Clinical Drug Research and Development on Alzheimer’s Disease
Pp. 28-87 (60)
Hailiang Yan, Daniel H.S. Lee and Yan Zhang
This chapter reviews the major pathological features and hypotheses in
Alzheimer’s disease (AD). Hypothesis-based and mechanism-based strategies of
clinical drug research and development for AD therapy and prevention are discussed.
The current available drugs and their applications are described. In addition, the
potential drugs in trials and under advanced stage of development are introduced.
AD displays 3 typical pathologies: loss of cholinergic neurons in the basal ganglia of
forebrain, β-amyloid (Aβ) plague deposition and neurofibrillary tangles (NFTs) of tau
protein. Aβ oliogmers and highly phosphorylated tau protein are generally considered to
be critical factors for the pathogenesis of AD. AD is also aggravated by distress.
Primary and experimental drugs for AD based on these hypotheses are generally
classified as follows: cholinergic drugs, antipsychotic drugs, Aβ and tau related drugs,
neuroprotective drugs, others with atypical hypothesized mechanisms of action. As for
patients, the drugs could be divided into drugs approved and drugs under clinical trials,
while the approved ones include drugs to treat AD and drugs to treat AD associated
As to the application of AD drugs, the most commonly prescribed drugs are classified
as cholinesterase inhibitors. Memantine, antagonist of the NMDA receptor, is the
second class of AD medicine that is approved for treatment of moderate to severe AD.
Antidepressant, anxiolytics and antipsychotics are used to treat AD associated
symptoms. Besides, antioxidant, statins, Non-steroidal anti-inflammatory drugs
(NSAIDs) are those that belong to the family of “old drugs with new actions”. Nonprescription
medications, like vitamin C and vitamin E, curcumin and ginko are
probably advised to prevent AD. Another effort has been made towards metabolically
non-reversible dimeric or hybrid compounds with multiple mechanisms of action.
The promising drugs loom in clinical trials since new strategies have been adopted to
address the etiology of AD, i.e. Aβ, NFTs and neuronal loss. The tau related drugs
include GSK-3β inhibitors, protein phosphatase 2A (PP2A) activators, paired helical
filaments (PHF) antibody, and methylene blue with unknown mechanisms. Aβ related
drugs include β-site APP-cleaving enzyme (BACE) inhibitors, γ-secretase inhibitors, γ-
secretase modulators, active and passive Aβ vaccination drugs, and human intravenous
immunoglobulin (IVIG). The neuroprotective drugs are those that would maintain the
homeostasis of microenvironment, including anti-inflammatory, anti-oxyidant, metal
chelators, statins and neurotrophic agents.
In conclusion, the patients would be prescribed tacrine, donepezil, rivastigmine,
galantamine or memantine to treat mild or moderate to severe AD respectively. In the
meantime, they would have taken antidepressants, anxiolytics and antipsychotics to deal
with AD associated symptoms. Besides those approved, the effort to develop new drugs
to cure AD never stops. The potential drugs are on their promising way through clinical
trials. Albeit the failures and setbacks, AD scientists and clinicians are feverishly
researching to deliver an effective therapy for the many patients.
AD, amyloid, clinical trial, drug development, efficacy,
neurodegeneration, neuronal loss, pathology, synaptic loss, tau, therapy.
College of Life Sciences, Room 219, Peking University, Beijing, 100871, China.