Resolving controversies on the path to Alzheimer's therapeutics.
Nat Med. 2011 Sep;17(9):1060-5.
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We should learn from the success of the vaccination against cervical cancer.
Selkoe’s article is timely and provocative. I am sure that many will agree with his view, “Of salient importance is testing in the mild phase of dementia—or even earlier.” But there appears to be a contradiction between the statement, “Importantly, alternative disease-modifying targets, especially tau and neuroinflammation, should also be vigorously pursued” and the schema in Figure 2, where he proposes that compounds should only move into clinical testing if they have met all the preclinical criteria, including lessening AD phenotypes in mouse models, which are based upon Aβ. Selkoe himself admits that the mouse models do not produce the full spectrum of Alzheimer's disease phenotypes. If we adopt this approach, there is a risk that truly novel therapies will be missed if they have to satisfy an amyloid mouse model.
In spite of disappointments (e.g., over statins), I believe we should not ignore approaches from epidemiology. But I support Selkoe that such approaches should be targeted at those with MCI. A recent example is our VITACOG trial of homocysteine-lowering B vitamins in subjects with MCI. A two-year treatment with folic acid, and vitamins B6 and B12 led to a slowing of the rate of brain atrophy and, in those with elevated baseline homocysteine, to a slowing of cognitive decline and an improvement in clinical status as shown by CDR and IQCODE (Smith at al., 2010; De Jager et al., 2011). The parallel effects on brain atrophy and on cognition suggest that this treatment is modifying the disease process. The results are consistent with an earlier homocysteine-lowering trial in patients with AD, where a slowing of cognitive decline was found in those with mild AD, but not in those with moderate AD (Aisen et al., 2008). Neither of these trials was predicated on prior animal experiments, but arose out of hypothesis-generating epidemiological studies.
Aisen PS, Schneider LS, Sano M, Diaz-Arrastia R, van Dyck CH, Weiner MF, Bottiglieri T, Jin S, Stokes KT, Thomas RG, Thal LJ, .
High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial.
JAMA. 2008 Oct 15;300(15):1774-83.
de Jager CA, Oulhaj A, Jacoby R, Refsum H, Smith AD.
Cognitive and clinical outcomes of homocysteine-lowering B-vitamin treatment in mild cognitive impairment: a randomized controlled trial.
Int J Geriatr Psychiatry. 2011 Jul 21;
Smith AD, Smith SM, de Jager CA, Whitbread P, Johnston C, Agacinski G, Oulhaj A, Bradley KM, Jacoby R, Refsum H.
Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial.
PLoS One. 2010;5(9):e12244.
Dr. Smith makes good points. I concur that some potentially disease-modifying trials (such as the promising approach of lowering homocysteine levels) that are not necessarily directed at the underlying histopathology of AD may not meet the criteria I set out in Fig. 2, but are nonetheless worthwhile pursuing. Regarding anti-tau approaches, I believe that tau accumulates abnormally and alters its phosphorylation state in some "bigenic" (mutant APP + mutant tau) mouse models. Therefore, tau-modulating agents could be tried preclinically in those models, or even in tau-only transgenic mice, as the agents may be efficacious whether the tau abnormality arises de novo from the tau gene/protein itself or secondary to AAβ accumulation.
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