Lessons Learned from Alzheimer Disease: Clinical Trials with Negative Outcomes

Challenges in Alzheimer's Disease Drug Discovery and Development: The Role of Modeling, Simulation, and Open Data

“…18 The amyloid precursor protein plus presenilin 1 (APP/PS1) and the 5X familial AD transgenic mice are both widely used AD models. 13,18 They recapitulate several pathological hallmarks of AD, such as Aβ plaques, gliosis, synaptic degeneration, and neuronal loss, and they also develop progressive cognitive deficits. 18 Despite the increasing number of complementary rodent models of AD (including genetic and nongenetic models), several issues limit the translatability of their findings to humans.…”

“…Animal models recapitulate only specific aspects of human AD. 13,[18][19][20] For example, while the APP/PS1 and the 5X familial AD mice models recapitulate the human amyloidosis, they lack tau pathology or cell death and have limited inflammatory modifications. 13,18 Recently tau transgenic models have made it possible to study the relationship between two of the major hallmarks of AD (e.g., Tg4510).…”

High Content, Phenotypic Assays and Screens for Compounds Modulating Cellular Processes in Primary Neurons

“…First, mitochondrial loss and dysfunction are common hallmarks of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease or Amyotrophic Lateral Sclerosis, which are characterized by a gradual, progressive and selective loss of certain neuronal systems in each disease (Nunnari & Suomalainen, 2012). The lack of biologically relevant screening platforms, validated targets and the high failure rate of clinical trials present an urgent need for novel screening technologies, new drugs and druggable targets (Cummings, 2018; Hawkes, 2018). Since the pathophysiology of neurodegenerative diseases is complex and not fully understood, the implementation of phenotypic screens for successful drug development is preferable over target-based approaches.…”

Advancements of the sFIDA method for oligomer‐based diagnostics of neurodegenerative diseases

“…Today, there are no preventive or curative options to treat Alzheimer's disease . However, disease‐modifying drugs are urgently needed to prevent, delay or treat the cognitive and behavioural symptoms of AD . In the past two decades, more than 400 medication candidates failed to reach the clinical endpoints , which has been mainly attributed to a lack of precise biomarkers for patient selection, therapy monitoring and measures of target engagement and outcome .…”