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Predicting Reduction of Cerebrospinal Fluid β-Amyloid 42 in Cognitively Healthy Controls

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Alzheimer disease has a long preclinical stage characterized by β-amyloid (Aβ) accumulation without symptoms. Several trials focus on this stage and use biomarkers to include Aβ-positive participants, but an even earlier prevention of Aβ accumulation may be an effective treatment strategy.


To determine whether people who appear to be Aβ negative but are at high risk for Aβ positivity within the near future can be identified.

Design, setting, and participants

Longitudinal biomarker cohort study involving 35 cognitively healthy individuals who underwent cerebrospinal fluid (CSF) sampling for up to 3 years during the study (October 24, 2005, to September 1, 2014). All participants had normal CSF Aβ42 levels at baseline.

Main outcomes and measures

Predictors of future Aβ positivity (levels of CSF Aβ42 declining below a previously validated cutoff level of 192 ng/L) tested by random forest models. Tested predictors included levels of protein in the CSF, hippocampal volume, genetics, demographics, and cognitive scores.


The CSF Aβ42 levels declined in 11 participants, and the CSF became Aβ positive. The baseline CSF Aβ42 level was a strong predictor of future positivity (accuracy, 79% [95% CI, 70%-87%]). Ten of 11 decliners had baseline CSF Aβ42 levels in the lower tertile of the reference range (<225 ng/L), and 22 of 24 nondecliners had baseline CSF Aβ42 levels in the upper 2 tertiles (≥225 ng/L). A high CSF P-tau level was associated with decline (accuracy, 68%; 95% CI, 55%-81%).

Conclusions and relevance

Baseline CSF Aβ42 levels in the lower part of the reference range are strongly associated with future Aβ positivity. This finding can be used in trials on very early prevention of Alzheimer disease to identify people at high risk for Aβ accumulation as defined by low CSF Aβ42 levels.

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