Plasma levels of Abeta42 and Abeta40 in Alzheimer patients during treatment with the acetylcholinesterase inhibitor tacrine.
Deregulation of amyloid precursor protein (APP) processing with increased production of amyloid beta-peptide (Abeta) is considered to be a key pathogenic event in Alzheimer's disease (AD). It has been suggested that stimulation of the muscarinic M(1) receptor subtype affects APP processing and leads to a change in Abeta concentration. To test the hypothesis that treatment with a cholinesterase inhibitor could change the levels of Abeta in plasma, we measured Abeta42 and Abeta40 plasma levels in AD subjects before tacrine treatment and at weeks 2 and 6 of treatment. Treatment with tacrine had no statistically significant effect on plasma Abeta42 and Abeta40 either at 2 weeks or at 6 weeks of administration compared to baseline levels. Plasma Abeta42 and Abeta40 levels showed large subject-to-subject variation but small variation within the same patient over the 3-sample interval. After 2 weeks of treatment with tacrine, there was a strong negative correlation between tacrine concentration and levels of Abeta42 (r = -0.64; p = 0.01) and Abeta40 (r = -0.55; p = 0.04). However, after 6 weeks there was no correlation between plasma concentrations of tacrine and Abeta42 (r = 0.33; p = 0.34) or Abeta40 (r = -0.22; p = 0.54) levels in plasma. After 2 weeks of treatment with an acetylcholinesterase inhibitor, we found a correlation between higher drug concentrations and lower beta-amyloid levels. This might indicate an effect on APP metabolism with an increased alpha-cleavage. But after 6 weeks of drug treatment, there was no obvious drug effect on beta-amyloid concentrations. This finding may indicate that compensatory mechanisms have started at 6 weeks and that no long-term effect on key pathological features in AD is to be expected by an inhibition of acetylcholinesterase.
Basun
Hans
H
Department of Neurotec, Karolinska Institutet, Huddinge University Hospital, Sweden. Hans.Basun@astrazeneca.com
Nilsberth
Camilla
C
Eckman
Christopher
C
Lannfelt
Lars
L
Younkin
Steven
S
D000544:Alzheimer Disease / Q000097:blood* / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000097:blood*; D002800:Cholinesterase Inhibitors / Q000097:blood / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D010446:Peptide Fragments / Q000097:blood*; D013619:Tacrine / Q000097:blood / Q000627:therapeutic use*
D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D013619:Tacrine