What Are the AT(N) Biomarkers for Alzheimer’s Disease?

Researchers have long been attempting to identify and validate specific biomarkers for Alzheimer’s disease (AD). AD is a neurodegenerative disorder that is characterized by brain atrophy resulting from neuronal loss. It is typically diagnosed following a series of clinical assessments that include neurological and mental examinations and brain imaging. However, since many other disorders also display AD-like symptoms, the only way to definitively diagnosis AD is by tying clinical assessment of the disease to the postmortem identification of its pathological hallmarks (i.e. senile plaques and neurofibrillary tangles). In 2018, a taskforce organized by the National Institutes of Aging and the Alzheimer’s Association (NIA-AA) proposed that the classification system for the AD continuum be based upon the presence or absence of accepted biomarkers instead of clinical symptoms. This biomarker system, termed AT(N), utilizes markers that reflect the main pathological hallmarks of AD: deposition of Amyloid beta (A-beta), pathological Tau, and neurodegeneration. The goal of this classification scheme is to provide basic and clinical researchers a standardization for defining AD and differentiating true AD from neurocognitive disorders that don’t display AD pathology. So, what are the AT(N) biomarkers?

A Biomarkers

Biomarkers in the A group reflect aggregated A-beta. A-beta peptides are generated following cleavage of Amyloid Precursor Protein by beta- and gamma-secretases. Though there are multiple isoforms of A-beta, approximately 90% of the A-beta peptides found in the brain are either A-beta (aa1-40) and A-beta (aa1-42). A-beta (aa1-42) is the major component of senile plaques. Elevated numbers of senile plaques are necessary for a neuropathologic diagnosis of AD. Senile plaques can be visualized using cortical amyloid positron emission tomography (PET) ligand binding; however, cerebral A-beta aggregation can also be identified by measuring A-beta (aa1-42) and (aa1-40) levels in cerebrospinal fluid (CSF) using non-radioactive, antibody-based techniques, such as ELISA. A characteristic feature of early AD is a reduction of CSF A-beta (aa1-42) levels, presumably due to the peptide aggregating in senile plaques. Some research, though, has suggested that the CSF A-beta (aa1-42)/(aa-140) ratio may be a better indicator of A-beta production and aggregation compared to A-beta (aa1-42) levels alone.

T Biomarkers

Biomarkers in the T group reflect aggregated Tau. Tau proteins are highly soluble microtubule-associated proteins (MAPs) that stabilize axonal microtubules. In AD, Tau is hyperphosphorylated, causing it to dissociate from microtubules. Unbound, hyperphosphorylated Tau is vulnerable to proteolytic cleavage, as well as self-aggregation into toxic oligomers and subsequently paired helical filaments (PHFs) and neurofibrillary tangles (NFTs). Aggregated Tau, specifically PHFs, can be detected with cortical Tau PET ligand binding. However, levels of phosphorylated Tau in CSF have been shown to also reflect Tau pathology. Neurons containing NFTs release phosphorylated Tau, which can be measured in the CSF using antibody-based immunoassays. Over 40 sites on Tau have been shown to be phosphorylated in AD; however, Tau phosphorylated at threonine 181 (pTau181) is one of the most thoroughly examined phosphorylated Tau biomarkers. Research has shown that CSF pTau181 is elevated in individuals with AD and highly correlates with the severity of Tau pathology postmortem. Additionally, this biomarker has been shown to be highly specific for AD as increased CSF pTau181 levels are not seen in other tauopathies. Tau phosphorylated at serine 199 (pTau199) and threonine 231 (pTau231) are also being investigated as potential biomarkers as pTau199 and pTau231 levels in the CSF tightly correlate with pTau181 CSF levels and show similar diagnostic accuracy.

(N) Biomarkers

Biomarkers in the (N) group reflect neurodegeneration. Axonal degeneration is a key feature of AD and is more closely linked to the onset of cognitive decline than other pathological features. Neurodegeneration in brains inflicted with AD can be detected with FDG PET hypometabolism and MRI. However, research has also shown that individuals with AD have increased concentrations of total Tau (t-Tau) in the CSF, and that CSF t-Tau levels highly correlate with the degree of neurodegeneration. Neurodegeneration, though, is not specific to AD and occurs in several nervous system disorders. However, when used in combination with other biomarkers, t-Tau can provide important information about the individual’s position on the AD continuum and the severity of their cognitive impairment. Additionally, other proteins are being investigated as potential CSF neurodegeneration biomarkers, such as Neurofilament Protein, Light Chain (NF-L), Visinin-like Protein-1 (VSNL1), Enolase 2/Neuron-Specific Enolase (NSE), and FABP3/H-FABP.

Other Biomarkers?

This new framework for defining AD based upon its biomarkers instead of clinical symptoms represents the latest belief that the pathological processes underlying AD begins years before the manifestation of symptoms. By using the cited imaging and CSF biomarkers, which reflect the presence of the pathological hallmarks of AD, individuals can be placed more precisely along the continuum of the pathologic progression of AD. This new framework is also highly flexible and allows of the addition of newly confirmed biomarkers into the existing AT(N) groups. Additionally, as biomarkers for other pathological processes are validated, such as TREM-2 and Chitinase 3-like 1 (also called YKL-40) for neuroinflammation, Neurogranin for synaptic dysfunction, or E-Selectin/CD62E and VCAM-1/CD106 for cerebrovascular disease, new groups can also be added to the AT(N) classification scheme.

References

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3. Jack, C.R. Jr. et al. (2018) Alzheimers Dement. 14:535.
4. Knopman, D.S. et al>. (2018) Alzheimers Dement. 14:563.
5. Lashley, T. et al. (2018) Dis. Model. Mech. 11: pii:dmm032781.
6. Silverberg, N. et al. (2018) Alzheimers Dement. 14:576.

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