. A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature. 2012 Aug 2;488(7409):96-9. PubMed.


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  1. This elegant and important study finds an association between a rare APP variant and a lower risk of AD, and it provides strong evidence to suggest that the protective effects of this variant may be attributable to reductions in BACE1-mediated APP cleavage. This study provides additional support for the amyloid hypothesis and the potential role of BACE1 inhibitors in the preclinical treatment of AD. It also illustrates the potential value of whole-genome sequencing studies, when used in conjunction with relevant basic scientific research, to advance the understanding of AD and the discovery of promising investigational treatments.

    This study only adds to the interest that my Alzheimer's Prevention Initiative (API) colleagues, other researchers, and I have in the possibility of evaluating suitable BACE1 inhibitors (and related agents) in persons at increased risk of developing AD, and our interest in learning more about safety, tolerability, and certain other effects in clinically affected patients. We see particular value in the possibility of evaluating anti-amyloid production treatments like these in ApoE4 carriers and young adult PS1 mutation carriers, since these agents might have the best chance to exert a profound benefit if started before the accumulation of significant fibrillar amyloid.

    View all comments by Eric M. Reiman
  2. I agree with the comments underlying the importance of this paper, which supports the pathogenic role of APP processing by BACE in sporadic AD. As noted in many comments, these findings also suggest that inhibition of BACE processing of APP will be a beneficial therapeutic approach for both familial and sporadic AD. Perhaps, this treatment may also improve performance in elderly with no obvious cognitive deficiency. BACE1 inhibitors may, however, have toxic effects related to the important biological functions of BACE processing of other substrates. Therefore, as noted by Dr. Tanzi, "inhibitors might need to be selective for APP in order to be safe enough for such long-term use." Interestingly, a molecule with these features has been recently described—MoBA, Modulator of Β-processing of APP (Tamayev et al., 2012), and may represent a leading compound to develop drugs that interfere with BACE1 processing of APP without inhibiting the proteolytic activity of BACE1 on the other substrates.

    However, contrary to what is said by many, I do not think that the finding validates or confirms the amyloid cascade hypothesis. Reduction of β-processing of APP will first result in a reduction of sAPPβ and β-CTFs. Therefore, this finding is also consistent with alternative hypotheses of AD pathogenesis which point to sAPPβ and/or β-CTFs, and not Aβ, as the main pathogenic APP-derived metabolites (Tamayev et al., 2012; Nikolaev et al., 2009; Tamayev and D'Adamio, 2012).

    View all comments by Luciano D'Adamio
  3. New APP Mutation Does Not Advance the Amyloid Hypothesis Debate
    In response to the question, Does β amyloid accumulation drive Alzheimer’s disease?, the answer is “most likely no,” and the new data presented by Jonsson et al. does not change that answer.

    That the amyloid hypothesis inadequately accounts for the current data has been known for some time. It lacks a theoretical foundation from which the physiological generation of Aβ can be understood, and therapeutic approaches based on its premises have all failed. Furthermore, there is no significant correlation between Aβ accumulation and cognitive deterioration in either humans or in mouse models, and Aβ-containing senile plaques have been found in the brains of approximately 30 percent of individuals with no signs of dementia (Crystal et al., 1988; Price et al., 2009).

    This does not necessarily indicate that Aβ is not a key factor in AD. The weakness of the amyloid hypothesis is not that it links Aβ and AD, but rather that it places Aβ as the key pathogenic trigger of the disease and, accordingly, ought to be the main target for therapeutic purposes. To date, all the available evidence—including clinical drug trials—indicates that this is an increasingly unlikely scenario.

