Decreased cerebrospinal fluid Abeta(42) 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-beta (Abeta)(40), Abeta(42), tau, and phosphorylated tau(181) (ptau(181)), and plasma Abeta(40) and Abeta(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 Abeta(42), correlated inversely with whole-brain volume in very mild and mild dementia of the Alzheimer type, whereas levels of CSF Abeta(42), but not tau or ptau(181), were positively correlated with whole-brain volume in nondemented control subjects.

Interpretation: Reduction in CSF Abeta(42), likely reflecting Abeta aggregation in the brain, is associated with brain atrophy in the preclinical phase of AD. This suggests that there is toxicity associated with Abeta 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.

Figure 1

Scatterplots showing the relationship between the various fluid and imaging measures in non-demented (CDR 0) subjects (n=69). Normalized whole brain volume (nWBV) in non-demented subjects is not correlated with levels of (A) CSF Aβ40, (C) CSF tau (even when the outlier is omitted, r=−0.0280, p=0.8210), or (D) plasma Aβ42 (even when the two outliers are omitted, r=0.0150, p=0.9170), but is positively correlated with (B) CSF Aβ42. E) In the subset (n=37) of subjects in this study who underwent in vivo amyloid imaging with Pittsburgh Compound B (PIB), all subjects with cortical amyloid (PIB-positive, mean cortical PIB binding potential ≥0.16) had low levels of CSF Aβ42 (<500 pg/mL) whereas the majority (83%) of PIB-negative subjects (mean cortical PIB binding potential <0.16) had high CSF Aβ42 (>500 pg/mL). F) As a group, non-demented subjects with CSF Aβ42 <500 pg/mL had significantly smaller brain volumes than subjects with CSF Aβ42 ≥500 pg/mL. CSF tau and plasma Aβ42 values surrounded by the open squares in panels C and D, respectively, indicate statistical outliers as defined by the Mahalanobis Distance and Cook's Distance methods.

Figure 2

Scatterplots showing the relationship between the various fluid and imaging measures in subjects with very mild/mild dementia of the Alzheimer type (DAT; CDR >0) (n=29). Normalized whole brain volume (nWBV) in subjects with early stage DAT is not correlated with levels of Aβ42 in (A) CSF (even when the two outliers are omitted, r=0.1920, p=0.3510) or (B) plasma, but is inversely correlated with (C) CSF tau and (D) CSF ptau181 (approaching significance even when the outlier is omitted, r=−0.3780, p=0.0520). CSF Aβ42 and ptau181 values surrounded by the open squares in panels A and D, respectively, indicate statistical outliers as defined by the Mahalanobis Distance and Cook's Distance methods.