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Pharmacotherapy of Alzheimer's Disease: Seeking Clarity in a Time of Uncertainty.

ABSTRACT: Alzheimer's disease (AD) is recognized as a major health hazard that mostly affects people older than 60 years. AD is one of the biggest medical, economic, and social concerns to patients and their caregivers. AD was ranked as the 5th leading cause of global deaths in 2016 by the World Health Organization (WHO). Many drugs targeting the production, aggregation, and clearance of A? plaques failed to give any conclusive clinical outcomes. This mainly stems from the fact that AD is not a disease attributed to a single-gene mutation. Two hallmarks of AD, A? plaques and neurofibrillary tangles (NFTs), can simultaneously induce other AD etiologies where every pathway is a loop of consequential events. Therefore, the focus of recent AD research has shifted to exploring other etiologies, such as neuroinflammation and central hyperexcitability. Neuroinflammation results from the hyperactivation of microglia and astrocytes that release pro-inflammatory cytokines due to the neurological insults caused by A? plaques and NFTs, eventually leading to synaptic dysfunction and neuronal death. This review will report the failures and side effects of many anti-A? drugs. In addition, emerging treatments targeting neuroinflammation in AD, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and receptor-interacting serine/threonine protein kinase 1 (RIPK1), that restore calcium dyshomeostasis and microglia physiological function in clearing A? plaques, respectively, will be deliberately discussed. Other novel pharmacotherapy strategies in treating AD, including disease-modifying agents (DMTs), repurposing of medications used to treat non-AD illnesses, and multi target-directed ligands (MTDLs) are also reviewed. These approaches open new doors to the development of AD therapy, especially combination therapy that can cater for several targets simultaneously, hence effectively slowing or stopping AD.

SUBMITTER: Husna Ibrahim N

PROVIDER: S-EPMC7105678 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Pharmacotherapy of Alzheimer's Disease: Seeking Clarity in a Time of Uncertainty.

Husna Ibrahim Nurul N Yahaya Mohamad Fairuz MF Mohamed Wael W Teoh Seong Lin SL Hui Chua Kien CK Kumar Jaya J

Frontiers in pharmacology 20200324

Alzheimer's disease (AD) is recognized as a major health hazard that mostly affects people older than 60 years. AD is one of the biggest medical, economic, and social concerns to patients and their caregivers. AD was ranked as the 5<sup>th</sup> leading cause of global deaths in 2016 by the World Health Organization (WHO). Many drugs targeting the production, aggregation, and clearance of Aβ plaques failed to give any conclusive clinical outcomes. This mainly stems from the fact that AD is not a ...[more]

PMID: 32265696

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Project description:IntroductionAlzheimer's disease (AD), a progressive neurodegenerative disease, is the main cause of dementia and one of the leading causes of death for elderly people in the USA. Lecanemab is a humanized IgG1 monoclonal antibody targeting amyloid protofibrils for the treatment of early AD [i.e., mild cognitive impairment (MCI) or mild AD dementia]. In a recent 18-month phase III trial, using a double-blind, placebo-controlled design, lecanemab treatment led to reduced brain amyloid burden and significant improvements in cognitive and functional abilities in individuals with early AD.MethodsAn evidence-based patient-level disease simulation model was updated to estimate the long-term health outcomes of lecanemab plus standard of care (SoC) compared to SoC alone in patients with early AD and evidence of brain amyloid burden, using recent phase III trial data and published literature. The disease progression is described by changes in the underlying biomarkers of AD, including measures of amyloid and tau, and their connection to the clinical presentation of the disease assessed through various patient-level scales of cognition and function.ResultsLecanemab treatment was estimated to slow the progression of AD to moderate and severe stages and reduce the time spent in these more advanced states. In individuals with early AD, lecanemab plus SoC was associated with a gain of 0.71 quality-adjusted life-years (QALYs), a 2.95-year delay in mean time to progression to AD dementia, a reduction of 0.11 years in institutional care, and an additional 1.07 years in community care as shown in the base-case study. Improved health outcomes were demonstrated with lecanemab treatment when initiated earlier based on age, disease severity, or tau pathology, resulting in estimated gains in QALYs ranging from 0.77 to 1.09 years, compared to 0.4 years in the mild AD dementia subset, as shown by the model.ConclusionThe study findings demonstrate the potential clinical value of lecanemab for individuals with early AD by slowing down disease progression and prolonging time in earlier stages of disease, which significantly benefits not only patients and caregivers but also society overall.Trial registrationClinicalTrials.gov identifier, NCT03887455.

Dataset Information

Pharmacotherapy of Alzheimer's Disease: Seeking Clarity in a Time of Uncertainty.

Publications

Pharmacotherapy of Alzheimer's Disease: Seeking Clarity in a Time of Uncertainty.

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