The severity of the Alzheimer’s disease (AD) problem in the US is indicated by recent statistics from the Alzheimer’s Association
]. Approximately 5.4 million Americans are currently diagnosed with AD, including one in eight individuals aged 65 and older. By 2025 the number of Americans aged 65 and older with AD is expected to reach 6.7 million. Payments for health care, long-term care, and hospice for AD patients, which are currently estimated at $200 billion, are expected to be $1.1 trillion (in 2012 dollars) by 2050.
Intravenous immunoglobulin (IVIG) products are being investigated as potential agents for treatment or prevention of AD. IVIG is prepared from plasma immunoglobulins from large numbers (>
10,000) of healthy donors. It is used to treat a range of autoimmune, infectious, and idiopathic disorders
]. The IVIG product Octagam (Octapharma) was shown by Dodel et al. in 2002 to contain antibodies to Aβ, suggesting that IVIG might be useful for treatment of AD
]. This provided the rationale for IVIG pilot studies in AD patients. The results of these studies were encouraging
], leading to phase II AD trials with these products. Positive results were reported for one of the two IVIG products
] but not the other one
]. More recently, negative results were reported in a phase III IVIG study
]. An additional phase III AD trial with another IVIG product is in progress.
As of this writing (May 2013) it is unclear whether any IVIG products will offer a breakthrough for treatment of AD. Because these preparations differ in their concentrations of antibodies to Aβ
] and tau protein
], there may be differences between them with regard to their efficacies in AD. This purpose of this review is to summarize the IVIG AD trials conducted to date, the issues raised by the potential use of IVIG for treatment of AD, and critical questions which remain.
Clinical trials with IVIG in AD patients
IVIG treatment of AD patients was first reported in a pilot study in 2004
]. Five patients with mild to moderate AD [Mini Mental State Examination (MMSE) mean score 19.4] received Octagam (Octapharma; dose = 0.4 g/kg) on 3 successive days, every 4 weeks for 6 months. MMSE scores improved slightly in four of the AD patients and were unchanged in the fifth one, while their Alzheimer's Disease Assessment Scale-Cognitive sub-scale (ADAS-cog) scores decreased, suggesting increased cognitive functioning, in four patients and did not change in the fifth one. In 2009 results were published
] from a pilot study in which eight AD patients (mean MMSE score 23.5) were administered Gammagard S/D (Baxter Healthcare). After 6 months of treatment the mean MMSE score increased to 26.0, reflecting increased scores for six patients and no change in scores for two patients. After a 3-month washout period, the mean MMSE score returned to baseline (23.9). Following an additional 9 months of treatment, MMSE scores were essentially unchanged (mean 24.0).
Before publishing these results, in 2006 Baxter began a double-blind Phase II AD trial with Gammagard. Improved outcomes were noted in the Gammagard-treated subjects compared to those initially treated with placebo at 3, 6, and 9 months
]. The four patients who received Gammagard at 0.4 g/kg every 2 weeks for 36 months showed no evidence of further cognitive or memory decline
The results of a double-blind, placebo-controlled, 24-week phase II AD trial with Octagam were published in January 2013
]. Octagam had no apparent effects on cognitive or functional scores in the AD patients. No increase was found for plasma Aβ1-40; this had been reported in the pilot studies and suggested that IVIG products might increase efflux of Aβ from the brain. The only positive finding reported in this study, less reduction in glucose metabolism in some brain regions in the Octagam-treated individuals, was of uncertain significance.
In May 2013, the results of a placebo-controlled phase III AD trial with Gammagard were announced
]. Three hundred ninety patients had been treated every 2 weeks for 18 months with 200 mg/kg Gammagard, 400 mg/kg Gammagard, or placebo. No significant differences were found for the rate of cognitive decline between the Gammagard-treated group and placebo group.
Two AD-related IVIG trials are still in progress. Flebogamma (Grifols Biologicals) is being evaluated, together with albumin, in an AD phase III trial, and NewGam (Octapharma) is being investigated by Sutter Health in a phase II trial to determine its effects in patients with amnestic mild cognitive impairment (MCI) and its influence on the risk for these patients to develop AD. A possible reason for the failures in the most recent IVIG trials is that by the time AD’s clinical features become evident, its pathology, including extensive neuronal loss, is already wellestablished. The trial with MCI patients should provide an indication of whether earlier IVIG treatment may be beneficial. The findings of a retrospective study
], that individuals 65 years of age and older who had received IVIG had a significantly reduced risk for developing AD and related disorders compared to subjects not receiving IVIG support this possibility.