Cerebrospinal fluid ratios with Aβ42 predict preclinical brain β-amyloid accumulation

Racine AM, Koscik RL, Nicholas CR, Clark LR, Okonkwo OC, Oh JM, Hillmer AT, Murali D, Barnhart TE, Betthauser TJ, Gallagher CL, Rowley HA, Dowling NM, Asthana S, Bendlin BB, Blennow K, Zetterberg H, Carlsson CM, Christian BT, Johnson SC

Alzheimers Dement (Amst). 2016;2:27-38.


INTRODUCTION: Biomarkers are urgently needed for the critical yet understudied preclinical stage of Alzheimer's disease (AD). METHODS: CSF collection, [C-11]PiB amyloid imaging, and MRI were acquired in n=104 cognitively healthy adults enriched with risk for sporadic AD. Image-derived cerebral B-amyloid (AB) burden, measured concurrently and longitudinally, was regressed on CSF measures of AB, neural injury, and inflammation, as well as ratios with AB42. Linear mixed effects regression was used to model the effect of the CSF measures that predicted longitudinal brain amyloid accumulation on longitudinal cognitive decline, measured by memory test scores. RESULTS: At baseline, AB42/AB40 and all CSF ratios to AB42 were associated with PiB binding in AD-vulnerable regions. Longitudinally, AB42/AB40 and ratios of total tau, phosphorylated-tau, neurofilament light protein, and monocyte chemoattractant protein-1 to AB42 were associated with increased B-amyloid deposition over two years, predominantly in lateral parietal and temporal cortex. However, these CSF ratios were not significantly associated with cognitive decline, and the effect seems to be largely driven by AB42 in the denominator. DISCUSSION: These results corroborate previous findings that t-tau/AB42 and p-tau/AB42 are the strongest candidate biomarkers during the preclinical timeframe. They support a framework in which neural injury and amyloid deposition are likely occurring simultaneously. It may be that neurodegenerative processes influence progressive amyloid accumulation, even in the preclinical time frame. CSF biomarkers for non-specific axonal injury and inflammation may provide more information at more advanced stages of the preclinical time course.


Contributing Lab Members