There is no consensus on the key mechanisms that can trigger a cascade of AD-causing processes. Furthermore, there is no agreement on how to implement specific, strategic pharmacotherapy.4 It is estimated that there were about 146 failed attempts to develop a potential drug for AD treatment between the period of 1998 and 2017. A possible contributing factor to these failures is a focus on a single target approach: the amyloid-β hypothesis.
At present there are no treatments to stop and/or delay underlying disease progression. Current prevalent therapies help to mask the symptoms, but they do not solve the underlying root cause(s).
A fundamental premise for effective treatment is to diagnose AD at the earliest feasible stage. The main symptoms are characterized by cognitive declines across a wide range of abilities: hippocampus-dependent spatial memory, visuospatial agnosia, constructional apraxia, and language and writing problems. Mental status testing, neuropsychological examination to assess patients’ thinking ability, and genetic testing (eg, to detect the presence of APOE-ε4 in serum) should be performed. Subsequent tests used to complement identification of AD include MRI, CT, and PET scans.
The following agents are FDA-approved medications to treat cognitive impairments: cholinesterase inhibitors (donepezil, rivastigmine, galantamine); N-methyl-D-aspartate receptor (NMDA)-antagonists (memantine); and the combination of memantine and donepezil (Namzaric). Donepezil and other cholinesterase inhibitors elevate acetylcholine in the brain. Increased activation of cholinergic receptors on microglia contribute to decreased release of cytokines.11
Glutamate may contribute to AD symptoms because of the over-activation of NMDA-receptors, which leads to neurotoxicity. Memantine blocks NMDA-receptors and inhibits glutamate excitatory neurotransmission.
The effectiveness of these drugs is dependent on individual tolerance. Namzaric, memantine, and donepezil can be prescribed at all stages of AD. Rivastigmine and galantamine are approved to treat mild and moderate conditions. These drugs have common adverse effects, including nausea, vomiting, muscle cramps, headache, and dizziness.
Use of antiviral and anti-inflammatory drugs is off-label for AD. Nevertheless, this kind of treatment supported by evidence-based research may slow the progression of dementia.12,13
Dr Aliev is President and Founder, International Research Institute, San Antonio, TX; Professor of Pharmacology, First Moscow State Medical University, Moscow; and Professor, Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, Russia. Dr Bachurin is Scientific Director and Professor of Chemistry, Institute of Physiologically Active Compounds, Russian Academy of Sciences. Ms Mikhaylenko is a PhD Student, Department of Pharmacology, Institute of Physiologically Active Compounds, Russian Academy of Sciences. Dr Bragin is President and Founder, Stress Relief and Memory Training Center, Brooklyn, NY. Dr Avila -Rodriguez is Leading Researcher, Health Sciences Faculty, Clinical Sciences Department, University of Tolima, Ibague, Colombia. Dr Somasundaram is Professor, Biology Department, Salem University, Salem, WV. Dr Kirkland is Professor, Biology Department and Executive Vice President, Salem University. Dr Tarasov is Chairman, Department of Pharmacology and Pharmacy, First Moscow State Medical University, Moscow. The authors report no conflicts of interest concerning the subject matter of this article.
Acknowledgments—This research was supported within the framework of the grant provided by CSP Ministry of the Health Russian Federation, and by the IPAC RAS State Targets Project # 0090-2019-0005; the Russian Academic Excellence Project “5-100” for the Sechenov University, in Moscow, Russia, also provided support for the research.
1. Alzheimer’s Association. Alzheimer disease facts and figures. Alzh Dem. 2019;15:321-387.
2. MacKenzie RJ. Quartet of papers provide a fresh look at sex differences in dementia. Technology Networks. July 19, 2019 [Epub].
3. Ashraf GM, Tarasov VV, Makhmutova A, et al. The possibility of an infectious etiology of Alzheimer disease. Mol Neurobiol. 2019;56:4479-4491.
4. Makin S. The amyloid hypothesis on trial. Nature. 2018; 559:4-7.
5. Sochocka M, Diniz BS, Leszek J. Inflammatory response in the CNS: friend or foe? Mol Neurobiol. 2017;54: 8071-8089.
6. Aliev G, Priyadarshini M, Reddy VP, et al. Oxidative stress mediated mitochondrial and vascular lesions as markers in the pathogenesis of Alzheimer disease. Curr Med Chem. 2014;21:2208-2217.
7. Bu XL, Yao XQ, Jiao SS, et al. A study on the association between infectious burden and Alzheimer disease. Eur J Neurol. 2015;22:1519-1525.
8. Doulberis M, Kotronis G, Thomann R, et al. Review: impact of helicobacter pylori on Alzheimer disease: what do we know so far? Helicobacter. 2018;23 [Epub].
9. Lövheim H, Gilthorpe J, Adolfsson R, et al. Reactivated herpes simplex infection increases the risk of Alzheimer disease. Alzh Dem. 2015;11:593-599.
10. Centers for Disease Control and Prevention. About Underlying Cause of Death, 1999-2017. http://wonder.cdc.gov/ucd-icd10.html. Accessed October 1, 2018.
11. Alzheimer Association. Medication for Memory. https://www.alz.org/alzheimers-dementia/treatments/medications-for-memory. Accessed October 1, 2019.
12. Fülöp T, Itzhaki RF, Balin BJ, et al. Role of Microbes in the Development of Alzheimer Disease: State of the Art. Presented at the 2017 IAGG Congress. San Francisco, CA: July 23-27, 2017.
13. U.S. National Library of Medicine. ClinicalTrials.gov. Antiviral Therapy in Alzheimer Disease. https://clinicaltrials.gov/ct2/show/NCT03282916. Accessed October 1, 2019.
14. Wozniak MA, Itzhaki RF. Antiviral agents in Alzheimer disease: hope for the future? Ther Adv Neurol Dis. 2010;3:141-152.
15. Dinan TG, Cryan JF. Gut instincts: microbiota as a key regulator of brain development, ageing, and neurodegeneration. J Physiol. 2017;595:489-503.
16. Dodiya HB, Kuntz T, Shaik SM, et al. Sex-specific effects of microbiome perturbations on cerebral Aβ amyloidosis and microglia phenotypes. J Exp Med. 2019;216:1542-1560.
17. Szekely CA, Zandi PP. Non-steroidal anti-inflammatory drugs and Alzheimer’s disease: the epidemiological evidence. CNS Neurol Disord Drug Targets. 2010;9:132-139.
18. Yip AG, Green RC, Huyck M, et al for the MIRAGE Study Group. Nonsteroidal anti-inflammatory drug use and Alzheimer disease risk: the MIRAGE study. BMC Geriatr. 2005;5:2.
19. Martyn C. Anti-inflammatory drugs and Alzheimer disease. BMJ. 2003; 327:353-354.
20. Abraham J, Johnson RW. Consuming a diet supplemented with resveratrol reduced infection-related neuroinflammation and deficits in working memory in aged mice. Rejuv Res. 2009;12:445-453.
21. Allen HB. Alzheimer disease: assessing the role of spirochetes, biofilms, the immune system, and amyloid- with regard to potential treatment and prevention. J Alzh Dis. 2016;53:1271-1276.❒