The concentration of tau in the cerebrospinal fluid drops with bapineuzumab treatment, according to a post-hoc analysis of Phase 2 clinical trial results published online April 2 in the Archives of Neurology. After one year of treatment with the humanized monoclonal anti-Aβ antibody, Alzheimer’s patients had lower levels of both phosphorylated and total tau in their CSF than they did at baseline. Compared to patients receiving placebo, that difference was statistically significant for the dip in phosphorylated tau only. The findings could mean that the antibody prevents neurodegeneration downstream of Aβ.

"I believe this is the first demonstration of a monoclonal [antibody] decreasing phospho-tau and [total] tau with therapy," said senior author Enchi Liu, Janssen Alzheimer Immunotherapy, San Francisco. "We hypothesize that bapineuzumab treatment may have some effect on the neurodegenerative process underlying AD." Previously, active immunization with AN1792 reduced CSF total tau (t-tau) levels in treated patients, but AN1792 is no longer in development (see Gilman et al., 2005).

The paper combines two sub-analyses within two Phase 2 clinical trials of bapineuzumab in patients with mild to moderate AD. A previous analysis of the larger sub-study had found a trend toward lower phosphorylated tau (p-tau) in treated patients just shy of statistical significance (see ARF related news story and Salloway et al., 2009). Liu and colleagues wanted to see what adding the data from the second sub-study would do to the finding.

In both Phase 2 trials, a subset of patients agreed to undergo two lumbar punctures so that researchers could measure their CSF biomarker changes. Each patient had the procedure at baseline (two weeks before the first drug infusion) and two weeks after the fourth infusion (at week 54). Twenty-seven bapineuzumab-treated patients and 19 patients on placebo participated.

Consistent with the study’s initial analysis, first author Kaj Blennow, University of Gothenburg,
Mölndal, Sweden, and colleagues this time around found a reduction of CSF p-tau—thought to reflect tau phosphorylation and tangle formation in the brain—in treated patients. On average, p-tau levels fell by 9.9 picograms per milliliter (pg/mL) after one year of treatment, whereas in control subjects, p-tau nudged downward by 2.6 pg/mL. Comparing the two patient groups, the difference was statistically significant. T-tau levels followed the same trend, whereby drug-treated participants had 72.3 pg/mL less at the end of 12 months than at the beginning of the trial, and the control group only lost 5.6 pg/mL. However, the difference did not reach statistical significance. CSF levels of Aβ42 and Aβ40 did not change with treatment or placebo.

"This paper hints that, with bapineuzumab therapy, there's an impact on the downstream neurodegenerative biomarkers," said Liu. Larger Phase 3 trials, set to yield results later this year, are designed to replicate this small study, she said. Many more patients will have received baseline and end-of-study lumbar punctures to see if t-tau and p-tau levels change. Additionally, the team will assess whether ApoE status has any bearing on the biomarker results, and whether the antibody benefits patients clinically. Previous results had hinted that bapineuzumab may improve aspects of cognition, but only in people who carried no ApoE4 allele (see ARF related news story on Salloway et al., 2009).

A decline in CSF p-tau accompanying lowered brain amyloid "does suggest there is a link between the plaque burden type of pathology and hyperphosphorylated tau pathology," commented Leslie Shaw, University of Pennsylvania, Philadelphia. Shaw was not involved in this study. Still, he added, researchers will need to image or autopsy these trial participants’ brains and look for correlations between lowered p-tau and cognitive performance to ascertain what that drop in p-tau levels really means.

Meanwhile, the research has broader implications, Shaw told Alzforum. "One of the questions surrounding CSF and other biomarkers is, Do they provide a reliable index of drug effect?" This is one of the first studies to provide an answer along those lines for monoclonal anti-Aβ antibodies, he said.

Why did the Aβ concentration seem unchanged in the CSF? After all, the antibody does clear brain amyloid, as a previous PIB-PET imaging sub-study reported plaque shrinkage in patients who received bapineuzumab for 18 months (see ARF related news story on Rinne et al,. 2010). Researchers do not know. For one thing, Aβ could have been cleared by other pathways that do not involve the CSF, the authors wrote. Alternatively, Aβ might have oligomerized or bound to chaperones or the antibody, masking a change in CSF levels as detectable with current assays.—Gwyneth Dickey Zakaib.

Reference:
Blennow K, Zetterberg H, Rinne JO, Salloway S, Wei J, Black R, Grundman M, Liu E. Effect of immunotherapy with bapineuzumab on cerebrospinal fluid biomarker levels in patients with mild to moderate Alzheimer disease. Arch Neurol 2012 April 2. Abstract

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  1. The interpretation that treatment of patients with the anti-Aβ monoclonal antibody bapineuzumab had an effect on lowering levels of phospho-tau is consistent with our findings in postmortem studies of the brains of patients actively immunized against Aβ (AN1792). In this study, we found that, as Aβ plaques are cleared from the brain, there is a reduction in the overall level of histologically detectable phospho-tau. Interestingly, the effect seemed to be restricted to phospho-tau in neuronal processes (both in plaque-associated dystrophic neurites and in neuropil threads), but with no change in phospho-tau located in the cell bodies (i.e., in effect, the tangles). As mentioned in this story, we also interpreted our observation as support for the amyloid hypothesis in that, as changing Aβ can alter phospho-tau, then this implies that tau phosphorylation is downstream of Aβ alterations.

    References:

    . Reduction of aggregated Tau in neuronal processes but not in the cell bodies after Abeta42 immunisation in Alzheimer's disease. Acta Neuropathol. 2010 Jul;120(1):13-20. PubMed.

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References

News Citations

  1. Chicago: Bapineuzumab’s Phase 2—Was the Data Better Than the Spin?
  2. Paper Alert-cum-SfN: Bapineuzumab Published, More AN1792 Presented
  3. PIB-PET Biomarker Study Confirms Bapineuzumab Lowers Amyloid

Paper Citations

  1. . Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology. 2005 May 10;64(9):1553-62. PubMed.
  2. . A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology. 2009 Dec 15;73(24):2061-70. PubMed.
  3. . 11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients with Alzheimer's disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study. Lancet Neurol. 2010 Apr;9(4):363-72. PubMed.
  4. . Effect of Immunotherapy With Bapineuzumab on Cerebrospinal Fluid Biomarker Levels in Patients With Mild to Moderate Alzheimer Disease. Arch Neurol. 2012 Apr 2; PubMed.

Further Reading

Papers

  1. . Bapineuzumab in Alzheimer's disease: where now?. Lancet Neurol. 2010 Feb;9(2):134-6. PubMed.
  2. . Effect of Immunotherapy With Bapineuzumab on Cerebrospinal Fluid Biomarker Levels in Patients With Mild to Moderate Alzheimer Disease. Arch Neurol. 2012 Apr 2; PubMed.

News

  1. Geneva: Biomarker News Morsels Amid Immunotherapy Review
  2. No Time to Waste? Elan-Wyeth Vaccine to Enter Phase 3 Trial
  3. Uppsala: Conference Puts Uppsala on Immunotherapy Map
  4. Chicago: Bapineuzumab’s Phase 2—Was the Data Better Than the Spin?
  5. Paper Alert-cum-SfN: Bapineuzumab Published, More AN1792 Presented
  6. PIB-PET Biomarker Study Confirms Bapineuzumab Lowers Amyloid

Primary Papers

  1. . Effect of Immunotherapy With Bapineuzumab on Cerebrospinal Fluid Biomarker Levels in Patients With Mild to Moderate Alzheimer Disease. Arch Neurol. 2012 Apr 2; PubMed.