New results on the first experimental vaccine for Alzheimer's disease (AD) have provided a glimmer of hope that the strategy could help combat the neurodegenerative disorder.

The concept was dealt a blow when a Phase IIa trial on a vaccine (AN-1792; Elan/ Wyeth) — which targets the amyloid-β (Aβ) peptide that forms the brain plaques in AD — was halted in January 2002 after four subjects developed inflammation of the central nervous system. In March 2002, Elan withdrew the vaccine from clinical trials after the number of patients with inflammation rose to 18.

But a follow-up of the trial subjects indicates that the vaccine might have benefited some patients. Data presented at the 9th International Conference on Alzheimer's Disease and Related Disorders in Philadelphia showed a trend in improved memory with vaccine responders compared with placebo. However, other cognitive analyses, such as Mini-Mental State Examination, showed no improvement, but the study was not powered for the various clinical endpoints and was halted after patients received only two doses. Together with four autopsy cases that showed a depletion of brain amyloid plaques, the data indicate that amyloid immunotherapy can elicit an immune response that in some cases could lead to amyloid clearance.

“AN-1792 clearly had a biological response,” says Dale Schenk, Chief Scientific Officer at Elan. “Now we need to better understand the observed effects.”

Perhaps counterintuitively, some study cohorts found that a positive response correlated with a reduction in brain volume, a factor widely thought to correlate with degeneration in the disease state.

Roger Nitsch from the University of Zurich Medical School, Switzerland, who investigated the Zurich cohort, observed that brain volume was reduced after one year, but that patients responding cognitively had a compensatory increase in brain volume after two years. Nitsch thinks that the loss in volume could be due to the clearance of amyloid plaques accompanied by a concurrent loss in activation of cells called astrocytes that support neuron function. With regards to the recovery in volume, Nitsch says, “in the best of all worlds, this could be a sign of regeneration taking place after amyloid removal.” Nitsch hopes other participating centres will collaborate on similar tests that will confirm or refute this hypothesis.

Ultimate success would not only provide a viable option for controlling the disease, but will also provide positive evidence for the amyloid hypothesis — that is, amyloid plaques are the primary cause of AD rather than the result of it. “The new studies provide additional proof of concept that β-amyloid plays a crucial role in Alzheimer's disease,” says Nitsch. But Stephen Robinson, Deputy Head, Department of Psychology, Monash University, Australia, takes a different tack. “Many outcomes of the study were either neutral or negative, and collectively they refute the amyloid hypothesis,” he says.

A paper by Frank LaFerla and colleagues adds weight to the amyloid hypothesis by showing that treatment with anti-Aβ antibodies in transgenic mice resulted in clearance of Aβ and a protein called tau (Oddo, S. et al. Neuron 43, 321–332 (2004)). Tau is another potential part of the AD equation, forming neurofibrillary tangles inside brain cells that kill the cells in AD. Aβ clearance occurred before tau clearance and only early forms of tau were cleared, indicating that early intervention with Aβ immunization might be useful for clearing both hallmark lesions of AD.

But AN-1792 was similarly successful in preclinical studies, only to lead to the Phase IIa results. “The trouble is that mouse models are not AD, and much of this strategy is based on the questionable hypothesis that AD is caused by Aβ accumulation,” says Patrick McGeer, from the Kinsmen Laboratory of Neurological Research, University of British Columbia, Canada.

In the meantime, Elan and Wyeth are developing 'next-generation' forms of immunotherapy that induce the favourable antibody response but avoid triggering the T-cell response that is thought to lead to the adverse inflammation. Given the lack of unequivocal information, Schenk says that all these issues require pragmatic solutions. “Now that we know that this approach can affect levels of beta-amyloid plaques,” he says, “we need to understand what clinical effects this might have for the patients.”