Longitudinal Cerebrospinal Fluid Biomarker Changes Predict Dementia

Changes in key biomarkers of Alzheimer's disease (AD) during midlife as seen in brain scans and cerebrospinal fluid (CSF) of healthy adults may help identify those who will develop dementia years later.

The three CSF biomarker analytes that reflect and demonstrate excellent diagnostic and prognostic utility of the core neuropathologies in AD, are β-amyloid 42 (Aβ42), the primary constituent of amyloid plaques, total tau ,a marker of neuronal injury and/or death, and hyperphosphorylated tau (P-tau) which forms intraneuronal neurofibrillary tangles. Other recently identified biomarkers, include visinin-like protein 1 (VILIP-1) and chitinase-3-like protein 1 (YKL-40).


Scientists at Washington University School of Medicine (St. Louis, MO, USA) and their colleagues enrolled over a ten year period 169 cognitively normal participants ages 45 to 75 when they entered the study. DNA was extracted from peripheral blood samples and genotyping of Apolipoprotein E (APOE) was performed. A sample of CSF (20–30 mL) was collected by routine lumbar puncture at 8 AM after overnight fasting. Samples were processed into 500 μL aliquots and immediately frozen at -80 °C.

The CSF samples were analyzed for Aβ and tau proteins using single-analyte enzyme-linked immunosorbent assays (ELISAs). Samples were analyzed for Aβ1-40 (Aβ40), Aβ1-42 (Aβ42), total tau, and tau phosphorylated at threonine 181 (P-tau181) using the Improved INNOTEST ELISA (Fujirebio Europe; Gent, Belgium). In parallel, Aβ40, Aβ42, and total tau were measured at the same time from the same sample aliquot using a set of second-generation precision-based and accuracy-based EUROIMMUN ELISAs (EUROIMMUN; Luebeck, Germany).

The scientists found that drops in amyloid beta 42 levels in the cerebrospinal fluid among cognitively normal participants ages 45 to 54 are linked to the appearance of plaques in brain scans years later. They also found that tau and other biomarkers of brain-cell injury increase sharply in some individuals as they reach their mid-50s to mid-70s, and YKL-40 rises throughout the age groups focused on in the study. All of these changes were more pronounced in participants who carried a form of a gene that significantly increases the risk of Alzheimer's disease. The gene is known as APOE, and scientists have known that people with two copies of a particular version of this gene have up to 10 times the risk of developing Alzheimer's as those with other versions of the gene.

Anne Fagan, PhD, a professor of neurology and senior author said, “It's too early to use these biomarkers to definitively predict whether individual patients will develop Alzheimer's disease, but we're working toward that goal. One day, we hope to use such measures to identify and treat people years before memory loss and other cognitive problems become apparent. Alzheimer's is a long-term process, and that means we have to observe people for a long time to catch glimpses of it in action.” The study was published on July 6, 2015, in the journal JAMA Neurology.

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