Current and Future Treatments in Alzheimer Disease: An Update

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Abstract

Disease-modifying treatment strategies for Alzheimer disease (AD) are still under extensive research. Nowadays, only symptomatic treatments exist for this disease, all trying to counterbalance the neurotransmitter disturbance: 3 cholinesterase inhibitors and memantine. To block the progression of the disease, therapeutic agents are supposed to interfere with the pathogenic steps responsible for the clinical symptoms, classically including the deposition of extracellular amyloid β plaques and intracellular neurofibrillary tangle formation. Other underlying mechanisms are targeted by neuroprotective, anti-inflammatory, growth factor promotive, metabolic efficacious agents and stem cell therapies. Recent therapies have integrated multiple new features such as novel biomarkers, new neuropsychological outcomes, enrollment of earlier populations in the course of the disease, and innovative trial designs. In the near future different specific agents for every patient might be used in a “precision medicine” context, where aberrant biomarkers accompanied with a particular pattern of neuropsychological and neuroimaging findings could determine a specific treatment regimen within a customized therapeutic framework. In this review, we discuss potential disease-modifying therapies that are currently being studied and potential individualized therapeutic frameworks that can be proved beneficial for patients with AD.

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A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease

Susanne Ostrowitzki, Robert A Lasser, Ernest Dorflinger … (2017)

Background Gantenerumab is a fully human monoclonal antibody that binds aggregated amyloid-β (Aβ) and removes Aβ plaques by Fc receptor-mediated phagocytosis. In the SCarlet RoAD trial, we assessed the efficacy and safety of gantenerumab in prodromal Alzheimer’s disease (AD). Methods In this randomized, double-blind, placebo-controlled phase III study, we investigated gantenerumab over 2 years. Patients were randomized to gantenerumab 105 mg or 225 mg or placebo every 4 weeks by subcutaneous injection. The primary endpoint was the change from baseline to week 104 in Clinical Dementia Rating Sum of Boxes (CDR-SB) score. We evaluated treatment effects on cerebrospinal fluid biomarkers (all patients) and amyloid positron emission tomography (substudy). A futility analysis was performed once 50% of patients completed 2 years of treatment. Safety was assessed in patients who received at least one dose. Results Of the 3089 patients screened, 797 were randomized. The study was halted early for futility; dosing was discontinued; and the study was unblinded. No differences between groups in the primary (least squares mean [95% CI] CDR-SB change from baseline 1.60 [1.28, 1.91], 1.69 [1.37, 2.01], and 1.73 [1.42, 2.04] for placebo, gantenerumab 105 mg, and gantenerumab 225 mg, respectively) or secondary clinical endpoints were observed. The incidence of generally asymptomatic amyloid-related imaging abnormalities increased in a dose- and APOE ε4 genotype-dependent manner. Exploratory analyses suggested a dose-dependent drug effect on clinical and biomarker endpoints. Conclusions The study was stopped early for futility, but dose-dependent effects observed in exploratory analyses on select clinical and biomarker endpoints suggest that higher dosing with gantenerumab may be necessary to achieve clinical efficacy. Trial registration ClinicalTrials.gov, NCT01224106. Registered on October 14, 2010. Electronic supplementary material The online version of this article (doi:10.1186/s13195-017-0318-y) contains supplementary material, which is available to authorized users.

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Randomized Trial of Verubecestat for Prodromal Alzheimer’s Disease

Michael Egan, James T Kost, Tiffini Smith Voss … (2019)

Prodromal Alzheimer’s disease offers an opportunity to test the effect of drugs that modify the deposition of amyloid in the brain before the onset of dementia. Verubecestat is an orally administered β -site amyloid precursor protein-cleaving enzyme 1 (BACE-1) inhibitor that blocks production of amyloid-beta (A β ). The drug did not prevent clinical progression in a trial involving patients with mild-to-moderate dementia due to Alzheimer’s disease. We conducted a randomized, double-blind, placebo-controlled, 104-week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had memory impairment and elevated brain amyloid levels but whose condition did not meet the case definition of dementia. The primary outcome was the change from baseline to week 104 in the score on the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB; scores range from 0 to 18, with higher scores indicating worse cognition and daily function). Secondary outcomes included other assessments of cognition and daily function. The trial was terminated for futility after 1454 patients had been enrolled; 485 had been assigned to receive verubecestat at a dose of 12 mg per day (the 12-mg group), 484 to receive verubecestat at a dose of 40 mg per day (the 40-mg group), and 485 to receive placebo. A total of 234 patients, 231 patients, and 239 patients per group, respectively, completed 104 weeks of the trial regimen. The estimated mean change from baseline to week 104 in the CDR-SB score was 1.65 in the 12-mg group, 2.02 in the 40-mg group, and 1.58 in the placebo group (P=0.67 for the comparison between the 12-mg group and the placebo group and P=0.01 for the comparison between the 40-mg group and the placebo group), suggesting a worse outcome in the higher-dose group than in the placebo group. The estimated rate of progression to dementia due to Alzheimer’s disease was 24.5, 25.5, and 19.3 events per 100 patient-years in the 12-mg group, the 40-mg group, and the placebo group, respectively (hazard ratio for 40 mg vs. placebo, 1.38; 97.51% confidence interval, 1.07 to 1.79, not adjusted for multiple comparisons), favoring placebo. Adverse events were more common in the verubecestat groups than in the placebo group. Verubecestat did not improve clinical ratings of dementia among patients with prodromal Alzheimer’s disease, and some measures suggested that cognition and daily function were worse among patients who received verubecestat than among those who received placebo. (Funded by Merck Sharp & Dohme; ClinicalTrials.gov number, .)

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Current and future treatments for Alzheimer's disease.

Konstantina Yiannopoulou, Lazaros G. Papageorgiou (2012)

Alzheimer's dementia (AD) is increasingly being recognized as one of the most important medical and social problems in older people in industrialized and non-industrialized nations. To date, only symptomatic treatments exist for this disease, all trying to counterbalance the neurotransmitter disturbance. Three cholinesterase inhibitors (CIs) are currently available and have been approved for the treatment of mild to moderate AD. A further therapeutic option available for moderate to severe AD is memantine, an N-methyl-D-aspartate receptor noncompetitive antagonist. Treatments capable of stopping or at least effectively modifying the course of AD, referred to as 'disease-modifying' drugs, are still under extensive research. To block the progression of the disease they have to interfere with the pathogenic steps responsible for the clinical symptoms, including the deposition of extracellular amyloid β plaques and intracellular neurofibrillary tangle formation, inflammation, oxidative damage, iron deregulation and cholesterol metabolism. In this review we discuss current symptomatic treatments and new potential disease-modifying therapies for AD that are currently being studied in phase I-III trials.

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Journal

Journal ID (nlm-ta): J Cent Nerv Syst Dis

Journal ID (iso-abbrev): J Cent Nerv Syst Dis

Journal ID (publisher-id): CNS

Journal ID (hwp): spcns

Title: Journal of Central Nervous System Disease

Publisher: SAGE Publications (Sage UK: London, England )

ISSN (Electronic): 1179-5735

Publication date (Electronic): 29 February 2020

Publication date Collection: 2020

Volume: 12

Electronic Location Identifier: 1179573520907397

Affiliations

[1 ]Memory Center, Neurological Department, Henry Dunant Hospital Center, Athens, Greece

[2 ]Cognitive Disorders/Dementia Unit, 2nd Neurological Department, National and Kapodistrian University of Athens, Attikon General University Hospital, Athens, Greece

Author notes

[*]Konstantina G Yiannopoulou, Memory Center, Neurological Department, Henry Dunant Hospital Center, 107 Mesogeion Avenue, 11526 Athens, Greece. Email: k.giannopoulou.14@ 123456hotmail.com

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Konstantina G Yiannopoulou https://orcid.org/0000-0002-4876-4566

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Publisher ID: 10.1177_1179573520907397 Publisher-manuscript ID: CNS-19-0024.R2

DOI: 10.1177/1179573520907397

PMC ID: 7050025

PubMed ID: 32165850

SO-VID: a3d7a833-89fd-49da-906d-09d7d5dad9a4

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This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

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Date received : 3 September 2019

Date accepted : 24 January 2020

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cover-date January-December 2020

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Keywords: alzheimer disease,disease-modifying drugs,anti-amyloid,anti-tau,individualized therapeutic frameworks

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Keywords: alzheimer disease, disease-modifying drugs, anti-amyloid, anti-tau, individualized therapeutic frameworks

Current and Future Treatments in Alzheimer Disease: An Update

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Alternative approaches to Alzheimer's Disease

Most cited references 60

A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease

Randomized Trial of Verubecestat for Prodromal Alzheimer’s Disease

Current and future treatments for Alzheimer's disease.

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