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From the Dementia Research Centre (Drs. Fox and Rossor), Institute of Neurology, London, UK; Wyeth Pharmaceuticals (Drs. Black and Jenkins), Collegeville, PA; Department of Neurology (Dr. Gilman), University of Michigan, Ann Arbor; and Elan Pharmaceuticals, Inc. (Drs. Griffith and Koller), San Diego, CA.
Address correspondence and reprint requests to Dr Fox, Dementia Research Centre, Institute of Neurology, Queen Square, London, WC1N 3BG, UK; e-mail: nfox{at}dementia.ion.ucl.ac.uk
Background: Alzheimer disease (AD) is characterized by progressive cerebral atrophy that may be measured using MRI. Reported are MRI findings of a Phase IIa immunotherapy trial in AD prematurely terminated owing to meningoencephalitis in a subset of patients.
Objective: To assess cerebral volume changes in patients immunized with AN1792 (ß-amyloid [Aß] 1 to 42) who were antibody responders (anti-AN1792 IgG titer of 
1:2,200) compared with placebo patients.
Methods: This randomized, multicenter, placebo-controlled, double-blind trial of AN1792 225 µg plus QS-21 50 µg included 372 patients with probable AD. Patients received one to three injections of AN1792/QS-21 or saline and were assessed for 12 months. Volumetric MRI was performed pre dose and at month 12 or early termination. Brain, ventricular, and hippocampal volume changes were measured from registered scan pairs.
Results: Two hundred eighty-eight patients had paired scans (mean interval 10.9 months). Antibody responders (n = 45) had greater brain volume decrease (3.12 ± 1.98 vs 2.04 ± 1.74%; p = 0.007), greater ventricular enlargement as a percentage of baseline brain volume (1.10 ± 0.75 vs 0.48 ± 0.40%; p < 0.001), and a nonsignificant greater hippocampal volume decrease (3.78 ± 2.63 vs 2.86 ± 3.19%; p = 0.124) than placebo patients (n = 57). Increased losses in brain volume were not reflected in worsening cognitive performance; a composite z score across a Neuropsychological Test Battery showed differences favoring antibody responders over placebo (0.03 ± 0.39 vs –0.24 ± 0.45; p = 0.008).
Conclusions: A dissociation between brain volume loss and cognitive function was observed in AN1792/QS-21 antibody responders. The reasons for this remain unclear but include the possibility that volume changes were due to amyloid removal and associated cerebral fluid shifts.
See also page 1553
Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the May 10 issue to find the title link for this article.
*See the Appendix for a list of Group members.
Sponsored by Elan Pharmaceuticals, Inc., and Wyeth Research. N.C.F. holds a Medical Research Council Senior Clinical Fellowship.
Drs. Fox and Rossor have received honoraria from Elan Pharmaceuticals, Inc., and Wyeth Research. Dr. Gilman served as chair of the Safety Monitoring Committee for the trial and received payment from Elan Pharmaceuticals, Inc., only for his time reviewing safety data. Drs. Griffith and Koller are employees of Elan Pharmaceuticals, Inc., and hold equity in its parent company, Elan Corporation plc. Drs. Jenkins and Black are employees of, hold equity in excess of $10,000 in, and have received honoraria in excess of $10,000 from Wyeth Research.
Presented in part at the Ninth International Conference on Alzheimer’s Disease, July 17 to 22, 2004, Philadelphia, PA.
Received August 12, 2004. Accepted in final form January 31, 2005.
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