With the development of population aging, as the world’s most populous country, China has entered an irreversible aging society, Alzheimer’s disease (AD) as a major threat to the physical and mental health of the elderly, has become the world’s “public enemy “AD is a common neurodegenerative disease.
AD is a common neurodegenerative disease, which mainly manifests as progressive memory impairment, cognitive dysfunction, personality change and language impairment, and other neuropsychiatric symptoms, thus seriously affecting patients’ social, occupational and life functions, and eventually leading to death.
The prevalence of AD increases with age, ranging from about 5% in people over 65 years old to 20% in people over 85 years old. Once targeted by this “killer”, the elderly will gradually lose their ability to live independently and require long-term care and nursing, resulting in a large amount of human, material and financial resources consumption, which brings a heavy economic burden to social development. How to defeat this “national enemy” is of great importance to our country and the world. In this paper, we will briefly analyze the progress of drug therapy related to the main mechanisms of AD pathogenesis in 2014.
1.Acetylcholinesterase inhibitors (AChEI)
Acetylcholine (ACh) is an important neurotransmitter in the brain and is released by cholinergic neurons. When the body analyzes new stimuli, the basal anterior cholinergic neurons are activated and the release of ACh in the cortex, hippocampus and other brain regions is altered with cognitive activities such as learning memory and exploratory behavior. Previous studies have shown that a decrease in cholinergic neurons in AD patients leads to a decrease in ACh synthesis, storage and release, followed by clinical symptoms dominated by memory impairment and recognition deficits. Thus, the therapeutic mechanism of AChEI for AD emerged.
In 2014, Paroni G et al. found that forkhead protein O1 antibody (FOXO1) was associated with the oxidative stress process in AD through their study. and in assessing the relationship between the FOXO1 locus and the efficacy of AChEI drugs in sporadic AD found that patients with poorer efficacy had a higher frequency of FOXO1rs7981045G/G genotype compared to those with better efficacy with AChEI drugs, and logistic (logistic) regression analysis likewise confirmed that patients with G/G genotype had a patients with G/G genotype also confirmed a poorer response to AChEI drugs.
Currently, AChEI has become the most widely used drug in the treatment of AD, playing a mainstay role.
2. Glutamate receptor antagonists
Glutamatergic neurotransmission disorders play an important role in the progression of AD, and glutamate can induce excitotoxicity and death of neurons through N-methyl-D-aspartate (NMDA) receptors during the pathogenesis of AD. Thus, both the progressive deterioration of glutamatergic synaptic function and the progression of excitotoxicity are part of the pathogenesis of AD.
Glutamate receptor antagonist memantine is effective in the treatment of AD
Memantine, a specific, non-competitive NMDA receptor antagonist, has been widely used in the treatment of patients with moderate-to-severe AD.
Two recent randomized, double-blind controlled trials in Japan have shown that memantine is effective and well tolerated in moderate-to-severe AD, especially in attention, practice, visuospatial ability and language, and also showed significant improvements in psychiatric behavioral and psychological symptoms.
Cédric? Cédric Annweiler et al. also showed for the first time that the combination of memantine with vitamin D inhibited degenerative changes in cortical neurons exposed to β-amyloid (Aβ) and glutamate neurotoxicity, and that this inhibition was stronger when memantine was combined with vitamin D than when the two drugs were used alone.
However, Dysken MW et al. found that the use of 2000 IU/d of vitamin E alone delayed cognitive impairment in patients with mild to moderate AD compared to the use of memantine alone or its combination with vitamin E, thereby reducing caregiver burden. This result also confirms what scientists suspected back in 2013.
Meperidine may work better in combination with AChEI-like drugs
In July 2014, a double-blind, placebo-controlled phase III drug trial in the United States showed that the combination of memantine with AChEI drugs was more cost-effective than AChEI drugs alone in treating patients with moderate-to-severe AD. Other retrospective studies have also shown that long-term combined use of memantine and AChEI in the treatment of elderly AD patients can significantly delay the progression of cognitive dysfunction and effectively avoid the occurrence of anxiety and aggressive behavior in patients.
In December of the same year, global generic giant Actavis and partner Adamas Pharmaceuticals announced that the new combination drug namzaric had been approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with moderate-to-severe AD who are receiving stable treatment with memantine hydrochloride and donepezil hydrochloride. to market this year.
