A Review of the Recent Advances in Alzheimer’s Disease Research and the Utilization of Network Biology Approaches for Prioritizing Diagnostics and Therapeutics
Abstract
:1. Introduction
2. Alzheimer’s Disease Pathophysiology
2.1. The Amyloid Hypothesis
2.1.1. APP
2.1.2. Tau
2.1.3. APOE, TERM2, SORL1, and ABCA7 Mutations
2.2. The Cholinergic Hypothesis
2.3. The Mitochondrial Cascade (Oxidative Stress) Hypothesis
2.4. Other Factors Affecting Disease Pathogenesis
3. Alzheimer’s Disease Classifications
Classification | Genetic Factors | Age Onset | Clinical Features | Risk Factors | Top Treatments | References |
---|---|---|---|---|---|---|
Early-onset | Yes | 40s–50s | Plaques of amyloid and tau proteins | Family history | Acetylcholinesterase inhibitors (Donepezil, Galantamine, and Rivastigmine) | [154] |
Late-onset | Yes (APOE) | ≥65 | (APOE) ε4 allele | Age ≥ 65 years, genetic and environmental factors | Acetylcholinesterase inhibitors (Donepezil, Galantamine, and Rivastigmine) and treatment of vascular risk factors and sleep and mood disorders | [155] |
Familial | Yes (PSEN1, PSEN2, APP) | 40s–50s | Mutations in PSEN1, PSEN2, and APP | Family history | Acetylcholinesterase inhibitors (Donepezil, Galantamine, and Rivastigmine) | [146,156,157] |
4. Alzheimer’s Disease Diagnosis
5. Epigenetic Changes in Alzheimer’s Disease
5.1. DNA Methylation
5.2. Mitochondrial DNA Methylation
5.3. DNA Hydroxymethylation
5.4. Histone Modifications
5.5. MicroRNA
6. Alzheimer’s Disease Biomarkers
7. Anti-Alzheimer’s Drugs
7.1. Drugs under Active Development
7.2. Withdrawn, Discontinued, or Suspended Drugs
8. Exploiting Network Biology Approaches in Alzheimer’s Disease Research
8.1. Previous Alzheimer’s Disease Drug Discovery Failures
8.2. Network Biology Approaches Hold the Promise to Revolutionize Alzhiemer’s Disease Research
8.3. Current Network Biology Efforts
8.4. Multi-Target-Directed Ligands as Network Biology Treatments
8.5. Suggested Disease Biomarkers and Disease Modifying Drugs
9. Artificial Intelligence and Machine Learning Approaches
10. Exploring Epigenetic Treatments
11. Genetic Treatments
12. Non-Pharmacological Treatment Options and Preventive Measures
13. Special Considerations for Clinical Trials
14. Conclusions
Author Contributions
Funding
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Biomarker Name | Population | Role | Highest Use Validity | Gene Symbol | |
---|---|---|---|---|---|
1 | Amyloid beta A4 protein | Mild Cognitive Impairment | Risk Factor | Recommended/Approved | APP |
2 | Amyloid beta A4 protein | All | Diagnosis | Recommended/Approved | APP |
3 | Amyloid beta A4 protein | Early Onset | Diagnosis | Recommended/Approved | APP |
4 | Apolipoprotein E | Mild Cognitive Impairment | Risk Factor | Recommended/Approved | APOE |
5 | beta-amyloid protein 42 | Mild Cognitive Impairment | Risk Factor | Recommended/Approved | |
6 | beta-amyloid protein 42 | All | Diagnosis | Recommended/Approved | |
7 | Glucose transporters and hexokinases | Mild Cognitive Impairment | Risk Factor | Recommended/Approved | |
8 | Glucose transporters and hexokinases | All | Diagnosis | Recommended/Approved | |
9 | Microtubule-associated protein tau | Mild Cognitive Impairment | Risk Factor | Recommended/Approved | MAPT |
10 | Microtubule-associated protein tau | All | Diagnosis | Recommended/Approved | MAPT |
11 | Presenilin-1 | All | Diagnosis | Recommended/Approved | PSEN1 |
12 | Presenilin-1 | Early Onset | Diagnosis | Recommended/Approved | PSEN1 |
13 | Presenilin-2 | All | Diagnosis | Recommended/Approved | PSEN2 |
14 | Presenilin-2 | Early Onset | Diagnosis | Recommended/Approved | PSEN2 |
Drug | Drug Targets | Managed Symptoms | Mechanism of Action | Disease Stage |
---|---|---|---|---|
Donepezil [270,271,272,273,274] | AChE | Improves cognition and behavior | Cholinesterase inhibitor; inhibition of various aspects of glutamate-induced excitotoxicity; the reduction of early expression of inflammatory cytokines; the induction of a neuroprotective isoform of AChE; the reduction of oxidative stress-induced effects | Mild to moderate AD |
Rivastigmine [272,273,274,275] | AChE; BChE | Improves cognitive functions and daily life activities | Cholinesterase inhibitor; increases cholinergic function | Mild to moderate AD |
Galantamine [272,273,274] | AChE; nicotinic ACh receptor | Improves behavioral symptoms, daily life activities, and cognitive functions | Cholinesterase inhibitor; binds to α-subunit of nicotinic ACh receptors and activates them | Mild to moderate AD |
Memantine [274,276] | NMDA receptor | Improves learning and memory | NMDA receptor antagonist (prevents over-activation of glutaminergic system that is involved in neurotoxicity in AD patients) | Moderate to severe AD |
Drug Category | Classification | Why Suggested | Why Failed |
---|---|---|---|
Monoclonal Antibodies (mABs) | Disease-modifying | These antibodies target the amyloid protein, and they predominate drug discovery efforts [154]. Amyloid has been considered a promising drug target since it is located outside the nerve cells, and it is toxic to the brain’s tissues [154]. | The mABs have not succeeded in eradicating AD because cognitive impairment predisposing dementia does not associate with amyloid precipitation [154]. |
Gamma (γ-) Secretase Inhibitors | Disease-modifying | It was proposed that targeting γ-secretase might reduce amyloid production, particularly Aβ42 isoform [160,161,162,163]. Phase II trials showed a dose-dependent decrease in both Aβ isoforms (Aβ40 and Aβ42) without significant decrease in tau protein, though the magnetic resonance imaging (MRI) recorded a cerebral atrophy following such treatment [154,165]. Patients showed some improvement at the beginning of treatment. | No distinct response of improvement nor worsening could be traced after 3 months of treatment [154,162]. Side effects were reported with higher doses, such as skin rashes, nausea, and diarrhea, accompanied by higher rate of skin cancer [154,164]. Furthermore, the narrow therapeutic window impeded their proceeding to Phase III [154,165]. |
Tau Inhibitors | Disease-modifying | The tau protein appeared as a potential target for AD dementia since an irregular phosphorylation of tau results in neurofibrillary tangle formation [166,167,168]. Clinical studies reported that AD progress is related to tangle formation more than that of Aβ [156]. Initially, tau aggregation inhibitors (TAIs) showed better response. | After long-term treatment (approximately 15 months), TAIs failed in AD treatment. Moreover, 15% of patients showed minor improvement without any co-administered therapy [169]. |
Neurochemical Enhancers | Symptomatic | Idalopiridine that inhibits 5-hydroxytryptamine 6 (5-HT6) receptors and consequently enhances the release of acetylcholine in the brain, i.e., pro-cholinergic effector [182,183]. Encenicline incites cholinergic response through activating α-7 nicotinic acetylcholine receptors [185,186,187]. | Further clinical studies declared that Idalopiridine does not show any promising effect in AD treatment [182,184]. Side effects of Encenicline were observed in Phase II trials at the maximum dose (2 mg) [185,186,187]. In addition, the Phase III trials, with doses of 2–3 mg, were terminated due to GI toxicity and eventually discontinued because there was no improvement in cognitive function [185,186,187]. |
Miscellaneous | Symptomatic | Dimebon is a histamine (H1) antagonist [188]. It affects α-adrenergic and serotonergic receptors, AMPA and NMDA glutamate receptors, and L-type voltage-gated calcium channels [189]. | It exerted a better response in AD patients and one Phase II trial in Russia [189], but it failed in Phase III trials in Austria, Europe, New Zealand, and the US [189]. |
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Hajjo, R.; Sabbah, D.A.; Abusara, O.H.; Al Bawab, A.Q. A Review of the Recent Advances in Alzheimer’s Disease Research and the Utilization of Network Biology Approaches for Prioritizing Diagnostics and Therapeutics. Diagnostics 2022, 12, 2975. https://doi.org/10.3390/diagnostics12122975
Hajjo R, Sabbah DA, Abusara OH, Al Bawab AQ. A Review of the Recent Advances in Alzheimer’s Disease Research and the Utilization of Network Biology Approaches for Prioritizing Diagnostics and Therapeutics. Diagnostics. 2022; 12(12):2975. https://doi.org/10.3390/diagnostics12122975
Chicago/Turabian StyleHajjo, Rima, Dima A. Sabbah, Osama H. Abusara, and Abdel Qader Al Bawab. 2022. "A Review of the Recent Advances in Alzheimer’s Disease Research and the Utilization of Network Biology Approaches for Prioritizing Diagnostics and Therapeutics" Diagnostics 12, no. 12: 2975. https://doi.org/10.3390/diagnostics12122975
APA StyleHajjo, R., Sabbah, D. A., Abusara, O. H., & Al Bawab, A. Q. (2022). A Review of the Recent Advances in Alzheimer’s Disease Research and the Utilization of Network Biology Approaches for Prioritizing Diagnostics and Therapeutics. Diagnostics, 12(12), 2975. https://doi.org/10.3390/diagnostics12122975