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: evoke and evoke+ are phase 3, randomized, placebo-controlled trials currently investigating the glucagon-like peptide-1 receptor agonist semaglutide as disease-modifying therapy (DMT) in persons with early Alzheimer's disease (AD). How the evoke and evoke+ trial populations compare with other phase 3 programs for DMTs in early AD has not been described.

Method: We compare the inclusion/exclusion criteria and baseline characteristics of the evoke/evoke+ trial populations with those of Clarity AD (lecanemab) and TRAILBLAZER-ALZ-2 (donanemab): two recent phase 3 trials assessing anti-amyloid monoclonal antibodies in persons with early AD.

Drug Development.

Background: Understanding the fundamental differences between the human and pre-human brain is a prerequisite for designing meaningful models and therapies for AD. Expressed CHRFAM7A, a human restricted gene with carrier frequency of 75% in the human population predicts profound translational significance.

Method: The physiological role of CHRFAM7A in human brain is explored using multiomics approach on 600 post mortem human brain tissue samples (ROSMAP).

Drug Development.

Background: There are no cures for Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by elevation of beta-amyloid and tau proteins besides neuronal death and causing cognitive impairment. Phosphodiesterase 5 (PDE5) is a cyclic guanosine monophosphate-degrading enzyme involved in numerous biological pathways including those relevant to memory formation. PDE5 inhibition offers the potential to attenuate AD progression by acting at the downstream level of beta-amyloid and tau elevation.

Drug Development.

Background: To bolster clinical trial infrastructure, there is a need to develop novel, valid, and reliable patient-reported outcome (PRO) measures capable of tracking clinically-relevant changes in Alzheimer's disease (AD), Mild Cognitive Impairment (MCI) and dementia over time. This research describes the development and validation of the Alzheimer's Disease-Health Index (AD-HI) as a tool to measure how patients feel and function in response to therapeutic intervention.

Method: We previously conducted semi-structured qualitative interviews and a national cross-sectional study with individuals with AD, MCI and dementia to ascertain the most prevalent and impactful symptoms identified by the participants.

Drug Development.

Background: Reducing fibrous aggregates of protein tau is a possible strategy for halting progression of Alzheimer's disease (AD). Previously we found that in vitro the D-peptide D-TLKIVWC fragments tau fibrils from AD brains (AD-tau) into benign segments, whereas its six-residue analog D-TLKIVW cannot. However, the underlying fragmentation mechanism remains unknown, preventing the further development of this type of drug candidate for AD.

Drug Development.

Background: The LatAm-FINGERS trial marks a pioneering initiative as the first non-pharmacological clinical trial encompassing participants from 12 Latin American countries, including Argentina, Brazil, Bolivia, Chile, Colombia, Costa Rica, Ecuador, Dominican Republic, Mexico, Peru, Puerto Rico, and Uruguay. This initiative represents a significant advancement in promoting inclusivity and diversity in clinical trial recruitment, particularly in underserved populations.

Method: The LatAm-FINGERS trial is a multicenter randomized clinical trial evaluating a lifestyle intervention tailored for the Latin American population.

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: A pathological hallmark of Alzheimer's disease (AD) is the accumulation of amyloid-beta peptide (Aß). Potential treatments targeting Aß production such as γ-secretase inhibitors have had limited success. A promising alternative approach involves addressing early synaptic dysfunction by modulating molecules like striatal-enriched protein tyrosine phosphatase (STEP), whose levels and activity are upregulated by Aß.

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.

Background: Alzheimer's disease (AD) clinical trials led to the recent successes with monoclonal antibodies targeting amyloid, which opens up many new directions for research into treatment for AD in the future. Gaining greater understanding from these successes and failures will help researchers to focus their efforts on avenues that have the highest potential benefit.

Method: We performed a meta-analysis of over a hundred studies of 70+ AD treatments.

Drug Development.

Background: Alzheimer's disease (AD) is characterized by progressive atrophy of the cerebral cortex and hippocampus, with concomitant increase in ventricular volume. Lomecel-B is a novel cell-based therapeutic approach to AD that targets neuroinflammation, microvascular dysfunction, and has the potential to stimulate endogenous tissue regeneration. We conducted MRI analysis of brain morphology in the CLEAR-MIND study, a 49-patient proof-of-concept study that tested 3 different dosing regimens of Lomecel-B vs placebo in patients with mild AD dementia.

Drug Development.