Namzaric is a once-daily oral capsule consisting of a fixed dose of memantine and donepezil for patients currently taking memantine (10 mg twice daily; or 28 mg extended-release tablets once daily) and donepezil (10 mg). In addition, the capsule can be opened and the contents spread over food to facilitate administration in patients who may have difficulty swallowing.
The combination of memantine and donepezil is a proven treatment regimen for patients with moderate to severe AD. namzaric helps to help reduce the burden of daily medication and improve patient compliance. namzaric includes 2 doses, 28mg/10mg and 14mg/10mg, the latter of which can be used in patients with severe renal impairment.
Prior to this, of the 5 drugs approved by the FDA for the treatment of AD, all 4 (tacrine, donepezil, galantamine, and carboplatin) were AChEI, except for memantine, which is an NMDA receptor antagonist.
The results of the above studies show that AChEI and glutamate receptor antagonists have become the first-line drugs in AD treatment today, especially for patients with moderate-to-severe AD. At the same time, the results of the new AD therapeutic drugs that are being researched in recent years at home and abroad are also very promising.
3.Drugs for Aβ toxicity hypothesis
The Aβ toxicity hypothesis is the dominant theory in the pathogenesis of AD. Aβ is mainly caused by the abnormal metabolism of amyloid precursor protein (APP) through α, β and γ secretase, and Aβ is neurotoxic.
A new direction of AD drug treatment was proposed, but the study results were not satisfactory
In 2014, several clinical trials were conducted in this area. Lore (RoherAE) et al. conducted a 76-week clinical trial in patients with pathologically confirmed AD with the gamma secretase inhibitor semagacestat. the trial examined Aβ levels in the cerebrospinal fluid of subjects before and after the intervention, as well as the BACE1, PS-1, APP genes and their expressed proteins hydrolyzed to produce the C-peptide terminus APP- CT99, APP-CT83 and γ-secretase hydrolysis products. The study showed an exponential increase in Aβ levels in the brains of the subjects compared to the control group, while there were no significant changes in the levels of APP, β-secretase, γ-secretase and their hydrolysates, or CT99/CT83 levels. This trial is the first study of semagacestat in humans, but the results it represents do not adequately describe the therapeutic effects of γ-secretase inhibitors in AD patients.
A phase III drug clinical trial conducted by Doody RS et al. on solanezumab, a human monoclonal antibody that preferentially binds soluble amyloid, showed that it did not improve cognitive dysfunction in AD patients, similar to the results obtained by Salloway S et al. in a study of a similar drug, bapineuzumab. In addition, a multicenter, double-blind, placebo-controlled study of PF-04447943, a potent, selective phosphodiesterase 9A inhibitor, showed that although safe and well tolerated, there was no significant change in cognitive, behavioral, or overall improvement in subjects compared to controls after 12 weeks of treatment. A similar study by GalaskoD et al. also showed that such receptor for advanced glycosylation end products (RAGE) inhibitor PF-04494700 was not significantly effective in patients with mild-to-moderate AD and could even exacerbate the degree of cognitive impairment.
In terms of animal experiments, several studies using APP and PS-1 transgenic mice as models illustrated and analyzed multiple targets for inhibiting Aβ production, suggesting new directions for AD therapeutic agents.
Overall, there was no certain definitive drug that inhibited the onset or development of AD in terms of Aβ toxicity in 2014. The lack of such findings may be due to the small sample size of the trials, the limited effect of single-target therapy, the late intervention time, or the difficulty in evaluating the relevance of the corresponding drugs to their efficacy due to external influences.
Results of early intervention studies are expected
Previous studies have shown that Aβ deposition occurs in the brain of AD patients several years before the onset of symptoms, and therefore, Aβ deposition has already occurred and is almost irreversible by the time drug trials are conducted with AD patients as subjects.
To address this problem, the University of Washington has recently conducted a clinical drug trial in asymptomatic mutation carriers, known as the Dominantly Inherited AD Network – Drug Trial Component (DIAN-TU), a randomized, double-blind, placebo-controlled, multicenter phase II/III drug trial, using The aim of the 2-year study was to investigate the safety, tolerability and efficacy of these two drugs, as well as to observe changes in the levels of Aβ in the cerebrospinal fluid of the subjects, using the monoclonal antibodies gantenerumab and solanezumab as the test drugs. The subjects were asymptomatic or had mild dementia [Clinical Dementia Rating Scale (CDR) = 0.5-1] and were within the age range of (age at onset of AD in family – 15 years, age at onset of AD in family + 10 years.) DIAN-TU was established in December 2012 and, as of September 2014, had enrolled nearly 200 mutation carriers. The study is currently being vigorously pursued, and in 2015, China will join it as a new pilot country.
