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High Cerebrospinal Fluid Tau and Low Amyloid 42 Levels in the Clinical Diagnosis of Alzheimer Disease and Relation to Apolipoprotein E Genotype

D. Galasko, MD; L. Chang, MD; R. Motter, MPH; C. M. Clark, MD; J. Kaye, MD; D. Knopman, MD; R. Thomas, PhD; D. Kholodenko, MS; D. Schenk, PhD; I. Lieberburg, PhD, MD; B. Miller, MD; R. Green, MD; R. Basherad, MS; L. Kertiles, MS; M. A. Boss, PhD; P. Seubert, PhD

Arch Neurol. 1998;55:937-945.

Objective  To evaluate cerebrospinal fluid (CSF) levels of amyloid protein ending at amino acid 42 (A42) and tau as markers for Alzheimer disease (AD) and to determine whether clinical variables influence these levels.

Design  Cohort study.

Setting  Six academic research centers with expertise in dementia.

Subjects  Eighty-two patients with probable AD, including 24 with very mild dementia (Mini-Mental State Examination score >23/30) (AD group); 60 cognitively normal elderly control subjects (NC group); and 74 subjects with neurological disorders, including dementia (ND group).

Main Outcome Measures  Levels of A42 and tau were compared among AD, NC, and ND groups. Relationships of age, sex, Mini-Mental State Examination score, and apolipoprotein E (Apo E) genotype with these levels were examined using multiple linear regression. Classification tree models were developed to optimize distinguishing AD from NC groups.

Results  Levels of A42 were significantly lower, and levels of tau were significantly higher, in the AD group than in the NC or ND group. In the AD group, A42 level was inversely associated with Apo E 4 allele dose and weakly related to Mini-Mental State Examination score; tau level was associated with male sex and 1 Apo E 4 allele. Classification tree analysis, comparing the AD and NC subjects, was 90% sensitive and 80% specific. With specificity set at greater than 90%, the tree was 77% sensitive for AD. This tree classified 26 of 74 members of the ND group as having AD. They had diagnoses difficult to distinguish from AD clinically and a high Apo E 4 allele frequency. Markers in CSF were used to correctly classify 12 of 13 patients who later underwent autopsy, including 1 with AD not diagnosed clinically.

Conclusions  Levels of CSF A42 decrease and levels of CSF tau increase in AD. Apolipoprotein E 4 had a dose-dependent relationship with CSF levels of A42, but not tau. Other covariates influenced CSF markers minimally. Combined analysis of CSF A42 and tau levels discriminated patients with AD, including patients with mild dementia, from the NC group, supporting use of these proteins to identify AD and to distinguish early AD from aging. In subjects in the ND group with an AD CSF profile, autopsy follow-up will be required to decide whether CSF results are false positive, or whether AD is a primary or concomitant cause of dementia.

From the Department of Neurosciences, University of California, San Diego (Drs Galasko and Thomas), and San Diego Veterans Affairs Medical Center (Drs Galasko and Thomas); the Department of Neurology, University of California, Los Angeles, Harbor Medical Center, Torrance (Drs Chang and Miller); Athena Neurosciences, Inc, South San Francisco, Calif (Mss Motter and Kholodenko and Drs Schenk, Lieberburg, and Seubert); the Department of Neurology, University of Pennsylvania, Philadelphia (Dr Clark); Aging and Alzheimer's Disease Center, Oregon Health Sciences University, Portland (Dr Kaye); the Department of Neurology, University of Minnesota Hospital, Minneapolis (Dr Knopman); the Memory Assessment Clinic and Alzheimer's Disease Program, College of Health and Human Sciences, Georgia State University, Atlanta (Dr Green); and Athena Diagnostics, Inc, Worcester, Mass (Messrs Basherad and Kertiles and Dr Boss).

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