Cerebrospinal beta-amyloid (1±42) in early Alzheimer's disease: association with apolipoprotein E genotype and cognitive decline M. Riemenschneider a, * , M. Schmolke b , N. Lautenschlager a , W.G. Guder b , H. Vanderstichele c , E. Vanmechelen c , A. Kurz a a Department of Psychiatry and Psychotherapy, Technische Universita È t Mu Ènchen, lsmaningerstrasse 22, 81675 Munich, Germany b Institute for Clinical Chemistry, Sta È dtisches Krankenhaus Mu È nchen-Bogenhausen, Munich, Germany c Innogenetics, Ghent, Belgium Received 20 January 2000; received in revised form 29 February 2000; accepted 1 March 2000 Abstract The concentration of beta-Amyloid (1±42) protein (Ab42) in cerebrospinal ¯uid (CSF) was determined in 75 Alzheimer's disease (AD) patients, 35 patients with other causes of dementia and 30 cognitively healthy age-matched controls. A signi®cant decrease of Ab42 concentration was found in AD patients, even in 25 subjects with very mild dementia as compared to patients with other causes of dementia and controls. Within AD patients we observed a signi®cant decline of Ab42 from very mild to mild and moderate dementia. In addition, Ab42 levels were negatively correlated with the severity of cognitive impairment and with the number of 14 alleles inherited. We conclude that measurement of Ab42 in CSF might be helpful for identifying AD at an early stage and also for tracking the clinical course. q 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Biomarker; Alzheimer's disease; Beta-amyloid; Cerebrospinal ¯uid; ApoE genotype Alzheimer's disease (AD) is clinically de®ned by the presence of the syndrome of dementia. This syndrome is characterized by multiple cognitive impairments which interfere with activities of daily living. However, before reaching the stage of clinical severity, patients pass through a predementia phase during which cognitive impairment is already present but not severe enough to ful®l the current criteria of dementia. With the advent of symptomatic treat- ments which work best when administrated early, it is of particular interest to identify biomarkers which allow the physician to establish the diagnosis before cognitive and functional abilities are severely compromised. The cere- brospinal ¯uid (CSF) bathes the brain and therefore the neurodegenerative process including neuro®brillary tangle formation and plaque deposition in AD could be re¯ected in changes of soluble proteins in the CSF. Neuro®brillary tangles are located intraneuronally and are primarily composed of the microtubule-associated protein tau. Senile plaques consist mainly of the b-amyloid protein (Ab) a 40± 42 amino acid peptide derived from proteolytic cleavage of the larger amyloid precursor protein (APP). The longer beta-Amyloid (1±42) isoform predominates in senile plaques, which are more numerous in patients homozygous for the 1 4 allele of the apolipoprotein E gene [11]. Decreased concentrations of Ab42 in CSF have been consistently demonstrated in mild to moderate AD [1,3,4,7] and recently in subjects with mild cognitive impairment (MCI) [2] as well as an 1 4 dose-dependent decline of CSF Ab42 levels [3,4]. Two studies have shown a signi®cant negative asso- ciation of CSF Ab42 levels with cognitive performance [9,12]. Therefore it is of particular interest to examine CSF Ab42 concentrations in very mild AD. In the present study, we found signi®cantly decreased CSF Ab42 levels even in very mild AD and a signi®cant association of Ab42 concentrations with cognitive performance, which is parti- cularly evident in AD patients who are homozygous for the 13 allele. We examined CSF Ab42 in 25 patients with very mild dementia in AD (Mini Mental State Examination (MMSE) score, 25±28), in 50 patients with mild to moderate demen- tia in AD (MMSE,25), in 35 patients with other causes of dementia (fronto temporal degeneration (FTD; n  10), cerebrovascular dementia (n  5), normal pressure hydro- Neuroscience Letters 284 (2000) 85±88 0304-3940/00/$ - see front matter q 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S0304-3940(00)00976-9 www.elsevier.com/locate/neulet * Corresponding author. Tel.: 1 49-89-41404214; fax: 149-89- 41404941. E-mail address: m.riemenschneider@lrz.tu-muenchen.de (M. Riemenschneider).