Alzheimer’s Dementia Does Not Respond to IV Immunoglobulin

Intravenous (IV) immunoglobulin (Ig) showed no benefits for improving cognition in patients with mild-to-moderate Alzheimer’s disease (AD) dementia, according to the final results of a phase 3 trial reported in Neurology.¹ This latest publication confirms results initially reported in 2014, although that trial failed to meet its primary end points: efficacy compared with placebo on the 11-item cognitive subscale of the Alzheimer’s Disease Assessment Scale17 (ADAS-Cog) and the 23-item Alzheimer’s Disease Cooperative Study Activities of Daily Living Scale18 (ADCS-ADL).

The Gammaglobulin Alzheimer Partnership (GAP) trial enrolled 390 participants from 41 sites in the United States and 4 in Canada from December 2008 to February 2013 to receive 1 of 2 doses (138 patients received 0.2 g/kg and 129 patients received 0.4 g/kg) of intravenous immunoglobulin or placebo (low-dose albumin; n=123) given as biweekly infusions for 18 months. The participants were all medically stable and diagnosed with probable dementia.

There was little difference between the effects of IVIg and placebo on either primary measure. Mean changes from baseline to 18 months on the ADAS-Cog scale were 7.42 for low-dose IVIg and 8.94 for high-dose IVIg compared with 8.43 for placebo, while changes in ADCS-ADL were −11.4 for both high-dose IVIg and placebo and −12.4 for low-dose IVIg. The lack of significant response also carried through all secondary outcomes, with no significant changes in scores on the Modified Mini-Mental State (3MS) exam, the Neuropsychiatric Inventory (NPI), the Quality of Life in Alzheimer’s Disease Scale (QOL-AD), or the Alzheimer’s Disease Cooperative Study Clinician’s Global Impression of Change (ADCS-CGIC) tests for either dose compared with placebo.

The investigators reported significant reductions in plasma Aβ42 levels compared with placebo, but no differences in other biomarker outcomes — including rates of edema or hemorrhage, or changes to whole brain volumes or hippocampal volumes — were evident on brain imaging studies.

The rationale for using IVIg for AD dates back to the early 1990s when the presence of naturally occurring anti-amyloid antibodies was first identified in human blood. In a 2014 article published in Clinical and Experimental Immunology that discussed the GAP study,² lead investigator Norman Relkin, MD, PhD, of Weill Cornell Medical College in New York, wrote, “IVIg treatment resulted in measurable alterations in plasma amyloid levels, suggesting that the naturally occurring antiamyloid antibodies may play a role in clearing amyloid from the body.”

The investigators concluded that the GAP results did not support the use of IVIg for the treatment of AD. Dr Relkin noted in his overview, “The original premise for testing IVIg as a treatment for AD related to promoting amyloid clearance; however, other mechanisms of action may be salient to AD treatment.”

“This is the final analysis of the GAP study,” co-investigator Paul Aisen, MD, director of the Alzheimer’s Therapeutic Research Institute at the University of California, San Diego told Neurology Advisor. “In my opinion, monoclonal antibodies are showing greater promise for AD than IVIg.”

References

1. Relkin NR, Thomas RG, Rissman RA, et al. A phase 3 trial of IV immunoglobulin for Alzheimer disease.  Neurology. 2017;88:1-8.
2. Relkin N. Intravenous Immunoglobulin for Alzheimer’s disease.  Clin Exper Immunol. 2014;178:27-19.