The gold-standard method for diagnosis of Alzheimer’s disease is post-mortem examination of the brain for amyloid plaques.12,15 The most well-established methods for diagnosis of Alzheimer’s disease in living persons are positron emission tomography (PET) of the brain and examination of CSF for Aβ (Aβ40, Aβ42) and tau (phosphorylated tau and total tau protein concentration) biomarkers.12,13,15
CSF levels of Aβ42/40 and tau are widely accepted markers of Alzheimer’s disease. A lower level Aβ42 in CSF generally correlates with a higher presence of Aβ plaques in the brain,16 and a lower Aβ42/40 CSF ratio is suggestive of an increased risk of Alzheimer’s disease.12,13,15 On the other hand, increased CSF phosphorylated tau (p-tau181) is associated with an increased risk of Alzheimer’s disease.12,13,15,16 However, levels of these markers may not always be directly correlated with symptoms or the presence of amyloid plaques.12,13,15
Similarly, imaging studies (PET, MRI) are useful for identifying neurodegenerative changes and amyloid plaques/neurofibrillary tangles, but findings do not necessarily correlate with clinical symptoms.12,13,15,16
The degree of correlation between both CSF biomarkers and imaging with symptoms depends on the place of an individual in the Alzheimer’s disease spectrum during the long period of disease progression.12,17 Several reported models take into account biomarker, imaging, and clinical data to predict the likelihood of Alzheimer’s disease.12,17
The National Institute of Aging (NIA)18,19 and the International Working Group (IWG-2)20 combine CSF biomarker (Aβ42/40, p-tau181) and imaging data with the presence and degree of cognitive impairment in the Alzheimer’s disease spectrum in their diagnostic criteria.12,16 According to the NIA and IWG-2, cognitive testing should include administration of at least 1 standardized and validated instrument for detection of cognitive impairment or dementia (eg, Montreal cognitive assessment test).18
The amyloid/tau/neurodegeneration (ATN) framework has also been proposed as a method to define the biological state of Alzheimer’s disease and identify individuals more likely to develop Alzheimer’s disease and who may be candidates for early intervention.20
Currently, CSF biomarkers are used in the diagnosis of Alzheimer’s disease in living individuals, but a sensitive and specific blood-based biomarker approach would represent a more accessible, affordable, and less invasive option. The development of blood-based markers is an area of active research—a plasma assay that uses an Aβ42/Aβ40 ratio that correlates with Aβ-PET status was recently approved in the United States and the European Union.12 In addition, Quest Diagnostics offers a clinically validated blood-based biomarker test that employs the Aβ42/Aβ40 ratio (see Sidebar, How the laboratory can help).