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

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.

Solving neurodegeneration: common mechanisms and strategies for new treatments

“…Since multiple disease pathologies are commonly associated with neurodegeneration, multifactorial disease therapies may prove more effective than monotherapies targeting one aspect of the disease [ 262 ]. Combination therapies have been successfully implemented in the treatment of previously life-threatening diseases such as cancer, tuberculosis and HIV/AIDs.…”

“…Combination therapies have been successfully implemented in the treatment of previously life-threatening diseases such as cancer, tuberculosis and HIV/AIDs. Since AD exhibits multiple co-occurring pathologies such as vascular brain injury, Lewy body pathology and TDP-43 inclusions [ 262 ], treatment to tackle these pathologies together may show more promise than previous failed attempts, such as clinical trials using anti-Aβ as a monotherapy. An example of such therapy might combine anti-Aβ to promote immune-clearance of Aβ aggregates, with an inhibitor of β-secretase, the enzyme responsible for the production of toxic Aβ [ 262 ].…”

“…Since AD exhibits multiple co-occurring pathologies such as vascular brain injury, Lewy body pathology and TDP-43 inclusions [ 262 ], treatment to tackle these pathologies together may show more promise than previous failed attempts, such as clinical trials using anti-Aβ as a monotherapy. An example of such therapy might combine anti-Aβ to promote immune-clearance of Aβ aggregates, with an inhibitor of β-secretase, the enzyme responsible for the production of toxic Aβ [ 262 ]. Similarly, glaucoma shares co-morbidity with systemic vascular diseases such as hypertension, and BRB breakdown has recently been highlighted as an important, yet overlooked disease mechanism [ 32 ].…”

Alzheimer’s disease – the journey of a healthy brain into organ failure

“…Future efforts will likely find effective prophylactic interventions for AD [ 268 ]. Although AD prevention trials are challenging to conduct, it is likely that robust, safe interventions that either target Aβ, the unknown factors through which Aβ drives tau pathology, or tau induced neurodegeneration would prove efficacious in these studies.…”

Neuroimaging within the Dominantly Inherited Alzheimer’s Network (DIAN): PET and MRI

“…Tau is also a candidate therapeutic target of AD [51][52][53] , given that it is proposed to accumulate immediately prior to symptom onset 8 , and is found to be highly predictive of cognitive decline 52,54,55 and structural atrophy 56 .…”