Drug Development.

Background: Increased APP gene dosage is both necessary and sufficient to result in Down Syndrome Alzheimer's Disease (DSAD) in humans and AD-related degenerative changes in mouse models of DS.

Method: We tested antisense oligonucleotides (ASOs) designed to suppress APP expression via RNAseH1-mediated degradation in the Dp(16)1Yey or Dp(16) model of Down Syndrome. Dp(16) is trisomic for human chromosome 21 syntenic regions on murine chromosome 16, containing 115 genes including APP.

Drug Development.

Background: Lecanemab, a novel humanized immunoglobulin G1 monoclonal antibody targeting both neurotoxic Aβ protofibrils and Aβ plaques, has demonstrated the ability to substantially reduce markers of amyloid and significantly slow clinical decline on multiple measures of cognition and function in early AD in phase 2 (Study 201) and phase 3 (Clarity AD) studies. In these clinical studies, several plasma biomarkers assessments (Aβ42/40 ratio, p-tau181, GFAP, and p-tau217) showed improvements comparing lecanemab with placebo. Herein, we utilized modelling and simulations to evaluate the long-term effects of lecanemab on biomarkers of neurodegeneration in plasma.

Drug Development.

Background: The Neurovascular Unit is a multicellular structure of the CNS known to become dysfunctional in Alzheimer's Disease (AD) and cerebral amyloid angiopathy. Amyloidosis disrupts the function of cerebrovascular endothelial cells (cECs) via extrinsic and intrinsic apoptosis, and induction of blood brain barrier (BBB) permeability. Findings in our lab demonstrated that pan-Carbonic Anhydrase inhibitors (CAi's) prevent mitochondria-mediated apoptotic mechanisms in cECs.

Drug Development.

Background: A traditional method for validating a surrogate endpoint typically involves assessing the correlation between changes in biomarkers and changes in clinical endpoints using Pearson's and/or Spearman's correlation. However, this approach may not provide an accurate representation of the true correlation due to several reasons: (i) it only considers the change from baseline to the last visit and does not use all post-baseline longitudinal data; (ii) the raw change has large variability; (iii) it does remove the within-subject variability. The objective of this presentation is to propose two alternative approaches that overcome these limitations and allow for a more accurate estimation of the true correlation using all available longitudinal data.

Drug Development.

Background: ABCA1-mediated cholesterol transport is a central feature in many lipid- dependent diseases including APOE4-associated Alzheimer's disease and atherosclerosis-CVD. ABCA1 upregulation of RNA transcription by nuclear factors (LXR, RXR) have been associated with liver side-effects because of the common promotor element for ABCA1 and Fatty Acid Synthase. The ABCA1 agonist CS6253, derived from the C-terminal of apoE was designed to stabilize and enhance ABCA1 function, thereby providing a safe alternative to transcriptional upregulation.

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.

Drug Development.

Background: Transcutaneous stimulation of the auricular branch of the vagus nerve (tVNS) was administered to participants diagnosed with mild cognitive impairment (MCI) to improve word-list memory (primary outcome) and other cognitive skills.

Method: A randomized, double-blind, placebo-controlled crossover design was used for this trial. Participants with MCI (n = 59) were sorted into one of two sequences: Sham-tVNS or tVNS-Sham.

Drug Development.

Background: Irisin is an exercise-induced myokine that elicits beneficial effects of exercise in fat, bone, and the brain. Previous work suggests that extracellular heat shock protein 90a (Hsp90a) mediates irisin-receptor interaction in bone and fat. Despite this, it remains unclear if Hsp90a is necessary for irisin signaling in the brain.

Drug Development.

Women account for almost two-thirds of Alzheimer's disease (AD) cases, yet evidence significantly less clinical benefit from recently deployed amyloid-lowering therapies. To close this disparity gap, there is an urgent need to identify biological drivers of sex differences in the manifestation and clinical response to AD therapeutics. A recent review of multi-omic studies of AD reported >75% of studies showed female-specific changes at the molecular level (vs.

Drug Development.

Background: Reactive astrocytes and neuron death by excitotoxicity are observed in Alzheimer's disease (AD). DHA-H (2-hydroxy-docosahexaenoic acid; 2-OH-C22:6 n-3) is a molecule under development that has demonstrated therapeutic efficacy in both cellular and 5xFAD mouse model of AD. DHA-H is metabolized through α-oxidation to yield HPA (Heneicosapentaenoic acid; C21:5 n-3).

Drug Development.

Background: Protein misfolding is a key pathological phenomenon driving neurodegenerative diseases that affect millions of people. Visualizing this misfolding process with smart imaging probes would greatly facilitate early diagnosis, etiology elucidation, disease progression monitoring, and drug discovery of neurodegeneration. Although numerous probes have been reported, several unmet needs still exist.

Drug Development.

Background: The prohibitive costs of drug development for Alzheimer's Disease (AD) emphasize the need for alternative in silico drug repositioning strategies. Graph learning algorithms, capable of learning intrinsic features from complex network structures, can leverage existing databases of biological interactions to improve predictions in drug efficacy. We developed a novel machine learning framework, the PreSiBOGNN, that integrates muti-modal information to predict cognitive improvement at the subject level for precision medicine in AD.

