Nicotinic acetylcholine receptor agonists for the treatment of Alzheimer\u27s dementia: An update

A significant portion of the clinical phenotype observed in Alzheimer\u27s disease (AD) occurs through nicotinic acetylcholine receptors (nAChRs). Degeneration of cholinergic neurons, combined with aberrant nAChR expression and activation partially through amyloid-beta peptide (Aβ)-nAChR leads to upregulation of pro-inflammatory pathways and subsequently the progressive cognitive decline of AD. Interestingly, the cholinergic anti-inflammatory pathway is also mediated through nAChR particularly α7 nAChR. Thus, agonists of these receptors will likely exert pro-cognitive benefits through multiple mechanisms including stimulating the cholinergic pathway, modulating inflammation, and buffering the effects of amyloid. Despite this promising theoretical use, trials thus far have been complicated by adverse effects or minimal improvement.This review will provide an update on several pharmacological nAChR agonists tested in clinical trials and reasons that further investigation of nAChR agonists is merited. Implications: nAChRs have consistently presented a promising theoretical use in the treatment of AD; however, trials thus far have been complicated by adverse effects or minimal improvement. This review will provide an update on several pharmacological nAChR agonists trialed and reasons that further investigation of nAChR agonists is merited

Therapeutic considerations for APOE and TOMM40 in Alzheimers disease: A tribute to Allen Roses MD

Introduction: Four years ago this Autumn, pioneering neurologist Prof. Allen. D. Roses passed away. Hence, we have taken time to reflect on his work and legacy in Alzheimer’s disease (AD) research. Prof. Roses rejected the widely accepted amyloid hypothesis, which identifies amyloid beta (Aβ) protein accumulation within the brain as the cause of AD. Instead, he proposed that the epsilon type 4 allele of apolipoprotein (APOE- Ɛ4) and translocase of outer mitochondrial membrane 40 homolog (TOMM40) were preeminent factors in the pathogenesis and progression of AD, particularly in late-onset AD (LOAD). This rejection of the amyloid hypothesis has generated new investigations into APOE and TOMM40 as risk factors for AD. Areas covered: We discuss the contributions of Prof. Roses to AD research, describe how APOE-Ɛ4 and TOMM40 have been posited to trigger neuropathological changes leading to AD, and explore paths to future clinical applications built on the foundations of his research. Expert opinion: The unconventional methodology of targeting APOE and TOMM40 offers great potential for the development of effective preventive and disease-modifying AD interventions. Future preclinical and clinical investigations will greatly benefit from the groundbreaking scientific discoveries of Prof. Roses

Tau immunotherapies for Alzheimer\u27s disease

INTRODUCTION: Alzheimer\u27s dementia (AD) is the most common form of dementia in the World. Pathologically, it is characterized by extracellular β-amyloid plaques and intraneuronal neurofibrillary tangles (NFTs). The latter is composed of irregular, pathological forms of the tau protein. Currently, FDA-approved symptomatic treatments are limited to the targeting of cholinergic deficits and glutamatergic dysfunctions. However, as understanding of β-amyloid plaques and NFTs expands, these dysfunctional proteins represent potential therapeutic interventions. The present review article evaluates active and passive immunotherapies in clinical development for AD to date and their potential to significantly improve the treatment of AD going forward. AREAS COVERED: All clinical trials that have targeted β-amyloid to date have produced somewhat disappointing results, leading to a shift in intervention focus to targeting tau protein. A key component in understanding the value of targeting tau in therapeutic paradigms has come from the conceptualization of prion-like pathological spread of tau isoforms from neuron to neuron, and referred to as \u27tauons\u27. Immunotherapies currently under investigation include approaches aiming at preventing pathological tau aggregation, stabilizing microtubules, and blocking of tauons. EXPERT OPINION: A multi-targeted approach that would use biologics targeting tau offers great promise to the development of effective AD therapeutic interventions

Dementia with Lewy bodies: emerging drug targets and therapeutics

Introduction: Dementia with Lewy bodies (DLB) is characterized by the toxic accumulation of α-synuclein protein inside neural cells; this results in neurodegeneration which is clinically accompanied by behavioral and psychological changes. DLB shares features with Parkinson’s disease (PD) and Parkinson’s disease dementia (PDD), but also overlaps neurochemically and pathologically with Alzheimer’s disease. Symptomatic treatments for LBD differ in their effectiveness while disease-modifying and curative approaches are much needed. Areas covered: We explore emerging therapeutics for DLB through the lens of repurposing approved drugs and survey their potential for disease modifying actions in DLB. Given the complexity of DLB with multiple pathologies, potential therapeutic targets that could affect Lewy body pathology, or metabolism or neurotransmitters or immunomodulation were surveyed. We queried PubMed and ClinicalTrials.gov searches 2017–2020. Expert opinion: DLB is not simply aredux ofAD or PD; hence, treatments should not be exclusively duplicative ofAD or PD directed treatments. This opens amyriad of possibilities for therapeutic approaches that are disease specific or repurposed

