metabolism occur in larger amounts after Ab42 aggregates and amyloid accumulates. Neuropathological studies have demon- strated the presence of tangles in certain brain regions (e.g. entorhinal cortex) as early as the ﬁfth decade of life (Braak & Braak, 1997). The relationship between tangles and CSF tau is not clear in non-demented individuals. Longitudinal data within individuals would be required to prove the sequence of neuropathological events during the natural course of preclinical AD. However, our data showing increases in CSF tau primarily in individuals who already have substantial amyloid (as detected by PET PIB) is consistent with results from transgenic mice in which Ab aggregation/deposition appears to exacerbate tauopathy and neurodegeneration regardless of the actual sequence of events (Gotz et al, 2001; Lewis et al, 2001; Oddo et al, 2003a,b). These data are also consistent with recent reports suggesting that PIB accumulation occurs with mild brain atrophy (Bakkour et al, 2009; Dickerson et al, 2009; Fagan et al, 2009) and prior to more marked atrophy (Jack et al, 2009). If conﬁrmed, this sequence has important implications for the detection of AD pathology and treatment. A correlation between levels of tau/ptau, presumed markers of neurodegeneration, and the amount of cortical amyloid in cognitively normal individuals suggests that increasing amyloid deposition is driving neurodegeneration in the preclinical period of AD, and that treatments aimed at lowering or preventing amyloid accumulation may have the potential to also reduce neurode- generation as reﬂected by CSF tau/ptau in the preclinical period. It will be important to see if reducing amyloid burden or halting its accumulation correlates with prevention of cognitive decline. We observed many non-demented individuals with the typical Ab-related AD biomarker pattern (high PIB binding and low CSF Ab42). The fact that one can be cognitively normal (CDR 0) and have cortical amyloid speaks to the feasibility of PET PIB and/or CSF Ab42 levels as being good identiﬁers of preclinical AD cases, but only if one can show that these individuals eventually go on to dement (Morris et al, 2009). Additional clinical follow-up is needed before strong conclu- sions can be drawn from this group of individuals. It is striking that, at least in some individuals, the brain can withstand a substantial amount of amyloid before they are detected as being clinically impaired, if they become impaired at all. It is likely that there exist additional genetic and/or epigenetic (environmental) factors that dictate or modify the brain’s response to amyloid. Perhaps those are the substrates of ‘cognitive reserve’. Regardless, it is becoming clear that an increase in CSF tau and ptau species, in the presence of cortical amyloid, likely marks a tipping point, as enough neuroﬁbrillary tangle formation/neuritic dystrophy and neuronal cell death has taken place to result in observable cognitive decline. Consistent with this idea, the CSF tau/Ab42 ratio has been reported by several groups, including our own, to predict future cognitive decline in cognitively normal elders (Fagan et al, 2007; Li et al, 2007) and in those with MCI/very mild dementia (Hansson et al, 2006; Mattsson et al, 2009; Snider et al, 2009). The ultimate goal of AD research is to develop treatments that will cure the disease or, at the least, delay its onset and/or slow its progression. Many strategies are being employed to this end Report Anne M. Fagan et al. (Raﬁi & Aisen, 2009; Salloway et al, 2008). As a complementary objective, AD biomarker research aims to develop markers (ﬂuid, imaging, genetic, cognitive, etc.) that will identify the presence of AD pathology with high sensitivity and speciﬁcity, especially in the preclinical and very early disease stages so new treatments will have the best chance of preserving normal brain function. However, in the shorter term, we propose that such biomarkers will be very useful for identifying early stage patients to enroll in clinical trials and, in certain cases, to evaluate treatment efﬁcacy. Many clinical trials testing various AD targets have been carried out but, unfortunately, have been considered failures since the test treatment did not prevent or slow cognitive decline (for review, see Raﬁi & Aisen, 2009). Given that so much AD pathology (plaques, neuroﬁbrillary tangles, inﬂammation and neuronal dysfunction) is already present in the apparent preclinical stages (Aizenstein et al, 2008; Fagan et al, 2006, 2007; Hulette et al, 1998; Mintun et al, 2006; Price & Morris, 1999), it seems logical that future secondary prevention trials should employ promising biomarkers (e.g. PET PIB, CSF Ab42, CSF tau/Ab42) to enrich treatment groups for non-demented, preclinical cases. Such a strategy would decrease the number of patients necessary to be enrolled, as well as potentially shorten the trial duration, thus getting us closer to ﬁnding a true treatment for this devastating disease. MATERIALS AND METHODS Participants Participants were cognitively normal, community-dwelling volunteers enrolled in longitudinal studies of healthy aging and dementia through the Washington University Alzheimer Disease Research Center (ADRC). Participants were 43–89 years of age and in good general health, having no neurological, psychiatric or systemic medical illness that could contribute importantly to dementia, nor medical contraindication to LP for CSF collection or PET with the amyloid imaging agent PIB (Klunk et al, 2004). Cognitive status was determined in accordance with standard protocols and criteria (Berg et al, 1998; Morris et al, 1988). A CDR (Morris, 1993) of 0 indicated no dementia. All CDR 0 participants who had an LP and a PIB scan within 2 years of each other were included in the analysis (n ¼ 189). The scan could be before or after the LP. In cases where participants had more than one LP or PIB scan, we analysed values from the tests most closely together in time. In this study, we defined a participant’s cognitive status from the clinical assessment just prior to LP. All studies were approved by the Human Studies Committee at Washington University, and written informed consent was obtained from all participants. APOE genotyping was kindly performed by the Washington University ADRC Genetics Core under the direction of Dr Alison Goate. Psychometric assessments Psychometric tests that assess a broad spectrum of abilities across multiple cognitive domains were administered to all participants by trained psychometricians usually a week or two after the clinical assessment. Participants in the present study receive one of two test batteries depending on the purpose of the study in which they were initially enrolled. The tests examined in this report were common to www.embomolmed.org EMBO Mol Med 1, 371–380 2009 EMBO Molecular Medicine 377