• Alzheimer’s disease;
  • amyloid;
  • congophilic angiopathy;
  • dementia;
  • pathogenesis;
  • tau


  1. Top of page
  2. Abstract
  3. Predictions of the amyloid hypothesis: have they been met?
  4. What have the ‘amyloid’ clinical trials taught us so far?
  5. Are there alternatives to the amyloid hypothesis which account for the genetic data?
  6. How should we move forward?
  7. References

The amyloid hypothesis has been the basis for most work on the pathogenesis of Alzheimer’s disease. Recent clinical trials based on this hypothesis have been inconclusive. In this article I review the current status of the hypothesis and suggest that a major scientific need is to understand the normal function of amyloid-β precursor protein (APP) and think how this may relate to the cell death in the disease process.

Abbreviations used

amyloid-β precursor protein


microtubule associated protein tau


Pittsburgh compound B



Increasingly over the last 3 years, there has been a chorus of concern that the amyloid hypothesis was not delivering effective therapies for the disease. Whether this chorus is like the dawn chorus, heralding a bright new era of Alzheimer research, or a malcontent’s chorus, merely whingeing that their grants go unfunded, is open to debate. As one of the two (inaccurately) credited with originating the amyloid hypothesis (Selkoe 1991; Hardy and Allsop 1991; Hardy and Higgins 1992. Hardy and Selkoe 2002), in this review, I offer my opinion.

The purpose of the amyloid hypothesis (see Fig. 1) was to focus research onto the topics we believed were more likely to yield useful clinical results. It was not intended as an academic exercise, and it should be judged, in the long run, by whether it has facilitated that goal. Everyone would agree that it has led to the focusing and structuring of research efforts. Before the amyloid hypothesis, anything could be considered to be a reasonable idea about Alzheimer’s pathogenesis. The amyloid hypothesis generated testable predictions, some of which have proved prescient and have been fulfilled and others which have not (yet) been shown to be true. It is worth considering some of those predictions.


Figure 1.  AD/FTDP-17 – pathways to degradation. AD, Alzheimer’s disease; FTDP, frontotemporal dementia with parkinsonism; PSEN, presenilin.

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Predictions of the amyloid hypothesis: have they been met?

  1. Top of page
  2. Abstract
  3. Predictions of the amyloid hypothesis: have they been met?
  4. What have the ‘amyloid’ clinical trials taught us so far?
  5. Are there alternatives to the amyloid hypothesis which account for the genetic data?
  6. How should we move forward?
  7. References

First, an explicit prediction was that other causes of Alzheimer’s disease would relate to amyloid production and clearance. This prediction was spectacularly fulfilled when presenilins were cloned (Sherrington et al. 1995; Rogaev et al. 1995;. Levy-Lahad et al. 1995) and shown to directly relate to amyloid production (De Strooper et al. 1998; Wolfe et al. 1999), with presenilin mutations increasing the production of Aβ42 in people with mutations (Scheuner et al. 1996), and in cells and transgenic mice (Borchelt et al. 1996; Duff et al. 1996). However, since the cloning of the presenilins, we have done less well. Apolipoprotein E4 is clearly the most important risk factor for the disease (Strittmatter et al. 1993; Coon et al. 2007) with apolipopotein E4 genotype correlating with increased Aβ deposition (Holtzman et al. 2000), and while transgenic animal data clearly suggests some relationship with amyloid deposition (Bales et al. 2000), we have no real idea on the mechanism of this relationship nor its specificity.

A second prediction was that amyloid/Aβ should be toxic and this is where the data are unconvincing and, in my view, have slipped into a sterile debate on what exactly is the toxic species of Aβ. This debate has obscured the fact that relevant Aβ toxicity has barely been demonstrated. While it is clear that Aβ oligomers have synaptic effects (Walsh et al. 2002; Wang et al. 2005), none of this amounts to convincing toxicity: these subtle alterations, which are likely to underpin the marginally beneficial behavioural improvements seen in amyloid-β precursor protein (APP) transgenic mice on Aβ immunization (Janus et al. 2000; Morgan et al. 2000; Dodart et al. 2002) are a far cry from the massive cell loss seen in Alzheimer’s disease. Recent elegant data using in vivo imaging show that plaque formation can be a rapid event which induces glial and neuritic changes (Meyer-Luehmann et al. 2008) but the only time that substantial Aβ induced degeneration has been seen is in the context of additional microtubule associated protein tau (MAPT) mutations (Lewis et al. 2001; Oddo et al. 2003), and in these cases, the MAPT mutations themselves lead to cell death (Lewis et al. 2000) and so this is an experiment where neurons are very severely compromised before toxicity is seen.

