that treatment with anti-Aβ monoclonal antibodies (mAbs) affects tau pathology.

Drug Development.

Background: The vicious cycle between depression and dementia increases the risk of Alzheimer's Disease (AD) pathogenesis and pathology. This study investigates therapeutic effectiveness versus side effects and the underlying mechanisms of intranasal dantrolene nanoparticles (IDNs) to treat depression behavior and memory loss in 5XFAD mice.

Method: 5XFAD and wild-type B6SJLF1/J mice were treated with IDNs (IDN, 5 mg/kg) in Ryanodex formulation for a duration of 12 weeks.

Drug Development.

Background: In Alzheimer's Disease trials, the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR) are commonly utilized as inclusionary criteria at screening. These measures, however, do not always reaffirm inclusionary status at baseline. Score changes between screening and baseline visits may imply potential score inflation at screening leading to inappropriate participant enrollment.

Drug Development.

Background: Clinical outcome assessments (COAs) are an important part of clinical trials to measure what is meaningful to patients and caregivers. This study aimed to examine trends in Alzheimer's Disease (AD) COAs used in clinical trials, given the FDA's recent emphasis on patient-focused drug development and early AD.

Method: ClinicalTrials.

Drug Development.

Background: CT1812 is an experimental therapeutic sigma-2 receptor modulator in development for Alzheimer's disease (AD) and dementia with Lewy bodies. CT1812 reduces the affinity of Aβ oligomers to bind to neurons and exert synaptotoxic effects. This phase 2, multi-center, international, randomized, double-blind, placebo-controlled trial assessed safety, tolerability and effects of CT1812 on cognitive function in individuals with AD.

Drug Development.

Background: Although novel treatments for Alzheimer's disease (AD) have begun to show modest therapeutic effects, agents that target hallmark AD pathology and offer neuroprotection are desired. Erythropoietin (EPO) is a glycoprotein hormone with neuroprotective effects but is faced with challenges including limited brain uptake and increased hematopoietic side effects with long-term dosing. Therefore, EPO has been modified and bound to a chimeric transferrin receptor monoclonal antibody (cTfRMAb); the latter shuttles EPO past the blood-brain barrier (BBB) into brain parenchyma and reduces its plasma exposure and potential for side effects.

Drug Development.

Background: Clinical trial sponsors rely on research sites to identify and enroll appropriate study participants and to correctly and reliably assess symptom severity and function over the course of the trial. Low-recruiting sites represent a large financial and operational burden and may negatively impact trial success either by selecting inappropriate participants and/or high prevalence of data quality issues. We previously reported that >60% of sites in schizophrenia clinical trials recruited ≤5 participants.

Drug Development.

Background: Alzheimer's disease (AD) trials report a high screening failure rate (potentially eligible trial candidates who do not meet inclusion/exclusion criteria during screening) due to multiple factors including stringent eligibility criteria. Here, we report the main reasons for screening failure in the 12-week screening phase of the ongoing evoke (NCT04777396) and evoke+ (NCT04777409) trials of semaglutide in early AD.

Method: Key inclusion criteria were age 55-85 years; mild cognitive impairment due to AD (Clinical Dementia Rating [CDR] global score of 0.

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: The Apolipoprotein E4 isoform (ApoE4), encoded by the APOE gene, stands out as the most influential genetic factor in late-onset Alzheimer's disease (LOAD). The ApoE4 isoform contributes to metabolic and neuropathological abnormalities during brain aging, with a strong correlation observed in APOE4-positive Alzheimer's disease cases between phosphorylated tau burden and amyloid deposition. Despite compelling evidence of APOE-mediated neuroinflammation influencing the progression of tau-mediated neurodegeneration, the molecular mechanisms underlying these phenomena remain largely unknown.

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: Accumulation of amyloid beta 42 (Aβ42) senile plaques is the most critical event leading to Alzheimer's disease (AD). Currently approved drugs for AD have not been able to effectively modify the disease. This has caused increasing research interests in health beneficial nutritious plant foods as viable alternative therapy to prevent or manage AD.

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: As amyloid-β (Aβ) aggregates are considered as the biomarkers and key factors in the pathology of Alzheimer's disease, there has been extensive investigation into Aβ-targeting compounds for the development of diagnostics and drug discovery related to the disorder. However, the polymorphic and heterogenous nature of Aβ aggregates impedes the structural understanding of their structure. Consequently it is a major challenge to develop new diagnostic and therapeutic development of AD and to study the mechanism of Aβ-targeting compounds.

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: 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: To improve clinical translatability of non-clinical in-vivo Alzheimer's disease (AD) models, a humanized APP knock-in mouse model (APP) was recently created (Xia, D. et al., 2022).

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: Studies suggest a potential link between stroke and Alzheimer's disease wherein stroke may serve as a trigger for the onset or acceleration of Alzheimer's pathogenesis as damage to the brain's blood vessels may lead to the accumulation of amyloid beta protein which is a hallmark of Alzheimer's disease. Recent research has shown that stroke treatment may hold the key to treating Alzheimer's disease. The anti-inflammatory potentials of Cholinergic signaling are a novel therapeutic target in memory decline associated with Alzheimer's.

Drug Development.

Background: Alzheimer's Disease (AD) poses a substantial global health burden, necessitating innovative therapeutic strategies. This study investigates the neuroprotective potential of a chrysin-loaded Nanostructured Lipid Carrier (NLC) drug delivery system in AD management. Employing the high-pressure homogenization method, chrysin-loaded NLCs were meticulously formulated to optimize drug delivery efficiency.