Critical Appraisal of Amyloid Lowering Agents in AD

Purpose of Review: According to the amyloid cascade hypothesis, removing amyloid beta (Aβ) should cure Alzheimer’s disease (AD). In the past three decades, many agents have been tested to try to lower Aβ production, prevent Aβ aggregation, and dissolve Aβ deposits. However, the paucity in definitive preventative or curative properties of these agents in clinical trials has resulted in more avant-garde approaches to therapeutic investigations. Immunotherapy has become an area of focus for research on disease-modifying therapies for neurodegenerative diseases. In this review, we highlight the current clinical development landscape of monoclonal antibody (mAb) therapies that target Aβ plaque formation and removal in AD. Recent Findings: Multiple potential disease-modifying therapeutics for AD are in active development. Targeting Aβ with mAbs has the potential to treat various stages of AD: prodromal, prodromal to mild, mild, and mild to moderate. Monoclonal antibodies discussed here include aducanumab, lecanemab, solanezumab, crenezumab, donanemab, and gantenerumab. Summary: The final decision by the FDA regarding the approval of aducanumab will offer valuable insight into the trajectory of drug development for mAbs in AD and other neurodegenerative diseases. Future directions for improving the treatment of AD will include more inquiry into the efficacy of mAbs as disease-modifying agents that specifically target Aβ peptides and/or multimers. In addition, a more robust trial design for AD immunotherapy agents should improve outcomes such that objective measures of clinical efficacy will eventually lead to higher chances of drug approval

Does Informant-Based Reporting of Cognitive Symptoms Predict Amyloid Positivity on Positron Emission Tomography?

Introduction: Researchers are searching for clinical instruments to predict amyloid positivity for disease classification. Informant-based reports could detect disease status. This study compares subjective memory complaints captured by informant-based reports between positron emission tomography (PET)€“positive and PET-negative patients and hypothesizes that amyloid PET positivity associates with increased informant-based cognitive complaints. Methods: Ninety-eight amnestic mild cognitive impairment or mild dementia subjects were studied. Subjective report was captured by the informant-driven Alzheimer\u27s Questionnaire (AQ) administered before PET. Differences in demographics and AQ score by diagnostic status and amyloid status were measured, and a receiver-operating characteristic curve was calculated. Results: Sixty-five mild cognitive impairment/Alzheimer\u27s disease amyloid PET-positive and 33 amyloid PET-negative subjects were included. AQ was significantly higher (12.51 ± 4.95) for amyloid PET-positive subjects (9.06 ± 3.65; P = .001). Conclusions: Amyloid PET-positive subjects with Alzheimer\u27s disease or mild cognitive impairment have more informant-based reports of cognitive decline, indicating utility for a brief informant measure

An international, randomized, placebo-controlled, phase 2b clinical trial of intepirdine for dementia with Lewy bodies (HEADWAY-DLB)

INTRODUCTION: A phase 2b clinical trial, HEADWAY‐DLB, was performed to assess treatment with intepirdine, a serotonin receptor antagonist, in patients with dementia with Lewy bodies (DLB). METHODS: HEADWAY‐DLB was a multinational, double‐blind, randomized, placebo‐controlled study. Two hundred sixty‐nine DLB patients were randomized to receive placebo, 70 mg/day intepirdine, or 35 mg/day intepirdine over 24 weeks. The primary endpoint was change from baseline to week 24 on the Unified Parkinson's Disease Rating Scale–Part III (UPDRS‐III). RESULTS: Both intepirdine groups did not demonstrate significant benefits over placebo at 24 weeks on the UPDRS‐III (35 mg/day: P = .1580, 70 mg/day: P = .6069). All other endpoints were not significant. Intepirdine was well tolerated, with a slightly higher incidence of gastrointestinal adverse events observed in the intepirdine groups versus placebo. DISCUSSION: Intepirdine treatment did not lead to improvements over placebo in patients with DLB. As one of the largest DLB studies to date, HEADWAY‐DLB demonstrates that international trials for DLB are feasible within a reasonable timeframe