A related (and third) prediction of the amyloid hypothesis is that amyloid/Aβ should initiate tangle dysfunction. The data on this are also disappointing. While, there is some cell work suggesting that Aβ toxicity is dependent on tau expression (Rapoport et al. 2002) and elegant transgenic work showing that tau expression can modulate Aβ toxicity (Roberson et al. 2007), we have no idea what the pathway between the two molecules is as yet (Mudher and Lovestone 2005).

A fourth implicit prediction of the amyloid hypothesis (which we did not make at first) is that tangle formation is a closer biological event to neuronal cell death. This has been demonstrated by the identification of MAPT mutations in FTDP17-T (Hutton et al. 1998; Poorkaj et al. 1998) and the modeling of tangle-associated cell death in transgenic mice (Lewis et al. 2000). Thus the finding of MAPT mutations in tangle-only disease is completely consistent with the amyloid hypothesis (Hardy et al. 1998).

Of course, the most important prediction of the amyloid/Aβ hypothesis is that reducing Aβ and plaques would ameliorate Alzheimer symptoms. As it is difficult to believe that most of the symptoms largely relate to anything other than the massive synaptic and cell loss which occurs in the disease (Davies et al. 1987; Masliah et al. 1991) and this has not been satisfactorily modeled in transgenic animals, this prediction has never been tested adequately addressed in such animals. The remarkable finding that Aβ immunization reduces amyloid load in animals (Schenk et al. 1999; Bard et al. 2000), and the observation that this immediately ameliorated the subtle behavioral alterations in transgenic APP animals was interpreted as indicating that this prediction had been fulfilled in animals (Janus et al. 2000; Morgan et al. 2000; Dodart et al. 2002), but as indicated above, perhaps this interpretation was premature.

What have the ‘amyloid’ clinical trials taught us so far?

  1. Top of page
  2. Abstract
  3. Predictions of the amyloid hypothesis: have they been met?
  4. What have the ‘amyloid’ clinical trials taught us so far?
  5. Are there alternatives to the amyloid hypothesis which account for the genetic data?
  6. How should we move forward?
  7. References

Three ‘amyloid’ trials have been publicly discussed. These have been the active immunization trial (Gilman et al. 2005), the passive immunization trial, and R-flurbuprofen (Tarenflurbil) as a modulator of γ-secretase (Weggen et al. 2001, Wilcock et al. 2008).

The immunization trials have seem to show that amyloid can be cleared from the brain, although there have been few biochemical analyses on the human tissue (Patton et al. 2006). The clearance of visible plaques is remarkable and runs completely counter to the previous wisdom that amyloid plaques were forever. If there is an effect of Aβ immunization on tangle formation and cell death, it is much less clear (Nicoll et al. 2003; Holmes et al. 2008).

The fact that the active immunization trial was stopped for vascular complications before it was completed, prevented clear interpretations of the clinical data being made (Atwood et al. 2003; Schenk 2004). The reduction of brain volume on treatment is also difficult to simply interpret though it may relate to some resolution of brain edema (Fox et al. 2005). The fact that the passive immunization stage 2 trial did not suffer these complications, and that the results were good enough to convince its sponsors to continue to stage 3, is encouraging. However, while it certainly remains possible that there will be a beneficial effect of amyloid immunization, it is also clear from the data from a limited number of cases, who have died after successful immunization (of events unrelated to treatment), that this approach will not give huge benefits at least when administered late in the disease (Holmes et al. 2008).

The R-flurbuprofen trial was stopped and deemed without benefit but it is not clear whether the concentration of the drug reaching the brain was sufficient and the fact that it is not a clean drug means that it is not possible to interpret the outcome of the trial in any useful way.

