Basic biomarker work up

The biomarker classification system for AD provides three main classes of biomarkers: amyloid-β (Aβ; A), tau (T), and neurodegeneration (N), denoted as A/T/(N).⁴ While abnormal Aβ and p-tau are considered to be key features of AD in this framework, neurodegeneration may be a feature of other neurodegenerative diseases, which is why it is written in parentheses.⁵ Biomarkers for Aβ include amyloid PET and cerebrospinal fluid (CSF) concentrations of Aβ.⁶ Tau biomarkers include tau-PET and CSF concentrations of p-tau.⁶ For neurodegeneration, biomarkers include FDG-PET, MRI atrophy, CSF concentrations of total tau and of neurofilament light chain.⁶ The A/T/(N) framework allows identification of biological AD in living individuals and the tracking of AD through preclinical, MCI, and dementia stages.⁶

Detection of increased levels of neuropathologies in specific brain regions before presentation of global abnormalities is a unique feature of PET imaging.⁶ Using PET, amyloid and tau pathology can be identified.⁶ Additionally, FDG-PET can be used as an index of tripartite synaptic activity, which is the coupling between energy usage by neurons and astrocytes.⁶ MRI on the other hand, is used to assess brain structure and can identify atrophy in regions of the brain such as the hippocampus.⁷

More recently, the development of ultrasensitive assays for Aβ and p-tau in plasma provides evidence that AD biomarker assessments using minimally invasive, scalable, and accessible methods, is a possibility.⁶ Similar to CSF samples, single blood samples make it possible to assess several aspects of the AD pathological processes.⁶ If available, plasma assessments may be used for routine pre-screening, while CSF or PET examinations are used to confirm the presence of pathology before the initiation of treatment.⁶

References:
1.Gauthier S, Rosa-Neto P, Morais JA, Webster C. World Alzheimer Report 2021: Journey through the diagnosis of dementia. Available at: https://www.alzint.org/u/World-Alzheimer-Report-2021.pdf. Accessed 15 November 2023.

2.National Institute for Health and Care Excellence. NICE clinical guideline NG97. 20 June 2018. Available at: www.nice.org.uk/guidance/ng97/resources/dementia-assessment-management-and-support-for-people-living-with-dementia-and-their-carers-pdf-1837760199109. Accessed 15 November 2023

3.Chételat G, Arbizu J, Barthel H, et al. Amyloid-PET and 18F-FDG-PET in the diagnostic investigation of Alzheimer’s disease and other dementias. Lancet Neurol 2020; 19 (11): 951–962.

4.Jack CR Jr, Bennett DA, Blennow K, et al. A/T/N: An unbiased descriptive classification scheme for Alzheimer disease biomarkers. Neurology 2016; 87 (5): 539–547.

5.Jack CR Jr, Bennett DA, Blennow K, et al. NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement 2018; 14 (4): 535–562.

6.Therriault J, Zimmer ER, Benedet AL, et al. Staging of Alzheimer’s disease: past, present, and future perspectives. Trends Mol Med 2022; 28 (9): 726–741.

7.Jack CR Jr, Knopman DS, Jagust WJ, et al. Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol 2013; 12 (2): 207–216.