Alzheimer’s disease (AD) is a major type of dementia and neurodegenerative disease, characterized by memory loss and cognitive decline. Over decades, significant efforts have been dedicated to finding its cause, pathogenic mechanisms, biomarkers for early detection, and clinical trials for its treatment. Earlier approved drugs mainly ameliorated the symptoms of AD, until recent years when two drugs targeting amyloid-beta (Aβ) protein were approved to slow down the progression of the disease. This review article encompasses the history of drug development in treating AD and clinical trials that failed and succeeded. Clinicaltrials.org website was systematically searched and screened for randomized controlled trials with results posted in the past 10 years. Among the 3,388 AD clinical trials, 211 interventional studies registered under AD have met eligibility. This review includes the interventional targets for drug discovery such as Aβ, tau, neurotransmitter receptors, neuroinflammation, multi-target studies, repurposing pharmacological agents, non-pharmacological interventions, and clinical therapy development for the neuropsychiatric symptoms of dementia. Current clinical trials are ongoing and no results are available as of yet. With the vast choices of drug targets that have been investigated, this review aims to present some insights into future AD drug design and trials and contribute to our ongoing efforts to find the cure.
Alzheimer’s disease (AD) has affected around 50 million people worldwide and is projected to reach 152 million by 2060. AD and other dementias ranked among the top 10 leading causes of death globally. Currently, there are about 24 million Alzheimer’s patients worldwide. It was suggested that gene changes can be a 70% risk factor for AD development. Three genes, also the main (high) risk factors for AD, are associated with early-onset AD. They are APP on 21q, PSEN1 on 14q and PSEN2 on 1q. The apolipoprotein E (APOE) gene is the strongest genetic (medium) risk factor for late-onset AD, located on chromosome 19q. Among the APOE gene variants, APOE4 is considered the strongest genetic risk factor for AD, and APOE2 is neuroprotective.
FDA-approved immunotherapy drugs targeting amyloid-beta (Aβ) work best to slow the cognitive declining at the early stages of AD for some people, unlike earlier approved cholinergic drugs that provide symptomatic relief without altering the disease progression. The majority of clinical trials are targeting intervention with AD therapeutic agents at early/mild to moderate stages of AD, and its early detection. This review aims to provide an overview of the current treatments for relieving some AD symptoms by targeting cholinergic and N-methyl-D-aspartic acid (NMDA) receptors, and clinical trials in halting the progression of AD, targeting removing the toxic proteins typical of AD, Aβ proteins (extracellular plaques) and various forms of tau proteins (intracellular tangles) or other targets and multi-target drugs.
The mainstay of current AD management targeting acetylcholinesterase is to make acetylcholine available for synaptic transmission. Five drugs (donepezil, rivastigmine, galantamine, memantine, and tacrine) are approved on the market with donepezil approved the earliest, in 1996. These drugs are used for all stages of AD, but inhibition of cholinesterase enzymes works best at the early stage of AD.
Among them, a rivastigmine patch or oral capsule is the only acetylcholinesterase inhibitor (ACEI) that provides inhibition for both acetylcholinesterase and butyrylcholinesterase and shows efficacy and safety in helping to relieve the cognitive symptoms of AD.
Current therapeutics to ameliorate and control the cognitive and behavioral symptoms by targeting the NMDA receptor prevent Ca 2+ induced excitotoxicity, and memantine was approved for this purpose in 2003. Memantine is more effective in providing cognitive and behavioral benefits and approved for patients with moderate to severe AD as monotherapy or combination therapy with donepezil. Finally, memantine is both a non-competitive NMDA receptor antagonist and a dopamine agonist for moderate to severe AD.
The FDA has approved two drugs for mild cognitive impairment (MCI) to early, mild stages of AD after years of failed clinical trials. They are aducanemab, and lecanemab, among which aducanemab received accelerated approval.
As of May 2024, there are a total of 3,388 Alzheimer’s disease clinical trials including all studies (clinicaltrials.gov). We chose to focus on the trials starting from 01/01/2015 and encompassing the past 10 years, including 2,030 studies. After excluding observational studies (with patient registries), and keeping all the interventional clinical trials, there are 1,596 studies registered under AD. After keeping the trials with results (excluding the ones without results), 211 studies remain with (early) phase 1 (n = 32), phase 2 (n = 78) trials on the safety and tolerability test, and phase 3 (n = 37) and phase 4 (n = 4) trials on slowing the cognitive decline. These trials were or are in the process of being carried out globally. This review includes the interventional targets for drug discovery such as neurotransmitter (receptors), Aβ, tau, neuroinflammation.
