Status and future directions of clinical trials in Alzheimer's disease

Amyloid-β (Aβ) senile plaques and neurofibrillary tangles of tau are generally recognized as the culprits of Alzheimer's disease (AD) and related dementia. About 25 years ago, the amyloid cascade hypotheses postulated a direct correlation of plaques with the development of AD, and it has been the dominant theory since then. In this period, more than 200 clinical trials focused mainly on targeting components of the Aβ cascade have dramatically failed, some of them in Phase III. With a greater than 99.6% failure rate at a cost of several billion from governments, industry, and private funders, therapeutic strategies targeting amyloid and tau are now under scrutiny. Therefore, it is time to reevaluate alternatives to targeting Aβ and tau as effective therapeutic strategies for AD. The diagnosis of AD is currently based on medical examination of symptoms including tests to assess memory impairment, attention, language, and other thinking skills. This is complemented with brain scans, such as computed tomography, magnetic resonance imaging, or positron emission tomography with the help of imaging probes targeting Aβ or tau deposits. This approach has contributed to the tunnel vision focus on Aβ and tau as the main culprits of AD. However, events upstream of these proteopathies (age-related impaired neuronal bioenergetics, lysosome function, neurotrophic signaling, and neuroinflammation, among others) are almost surely where the development of alternative therapeutic interventions should be targeted. Here, we present the current status of therapeutic candidates targeting diverse mechanisms and strategies including Aβ and tau, proteins involved in Aβ production and trafficking (ApoE, α/β/γ-secretases), neuroinflammation, neurotransmitters, neuroprotective agents antimicrobials, and gene and stem cell therapy. There are currently around 33 compounds in Phase III, 78 in Phase II, and 32 more in Phase I trials. With the current world health crisis of increased dementia in a rapidly aging population, effective AD therapies are desperately needed.