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

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 β-amyloid (Aβ) burden, measured concurrently and longitudinally, was regressed on CSF measures of Aβ, neural injury, and inflammation, as well as ratios with Aβ42 . 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, Aβ42 /Aβ40 and all CSF ratios to Aβ42 were associated with PiB binding in AD-vulnerable regions. Longitudinally, Aβ42 /Aβ40 and ratios of total tau, phosphorylated-tau, neurofilament light protein, and monocyte chemoattractant protein-1 to Aβ42 were associated with increased β-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 Aβ42 in the denominator.

DISCUSSION: These results corroborate previous findings that t-tau/Aβ42 and p-tau/Aβ42 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.