Biomarkers as Predictors for Conversion from Mild Cognitive Impairment to Alzheimer-Type Dementia: Implications for Trial Design

Abstract

Disease modifying drugs for Alzheimer's disease (AD) are likely to be most effective when given in non-demented subjects. In this review we summarized biomarkers in cerebrospinal fluid (CSF) and blood that can predict AD-type dementia in subjects with mild cognitive impairment (MCI). In addition, we investigated whether these markers could reduce sample size and costs if used to select subjects for trials on the prevention of AD in subjects with MCI. A meta-analysis of markers that had been investigated in multiple studies showed that the combination of amyloid-beta (Abeta1-42 and tau in CSF had the best predictive accuracy for AD (odds ratio (OR) 18.1, 95% confidence interval (CI) 9.6-32.4). Abeta1-42, total tau, and phosphorylated tau in CSF also predicted conversion, but with lower accuracy (OR 7.5 to 8.1). Plasma levels of Abeta1-40, Abeta1-42, the ratio Abeta1-42/Abeta1-40 and homocysteine did not predict outcome. In a fictive trial design, the use of the combination of Abeta1-42 and tau in CSF in the selection of subjects could reduce sample size by 67% and trial costs by 60% compared to a trial in which unselected subjects with MCI would be enrolled. In conclusion, the combination of Abeta1-42 and tau in CSF is useful to select subjects for trials that aim to slow down the progression from MCI to AD-type dementia.

Brief review: Anesthetic neurotoxicity in the elderly, cognitive dysfunction and Alzheimer’s disease

“…Biomarkers derived from structural and functional neuroimaging studies and those measured in cerebrospinal fluid, show great promise for identifying preclinical pathology and for monitoring change over time and after anesthetic exposure. 66,67 Since adequately powered clinical trials examining these questions will require many years to conduct and to analyze, there is an immediate need for further animal studies to define the effects of both anesthesia and surgery on the pathogenesis of AD. These studies will complement ongoing clinical trials by establishing mechanistic hypotheses, vulnerable windows, and less provocative anesthetics.…”

Plasma Aβ and PET PiB binding are inversely related in mild cognitive impairment

“…In a metaanalysis of 4 studies that examined plasma A␤ measures but without amyloid imaging, an increase in plasma A␤40 levels, but not A␤42 or the A␤42/ A␤40 ratio, was weakly associated with MCI conversion to AD. 25 In AD, there is decreased clearance of both A␤40 and A␤42 without any difference in production rates.…”

Cognitive function is associated with impaired heart rate variability in ageing adults: the Irish longitudinal study on ageing wave one results

“…The conversion rate from MCI to dementia is 14 % annually [30]. Predictors of conversion from MCI to dementia currently include cerebrospinal fluid biomarkers, neuropsychological tests and structural magnetic resonance imaging (MRI) morphometry [8,11,42].…”