HONOLULU – Reearchers are making small steps toward untangling the mysteries of tau – the protein that twists around neurons and destroys cognitive ability in Alzheimer's disease.
The beta amyloid protein, which forms the sticky brain plaques characteristic of the disease, is now considered the “upstream” lesion of Alzheimer's – a prodromal manifestation that appears before the onset of symptoms. The neurofibrillary tangles of phosphorylated tau that appear in both the neuronal cell bodies and dendritic spines occur later and directly correlate with cognitive decline.
In several studies presented at the meeting, which was sponsored by the Alzheimer's Association, scientists gave tantalizing clues to the connection between beta amyloid (Abeta) and tau, and the possible effects of untangling tau's destructive web with immunotherapy.
“Importantly, these studies teach us more not only about tau-targeted therapies, but also about the progression of Alzheimer's disease,” William Thies, Ph.D., said at a press briefing on the studies. “It may be that amyloid changes in the brain happen early in the disease and the tau-related changes happen 'downstream,' where they have a more direct effect on cognitive function,”Hsaid Dr. Thies, chief medical and scientific officer of the Alzheimer's Association.
Dr. Kaj Blennow of the University of Gothenburg (Sweden), discussed a pooled analysis of data collected from two randomized, placebo-controlled studies of bapineuzumab (Janssen and Pfizer Inc.), an antibody to Abeta plaques. The drug iscin phase III trials. It induces anti-Abeta antibodies, which have been shown to reduce Abeta plaques.
The subgroup analysis consisted of 46 Alzheimer's patients who were enrolled in either Study 201 (United States) or Study 202 (United Kingdom and Finland). Of these patients, 27 received bapineuzumab and 19 received placebo.
In Study 201, the active group showed a nonsignificant decrease in phosphorylated tau – the kind associated with neuronal death – in cerebrospinal fluid, compared with the control group. In study 202, there were no tau-related treatment effects. When the data were combined, however, Dr. Blennow and his colleagues found a significantly greater decrease in phosphorylated tau in bapineuzumab-treated patients, compared with placebo-treated patients (−9.5 picograms/mL vs. −0.5 picograms/mL). In the pooled data, Dr. Blennow also found a trend toward a decrease in total CSF tau in the active group, compared with the control group.
“These observations suggest that immunotherapy targeting amyloid may also alter neurodegenerative processes that occur later in the disease process and that are more directly associated with loss of function,” Dr. Blennow said at the briefing.
Delphine Boche, Ph.D., of the University of Southampton (England), studied the tau effects of another Abeta immunotherapy agent called AN1792, which was pulled from development in 2002 after 6% of the patients who received it developed serious brain inflammation and subsequent brain atrophy.
A number of the patients in the AN1792 trial have since died. Researchers continue to examine their brains to discover other effects of the vaccine, which was designed to reduce brain plaques. Dr. Boche compared samples from the brains of 10 immunized Alzheimer's patients with samples from the brains of 28 nonimmunized patients.
Dr. Boche and her team quantified Abeta-42 – the plaque-forming length of the Abeta peptide – and phosphorylated tau in six brain areas affected by Alzheimer's pathology: the superior and middle temporal gyrus, medial frontal gyrus, inferior parietal lobule, entorhinal cortex, and subiculum and CA1 regions of the hippocampus.
The researchers found that immunized brains had a significantly lower percentage of cerebral cortex covered by Abeta plaque than did the nonimmunized brains (1.4% vs. 5.25%). There was also a significantly lower load of phosphorylated tau in immunized patients in the same regions (0.72% vs. 1.08%).
Dr. Boche also examined neurons to determine whether the tau changes were intra- or extracellular. “The load was significantly lower in the fine dendritic branches compared with the neuron body,” she said. “When the Abeta was removed, the dystrophic neurites also disappeared. But there was no significant difference in the level of tau within the nerve body.”
Unfortunately, the physiologic changes did not translate into any clinical benefit. “All the vaccinated patients [who are still alive] are still deteriorating despite the treatment,” she said.
The final study examined the effect of an active tau immunotherapy on mice engineered to develop neurofibrillary tau tangles. Allal Boutajangout, Ph.D., of New York University, New York, and his colleagues used a monoclonal antibody called PHF1, which recognizes and attacks phosphorylated tau.
Mice that were 2-3 months old received 13 peritoneal injections of the antibody or 13 injections of mouse immunoglobulin G. At 5-6 months old, their behavior was assessed and then they were sacrificed for brain pathology.