Investigational drugs for the treatment of AD: what can we learn from negative trials?

Given the level of interest and activity in the race to find a treatment for Alzheimer's disease, it is expected that a reasonably safe and effective drug will be identified within the next decade. It may be worthwhile to pause periodically during the course of this race to take stock of what we have learned. Over the past few years, a number of trials have been conducted with promising new compounds (including some with novel mechanisms of action) that failed to meet primary endpoints and so were discontinued from clinical development. This article reviews a set of molecules with a range of mechanisms that have been trialed but with negative results. This article also examines the reasons for the negative findings and summarizes some of what we have learned from these experiences

New Acetylcholinesterase Inhibitors for Alzheimer's Disease

Acetylcholinesterase (AChE) remains a highly viable target for the symptomatic improvement in Alzheimer's disease (AD) because cholinergic deficit is a consistent and early finding in AD. The treatment approach of inhibiting peripheral AchE for myasthenia gravis had effectively proven that AchE inhibition was a reachable therapeutic target. Subsequently tacrine, donepezil, rivastigmine, and galantamine were developed and approved for the symptomatic treatment of AD. Since then, multiple cholinesterase inhibitors (ChEI) continue to be developed. These include newer ChEIs, naturally derived ChEIs, hybrids, and synthetic analogues. In this paper, we summarize the different types of ChEIs in development and their respective mechanisms of actions. This pharmacological approach continues to be active with many promising compounds

Potential Peripheral Biomarkers for the Diagnosis of Alzheimer's Disease

Advances in the discovery of a peripheral biomarker for the diagnosis of Alzheimer's would provide a way to better detect the onset of this debilitating disease in a manner that is both noninvasive and universally available. This paper examines the current approaches that are being used to discover potential biomarker candidates available in the periphery. The search for a peripheral biomarker that could be utilized diagnostically has resulted in an extensive amount of studies that employ several biological approaches, including the assessment of tissues, genomics, proteomics, epigenetics, and metabolomics. Although a definitive biomarker has yet to be confirmed, advances in the understanding of the mechanisms of the disease and major susceptibility factors have been uncovered and reveal promising possibilities for the future discovery of a useful biomarker

Probable Early-Onset Alzheimer's Disease in an Apolipoprotein E2 Homozygote

Objective: To describe a case of early-onset Alzheimer's disease (AD) in an apolipoprotein (Apo) epsilon 2/epsilon 2 homozygote. Background: Apo epsilon 2/epsilon 2 is the rarest of the ApoE genotypes, representing only 1.4% of the population. Cognitive decline in ApoE epsilon 2 homozygotes has rarely been reported. Case Report/Methods: We report a 58-year-old Apo epsilon 2/epsilon 2 female who meets clinical criteria for probable AD as confirmed by neuropsychological testing, positron emission/computed tomography scan, CSF analysis and genetic screening for known mutations. Results: The clinical course is typical of AD, with progressive cognitive and functional decline. Conclusion: Clinically confirmed early-onset AD is atypical in ApoE2 homozygotes but can occur. Copyright (C) 2010 S. Karger AG, Base

Increasing Precision of Clinical Diagnosis of Alzheimer\u27s Disease Using a Combined Algorithm Incorporating Clinical and Novel Biomarker Data

Establishing the in vivo diagnosis of Alzheimer€™s disease (AD) or other dementias relies on clinical criteria; however, the accuracy of these criteria can be limited. The diagnostic accuracy is 77% for a clinical diagnosis of AD, even among experts. We performed a review through PubMed of articles related to specific diagnostic modalities, including APOE genotyping, cerebrospinal fluid (CSF) testing, fludeoxyglucose F 18 positron emission tomography (PET), amyloid PET, tau PET, computed tomography (CT), single-photon emission CT, magnetic resonance imaging (MRI), and B12 and thyroid-stimulating hormone screening, to determine the specificity and sensitivity of each test used in the clinical diagnosis of AD. We added a novel immunomagnetic reduction assay that provides ultrasensitivity for analyzing the levels of plasma tau and beta amyloid 42 (Aβ42). The sensitivity and specificity of the current diagnostic approach (structural CT or MRI with screening labs) remain low for clinical detection of AD and are primarily used to exclude other conditions. Because of limited diagnostic capabilities, physicians do not feel comfortable or skilled in rendering a clinical diagnosis of AD. Compounding this problem is the fact that inexpensive, minimally invasive diagnostic tests do not yet exist. Biomarkers (obtained through CSF testing or PET imaging), which are not routinely incorporated in clinical practice, correlate well with pathologic changes. While PET is particularly costly and difficult to assess, CSF measures of tau and beta amyloid are not costly, and these tests may be worthwhile when the tiered approach proposed here warrants further testing. There is a need for developing bloodborne biomarkers that can aid in the clinical diagnosis of AD. Here we present a streamlined questionnaire-enriched, biomarker-enriched approach that is more cost-effective than the current diagnosis of exclusion and is designed to increase clinical confidence for a diagnosis of dementia due to AD

