150 Current Alzheimer Research, 2009, Vol. 6, No. 2 tion due to disease progression. For all cognitive outcomes, there were relatively fewer placebo-treated patients eligible for cognitive testing than antibody responders. Therefore, comparisons of cognitive function in this follow-up study may not be representative of the entire placebo-treated group, and may favor the assessment of placebo-treated pa- tients who were less impaired and capable of undergoing cognitive testing. Despite this potential bias to include bet- ter-performing placebo-treated patients in the cognitive analyses, antibody responders tended to perform better on the memory component of the NTB. They demonstrated sig- nificantly less decline on a memory subtest of the NTB (Rey Auditory Verbal Learning Test – Delayed Recall) and simi- lar declines compared with placebo on the other cognitive outcomes. A similar overall incidence of SAEs for placebo-treated patients compared with antibody responders was observed. No SAEs were considered by the investigator to be treatment related. Although dosing in the phase 2a study was halted after 18 patients (6.0%) developed encephalitis, no new cases of encephalitis were reported after 4.6 years in this follow-up study, and similar survival was observed between treatment groups. Antibody responders in the phase 2a study demonstrated increased brain volume loss and increased ventricular en- largement over 11 months of follow up. In the small sample of patients who had MRI scans in this follow-up study, brain volume loss in antibody responders from the time of the last phase 2a study visit was similar to changes observed in pla- cebo-treated patients. Ventricular enlargement was still sig- nificantly greater in antibody responders when compared with baseline measurements in the phase 2a study, but not when compared with the final scan. When compared with the final scan performed in the original study we were not able to show significant differences between antibody responders and placebo-treated patients on any MRI measures (whole brain or hippocampal loss and ventricular enlargement). It is tempting to speculate that rates of loss were similar between the two groups after the end of the phase 2a study; however, due to the small numbers of subjects, the study had very lim- ited power to detect any such differences. Although firm conclusions cannot be drawn, this suggests that there contin- ues to be dissociation, as observed in our original report, of better cognitive or functional performance despite greater brain volume loss [10]. This implies that whatever accounted for the increased loss on MRI measures it was not neuronal degeneration. Results from a phase 1 study of patients with mild-to- moderate AD treated with AN1792 demonstrated reduction in functional decline as measured by DAD that did not reach statistical significance until approximately 20 months [7]. The phase 2a study represents an independent patient group treated with AN1792. Differences in DAD score between antibody responders and placebo-treated patients similarly did not reach significance at 1 year, but did eventually show statistically significant differences after 4.6 years [9]. This finding is particularly noteworthy because only residual low titers were observed after long-term follow up. One obvious question this follow-up study raises is what clinical effects might have been observed had antibody responders retained Vellas et al. a higher antibody titer (ie, 2,200) over the length of follow up. The NTB scale, comprised of 9 well-known and vali- dated cognitive tests, was utilized in the previous AN1792 phase 2a study [9, 17]. In the follow-up study reported here, a greater percentage of antibody responders performed the NTB than placebo-treated patients. Similarly, relatively fewer placebo-treated patients were administered the ADAS- Cog and MMSE compared with antibody responders. No apparent benefits were detected in antibody responders com- pared with placebo-treated patients among the testable sub- jects on the ADAS-Cog or MMSE. It is possible that amy- loid-targeted immunotherapies have a greater effect on the retention of memory-related functions than on other cogni- tive domains. Alternatively, the lack of benefit seen on the MMSE and ADAS-Cog may be confounded if only the less impaired placebo-treated patients capable of undergoing cognitive testing were assessed. The latter explanation is supported by the significant treatment effects seen on the DAD and Dependence Scale in whom data on more patients was available. A limitation of this study was that only a small propor- tion of the subjects could be reassessed this long after the start of the original phase 2a study; the proportion that could be restudied with MRI was inevitably even smaller. None- theless, it is interesting to note that after approximately 4.6 years, patients classified as responders to initial therapy with AN1792 retained detectable levels of anti-AN1792 antibody. Moreover, antibody responders demonstrated functional and dependence benefits compared with placebo-treated patients, with comparable safety and survival observed between treatment groups. No SAEs were considered treatment re- lated, and no additional cases of encephalitis were reported. Placebo-treated patients and antibody responders did not demonstrate significant differences in loss of brain volume approximately 3.6 years from the end of the phase 2a study. These studies suggest that A remains a valid target for the treatment of mild-to-moderate AD, demonstrating that strategies to reduce A may have the potential to sustain important clinical benefits in patients with AD. A number of different immunotherapeutic approaches to the treatment of AD are currently being studied. DISCLOSURES C. Leibman and M. Grundman are employees of Elan Pharmaceuticals and have stock in the company. R. Black and M. Pomfret are employees of Wyeth Research. R. Black holds stock in the company. N. Fox has received honoraria from Elan Pharmaceuticals and Wyeth Research. The De- mentia Research Centre has conducted MRI analyses spon- sored by Elan Pharmaceuticals and Wyeth Research. ACKNOWLEDGEMENT The authors would like to thank Norman G. Nagl, Jr. and Gregory Thompson for assistance and editorial support in drafting the manuscript. APPENDIX The AN1792 (QS-21)-251 Study Team comprises: