Aβ and NFTs? No, not 'non-fungible tokens' sold on the internet

  Unlike my last blog post, this post will focus on the current methods of intervention as well as the potential methods of intervention aimed at prevention of progression. AD has 5 well known biomarkers and each can help indicate the status of progression. These biomarkers are Beta-amyloid (Aβ) plaque, Tau Neurofibrillary Tangle (NFT), Apolipoprotein-E (Apoe), structural changes, and functional changes related to cognition (Weller & Budson, 2018). Through a complex cascade of events, Aβ aggregates both intracellularly and extracellularly creating plaques. These plaques disrupt neuronal function and can lead to cell death (Tönnies & Trushina, n.d.). Additionally, Aβ is thought to induce NFT translocation further adding to synaptic dysfunction (Tönnies & Trushina, n.d.). This synaptic dysfunction can affect multiple domains of memory including memory, executive function, attention, language, and visuospatial skills (Albert et al., 2011). Currently, there are two classes of pharmacological therapies that can enhance some of these domains of cognition (Weller & Budson, 2018). The first is a class of cholinesterase inhibitors which decrease the breakdown of acetylcholine thereby increasing synaptic physiology. The second type of therapy is a class of drugs that act as an NMDA antagonist as well as a dopamine agonist (Weller & Budson, 2018). During the progression of AD, it is thought that over-activation of these NMDA receptors leads to neurotoxic environments found in AD pathology (Kuns et al., 2022). The NMDA receptor is a ligand gated ionotropic glutamate receptor and can be found abundantly throughout the hippocampus and cerebral cortex (Kuns et al., 2022). While these drugs can mediate symptoms related to AD, they can’t prevent or reverse AD pathology.

Developing treatment at early/preclinical stages is thought to be the most plausible approach at preventing AD (Weller & Budson, 2018). Therapy targeting Aβ involves antibodies that target abnormal Aβ and promote its removal from the brain (Weller & Budson, 2018). Another method targets the amyloid precursor protein (APP) preventing the production of Aβ (Weller & Budson, 2018). Research on NFT pathology is ongoing, but is also a potential method of intervention. The problems with these approaches have to do with preclinical administration for those presenting early signs of these two biomarkers. In theory this seems relatively simple, but the tests used to detect these are not commonly done unless there’s signs/symptoms related to AD or a form of dementia. Furthermore, the progression varies from person-person and can happen early, late, fast, or even slowly. The variability of AD pathology in itself as well as the variability from case to case makes therapeutic research on AD very complex.

References 

Albert, M. S., DeKosky, S. T., Dickson, D., Dubois, B., Feldman, H. H., Fox, N. C., Gamst, A., Holtzman, D. M., Jagust, W. J., Petersen, R. C., Snyder, P. J., Carrillo, M. C., Thies, B., & Phelps, C. H. (2011). The diagnosis of mild cognitive impairment due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s & Dementia : The Journal of the Alzheimer’s Association, 7(3), 270–279. https://doi.org/10.1016/j.jalz.2011.03.008

Kuns, B., Rosani, A., & Varghese, D. (2022). Memantine. In StatPearls. StatPearls Publishing. http://www.ncbi.nlm.nih.gov/books/NBK500025/

Tönnies, E., & Trushina, E. (n.d.). Oxidative Stress, Synaptic Dysfunction, and Alzheimer’s Disease. Journal of Alzheimer’s Disease, 57(4), 1105–1121. https://doi.org/10.3233/JAD-161088

Weller, J., & Budson, A. (2018). Current understanding of Alzheimer’s disease diagnosis and treatment. F1000Research, 7, F1000 Faculty Rev-1161. https://doi.org/10.12688/f1000research.14506.1