Alzheimer's disease (AD) is a chronic neurodegenerative disease associated with 
intracerebral accumulation of aggregated amyloid-beta (Aβ) and tau proteins, as 
well as neuroinflammation. Human intravenous immunoglobulin (IVIG) is a mixture 
of polyclonal IgG antibodies isolated and pooled from thousands of healthy human 
donors. The scientific rationale for testing IVIG as a potential AD treatment 
include its natural anti-Aβ antibody activity, its favorable safety profile and 
inherent anti-inflammatory/immunomodulatory properties. Over the past decade, 
several clinical and pre-clinical experimental findings, advanced our knowledge 
about biological and therapeutic properties of IVIG that are relevant to AD 
therapy. Anti-amyloid antibodies in IVIG show significantly higher binding 
avidity for amyloid oligomers and fibrils than for Aβ monomers. In a double 
transgenic murine model of AD, intracerebral injection of IVIG causes 
suppression of Aβ fibril pathology whereas long term peripheral IVIG treatments 
causes elevation of total brain Aβ levels with no measurable impact on Aβ 
deposits or tendency for inducing cerebral microhemmorhage. Furthermore, chronic 
IVIG treatment suppressed neuroinflammation and fostered adult hippocampal 
neurogenesis. In clinical studies with AD patients, IVIG showed an acceptable 
safety profile and has not been reported to increase the incidence of amyloid 
related imaging abnormalities. Preliminary studies on small number of patients 
reported clinical benefits in mild to moderate stage AD patients. However, 
double blind, placebo controlled studies later did not replicate those initial 
findings. Interestingly though, in APOE4 carriers and in moderate disease stage 
subgroups, positive cognitive signals were reported. Nevertheless, both clinical 
and experimental (mouse) studies show that antibodies in IVIG can accumulate in 
CNS and its biological activities include neutralization of Aβ oligomers, 
suppression of neuroinflammation and immunomodulation. Identifying mediators of 
IVIG's effects at the cellular and molecular level is warranted. In light of its 
favourable safety profile and aforementioned biological properties, IVIG is 
still an enigmatic experimental candidate with enormous potential for being an 
AD therapeutic.