Recently, JAMA (1) reported that the Phase 3 clinical trial of Tarenflurbil, aka flurizan, a γ-secretase modulator, has failed, which confirms that one would consider that the amyloid hypothesis is no longer valid, or, that targeting amyloid is not effective to reduce amyloid level in patients’ brains. However, their cognitive function could not be recovered. In the case of mice, the anti-amyloid treatment can recover cognitive disability. We should consider that there might be a pathogenic difference between humans and mice.

Montine and Larson (2) also expressed a slightly more disheartening explanation for the trial’s failure. “Commonly used experimental models of Alzheimer disease may inadequately reflect the complexity of cognitive impairment and dementia in older patients and thereby provide falsely promising leads.”

However, we don’t know why such a different pathology exists between humans and mice. But, in general, it is accepted that human brain function is very different from that of mice, which consequently induces the different pathogenic process between...  Read more

Recently, JAMA (1) reported that the Phase 3 clinical trial of Tarenflurbil, aka flurizan, a γ-secretase modulator, has failed, which confirms that one would consider that the amyloid hypothesis is no longer valid, or, that targeting amyloid is not effective to reduce amyloid level in patients’ brains. However, their cognitive function could not be recovered. In the case of mice, the anti-amyloid treatment can recover cognitive disability. We should consider that there might be a pathogenic difference between humans and mice.

Montine and Larson (2) also expressed a slightly more disheartening explanation for the trial’s failure. “Commonly used experimental models of Alzheimer disease may inadequately reflect the complexity of cognitive impairment and dementia in older patients and thereby provide falsely promising leads.”

However, we don’t know why such a different pathology exists between humans and mice. But, in general, it is accepted that human brain function is very different from that of mice, which consequently induces the different pathogenic process between humans and mice.

Recently, Hasegawa et al. have reported that homocysteic acid (HA), which is metabolized from homocysteine and/or methionine by cystathionine β-synthase (CBS) in the presence of active oxygen or peroxides, is a pathogen for Alzheimer disease (3). This HA is known to increase under stress conditions (4) or when presenilin is mutated (3). In normal conditions, mice may increase HA level by presenilin gene activation. However, humans may increase HA levels by various stress conditions and also presenilin activation. In humans, HA levels also increase much higher than in mice. In other words, human brain function increases HA levels more than that of the mouse.

Since human Alzheimer’s pathogenic process is more complex than that of mice, anti-amyloid treatments should consider these issues. Especially, the treatment of HA toxicity should be considered in human cases in addition to anti-amyloid treatment.

References:
1. Green RC, Schneider LS, Amato DA, Beelen AP, Wilcock G, Swabb EA, Zavitz KH for the tarenflurbil Phase 3 Study Group. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease. A randomized controlled trial. JAMA 2009 December 16;302:2557-2564. Abstract

2. Montine TJ, Larson EB. Late-life dementias. Does this unyielding global challenge require a broader view? JAMA 2009 December 16;302:2593-2594. Abstract

3. Hasegawa T, Mikoda N, Kitazawa M, LaFerla FM (2010) Treatment of Alzheimer's Disease with Anti-Homocysteic Acid Antibody in 3xTg-AD Male Mice. PLoS One. 2010 Jan 20;5(1):e8593. Abstract

4. Do KQ, Benz B, Sorg O, Pellerin L, Magistretti PJ., beta-Adrenergic stimulation promotes homocysteic acid release from astrocyte cultures: evidence for a role of astrocytes in the modulation of synaptic transmission., J Neurochem. 1997 68(6):2386-94. Abstract

View all comments by Tohru Hasegawa

One does not have to go so far as to postulate a different pathology in mice vs. humans to understand the discrepancy. The Aβ-induced cognitive defects in mice could become apparent because of the tremendous overexpression in mice. In humans, Aβ probably has the same action, but because of lower steady-state levels, the effect does not reach statistical significance. In humans, the dementia may, therefore, not reflect the steady-state toxicity of Aβ on synaptic function, but rather the integrated loss of neuronal structure due to tau pathology, which transgenic mice based solely on APP biology don't have. The key to understand the mouse/human differences lies probably in the biology of tau.

View all comments by Hanno Roder

I agree with Dr. Hasegawa that we may need to rethink how we are doing (and interpreting) our mouse studies.

However, it is a little premature to deliver a eulogy for the amyloid hypothesis. It could simply be that Tarenflurbil was not a potent enough compound. For instance, in the Phase 1 study, Tarenflurbil failed to lower CSF Aβ (1). Although this raised some red flags, the decision was made to proceed because of promising clinical outcomes in the Phase 2 trial (2). So, until we have definitive evidence that removal of amyloid from the brain results in no improvement (or better, that blocking amyloid deposition in early-stage disease does not affect progression), the amyloid cascade hypothesis is still our best option.

References:
1. Galasko DR, Graff-Radford N, May S, Hendrix S, Cottrell BA, Sagi SA, Mather G, Laughlin M, Zavitz KH, Swabb E, Golde TE, Murphy MP, Koo EH. Safety, tolerability, pharmacokinetics, and Abeta levels after short-term administration of R-flurbiprofen in healthy elderly individuals. Alzheimer Dis Assoc Disord. 2007 Oct-Dec;21(4):292-9. Abstract

2. Wilcock GK, Black SE, Hendrix SB, Zavitz KH, Swabb EA, Laughlin MA; Tarenflurbil Phase II Study investigators. Lancet Neurol. 2008 Jun;7(6):483-93. Epub 2008 Apr 29. Erratum in: Lancet Neurol. 2008 Jul;7(7):575. Abstract

View all comments by M. Paul Murphy

A Chinese article (1) has previously reported that homocysteic acid (HA) levels in blood were higher in cerebral infarction with dementia than in cerebral infarction without dementia. The article also reported that HA levels increased in parallel with the severity of dementia. This indicates that HA is involved in dementia, that is, HA impaired the cognitive ability of humans.

Our findings that HA rescued the memory impairment of 3xTg-AD mice is strongly supported by this Chinese article. Both studies indicate that human cognitive ability is controlled by HA, and that we might treat human Alzheimer disease with an HA vaccine.

References:
1. Bin Zhao, Junjian Zhang, Shifeng Wang, Guanghui Chen, Fayun Hu. Combined measurement of thyroid and plasma homocysteic acid for detecting the severity of vascular dementia. Neural Regeneration Research. 2006;1(8).

View all comments by Tohru Hasegawa