Report Anne M. Fagan et al. Figure 3. Cortical amyloid as detected by PET PIB and its relationship to plasma Ab42 and Ab40 species in CDR 0 participants (n ¼ 189). No relationship was observed between mean cortical PIB binding and plasma A. Ab1–40 (r ¼ 0.0724, p ¼ 0.3234), B. Abx–40 (r ¼ 0.04583, p ¼ 0.5323), C. Ab1–42 (r ¼ 0.1015, p ¼ 0.1658) or D. Abx–42 (r ¼ 0.03869, p ¼ 0.5981). Five participants had levels of plasma Abx–42 below the level of detection so they are represented as having 0 pg/ml. All Pearson correlation coefficients are corrected for age. n.s., not significant. load and plasma levels of Ab42, Abx–42, Ab40 or Abx–40 (Fig. 3). Our previous study reported the same results in a much smaller, clinically mixed cohort. Furthermore, for the present study we used the xMAP plasma kit (Inno-Bia Plasma Ab Forms Multiplex Assay) which generates reliable values in the lower pg/ml range required for plasma measures (Blennow et al, 2009; Lachno et al, 2009). We obtained reliable values (with low coefﬁcients of variability) for all but ﬁve samples; these ﬁve had very low levels of Abx–42 that were below the level of detection so they were assigned a value of 0 pg/ml. Importantly, analysis of this CDR 0 cohort revealed a novel pattern of increases in CSF tau (and ptau181) with increasing cortical amyloid deposition (Fig 4A,B). Elevations in CSF tau in general did not appear to occur substantially in participants with an MCBP less than 0.5 but did increase in many, but not all, participants with binding potentials 0.5 and greater. Regression analyses correcting for age revealed a linear relationship between CSF tau (and ptau181) and PIB binding (Fig 4A,B). In addition, the ratios of CSF tau/Ab42 and ptau181/Ab42 also increased linearly with amyloid deposition and the correlations were particularly robust (Fig 4C,D). Similar to what we observed for CSF tau and ptau181, the ratios of tau and ptau181 to CSF Ab42 were generally not elevated until substantial PIB binding values were reached. All participants in this cognitively normal cohort were administered a common battery of psychometric tests, including Selective Reminding (a measure of episodic memory) (Grober et al, 1988), Animal Naming (assesses semantic memory) (Goodglass & Kaplan, 1983) and a speeded visuospatial test with two parts: Trailmakings A and B (Armitage, 1946). None of the biomarker measures showed signiﬁcant associations with performance on any of the psychometric tests, with the exception of negative correlations between Trailmaking A and CSF Ab38 (r ¼ 0.14621, p ¼ 0.0464) and plasma Ab1–40 (r ¼ 0.24069, p ¼ 0.0009). Due to the number of statistical tests conducted overall, however, some statistically signiﬁcant differences could be due to chance. DISCUSSION The data presented here are part of an ongoing longitudinal study investigating ﬂuid and imaging measures as possible antecedent (preclinical) biomarkers of AD. Importantly, they shed light on what may be the pathophysiology of the earliest events in the disease process and their relationship with CSF biomarkers. Consistent with our previous, smaller studies which included both non-demented and demented individuals (Fagan et al, 2006, 2007), we observed a robust relationship between cortical PIB binding and levels of CSF Ab42 but not CSF Ab40 (or Ab38) in this large cohort of cognitively normal participants. While this relationship is linear, visual inspection of the graphs gives the impression of CSF Ab42 levels dropping early in the disease process and staying low as the amount of cortical amyloid increases. The lack of correlation we observed between CSF Ab38 and the amount of cortical amyloid is consistent with other studies suggesting this Ab species does not change with dementia status (Mehta & Pirttila, 2005; Welge et al, 2009). However, these studies suggested that the ratio of Ab38 to Ab42, as opposed to Ab38 alone, may have better speciﬁcity for distinguishing AD from controls or other non-AD dementias, although not all studies have reported this (Schoonenboom et al, 2005). The positive correlation we www.embomolmed.org EMBO Mol Med 1, 371–380 2009 EMBO Molecular Medicine 375