HIGH CEREBROSPINAL-FLUID TAU AND LOW AMYLOID BETA-42 LEVELS IN THE CLINICAL-DIAGNOSIS OF ALZHEIMER-DISEASE AND RELATION TO APOLIPOPROTEIN-EGENOTYPE

Objective: To evaluate cerebrospinal fluid (CSF) levels of amyloid bet a protein ending at amino acid 42 (A beta 42) and tau as markers for A lzheimer disease (AD) and to determine whether clinical variables infl uence these levels. Design: Cohort study. Setting: Six academic resear ch centers with expertise in dementia. Subjects: Eighty-two patients w ith probable AD, including 24 with very mild dementia (Mini-Mental Sta te Examination score >23/30) (AD group); 60 cognitively normal elderly control subjects (NC group); and 74 subjects with neurological disord ers, including dementia (ND group). Main Outcome Measures: Levels of A beta 42 and tau were compared among AD, NC, and ND groups. Relationsh ips of age, sex, Mini-Mental State Examination score, and apolipoprote in E (Apo E) genotype with these levels were examined using multiple l inear regression. Classification tree models were developed to optimiz e distinguishing AD from NC groups. Results: Levels of A beta 42 were significantly lower, and levels of tau were significantly higher, in t he AD group than in the NC or ND group. In the AD group, A beta 42 lev el was inversely associated with Apo E epsilon 4 allele dose and weakl y related to Mini-Mental State Examination score; tau level was associ ated with male sex and 1 Apo E epsilon 4 allele. Classification tree a nalysis, comparing the AD and NC subjects, was 90% sensitive and 80% s pecific. With specificity set at greater than 90%, the tree was 77% se nsitive for AD. This tree classified 26 of 74 members of the ND group as having AD. They had diagnoses difficult to distinguish from AD clin ically and a high Apo E epsilon 4 allele frequency. Markers in CSF wer e used to correctly classify 12 of 13 patients who later underwent aut opsy, including 1 with AD not diagnosed clinically. Conclusions: Level s of CSF A beta 42 decrease and levels of CSF tau increase in AD. Apol ipoprotein E epsilon 4 had a dose-dependent relationship with CSF leve ls of A beta 42, but not tau. Other covariates influenced CSF markers minimally. Combined analysis of CSF A beta 42 and tau levels discrimin ated patients with AD, including patients with mild dementia, from the NC group, supporting use of these proteins to identify AD and to dist inguish early AD from aging. In subjects in the ND group with an AD CS F profile, autopsy follow-up will be required to decide whether CSF re sults are false positive, or whether AD is a primary or concomitant ca use of dementia.