Decreased Cerebrospinal Fluid Aβ42 Correlates with Brain Atrophy in Cognitively Normal Elderly

Objective: For therapies for Alzheimer's disease (AD) to have the greatest impact, it will likely be necessary to treat individuals in the "preclinical" (presymptomatic) stage. Fluid and neuroimaging measures are being explored as possible biomarkers of AD pathology that could aid in identifying individuals in this stage to target them for clinical trials and to direct and monitor therapy. The objective of this study was to determine whether cerebrospinal fluid (CSF) biomarkers for AD suggest the presence of brain damage in the preclinical stage of AD. Methods: We investigated the relation between structural neuroimaging measures (whole-brain volume) and levels of CSF amyloid-beta (A beta)(40) A beta(42), tau, and phosphorylated tau(181) (ptau(181)), and plasma A beta(40) and A beta(42) in well-characterized research subjects with very mild and mild dementia of the Alzheimer type (n = 29) and age-matched, cognitively normal control subjects (n = 69). Results: Levels of CSF tau and ptau(181), but not A beta(42), correlated inversely with whole-brain volume in very mild and mild dementia of the Alzheimer type, whereas levels of CSF A beta(42), but not tau or ptau(181) were positively correlated with whole-brain volume in nondemented control subjects. Interpretation: Reduction in CSF A beta(42), likely reflecting A beta aggregation in the brain, is associated with brain atrophy in the preclinical phase of AD. This suggests that there is toxicity associated with A beta aggregation before the onset of clinically detectable disease. Increases in CSF tau (and ptau(181)) are later events that correlate with further structural damage and occur with clinical onset and progression.