Blood-Based Kinase Assessments in Alzheimer's Disease

Alzheimer's disease (AD) is marked by memory disturbances followed by aphasia, apraxia and agnosia. Brain lesions include the accumulation of the amyloid peptide in extracellular plaques, neurofibrillary tangles with abnormally phosphorylated tau protein and synaptic and neuronal loss. New findings have suggested that brain lesions could occur one or two decades before the first clinical signs. This asymptomatic preclinical phase could be an opportunity to put in place a secondary prevention but the detection of these brain lesions can only be achieved so far by cerebrospinal fluid (CSF) evaluation or molecular amyloid and tau PET imaging. There is an urgent need to find out simple and easily accessible new biomarkers to set up an efficient screening in adult and aging population. Neuropathological and biochemical studies have revealed that abnormal accumulations of potentially toxic kinases are present in the brains of AD patients. Kinase activation leads to abnormal tau phosphorylation, amyloid production, apoptosis and neuroinflammation. Increased levels of these kinases are present in the CSF of mild cognitive impairment (MCI) and AD patients. Over the last years the search for abnormal kinase levels was performed in the blood of patients. Glycogen synthase kinase 3 (GSK 3), protein kinase R (PKR), mamalian target of rapamycin (mTOR), dual specificity tyrosine-phosphorylation-regulated kinase 1A (DIRK1A), c-Jun N-terminal kinase (JNK), protein 70 kD ribosomal protein S6 kinase (P70S6K), ERK2 and other kinase concentrations were evaluated and abnormal levels were found in many studies. For example, GSK3 levels are increased in MCI and AD patients. PKR levels are also augmented in peripheral blood mononuclear cells (PBMC) of AD patients. In the future, the assessment of several blood kinase levels in large cohorts of patients will be needed to confirm the usefulness of this test at an early phase of the disease.