Overcoming translational barriers impeding development of Alzheimer's disease modifying therapies

Abstract

It has now been~30 years since the Alzheimer's disease (AD) research entered what may be termed the 'molecular era' that began with the identification of the amyloid b protein (Ab) as the primary component of amyloid within senile plaques and cerebrovascular amyloid and the microtubule-associated protein tau as the primary component of neurofibrillary tangles in the AD brain. These pivotal discoveries and the subsequent genetic, pathological, and modeling studies supporting pivotal roles for tau and Ab aggregation and accumulation have provided firm rationale for a new generation of AD therapies designed not to just provide symptomatic benefit, but as disease modifying agents that would slow or even reverse the disease course. Indeed, over the last 20 years numerous therapeutic strategies for disease modification have emerged, been preclinically validated, and advanced through various stages of clinical testing. Unfortunately, no therapy has yet to show significant clinical disease modification. In this review, I describe 10 translational barriers to successful disease modification, highlight current efforts addressing some of these barriers, and discuss how the field could focus future efforts to overcome barriers that are not major foci of current research efforts.

Short Aβ peptides attenuate Aβ42 toxicity in vivo

“…These studies are therapeutically relevant, as GSMs that increase short Aβ peptides remain in both clinical and preclinical development for AD ( Wagner et al, 2012 ; Golde et al, 2013 ). As emerging clinical data continue to reinforce the hypothesis that Aβ production inhibitors are likely to be most effective as prophylactic therapies to prevent development of AD, safety of the inhibitor becomes of paramount importance ( Golde et al, 2011 ; Golde, 2016 ). These studies provide clear-cut preclinical data that short Aβ peptides are not themselves toxic and in certain circumstances may also be protective.…”

Weighted Protein Interaction Network Analysis of Frontotemporal Dementia

“… 15 However, breakthroughs of this magnitude require decades of intense cell biology and animal-model-based studies, suggesting these approaches are still not entirely efficient as well as underpowered to comprehensively explain disease mechanisms in a timely manner. 16 …”

Harnessing Immunoproteostasis to Treat Neurodegenerative Disorders

“…Despite major advances in understanding key initiating events underlying various neurodegenerative disorders, there are limited efficacious treatment options for patients (Cummings et al, 2014;Golde, 2016). Approved therapies are primarily symptomatic in nature and do not dramatically modify disease course.…”

“…Indeed, there is growing recognition and evidence from clinical trials that targeting the proteinopathies will have the best chance for showing efficacy if treatment is initiated well before disease-defining symptoms appear (Bateman et al, 2017;Golde et al, 2013;Reiman et al, 2011;Sperling et al, 2014). There is cautious optimism that such therapies intended to target early steps in the disease process, when tested in primary or secondary prevention trials, will have major impact on disease course; however, the timelines for possible regulatory approval and widespread deployment of effective prophylactic therapies remain uncertain (Golde, 2016).…”