Immunomodulation and AD--down but not out

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and is the most common cause of dementia in the elderly. Interventions that remove existing fibrillar and oligomeric amyloid-β (Aβ) are believed to be essential for the success of any attempt at stabilization of brain function and mitigation of cognitive decline. Many of these strategies have focused on Aβ vaccination and administration of anti-Aβ antibodies. Both active and passive immunotherapies have been successful in mouse models, but both have had limited effect in clinical trials. Intravenous immunoglobulin (IVIG) has been proposed as a potential treatment for AD following evidence for behavioral benefit in AD models and cognitive benefit in early phase 1 and phase 2 clinical trials. A phase 3 trial IVIG trial failed to meet its primary outcomes. While there was a statistically significant benefit in moderate stage AD patients who carried an APOE ε4 allele, this stabilization of cognition was evident only on neuropsychological examination. No benefit on activities of daily living was evident, therefore failing to qualify AD as a new indication for IVIG. Identifying the biologically active component (s) responsible for the neuropsychological benefit in APOE ε4-positive AD patients could enable the development of a compound with greater potency that would qualify for FDA (US Food and Drug Administration) registration.