Could Immunotherapy Be the Future of Alzheimer’s Therapy?

VBCN - July 2014 Volume 1, No 2

Philadelphia, PA—Immunization against amyloid-beta and tau protein, starting in the preclinical period, may represent the future in the treatment of Alzheimer’s disease (AD), said David M. Holtzman, MD, Chairman of Neurology, Washington University, St Louis, MO, during the presidential plenary session at the 2014 American Academy of Neurology meeting.

The 2 main features of AD are (1) aggregation and deposition of amyloid-beta protein in the extracellular space, which produce a strong neuroinflammatory response, and (2) accumulation of the cytoplasmic tau protein in neurofibrillary tangles. In certain dementias other than AD, tau accumulation may be the key event.

“There is overwhelming evidence that the aggregation of the amyloid beta peptide into different conformations leads to both local toxicity and inflammation, but importantly, it also contributes to exacerbation of tau, not just forming during normal aging in the hippocampus and adrenal cortex, but is spread into other parts of the neocortex,” said Dr Holtzman.

Mutations in the amyloid precursor protein (APP) associated with early­onset AD increase the production of amyloid beta42, which is more fibrillogenic than other amino acids that make up APP. Cerebrospinal fluid tau and amyloid beta42 predict progression from cognitively normal to very mild cognitive impairment (MCI) and from MCI to AD.

Support for an immunologic approach was provided by studies showing that active immunization with amyloid beta42 in animals with certain phenotypes results in a marked decrease in amyloid-beta deposits and improved learning. Subsequent studies showed that providing monoclonal antibodies to the amyloid-beta peptide before amyloid deposition onset reduces amyloid­beta deposits.

Two humanized anti–amyloid-beta antibodies—bapineuzumab (3D6) and solanezumab (m266)—entered clinical trials in patients with AD.

Antibodies against amyloid beta work by several mechanisms, depending on the conformation the antibody is directed against, said Dr Holtzman. One mechanism is the clearance of amyloid plaques by phagocytosis. Another is shifting the equilibrium from amyloid plaques to amyloid-beta monomers, “analogous to turning off the water faucet with a full sink of water but the stopper is slightly leaky,” he said.

The blockade of soluble amyloid-beta toxicity, analogous to neutralizing the part of amyloid-beta damage that damages nerve cells, is another potential mechanism.

Immunotherapy Too Late in Progressed Disease?
When given to older animals with amyloid plaques, m266 could not remove plaques from the brain, but it was associated with rapid improvement in behavioral tests.

The first clinical trials of passive immunization were in patients with “massive amounts of amyloid deposition throughout the neocortex” and a lot of neurofibrillary pathology, Dr Holtzman said.

Phase 3 trials of bapineuzumab and solanezumab in patients with mild­to-moderate AD had no effect on cognitive decline.

Certain secondary cognitive end points favored solanezumab in its 2 trials, and when the patients with mild dementia were considered separately, solanezumab was associated with a significant 33% reduction in cognitive decline.

One interpretation is that starting anti–amyloid-beta therapies in patients with moderate dementia is “likely to be too late for this approach,” Dr Holtzman said. “Because solanezumab appeared to slow cognitive decline in mild dementia, it is being tested specifically in a third large phase 3 trial in mild AD. This makes sense.”

Neither solanezumab nor bapineuzumab appear effective at removing existing amyloid plaques, he said, although they can potentially neutralize toxic species of amyloid beta. Combination therapies may have a better chance at removing amyloid plaques and decreasing amyloid-beta toxicity.

Targeting Tau
Animal experiments show that antitau antibodies can strongly decrease tau pathology and improve behavior, which suggests the potential of tau immunotherapy as a therapeutic approach, said Dr Holtzman. Several studies are scheduled to begin in humans to determine the safety of tau immunotherapy. If successful, tau immunotherapy will proceed to efficacy studies in AD and other dementias.

Related Items

Subscribe to
Value-Based Care in Neurology

Stay up to date with personalized medicine by subscribing to recieve the free VBCN e‑Newsletter.

I'd like to recieve: