What works and what does not work in Alzheimer’s disease? From interventions on risk factors to anti‐amyloid trials

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with no approved disease-modifying therapy (DMT). In this review, we summarize the various past approaches taken in an attempt to find treatments capable of altering the longterm course for individuals with AD, including: translating epidemiological observations into potential treatment options; seeking a single-treatment approach across the continuum of AD severity; utilizing biomarkers for assessing target engagement; using biomarkers as early surrogates of clinical efficacy; and enriching study populations to demonstrate adequate placebo decline during the limited duration of clinical trials. Although targeting the amyloid-β (Aβ) pathway has been central to the search for an effective DMT, to date, trials of anti-Aβ monoclonal antibodies have failed to consistently demonstrate significant clinical efficacy. Key learnings from these anti-Aβ trials, as well as the trials that came before them, have shifted the focus within clinical development programs to identifying target populations thought most likely to benefit from treatments (i.e., individuals at an earlier stage of disease). Other learnings include strategies to increase the likelihood of showing measurable improvements within the clinical trial setting by better predicting decline in placebo participants, as well as developing measures to quantify the needed treatment exposure (e.g., higher doses). Given the complexity associated with AD pathology and progression, treatments targeting non-amyloid AD pathologies in combination with anti-amyloid therapies may offer an alternative for the successful development of DMTs.

Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis

“…1163 Developing disease-modifying therapies for AD presents an immense challenge, with little success despite intense work over decades. 314,[1164][1165][1166][1167] Some of the reasons why drug development for AD continues to fail include: (a) in vitro experiments poorly mimic in vivo conditions, (b) Aβ and tau exist in multiple covalent and aggregated forms of uncertain relevance to pathology and we have a poor knowledge of their structures, and (c) the limitations of animal models. 314 Amongst animal models, genetically-modified mouse lines are invaluable and widely used models for understanding genes, proteins, and biological pathways, evaluating disease progression, and assessing safety of molecules for therapeutic purposes in many diseases including neurodegenerative diseases, cancer and diabetes.…”

An “epitomic” analysis of the specificity of conformation-dependent, anti-Aß amyloid monoclonal antibodies

“…Twenty-six of the monoclonals clearly recognize an Aß-related epitope that is located in the amino terminal ( 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ) or central ( 7 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ) third of the molecule or both ( Fig. 2 ).…”

“…Monoclonal antibodies against Aß are a leading class of therapeutic for AD. Many of these antibodies have been evaluated in clinical trials, but so far none have demonstrated consistent therapeutic activity in slowing the progression of AD and none have been approved by the FDA (reviewed in (4,5)). Conformation-dependent monoclonal antibodies against Aβ are also an invaluable tool for research in the role of amyloids in Alzheimer's disease because they recognize epitopes that are differentially displayed on distinct structural polymorphs or folded states of the peptide, providing insight into the role of polymorphisms in the pathogenic spectrum of the disease (6).…”

“…Monoclonal antibodies against Aß are a leading class of therapeutic for AD. Many of these antibodies have been evaluated in clinical trials, but so far none have demonstrated consistent therapeutic activity in slowing the progression of AD and none have been approved by the US Food and Drug Administration (reviewed in ( 4 , 5 )).…”

Epitomic analysis of the specificity of conformation-dependent, anti-Aß amyloid monoclonal antibodies

“…Monoclonal antibodies against Aß are a leading class of therapeutic for AD. Many of these antibodies have been evaluated in clinical trials, but so far none have demonstrated consistent therapeutic activity in slowing the progression of AD and none have been approved by the FDA (reviewed in (4,5)).…”