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Vaccination against ?-Amyloid as a Strategy for the Prevention of Alzheimer's Disease.

ABSTRACT: Vaccination relies on the phenomenon of immunity, a long-term change in the immunological response to subsequent encounters with the same pathogen that occurs after the recovery from some infectious diseases. However, vaccination is a strategy that can, in principle, be applied also to non-infectious diseases, such as cancer or neurodegenerative diseases, if an adaptive immune response can prevent the onset of the disease or modify its course. Immunization against ?-amyloid has been explored as a vaccination strategy for Alzheimer's disease for over 20 years. No vaccine has been licensed so far, and immunotherapy has come under considerable criticism following the negative results of several phase III clinical trials. In this narrative review, we illustrate the working hypothesis behind immunization against ?-amyloid as a vaccination strategy for Alzheimer's disease, and the outcome of the active immunization strategies that have been tested in humans. On the basis of the lessons learned from preclinical and clinical research, we discuss roadblocks and current perspectives in this challenging enterprise in translational immunology.

SUBMITTER: Mantile F

PROVIDER: S-EPMC7761159 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Vaccination against β-Amyloid as a Strategy for the Prevention of Alzheimer's Disease.

Mantile Francesca F Prisco Antonella A

Biology 20201127 12

Vaccination relies on the phenomenon of immunity, a long-term change in the immunological response to subsequent encounters with the same pathogen that occurs after the recovery from some infectious diseases. However, vaccination is a strategy that can, in principle, be applied also to non-infectious diseases, such as cancer or neurodegenerative diseases, if an adaptive immune response can prevent the onset of the disease or modify its course. Immunization against β-amyloid has been explored as ...[more]

PMID: 33260956

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Project description:IntroductionAlzheimer's disease (AD) is a progressive neurodegenerative disease that currently affects 6.2 million people in the United States and is projected to impact 12.7 million worldwide in 2050 with no effective disease-modifying therapeutic or cure. In 2011 as part of the National Alzheimer's Project Act, the National Plan to Address Alzheimer's Disease was signed into law which proposed to effectively prevent AD by 2025, which is rapidly approaching. The preclinical phase of AD can begin 20 years prior to diagnosis, which provides an extended window for preventive measures that would exert a transformative impact on incidence and prevalence of AD.MethodsA novel combination of text-mining and natural language processing strategies to identify (1) AD risk factors, (2) therapeutics that can target risk factor pathways, and (3) studies supporting therapeutics in the PubMed database was conducted. To classify the literature relevant to AD preventive strategies, a relevance score (RS) based on STRING (search tool for the retrieval of interacting genes/proteins) score for protein-protein interactions and a confidence score (CS) on Bayesian inference were developed. To address mechanism of action, network analysis of protein targets for effective drugs was conducted. Collectively, the analytic approach, referred to as a targeted-risk-AD-prevention (TRAP) strategy, led to a ranked list of candidate therapeutics to reduce AD risk.ResultsBased on TRAP mining of 9625 publications, 364 AD risk factors were identified. Based on risk factor indications, 629 Food and Drug Administration-approved drugs were identified. Computation of ranking scores enabled identification of 46 relevant high confidence (RS & CS > 0.7) drugs associated with reduced AD risk. Within these candidate therapeutics, 16 had more than one clinical study supporting AD risk reduction. Top-ranked therapeutics with high confidence emerged within lipid-lowering, anti-inflammatory, hormone, and metabolic-related drug classes.DiscussionOutcomes of our novel bioinformatic strategy support therapeutic targeting of biological mechanisms and pathways underlying relevant AD risk factors with high confidence. Early interventions that target pathways associated with increased risk of AD have the potential to support the goal of effectively preventing AD by 2025.

Project description:With recent advances in our understanding of the continuous pathophysiological changes that begin many years prior to symptom onset, it is now apparent that Alzheimer's disease cannot be adequately described by discrete clinical stages, but should also incorporate the continuum of biological changes that precede and underlie the clinical representation of the disease. By jointly considering longitudinal changes of all available biomarkers and clinical assessments, variation within individuals can be integrated into a single continuous measure of disease progression and used to identify the earliest pathophysiological changes. Disease time, a measure of disease severity, was estimated using a Bayesian latent time joint mixed-effects model applied to an array of imaging, biomarker and neuropsychological data. Trajectories of regional amyloid β and tau PET uptake were estimated as a function of disease time. Regions with early signs of elevated amyloid β uptake were used to form an early, focal composite and compared to a commonly used global composite, in a separate validation sample. Disease time was estimated in 279 participants (183 cognitively unimpaired individuals, 61 mild cognitive impairment and 35 Alzheimer's disease dementia patients) with available amyloid β and tau PET data. Amyloid β PET uptake levels in the posterior cingulate and precuneus start high and immediately increase with small increases of disease time. Early elevation in tau PET uptake was found in the inferior temporal lobe, amygdala, banks of the superior temporal sulcus, entorhinal cortex, middle temporal lobe, inferior parietal lobe and the fusiform gyrus. In a separate validation sample of 188 cognitively unimpaired individuals, the early, focal amyloid β PET composite showed a 120% increase in the accumulation rate of amyloid β compared to the global composite (P < 0.001), resulting in a 60% increase in the power to detect a treatment effect in a primary prevention trial design. Ordering participants on a continuous disease time scale facilitates the inspection of the earliest signs of amyloid β and tau pathology. To detect early changes in amyloid β pathology, focusing on the earliest sites of amyloid β accumulation results in more powerful and efficient study designs in early Alzheimer's disease. Targeted composites could be used to re-examine the thresholds for amyloid β-related study inclusion, especially as the field shifts to focus on primary and secondary prevention. Clinical trials of anti-amyloid β treatments may benefit from the use of focal composites when estimating drug effects on amyloid β and tau changes in populations with minimal amyloid β and tau pathology and limited expected short-term accumulation.

Dataset Information

Vaccination against ?-Amyloid as a Strategy for the Prevention of Alzheimer's Disease.

Publications

Vaccination against β-Amyloid as a Strategy for the Prevention of Alzheimer's Disease.

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