Background: VY-TAU01 is a recombinant humanized IgG4 monoclonal antibody (mAb) directed against pathological tau for the treatment of patients with mild dementia or mild cognitive impairment due to Alzheimer's disease (AD). Both VY-TAU01 and its parental mouse IgG1 mAb Ab-01 target an epitope in the C-terminus of tau, bind pathological tau with high affinity and selectivity over wild-type tau, block paired helical filament seed-induced tau aggregates in vitro, and selectively stain tau tangles in AD and P301S mouse (C57/B6J-Tg[Thy1-MAPT*P301S]2541Godt) brain. Ab-01 robustly inhibits seeding and propagation of pathological tau in a P301S mouse seeding model.

Drug Development.

Background: TAR-DNA-binding protein 43 (TDP43), is a pathologic marker in neurodegenerative diseases including frontotemporal lobar degeneration and amyotrophic lateral sclerosis. The aggregation of TDP-43, a crucial RNA-binding protein, is a consequence of post-translational modifications (PTMs) that disrupt its normal function. PTMs such as phosphorylation and ubiquitination contribute to the aberrant accumulation of TDP-43 aggregates, leading to neurodegenerative disorders like amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD).

Drug Development.

Background: Hypertension is a risk factor for cognitive impairment and dementia. Anti-hypertensives (AHT) are commonly used in old age, but their association with cognition and brain pathology is not well understood.

Method: To investigate the relation of AHT with change in cognitive function and postmortem brain pathology, we evaluated 4,207 older persons without known dementia at enrollment and a subset of 1880 participants who died and came to autopsy.

Drug Development.

Background: Homozygosity for the rare APOE3-Christchurch (APOE3Ch) variant, encoding for apoE3-R136S (apoE3-Ch), was linked to resistance against an aggressive form of familial Alzheimer's disease (AD). Carrying two copies of APOE3Ch was sufficient to delay autosomal AD onset by 30 years. This remarkable protective effect makes it a strong candidate for uncovering new therapies against AD.

Drug Development.

Background: Oral ALZ-801 (valiltramiprosate), a brain-penetrant agent that inhibits amyloid-oligomer formation is being evaluated in a fully enrolled APOLLOE4 Phase 3 trial in APOE4/4 homozygotes with Early Alzheimer's disease (AD). ALZ-801 effects on plasma AD biomarkers were evaluated in a 104-week Phase 2 study in APOE4-carriers with CSF+ AD biomarkers. APOE4 is a major risk factor for amyloid-related imaging abnormalities (ARIA) in AD patients.

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: Alzheimer's disease (AD) is a neurodegenerative disorder primarily associated with aging, but manifests as a complex interplay of multiple factors. Decline in sex-hormones, particularly 17-beta estradiol, is linked to the aging process. The risk for onset of AD significantly increases with aging and loss of estradiol.

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: It is essential that both drug and lifestyle-based interventions aimed at delaying the functional decline in conditions like Alzheimer's disease and related dementias (ADRDs) capture change in functioning that incorporates the person's voice. Such brain health priorities can vary across populations and it is unclear to what degree findings from the ePSOM program in the UK might apply to the US.

Methods: We conducted an online nationwide study to understand what matters to people aged 50 and older about their brain health in the US.

Drug Development.

Background: In Alzheimer's disease (AD) clinical trials, participants must enroll with a study partner informant who accompanies them to visits and completes validated instruments. Mid-trial informant replacement (IR) has been found to impact academic trial results. We hypothesized that a similar impact would be observed in industry-sponsored trials.

Drug Development.

Lecanemab, a humanized IgG1 monoclonal antibody that binds with high affinity to amyloid-beta (Aβ) protofibrils, was formally evaluated as a treatment for early Alzheimer's disease in a phase 2 study (Study 201) and the phase 3 Clarity AD study. These trials both included an 18-month, randomized study (core) and an open-label extension (OLE) phase where eligible participants received open-label lecanemab for up to 30 months to date. Clinical (CDR-SB, ADAS-Cog14, and ADCS-MCI-ADL), biomarker (PET, Aβ42/40 ratio, and ptau181) and safety outcomes were evaluated.

Drug Development.

Background: Alzheimer's Disease (AD) is a neurodegenerative disorder whose pathological hallmarks include tau and amyloid beta aggregation, a phenomenon that has been linked to inflammation and degradation of brain tissue. Prior data published in the Wang lab suggests that carbon dots (CDs) synthesized from citric acid and urea can inhibit aggregation. We sought to characterize the inhibitory effects of a new class of CDs synthesized from varied ratios of Congo red and citric acid.

Drug Development.

Background: We report the case of a 79-year-old woman with Alzheimer's disease who enrolled in a clinical study of lecanemab. After the third, biweekly infusion she suffered a seizure followed by aphasia and progressive encephalopathy. Magnetic resonance imaging revealed multifocal cerebral edema and an increased burden of cerebral microhemorrhages compared to pre-trial imaging.