Drug Development.

Background: Lecanemab is an approved anti-amyloid monoclonal antibody that binds with highest affinity to soluble Aβ protofibrils, which are more toxic than monomers or insoluble fibrils/plaque. In clinical studies, biweekly lecanemab treatment demonstrated a slowing of decline in clinical (global, cognitive, functional, and quality of life) outcomes, and reduction in brain amyloid in early Alzheimer's disease (AD). Herein, we describe the impact of lecanemab treatment on tau PET.

Dementia Care Research and Psychosocial Factors.

Background: Prior research has demonstrated the positive association between social support and cognition. Specifically, greater social support has been linked with improved cognitive performance and reduced risk of dementia. In particular, emotional support has been identified as a key dimension in the relationship between social support and cognition.

Drug Development.

Background: Focused Ultrasound-induced Blood-Brain Barrier Opening (FUS-BBBO) has demonstrated preventative and therapeutic efficacy for improving cognitive and pathological decline in Alzheimer's Disease (AD). Previous work has demonstrated highly specific binding of a novel Re complex (Re-1) complex to amyloid-β (Aβ) in vitro, subsequently inhibiting fibril formation and reducing Aβ-induced cytotoxicity in neuronal cell cultures. The aim of this preliminary study is to evaluate the efficacy of early intervention combining FUS-BBBO and Re-1 for anxiety amelioration and memory improvement in a triple transgenic (3xTg)-AD mouse model.

Drug Development.

Background: Despite some advances in treatment, a cure for Alzheimer's disease (AD) remains elusive. Disease hallmarks include heightened neuroinflammation and oxidative stress, associated with progressive decline in mobility and cognitive functions. Natural compounds provide a valuable reservoir of novel bioactive substances with therapeutic potential, fewer side effects, and increased affordability.

Drug Development.

Background: Amid recent approvals, early Alzheimer's disease (AD) remains an active area of treatment development, but research on the utility of recruitment incentives in early AD trials remains limited. We examined how trial design features impact enrollment decisions among Mild Cognitive Impairment (MCI) patients and their family members.

Method: We performed a conjoint analysis experiment to compare early AD patients' preferences for trial features.

Drug Development.

Background: VG-3927 is a highly potent, selective, brain penetrant, oral small molecule TREM2 agonist that is currently under development for the treatment of Alzheimer's disease (AD). TREM2, a receptor expressed on microglia in the brain is critical to microglial function in health and in disease. Among microglia-associated AD risk genes, partial loss-of-function variants of TREM2 confer 2-3 fold increase in risk for developing AD, motivating efforts to identify pharmacological agonists targeting TREM2 as a therapeutic option.

Drug Development.

The most recent Alzheimer's clinical trials, including those which reported successful outcomes, use neuroimaging biomarkers of both amyloid and tau for screening participants and demonstrating a treatment effect on pathology. Some of these trials, notably Lecanemab, hint at a potential sex bias in treatment outcome, alluding to major implications for clinical practice when recommending treatment options. Sex differences in treatment response are not surprising given that women are at greater risk of progression to AD dementia, particularly if they carry APOEe4.

Drug Development.

Background: Dementia, a growing health crisis, disproportionally affects persons from racial/ethnic backgrounds and individuals with comorbidities. Latelife change in cognition is complex and nonlinear, as well as differential for these individuals. These individuals are also largely underrepresented in clinical trials.

Drug Development.

Lecanemab is a humanized IgG1 monoclonal antibody binding with high affinity to protofibrils of amyloid-beta (Aβ) protein. In 18-month clinical studies, lecanemab has been shown to reduce a complex group of protein interactions associated with early symptomatic Alzheimer's disease (AD) and slow decline on clinical endpoints of cognition and function for up to 30 months to date. In prior research, results from the phase 2 study gap period (no study drug treatment) between the end of the study core and the beginning of retreatment in the open-label extension (OLE) provides evidence regarding the need for continued maintenance therapy beyond 18 months.

Drug Development.

Background: ALZ-801 (valiltramiprosate), an oral brain-penetrant amyloid-oligomer inhibitor in Phase 3 testing in APOE4/4 homozygotes (APOLLOE4 trial). A 2-year Phase 2 biomarker study was completed evaluating ALZ-801 (265 mg BID) on plasma biomarkers, MRI, cognition, and clinical benefit in EAD APOE4 carriers. At trial end, subjects could enroll in a 1-year long-term extension with an ongoing biomarker and cognition analysis.

Drug Development.

Background: Aerobic exercise may positively affect brain health, although relationships with cognitive change are mixed. This likely is due to individual differences in the systemic physiological response to exercise. However, the acute effects of exercise on brain metabolism and biomarker responses are not well characterized in older adults or cognitively impaired individuals.

Dementia Care Research and Psychosocial Factors.

Background: Most assisted living (AL) settings organize and provide opportunities for residents to participate in activities (e.g., exercise, music, arts and craft, cognitive activities, religious services, community outings).

Drug Development.

Alzheimer's disease (AD) is a common copathology in Lewy body dementia (LBD). The presence of AD is associated with a distinct clinical presentation, faster progression, and shorter survival in LBD. However, the relationship between-alpha synuclein and AD remains incompletely understood.