A variety of biochemical changes have been associated with Alzheimer’s disease pathology and are being evaluated to aid in the diagnosis of Alzheimer’s disease (AD). Some of the most commonly studied biomarkers are amyloid beta peptide 1-42 (AB-42), and total or phosphorylated tau protein (T-tau or P-tau) in cerebrospinal fluid (CSF).
The diagnosis of AD is divided into 3 categories: possible, probable, and definite AD. (1) A diagnosis of definite AD requires post-mortem confirmation of AD pathology, including the presence of extracellular beta amyloid plaques and intraneuronal neurofibrillary tangles in the cerebral cortex. (2) Probable AD dementia is diagnosed clinically when the patient meets core clinical criteria for dementia and has a typical clinical course for AD. A typical clinical course is defined as an insidious onset, with the initial and most prominent cognitive deficits being either amnestic or non-amnestic, e.g., language, visuospatial, or executive function deficits, and a history of progressively worsening cognition over time. A diagnosis of possible AD dementia is made when the patient meets the core clinical criteria for AD dementia but has an atypical course or an etiologically mixed presentation.
Mild cognitive impairment (MCI) may be diagnosed when there is a change in cognition, but not sufficient impairment for the diagnosis of dementia. (3) Features of MCI are evidence of impairment in one or more cognitive domains and preservation of independence in functional abilities. In some patients, MCI may be a predementia phase of AD. Patients with MCI or suspected AD may undergo ancillary testing (e.g., neuroimaging, laboratory studies, and neuropsychological assessment) to rule out vascular, traumatic, and medical causes of cognitive decline and to evaluate genetic factors. Because clinical diagnosis can be difficult, particularly early in the course of disease, there has been considerable interest in developing an accurate laboratory test for AD. There are several potential biomarkers of AD that are associated with Alzheimer’s disease pathology (i.e., beta amyloid plaques and neurofibrillary tangles).
Elevated cerebrospinal fluid (CSF) levels of P-tau or T-tau or an amyloid beta peptide such as AB-42 have been found in patients with AD. Other potential CSF peptide markers have also been explored. (4, 5) The tau protein is a microtubule-associated molecule that is found in the neurofibrillary tangles that are typical of AD. This protein is thought to be related to degenerating and dying neurons, and high levels of tau proteins in the CSF have been associated with AD. AB-42 is a subtype of amyloid beta peptide that is produced following the metabolism of amyloid precursor protein. AB-42 is the key peptide deposited in the amyloid plaques characteristic of AD. Low levels of AB-42 in the CSF have been associated with AD, perhaps because AB-42 is deposited in amyloid plaques instead of remaining in solution. Finally, investigators have suggested a Tau/AB-42 ratio, a potentially more accurate diagnostic marker than either alone. (6) A variety of kits are commercially available to measure AB-42 and tau proteins, and there is large between-laboratory variability in cerebrospinal fluid (CSF) biomarker measurement. (7)
Neural thread protein is associated with the neurofibrillary tangles of AD. Both CSF and urine levels of this protein have been investigated as a potential marker of AD. Urine and CSF tests for neural thread protein may be referred to as the AD7C™ test, as developed by Nymox Pharmaceutical Corporation.
Abnormal levels of the tau protein have been discovered in nasal mucosa tissue of patients with AD. These changes were detected in autopsy derived material of confirmed AD cases as well as clinically definite AD patients.
Heavy metal mercury blood levels are under investigation as a marker of AD. In clinical studies, blood mercury levels were more than two-fold higher in patients with AD as compared to the control groups. Mercury exposure may be from an environmental factor that influences the risk of acquiring AD or it may be released from brain tissue with the advancement of neuronal death that occurs as the AD progresses.