What do these trials tell us? Sadly, they leave little certainty. Amyloid immunization teaches us that we can massively reduce amyloid burden, but when administered late in the disease, it is not a miracle cure. It may have clinically relevant benefits and it may lead to better outcomes if it is given early in the disease or presymptomatically but we simply do not have data to address these issues.

Are there alternatives to the amyloid hypothesis which account for the genetic data?

  1. Top of page
  2. Abstract
  3. Predictions of the amyloid hypothesis: have they been met?
  4. What have the ‘amyloid’ clinical trials taught us so far?
  5. Are there alternatives to the amyloid hypothesis which account for the genetic data?
  6. How should we move forward?
  7. References

Despite the rather widespread and vocal dissatisfaction with the amyloid hypothesis, there have been only two attempts to formulate alternate molecular hypotheses which account for the genetic data. These are the presenilin inhibition hypothesis (Sambamurti et al. 2006; Shen and Kelleher 2007) and the double hit hypothesis (Small and Duff 2008).

The presenilin inhibition hypothesis

This hypothesis suggests that the key event in the interaction between APP and the presenilins, which is altered by pathogenic APP and presenilin mutations, is the efficiency by which presenilins can cleave all their substrates (Sambamurti et al. 2006; Shen and Kelleher 2007). γ-Secretase has many substrates beyond APP (De Strooper et al. 1999): presenilin mutations seem to lead to a reduced flux through the pathway (Walker et al. 2005; De Strooper 2007), and therefore some other substrate may be critical and lead to neuronal damage and death. Additionally, as APP is a highly expressed substrate (probably the most highly expressed γ-secretase substrate), mutations in it could plausibly act as competitive inhibitors of flux through the pathway and have the same effect.

Prima facie, this hypothesis was consistent with the genetic data. But it suffers from lack of experimental data to support it. Inhibition of flux in the metabolism of other substrates through γ-secretase by APP mutations has not been demonstrated, and, of course, the most straightforward prediction of the hypothesis would be that presenilin mutant mice would show tau-related neurodegeneration which they do not. Thus, its predictive value in transgenic mice is no better than the amyloid hypothesis. A central piece of data, used to support the hypothesis, suggesting that some presenilin mutations may lead directly to tangle disease in humans (Shen and Kelleher 2007) is probably not correct (Pickering-Brown et al. 2006). Furthermore, it ignores the analogy of British dementia, another plaque and tangle disease, in which γ-secretase does not seem to be involved (Vidal et al. 1999). A prediction of the hypothesis is that γ-secretase inhibition, presently considered as a therapeutic amyloid therapy, would make things worse.

The double hit hypothesis

This hypothesis (Small and Duff 2008) suggests that while the amyloid hypothesis may be basically correct for the cases with autosomal dominant disease, there is a second, presumably additional, way by which tau-induced neurodegeneration can be induced which relate to the molecular etiology of late-onset disease.

While this hypothesis is appealing in some ways, it leaves unanswered, the same major question left unanswered by the amyloid hypothesis: what is the relationship between APP/Aβ and tau? It is also unclear as to the nature and mechanism of the second hit.

A general concern

A major concern about the amyloid hypothesis is that we have very little idea as to the functions of APP or the possible function of Aβ. It is surprising that, despite the fact that it is more than 20 years since the APP gene was cloned (Kang et al. 1987), we have very little idea of its function and almost no idea as to whether Aβ has a function or not. One reason for this lack of knowledge is that APP knockout mice have very little overt phenotype (Heber et al. 2000) but the major reason for this lack of knowledge is that this has not been a major research priority. We also have no idea as to whether Aβ has a function or not. The one clear function we know about is that the extracellular domain of the protease nexin form of APP (APP751/770) is part of the clotting cascade (Xu et al. 2005).