In addition, a clinical drug trial of crenezumab conducted in Colombia in 2013 also targeted a preclinical AD population (containing the PSEN1, E280A gene mutation) and tested subjects for changes in cerebrospinal fluid Aβ levels.
The results of these two studies are of great interest to scholars worldwide because they provide very early intervention in AD carriers who are asymptomatic or only mildly symptomatic, avoiding the effects of large irreversible Aβ deposits in the subject’s brain on drug efficacy. We expect that this clinical trial of drugs related to AD biomarkers will open the door to AD treatment and give hope to AD patients.
4.Drugs targeting Tau protein
Under normal conditions, human Tau protein is phosphorylated and dephosphorylated, and the two are in balance. However, in AD patients, this balance is broken and Tau protein becomes hyperphosphorylated. The ability of phosphorylated Tau protein to bind to microtubules is greatly reduced, and eventually large amounts of phosphorylated Tau protein are gradually deposited to form double helix filaments and neurofibrillary tangles. In addition, it has been shown that deposition of Aβ fibers can induce Tau protein aggregation, while abnormal aggregation of Tau protein can also promote Aβ deposition, suggesting that these two pathological changes promote each other and jointly cause the occurrence of AD. Therefore, Tau protein, like Aβ, is an important target for AD drug development. As mentioned earlier, drug development for Aβ has recently reached a stalemate, and more and more investigators have shifted their focus to drug research targeting Tau proteins. The targets can be divided into three main types, namely Tau protein aggregation inhibitors, complexes that promote Tau proteolysis, and inhibitors of Tau protein hyperphosphorylation.
Methylene blue (MTC) has been considered by many researchers as one of the most promising inhibitors of Tau protein aggregation because it not only acts as an antioxidant, but also reduces Aβ oligomerization, and more importantly, MTC has a better inhibitory effect on Tau protein aggregation. phase II clinical studies of MTC have demonstrated its therapeutic effect in patients with mild-moderate AD, and phase III clinical studies are being initiated. In 2014, a study showed that a new stable reduced methylene blue (LMTX) significantly improved the tolerability of AD treatment.
The dual specific tyrosine phosphorylation-regulated kinase 1A (DYRK1A) gene is located in the corresponding region of the Down syndrome gene on chromosome 21 and is observed in patients with Down syndrome with early-onset AD, suggesting that this gene may be somehow associated with pathological changes in Aβ and Tau protein phosphorylation in the brain of patients with early-onset AD. This led to a number of studies in 2014 suggesting that certain potential therapeutic targets may be able to inhibit DYRK1A-induced Tau protein phosphorylation, Aβ production and the effects of Aβ on phosphorylated Tau proteins, for example, Tau protein aggregation.
For animal experiments, Castro-Alvarez JF et al. found that knockdown of the cycle-dependent protein kinase 5 (CDK5) gene reversed Tau aggregation in the brains of experimental animals, which might have an effect on AD treatment. Adwan L et al. found that tolfenamic acid reduced levels of AD-related proteins, such as Aβ, Tau and CDK5, in the brain, raising the possibility of a novel drug.
There are many more studies such as these, but this is still a long way from the proposal of a new drug.
From this, we can conclude that although such drugs targeting Tau protein may have a good trend to block the disease process and improve the prognosis of patients, however, since AD is a comprehensive disease in which genetic and environmental factors are involved, a single hypothesis cannot explain all the pathogenetic features of AD, and such novel drugs generally only have a blocking effect on one part of AD, which may be the basis of the above drug This may be the main reason why the above-mentioned drugs have been effective in basic and preclinical studies but failed in repeated phase III clinical trials.
⑤ Conclusion
In conclusion, from the current situation, it is of great clinical importance to intervene in the very early stage of AD or even before the onset of the disease, and to find a multi-target drug that can attack this “universal enemy” from many aspects, which is the core of future drug development and research.