**11. IVIg in therapy of Alzheimer's disease (AD)**

Alzheimer's Disease (AD) is the most common neurodegenerative disorder leading to dementia. The pathological hallmarks of AD are extracellular accumulation of Ab peptides, as senile plaques and intracellular neurofibrillary tangles composed of tau proteins.

Clinical studies of active immunization in humans with AD were complicated by the development of meningoencephalitis in 6% of the patients treated with vaccine AN1792 in a phase II clinical trial. Furthermore, only 20% of the patients immunized with AN1792 developed a twofold increase in anti-Ab antibodies.

However, progress was made with the discovery that peripheral administration of antibodies against Ab peptide could reduce amyloid burden to a similar extent as active immunization. Passive immunization had the advantage that the potentially harmful activation of host T cells could be avoided.

Based on the finding that externally administered antibodies were able to protect mice from AD, it was hypothesized that high titres of natural anti-Ab antibodies may protect humans from AD, while low levels may predispose certain individuals to the development of AD. Studies have found reduced levels of anti-Ab antibodies both in the serum and CSF of patients with AD. Autoantibody-decorated plaques were found frequently in patients with AD and patients with low antibody-levels were shown to harbour more diffuse plaques than patients with high levels. Autoantibodies against Ab may therefore be important for maintaining plaque homeostasis.

IVIg has been shown to contain autoantibodies against many states of Ab peptide aggregation including monomers, oligomers and fibrils and may therefore have a distinct advantage over monoclonal anti-Ab until the precise pathogenic state(s) of the Ab peptide is known (Hughes et al, 2008).

Recently, commercially available IVIg have been used in small pilot trials for the treatment of patients with AD, based on the hypothesis that IVIG contains naturally occurring autoantibodies (nAbs-Abeta) that specifically recognize and block the toxic effects of Abeta. Furthermore, these nAbs-Abeta are reduced in AD patients compared with healthy controls, supporting the notion of replacement with IVIg. Beyond the occurrence of nAbs-Abeta, evidence for several other mechanisms associated with IVIg in AD has been reported in preclinical experiments and clinical studies. In 2009, a phase III clinical trial involving more than 360 AD patients was initiated and may provide conclusive evidence for the effect of IVIg as a treatment option for AD in 2011(Dodel et al, 2010).
