Clinical Information

Currently, the diagnosis of probable Alzheimer disease (AD) is made based on clinical symptoms, largely by the exclusion of other causes of dementia, with postmortem evidence of AD pathology required to confirm the diagnosis. Two common neuropathologic features found in the brain of patients with AD dementia are the presence of plaques composed of beta-amyloid (Abeta) peptides and intracellular neurofibrillary tangles containing hyperphosphorylated Tau (tubulin-associated unit) proteins. These 2 groups of molecules are the most established biomarkers of the disease used in clinical and research practice. Positron emission tomography (PET) imaging using US Food and Drug Administration approved amyloid radiotracer to visualize the presence of amyloid lesions in the cerebral cortex is available in some specialized centers. Measuring Abeta peptides and Tau proteins in cerebrospinal fluid (CSF) is being proposed as an alternative/adjunct to imaging studies to assess AD pathology. Recently the use of these biomarkers has been included in the new consensus research diagnostic criteria for AD, mild cognitive impairment (MCI), and preclinical AD, proposed by the National Institute on Aging and Alzheimer's Association Research Framework.

The CSF assays included in this evaluation are beta-amyloid (1-42; Abeta42), total-Tau (t-Tau), and phosphorylated-Tau (p-Tau181).

Abeta42 is approximately 4-kDa protein of 42 amino acids that is formed following proteolytic cleavage of a transmembrane protein known as amyloid precursor protein. Due to its hydrophobic nature, Abeta42 has the propensity to form aggregates and oligomers. Oligomers form fibrils that accumulate into amyloid plaques. These pathological changes in Abeta42 are reflected by the decrease in the CSF concentrations of Abeta42 and/or by the increase in the brain uptake of specific tracers during beta-amyloid PET.

Tau is present as six isoforms in human brain tissue. These isoforms are generated by alternative splicing of the pre-mRNA. The t-Tau assay measures all these isoforms. The most common post-translational modification of Tau proteins is phosphorylation. During neurodegeneration, abnormal phosphorylation leads to the formation of intracellular neurofibrillary tangles composed of the Tau protein that has undergone hyper-phosphorylation and developed aggregates of hyper-phosphorylated Tau proteins called p-Tau. The p-Tau assay detects phosphorylated Tau at threonine 181 (p-Tau181).

Pathological changes associated with AD are reflected by an increase in the CSF concentrations of t-Tau and p-Tau. Increases in CSF t-Tau reflect the intensity of the neuronal and axonal damage and degeneration and are associated with a faster progression from MCI to AD. Increases in CSF p-Tau concentrations are also associated with a faster progression from MCI to AD with more rapid cognitive decline in AD patients and in mild AD dementia cases.

The Alzheimer's Association has developed appropriate use criteria in order to guide safe and optimal use of CSF testing for AD pathology detection in the diagnostic process. The use of CSF biomarker testing may be indicated for the following patient groups:

1) Patients with subjective cognitive decline who are considered to be at increased risk for AD

2) Patients with MCI that is persistent, progressing, and unexplained

3) Patients with symptoms that suggest possible AD

4) MCI or dementia with an onset at an early age (less than 65)

5) Patients meeting core clinical criteria for probable AD with typical age of onset

6) Patients whose dominant symptom is a change in behavior (eg, Capgras syndrome, paranoid delusions, unexplained delirium, combative symptoms, and depression) and where AD diagnosis is being considered.

Ultimately, the decision to initiate CSF testing for the evaluation of suspected AD is also based on the clinical judgment of expert providers and the patient's individual presentation.