Decreased cerebrospinal fluid Aβ42 correlates with brain atrophy in cognitively normal elderly

Abstract

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‐β (Aβ)₄₀, Aβ₄₂, tau, and phosphorylated tau₁₈₁ (ptau₁₈₁), and plasma Aβ₄₀ and Aβ₄₂ 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 ptau₁₈₁, but not Aβ₄₂, correlated inversely with whole‐brain volume in very mild and mild dementia of the Alzheimer type, whereas levels of CSF Aβ₄₂, but not tau or ptau₁₈₁, were positively correlated with whole‐brain volume in nondemented control subjects. Interpretation Reduction in CSF Aβ₄₂, likely reflecting Aβ aggregation in the brain, is associated with brain atrophy in the preclinical phase of AD. This suggests that there is toxicity associated with Aβ aggregation before the onset of clinically detectable disease. Increases in CSF tau (and ptau₁₈₁) are later events that correlate with further structural damage and occur with clinical onset and progression. Ann Neurol 2009;65:176–183