Sadmaan Sarker

Introduction: Alzheimer Disease is a neurodegenerative disease of the cerebral cortex that is characterized by slow-onset memory-loss ad degeneration of cognitive functions such as emotions, speech, judgement, etc.¹  It is the most common form of neurodegenerative disease and the largest cause of dementia worldwide, with a prevalence of 50 million.¹ The current understanding of Alzheimer Disease pathogenesis revolves around the accumulation of amyloid β, with the accumulation of tau fibers and neurodegeneration occurring downstream.¹ Current biomarkers of Alzheimer Disease are focused on CSF markers, with amyloid β and tau proteins being the core biomarkers.^2,3 In terms of diagnoses, PET scans that isolate tau and amyloid beta are the current major diagnostic tool.^2,3  Methods: The analyzed papers investigated potential biomarkers using various methodologies. Plasma p-tau181 was investigated using an in-house assay that use a combination of two different monoclonal antibodies to measure forms of p-tau181.⁵ Secondary amyloid β structure changes were discovered using PET scans and an immuno-infrared-sensor that extracted all soluble amyloid β from blood plasma. This amyloid β secondary structure shift was then compared to CSF amyloid changes.⁴ Gut biomarkers such as LPS, SCFA, and cytokines were measured by ELISA, mass spectrometry, and PCR of older patients with varying cognitive performances.⁶  Results: Plasma p-tau181 was found to elevate just as early as CSF p-tau181 over the course of the disease. Plasma+/CSF- groups and plasma-/CSF+ groups occurred in almost identical proportions and had comparable cognitive performance.⁵ For amyloid structural change, those with Alzheimer Disease showed to have a shift in their amyloid-B peptides towards a β-sheet-enriched secondary structure.⁴ In vitro, LPS was also shown to potentiate amyloid β fibril formation and reproduced many pathological features of Alzheimer Disease in rats. Butyrate, an SCFA, showed inhibitory characteristics to the aggregation of neurotoxic amyloid β in vitro by interfering with early protein-protein interactions.⁶ Discussion: The exact pathophysiology and biomarkers of Alzheimer Disease are topics that are still not very well understood and require further research to develop better monitoring and treatment plans. The identification of peripheral markers for Alzheimer Disease can not only provide additional insight into the pathology of Alzheimer Disease, but also drastically improve the monitoring of Alzheimer progression in order to treat the disease at an earlier stage before symptoms show. Blood biomarkers in particular can be a powerful screening tool for first in-line clinical evaluation.^3,4

1. Knopman, D. S., Amieva, H., Petersen, R. C., Chételat, G., Holtzman, D. M., Hyman, B. T., Nixon, R. A., & Jones, D. T. (2021). Alzheimer disease. Nature reviews. Disease primers, 7(1), 33. https://doi.org/10.1038/s41572-021-00269-y
2. Sun M, Wang Y, Sundquist J, Sundquist K, Ji J. The Association Between Cancer and Dementia: A National Cohort Study in Sweden. Front Oncol. 2020;10:73. Published 2020 Feb 4. doi:10.3389/fonc.2020.00073
3. Blennow K, Zetterberg H. Biomarkers for Alzheimer’s disease: current status and prospects for the future. J Intern Med. 2018;284(6):643-663. doi:10.1111/joim.12816
4. Nabers A, Perna L, Lange J, et al. Amyloid blood biomarker detects Alzheimer’s disease. EMBO Mol Med. 2018;10(5):e8763. doi:10.15252/emmm.201708763
5. Guo Y, Huang YY, Shen XN, et al. Characterization of Alzheimer’s tau biomarker discordance using plasma, CSF, and PET. Alzheimers Res Ther. 2021;13(1):93. Published 2021 May 4. doi:10.1186/s13195-021-00834-3
6. Marizzoni M, Cattaneo A, Mirabelli P, et al. Short-Chain Fatty Acids and Lipopolysaccharide as Mediators Between Gut Dysbiosis and Amyloid Pathology in Alzheimer’s Disease. J Alzheimers Dis. 2020;78(2):683-697. doi:10.3233/JAD-200306