The informed road map to prevention of Alzheimer Disease: A call to arms

Eric Mcdade,David M Holtzman,Randall J Bateman,John C Morris,Jorge J Llibre-Guerra

doi:10.1186/s13024-021-00467-y

Abstract

Alzheimer disease (AD) prevention trials hold the promise to delay or prevent cognitive decline and dementia onset by intervening before significant neuronal damage occurs. In recent years, the first AD prevention trials have launched and are yielding important findings on the biology of targeting asymptomatic AD pathology. However, there are limitations that impact the design of these prevention trials, including the translation of animal models that recapitulate key stages and multiple pathological aspects of the human disease, missing target validation in asymptomatic disease, uncertain causality of the association of pathophysiologic changes with cognitive and clinical symptoms, and limited biomarker validation for novel targets. The field is accelerating advancements in key areas including the development of highly specific and quantitative biomarker measures for AD pathology, increasing our understanding of the course and relationship of amyloid and tau pathology in asymptomatic through symptomatic stages, and the development of powerful interventions that can slow or reverse AD amyloid pathology. We review the current status of prevention trials and propose key areas of needed research as a call to basic and translational scientists to accelerate AD prevention. Specifically, we review (1) sporadic and dominantly inherited primary and secondary AD prevention trials, (2) proposed targets, mechanisms, and drugs including the amyloid, tau, and inflammatory pathways and combination treatments, (3) the need for more appropriate prevention animal models and experiments, and (4) biomarkers and outcome measures needed to design human asymptomatic prevention trials. We conclude with actions needed to effectively move prevention targets and trials forward.

Highlights

In the absence of highly effective disease-modifying treatments and against a backdrop of an aging population, the number of adults with dementia worldwide is projected to more than triple by 2050 [1–3]
Given the large number of Amyloid-β peptide (Aβ) specific clinical trials that have been conducted without clear success to date, below we summarize priorities for animal model studies to increase the probability of success in Alzheimer disease (AD) prevention studies [46]
That ~65% of people with symptomatic AD carry at least one E4 allele; (2) APOE isoforms have been implicated in numerous processes, including crosstalk with Aβ [133, 134], tau phosphorylation [126], lipid metabolism, vascular function [135, 136] and inflammation [137], the molecular mechanisms that mediate the pathological effects of APOE-ε4 in AD development remain to be determined; (3) most animals models in AD express non-physiological levels of expression of Aβ and tau, it is difficult to assess if findings from APOE modification in these models will yield similar results in human clinical trials

Summary

Introduction

In the absence of highly effective disease-modifying treatments and against a backdrop of an aging population, the number of adults with dementia worldwide is projected to more than triple by 2050 [1–3].

Results

Conclusion