Report CSF Ab42 and tau in relation to amyloid in humans Figure 4. Cortical amyloid as detected by PET PIB and its relationship to CSF tau and ptau181 and the ratios of CSF tau/Ab42 and ptau181/Ab42 in CDR 0 participants (n ¼ 189). A linear relationship is observed between the amount of cortical amyloid and A. the levels of CSF tau B. the levels of CSF ptau181 C. the ratios of CSF tau/Ab42 and D. the ratios of the ptau181/Ab42. The correlations between the CSF tau(s)/Ab42 ratios and MCBP remain significant even when the statistical outlier (high PIB, high ratio) is omitted from the analysis (tau/Ab42, r ¼ 0.74227, p < 0.0001; ptau181/Ab42, r ¼ 0.73510, p < 0.0001). All Pearson correlation coefficients are corrected for age. observed between cortical amyloid and the ratio of Ab38 to Ab42 is likely driven by the drop in Ab42, as suggested by others (Mehta & Pirttila, 2005). We were also now able to measure, with great sensitivity and reliability, a number of Ab species in plasma, including Ab1–40, Abx–40, Ab1–42 and Abx–42. However, the level of these species did not in any way relate to the presence or amount of amyloid in the brain. Previous studies investigating the utility of plasma Ab species have reported mixed results. While plasma Ab42 has been reported to be neither speciﬁc nor sensitive for a clinical diagnosis of mild cognitive impairment (MCI) or AD (Fukumoto et al, 2003), nor in predicting the probability of progression from MCI to AD (Hansson et al, 2008), other studies have reported that the ratio of plasma Ab42/Ab40 may be useful as an antecedent marker for identifying risk for developing cognitive impairment in cognitively normal elders (Graff-Radford et al, 2007). Others have reported alterations in the direction of change in plasma Ab species over the course of the disease (Schupf et al, 2008). Using the same protocol as we used in the present study, a very recent study reported signiﬁcant decreases in the levels of plasma Ab42 and the Ab42/Ab40 ratio in those who were classiﬁed as having AD or MCI that would progress to AD (with subjects preselected based on clinical and CSF biomarker proﬁles) compared to those who did not have the ‘abnormal’ proﬁle (Lewczuk et al, 2009). However, this decrease was not particularly robust, on the order of 10–15%, with great overlap between the groups. Thus, while the mechanism(s) underlying potential changes in Ab metabolism in plasma is still unclear, our cross-sectional data indicate that Ab42 levels in plasma do not reﬂect the amount of amyloid in the brain in cognitively normal individuals (nor are they related to the level of Ab42 in the CSF, data not shown). In this large cohort we now observed a new grouping of participants; those who had low CSF Ab42 levels in the absence of cortical PIB binding. It is unlikely that this is simply an APOE effect (Sunderland et al, 2004) since the frequency of the e4 allele did not differ between the low PIB groups with low versus high CSF Ab42. Instead, these data suggest that CSF Ab42 may drop prior to amyloid becoming detectable by PIB, or this drop may reﬂect the presence of diffuse plaques and/or oligomeric Ab species, consistent with the participant in the lower (low PIB/low CSF Ab42) quadrant who has come to autopsy with abundant diffuse, but few amyloid (neuritic), plaques (Cairns et al, 2009). However, we cannot rule out the possibility that an absence of PIB binding in the face of low CSF Ab42 simply reﬂects amyloid- free individuals who are at the low end of the normal spectrum of CSF Ab42 levels. Longitudinal follow-up (with clinical, PIB and CSF measures) of such subjects will be important for under- standing the biological relevance of this pattern. Finally, we report the novel ﬁnding of a positive linear correlation between CSF tau and ptau181 with the amount of cortical amyloid in cognitively normal individuals. However, neither the amount of amyloid nor the levels of CSF Ab42 or tau/ ptau correlated with psychometric test performance. Although we did observe a signiﬁcant correlation between Trailmaking A and plasma Ab1–40, this ﬁnding awaits replication since it could be due to chance considering the large number of statistical tests conducted overall. Interestingly, those who developed elevated CSF tau, ptau181 or an elevated tau(s)/Ab42 ratio appear to be individuals who have already developed a substantial amyloid load. Together, these human data are consistent with the idea that in the natural progression of AD neuropathology, changes in brain Ab42 metabolism and amyloid formation occur early in disease pathogenesis, and that disruptions in CSF tau 376 2009 EMBO Molecular Medicine EMBO Mol Med 1, 371–380 www.embomolmed.org