    Rather, the hypothesis that best fits the current body of evidence in the AD field, including the work by Jonsson et al., is that Aβ is a key element of the brain’s adaptive response to stress. The idea of an adaptive response to stress in the brain, in the context of both aging and AD pathogenesis, has been put forward in various forms by scientists including George Perry, Mark Smith, Karl Herrup, and others (Stranahan et al., 2011; Stranahan and Mattson, 2012; Nunomura et al., 2001; Pappolla et al., 2002; Castellani et al., 2009; Herrup, 2010; Castello and Soriano, 2012). The idea is that failure of this adaptive response, or its chronic activation, is what leads to sporadic AD, instead of overproduction of Aβ itself. The nature of that stress in the brain is wide ranging, encompassing microglia activation, accumulation of reactive oxygen species, and cholesterol dysregulation, and the adaptive response it elicits involves regulation of APP through its cleavage products, including Aβ and sAPPα (Castello and Soriano, 2012; Stranahan and Mattson, 2012; Castellani et al., 2009).

    In the case of the A673T mutation, all other factors being comparable, the combination of lesser Aβ levels, changes in APP-driven cholesterol regulation, and/or higher levels of sAPPα would all result in a more efficient adaptive response, accounting for the delay in AD age of onset described by Jonsson et al. (Castello and Soriano, 2012). Note also that the A673T mutation, creating a stronger adaptive response, is also consistent with the superior performance in cognitive tests of patients with the mutation. Mutation carriers retain cognitive ability for a longer period of time even when they do develop AD, as is visually demonstrated by the supplementary figures in Jonsson et al.

    Overall, the message is that we should not rush back into the race to find the best BACE inhibitors to fight AD, as many commentators and scientists have suggested here and in the media. The line of inquiry involving BACE biology in AD has been in progress for over a decade, with negative outcomes, recent examples of which appear in the sidebar next to this very article (ARF related news story; ARF news story).

    We need to reassess the way we approach research in the AD field. Instead of continuing a never-ending search for the elusive final proof that the amyloid hypothesis is correct, we should begin first by restructuring AD diagnosis to focus on symptomatic changes rather than the neuropathological identification of amyloid plaques, as has been suggested (Dubois et al., 2010). The pathological process of AD suggests variations of the same stress response. Therefore, our research should focus on the primary issue—the sources of stress that create a need for the adaptive response involving APP and Aβ.

    View all comments by Matthew Zabel
  4. This is a nice finding by Jonsson et al., and adds more evidence to the idea published in 2009 by an Italian group that changes to this amino acid position in APP can prevent or facilitate aggregation of human Aβ.

    It seems that amino acids at position 2 of hAβ with larger side chains than alanine may prevent aggregation. Di Fede showed that a transition, A2V, in Aβ was protective in heterozygotes, whereas homozygotic individuals had a higher risk in the studied family tree.

    They also presented aggregation profiles of pure and mixed Aβ species that nicely supported the aggregation idea. Thus, the question remains whether it is indeed a BACE-related mechanism or just an aggregation problem of these Aβ species due to stereology. In our hands, cerebral injection and chronic infusion of A2V Aβ1-6 peptides reduced plaque formation in mice. That could be exploited as a treatment option (unpublished data).

    As we know, mouse Aβ is different in three amino acids at the N-terminal, and these differences completely prevent plaque formation and fibril generation in mice.

    View all comments by Jens Pahnke
  5. This study provides elegant genetic evidence that reducing the BACE processing of APP protects against late-onset AD. The finding complements the long-standing observations that increased BACE processing (APPswe mutation or elevated BACE levels [1]) enhances the risk for AD.

    What gets ignored in ensuing discussions, however, is the fact that BACE processing of APP generates not only Aβ peptides, but also β-CTFs and AICD peptides (studies from three groups show that BACE processing enhances AICD generation and signaling [2-4]). Since both β-CTF and AICD cause AD-like pathological features in vivo in mouse models (5,6), the present study is consistent with, but cannot be claimed to support, the amyloid hypothesis (the causal role of Aβ in AD).

    Nonetheless, this study is important because it identifies a unique human population (A673T carriers) that can be used to further validate neuroimaging (PIB imaging) and CSF biomarkers. Indeed, it will be very informative to see whether biomarker changes in this population appear at the same time as in the non-carriers or are significantly delayed.

    View all comments by Sanjay Pimplikar