Longitudinal Stability of CSF Tau Levels in Alzheimer Patients Trey Sunderland, Benjamin Wolozin, Douglas Galasko, James Levy, Ruth Dukoff, Marcel Bahro, Robert Lasser, Ruth Motter, Terho Lehtima ¨ki, and Peter Seubert Background: Antemortem levels of tau in the cerebrospi- nal fluid (CSF) of Alzheimer’s disease (AD) patients have repeatedly been demonstrated to be elevated when com- pared to controls. Although CSF tau has been reported to be elevated even in very mild AD, it is unknown how tau levels change during the course of the disease. Methods: We have followed 29 mild-to-moderately af- fected AD subjects over 2 years with repeated CSF taps. Clinical measures of dementia severity (Clinical Dementia Rating Scale, Global Deterioration Scale and Mini-Mental Status Examination) were obtained at the start and con- clusion of the observation period, and CSF tau was measured with a standard enzyme-linked immunoabsor- bent assay (ELISA) using two monoclonal antibodies. Results: Despite significant changes in the clinical mea- sures consistent with progression of the disease, no significant overall change in CSF tau levels (548  355 vs. 557275 pg/mL, NS) was observed. None of the clinical variables was significantly correlated with either baseline measures of CSF tau or delta CSF tau (last-first). Similarly, CSF tau at baseline and changes over time were not significantly related to Apolipoprotein E (APO E) phenotype. Conclusions: These data suggest that CSF tau levels are stable over extended periods of time in a group of mild-to-moderately demented AD subjects and that CSF tau levels do not predict the severity or rate of progression of AD, at least not during the middle stages of the illness. Biol Psychiarty 1999;46:750 –755 Key Words: Cerebrospinal fluid, tau, dementia, surrogate marker Introduction R esearch criteria for the diagnosis of Alzheimer’s disease (AD) have existed for over 15 years (McKhann et al 1984; American Psychiatric Association 1987), but the de- finitive diagnosis of AD is still relatively elusive. Although the clinical diagnosis of AD can be highly accurate, the only way to confirm the diagnosis is pathologically by autopsy or in rare circumstances with antemortem cortical biopsy (Men- dez et al 1992; DeKosky et al 1992; Victoroffet al 1995). The recent discoveries of elevated cerebrospinal fluid (CSF) measures of the microtubule-associated protein tau in AD (Motter et al 1995; Arai et al 1995; Vigo-Pelfrey et al 1995; Vandermeeren et al 1993; Munroe et al 1995; Jensen et al 1995; Tato et al 1995) have generated considerable interest in the possibility of biologic markers as an antemortem diag- nostic aid in dementia evaluations. Because abnormally phosphorylated tau is a major build- ing block of the paired helical filaments found to accumulate in the neurofibrillary tangles (NFTs) of AD and there is a correlation between dementia severity and numbers of NFTs in AD brains (Terry 1994; Samuel et al 1994), it has been suggested that elevations of CSF tau might reflect the pathologic process in the brains of AD subjects (Galasko et al 1995). Although it might be appealing to attribute the rise in CSF tau to the dystrophic neurites and NFTs associated with AD, there have not yet been adequate studies of such clinicopathologic correlations. Furthermore, it does seem that the elevated CSF tau is not simply a measure of dying neurons, because CSF levels of the more general marker, neuron specific enolase, have not been found to be elevated in AD subjects as compared with controls (Parnetti et al 1995). Another unknown is whether CSF tau levels change with the progression of AD and thereby offer a biological index of the illness. In this study, we report on the course of CSF tau in a group of clinically diagnosed AD subjects who have been followed for several years. Methods and Materials Patient Population Twenty-nine patients with probable AD (11 M/18 F) were included in this longitudinal cerebrospinal fluid study. These From the Geriatric Psychiatry Branch, National Institute of Mental Health, Bethesda, Maryland (TS, BW, JL, RD, MB, RL); Department of Neuro- sciences, University of California, San Diego, California (DG); Department of Clinical Chemistry, University of Tampere, Tampere, Finland (TL); and Athena Neurosciences, San Francisco, California (RM, PS). Address reprint requests to Trey Sunderland, MD, Bldg. 10, Rm. 3N228, NIMH, NIH, Clinical Center, 10 Center Dr. MSC 1275, Bethesda, MD 20892-1275. Received July 17, 1998; revised April 12, 1999; accepted June 4, 1999. 0006-3223/99/$20.00 PII S0006-3223(99)00149-3