One worrying possibility is that APPs (and possibly Aβ) are damage response proteins. While others have argued that Aβ might have some protective role (Lee et al. 2005), this possibility has not been rigorously investigated. The concern is that APP up-regulation (and even perhaps Aβ deposition) is an acute response to damage (perhaps vascular damage (Atwood et al. 2002; Kumar-Singh et al. 2005; Cullen et al. 2006; Weller et al. 2008), in line with the role of APP in the regulation of blood clotting (Xu et al. 2005) which in the presence of chronic damage adds to the problem. This general scheme of acute damage response segueing into chronic damage causation is consistent with other diseases of the elderly (such as macular degeneration and rheumatoid arthritis). This suggestion which could be thought of as a variant of the double hit hypothesis is also consistent with others’ previous suggestions of Alzheimer pathogenesis (McGeer and Rogers 1992; McGeer and McGeer 2004). In such a scenario, those people with APP and presenilin (PSEN) mutations, or with Down’s syndrome, would be postulated to have an over-primed damage response (Fig. 2). This hypothesis is consistent with the amyloid hypothesis but with the important distinction that a ‘second hit’ is vascular damage (Petrovitch et al. 2000) and this can both initiate amyloid damage or be caused by this deposition.


Figure 2.  AD. A vascular pathway to neurodegeneration? AD, Alzheimer’s disease; PSEN, presenilin.

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How should we move forward?

  1. Top of page
  2. Abstract
  3. Predictions of the amyloid hypothesis: have they been met?
  4. What have the ‘amyloid’ clinical trials taught us so far?
  5. Are there alternatives to the amyloid hypothesis which account for the genetic data?
  6. How should we move forward?
  7. References

Clearly, the aim is to develop a strategy to prevent Alzheimer’s disease. The data summarized above suggest that this is going to be a difficult goal (and this article has not dealt with the formidable problems in designing prevention trials). With this background, the following should be among our priorities.

  • 1
     From a basic science perspective, we need a focused effort to understand the functions of APP and the possible functions of Aβ. The recent data showing that the extracellular domain of APP may have a role in axonal resculpting is an encouraging start in this direction (Nikolaev et al. 2009).
  • 2
     We need to understand the nature of disease propagation: is permissive templating of Aβ (Hardy 2005; Meyer-Luehmann et al. 2006) and MAPT (Frost et al. 2009) the reason for both the characteristic neuroanatomy of the disease (Braak and Braak 1991) as well as the reason that the disease seems to become self-propagating once it has started (Oddo et al. 2004, Santacruz et al. 2005).
  • 3
     Clinical trials need to be organized in those in the very earliest stages of the disease. Whether this can be carried out genetically (e.g., by using E4 homozygotes) or by imaging [using Pittsburgh compound B (PIB): Klunk et al. 2004, 2007] or some combination of both is not clear. Of course, it could be argued that even any who show PIB signals are already too far down the disease progression for therapy and that it should be aimed even before this stage. Certainly, even those with mild Alzheimer’s disease have profound cell loss (Gómez-Isla et al. 1996).
  • 4
     Separate, although clearly related to this, anti-amyloid trials need to be carried out in individuals with APP and PSEN individuals or those with Down’s syndrome. In these individuals we can be sure that the amyloid hypothesis is basically true and potentially, this sort of trial can be a true test of the approach.
  • 5
     Trials need to be fully reported so that definitive conclusions can be reached. Negative trials, in particular, are not fully reported and this means that the reasons for failure do not become clear.
  • 6
     Biomarker studies should be included in trial designs so that the researchers can form, as clearly as possible, informed opinions as to whether the drug has hit the proposed target.

These are six difficult objectives. Additionally, it makes sense to pursue other targets beyond Aβ (Noble et al. 2005). Over the last 16 years much progress has been made in understanding the molecular biology of the disease pathogenesis but it looks like there is further left to go before we have effective treatments than we had anticipated. Given the ageing population and the concomitant increase in the number of Alzheimer sufferers, attaining this goal is an extremely important societal priority. To achieve this goal, all the choir need to sing from the same hymn sheet.


  1. Top of page
  2. Abstract
  3. Predictions of the amyloid hypothesis: have they been met?
  4. What have the ‘amyloid’ clinical trials taught us so far?
  5. Are there alternatives to the amyloid hypothesis which account for the genetic data?
  6. How should we move forward?
  7. References
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