Alzheimer\u27s Disease Drug Development Pipeline: 2019

Introduction Alzheimer\u27s disease (AD) has few available treatments, and there is a high rate of failure in AD drug development programs. Study of the AD drug development pipeline can provide insight into the evolution of drug development and how best to optimize development practices. Methods We reviewed clinicaltrials.gov and identified all pharmacologic AD trials of all agents currently being developed for treatment of AD. Results There are 132 agents in clinical trials for the treatment of AD. Twenty-eight agents are in 42 phase 3 trials; 74 agents are in 83 phase 2 trials; and 30 agents are in 31 phase 1 trials. There is an increase in the number of agents in each phase compared with that in the 2018 pipeline. Nineteen agents in trials target cognitive enhancement, and 14 are intended to treat neuropsychiatric and behavioral symptoms. There are 96 agents in disease modification trials; of these, 38 (40%) have amyloid as the primary target or as one of several effects. Eighteen of the antiamyloid agents are small molecules, and 20 are monoclonal antibodies or biological therapies. Seven small molecules and ten biologics have tau as a primary or combination target (18%). Amyloid is the most common specific target in phase 3 and phase 2 disease modification trials. Novel biomarkers (e.g., neurofilament light), new outcomes (e.g., AD Composite Score [ADCOMS]), enrollment of earlier populations, and innovative trial designs (e.g., Bayesian adaptive designs) are new features in recent clinical trials. Discussion Drug development continues robustly at all phases despite setbacks in several programs in the recent past. Continuing unmet needs require a commitment to growing and accelerating the pipeline

Altered resting-state functional connectivity and dynamic network properties in cognitive impairment: an independent component and dominant-coactivation pattern analyses study

IntroductionCognitive impairment (CI) due to Alzheimer’s disease (AD) encompasses a decline in cognitive abilities and can significantly impact an individual’s quality of life. Early detection and intervention are crucial in managing CI, both in the preclinical and prodromal stages of AD prior to dementia.MethodsIn this preliminary study, we investigated differences in resting-state functional connectivity and dynamic network properties between 23 individual with CI due to AD based on clinical assessment and 15 healthy controls (HC) using Independent Component Analysis (ICA) and Dominant-Coactivation Pattern (d-CAP) analysis. The cognitive status of the two groups was also compared, and correlations between cognitive scores and d-CAP switching probability were examined.ResultsResults showed comparable numbers of d-CAPs in the Default Mode Network (DMN), Executive Control Network (ECN), and Frontoparietal Network (FPN) between HC and CI groups. However, the Visual Network (VN) exhibited fewer d-CAPs in the CI group, suggesting altered dynamic properties of this network for the CI group. Additionally, ICA revealed significant connectivity differences for all networks. Spatial maps and effect size analyses indicated increased coactivation and more synchronized activity within the DMN in HC compared to CI. Furthermore, reduced switching probabilities were observed for the CI group in DMN, VN, and FPN networks, indicating less dynamic and flexible functional interactions.DiscussionThe findings highlight altered connectivity patterns within the DMN, VN, ECN, and FPN, suggesting the involvement of multiple functional networks in CI. Understanding these brain processes may contribute to developing targeted diagnostic and therapeutic strategies for CI due to AD

Long-Term Storage Effects on Stability of Aβ1–40, Aβ1–42, and Total Tau Proteins in Human Plasma Samples Measured with Immunomagnetic Reduction Assays

Background: The stability of Alzheimer’s disease (AD) biomarkers in plasma, measured by immunomagnetic reduction (IMR) after long-term storage at –80°C, has not been established before. Method: Ninety-nine human plasma samples from 53 normal controls (NCs), 5 patients with amnestic mild cognitive impairment (aMCI), and 41 AD patients were collected. Each plasma sample was aliquoted and stored as single-use aliquots at –80°C. The baseline measurements for Aβ1–40, Aβ1–42, and total Tau protein (T-Tau) concentrations for each sample were done within 3 months of blood draw by IMR. They are referred to as baseline concentrations. A separate aliquot from each sample was assayed with IMR to assess the stability of the measured analytes during storage at –80°C between 1.1 and 5.4 years. This is referred to as a repeated result. Results: IMR shows that plasma levels of Aβ1–40 and Aβ1–42 exhibit stability over 5-year storage at –80°C and that plasma levels of T-Tau are less stable (approximately 1.5 years). Conclusion: Although the measured concentrations of T-Tau in human plasma may alter during storage, the diagnostic utility of the results are only slightly affected when the product of Aβ1–42 and T-Tau concentrations are used. The results show that the overall agreement between baseline and repeated measurements in the ability of discriminating NCs from aMCI/AD patients is higher than 80%