Relations between brain tissue loss, CSF biomarkers, and the ApoE genetic profile: a longitudinal MRI study

Abstract

Previously it was reported that Alzheimer's disease (AD) patients have reduced beta amyloid (Abeta(1-42)) and elevated total tau (t-tau) and phosphorylated tau (p-tau(181p)) in the cerebrospinal fluid (CSF), suggesting that these same measures could be used to detect early AD pathology in healthy elderly individuals and those with mild cognitive impairment (MCI). In this study, we tested the hypothesis that there would be an association among rates of regional brain atrophy, the CSF biomarkers Abeta(1-42), t-tau, and p-tau(181p) and apolipoprotein E (ApoE) epsilon4 status, and that the pattern of this association would be diagnosis-specific. Our findings primarily showed that lower CSF Abeta(1-42) and higher tau concentrations were associated with increased rates of regional brain tissue loss and the patterns varied across the clinical groups. Taken together, these findings demonstrate that CSF biomarker concentrations are associated with the characteristic patterns of structural brain changes in healthy elderly and mild cognitive impairment subjects that resemble to a large extent the pathology seen in AD. Therefore, the finding of faster progression of brain atrophy in the presence of lower Abeta(1-42) levels and higher tau levels supports the hypothesis that CSF Abeta(1-42) and tau are measures of early AD pathology. Moreover, the relationship among CSF biomarkers, ApoE epsilon4 status, and brain atrophy rates are regionally varying, supporting the view that the genetic predisposition of the brain to beta amyloid and tau mediated pathology is regional and disease stage specific.

Figure 1

Association between baseline CSF Aβ_1-42 concentrations and absolute cortical thickness in CN group. [top row: cortical maps of regression coefficients β_Aβ1-42 from GLME models. bottom row: resulting FDR corrected p-value map from pair-wise ML F-tests.]

Figure 2

Top row: Distribution of effects of lower baseline CSF Aβ_1-42 concentrations on higher rate of cortical thinning in MCI group, expressed in terms of a regression coefficient beta (in mm³/(year*pg/ul)). Bottom row: Also displayed are the corresponding significance maps (p-values, FDR corrected) derived from pair-wise maximum likelihood F-tests between GLME models with and without an interaction between biomarker concentration and atrophy rate.

Figure 3

Effects of baseline CSF p-tau_181p concentrations on the rates of cortical atrophy in MCI group. [top row: cortical maps of regression coefficients β_{Years:p-tau181p} from GLME models. bottom row: resulting FDR corrected p-value map from pair-wise ML F-tests.]

Figure 4

Effects of baseline CSF t-tau concentrations on rate of cortical atrophy in MCI group. [top row: cortical maps of regression coefficients β_{Years: t-tau} from GLME models. bottom row: resulting FDR corrected p-value map from pair-wise ML F-tests.]