Report CSF Ab42 and tau in relation to amyloid in humans quadrant’) group did, however, differ signiﬁcantly from that of the low PIB/high CSF Ab42 (‘upper quadrant’) group ( p ¼ 0.0003). We did not observe any signiﬁcant associations between quadrant membership and performance on any of the psychometric tests when adjusted for age (Selective Reminding, p ¼ 0.2486; Animal Naming, p ¼ 0.1209; Trailmaking A, p ¼ 0.8561; Trailmaking B, p ¼ 0.2817). The groups also did not differ in the percentage of self-reported presence or absence of heart disease, diabetes, history of stroke and/or TIAs, prior head trauma (with loss of consciousness) or NSAID use (all p > 0.05, Fisher’s exact test). However, the low PIB/low CSF Ab42 group (‘lower quadrant’) had a greater frequency of reported hypertension than the low PIB/high CSF Ab42 group (‘upper quadrant’) (50% vs. 29.6%, respectively, p ¼ 0.0469) and a greater frequency of arthritis than the low PIB/high CSF Ab42 group (14.3% vs. 3.03%, respectively, p ¼ 0.0323). The biological signiﬁcance of these ﬁndings, if any, remains unclear but warrants further investigation. Overall, longitudinal PIB follow-up of the participants in this lower quadrant will be Figure 2. Cortical amyloid as detected by PET PIB and its relationship to CSF Ab in CDR 0 participants (n ¼ 189). A. A high percentage (84%) of participants with low PIB values (MCBP < 0.18) had high CSF Ab42 levels (mean (SD) ¼ 705 pg/ml (211)) whereas the vast majority of participants (86%) in the cohort who had high PIB binding (MCBP 0.18) had low CSF Ab42 (mean (SD) ¼ 362 pg/ml (115)). Horizontal lines represent the group means, and these means are statistically different from each other (asterisk, p < 0.0001). B. Relationship between CSF Ab42 levels and cortical amyloid. Most participants had low MCBP values. The vast majority (86%) of participants with MCBPs 0.18 had low CSF Ab42 levels. These CDR 0 participants are hypothesized to have preclinical AD. The box outlined by dashed lines identifies the 28 individuals who have low cortical PIB binding (MCBP < 0.18) with low CSF Ab42. There is a linear relationship between CSF Ab42 and the amount of cortical amyloid although CSF Ab42 appears to drop and then stay low as the amyloid load increases. C. MRI (left) and PET PIB (right) images of a representative low PIB (MCBP ¼ 0.0270) CDR 0 participant (top panel), a high PIB (MCBP ¼ 0.7790) CDR 0 participant (middle panel), and a high PIB (MCBP ¼ 0.7812) CDR > 0 participant (bottom panel). The amount of cortical PIB binding (yellow-red corresponds to high binding) in the high PIB CDR 0 participant and the high PIB CDR > 0 participant is comparable, whereas there is only background PIB binding (green) in white matter tracks in the low PIB CDR 0 participant. D,E. No relationship between CSF Ab40 (D) and CSF Ab38 (E) levels and cortical amyloid was observed in this cognitively normal cohort (r ¼ 0.0287, p ¼ 0.6963; r ¼ 0.06851, p ¼ 0.3515, respectively). F. A negative correlation was found between cortical amyloid and the CSF Ab38/Ab42 ratio. All Pearson correlation coefficients are corrected for age. n.s., not significant. required to understand whether their low CSF Ab42 represents Ab aggregation in diffuse (PIB-negative) plaques, oligomeric forms prior to substantial ﬁbrillar (PIB-positive) Ab deposition or simply reﬂects the low end of the normal spectrum of CSF Ab42 levels. It is interesting to note that one of the individuals in this quadrant (having no cortical PIB binding but low CSF Ab42) has come to autopsy 2 years after LP and PIB testing. This participant was CDR 0 at the time of LP and PIB (6 months apart) but received a CDR rating of 0.5 (very mild dementia) just prior to death. Subsequent histological analysis of the brain revealed abundant diffuse but few neuritic (amyloid) plaques, (Cairns et al, 2009) consistent with the ﬁrst proposed hypothesis. Despite the strong relationship between PIB binding and CSF Ab42, we observed no relationship between cortical amyloid 374 2009 EMBO Molecular Medicine EMBO Mol Med 1, 371–380 www.embomolmed.org