Alois Alzheimer made a major breakthrough when he discovered senile plaques in the brains of dementia patients, and his work ultimately led to the discovery of amyloid-β and to the amyloid cascade hypothesis. But that cascade is only part of a much bigger drama, and may even be one of the later acts. Researchers are still very much in the dark about what triggers amyloid buildup in most late-onset AD cases and what happens early in the lead-up toward AD.

Karl Herrup at Rutgers University, Piscataway, New Jersey, believes that the time has come to reassess what we know about AD, focusing less on amyloid and more on age-related changes that create the conditions for the disease to take hold. In a recent Disease Focus article in the Journal of Neuroscience, Herrup laid out a new model, of which the amyloid cascade is but one of many parts. His emphasis is less on amyloid and more on age-related changes that trigger pathology.

On 27 April 2011, this Webinar explored these ideas. Herrup presented his hypothesis and was joined for a panel discussion by Michael Heneka, University of Bonn, Germany; Dave Morgan, University of South Florida, Tampa; Mary Sano, Mount Sinai School of Medicine, New York; and Michael Wolfe, Brigham and Women’s Hospital, Boston, Massachusetts. Read the article, and submit your own ideas on Alzheimer’s etiology. The Alzforum editors gratefully acknowledge the Society for Neuroscience, which granted our readers open access to this article to facilitate discussion and stimulate new research directions.

Listen to the Webinar

Karl Herrup: 0:00
Michael Wolfe: 24:40
Michael Heneka: 35:12
Mary Sano: 43:51
Dave Morgan: 49:22
Discussion: 56:13

Karl Herrup's Presentation

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Michael Wolfe's Presentation

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Michael Heneka's Presentation

Mary Sano's Presentation

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Dave Morgan's Presentation

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Background Text
By Tom Fagan

The identification of amyloid-β peptides in senile plaques was a major breakthrough in Alzheimer’s research, and ultimately led to the amyloid cascade hypothesis. That hypothesis contends that accumulation of Aβ is the major driving force in AD pathology. The theory also became a major driving force in AD research, leading to a wealth of new information. But roughly over10 years later, researchers are still trying to get a handle on what causes most cases of Alzheimer’s disease. For rare, inherited forms that are driven by mutations in amyloid precursor protein or the presenilins that cleave amyloid-β from it, the cause is clear. But for the vast majority of late-onset cases, the trigger remains uncertain.

The strongest risk factor for late-onset AD, by far, is age. In his article in the Journal of Neuroscience, Herrup argues that the etiology of the disease should be considered in that context. Age brings a slowing of cognition, a deterioration in motor function, a loss of synaptic complexity in the brain, and a weakening of immune defenses, all of which could set the stage for subsequent neurodegeneration. How does a signature pathology of Alzheimer’s emerge from this state?

Herrup cites hip fracture as a useful analogy. There are many risk factors that lead to hip fractures—weakening bones due to osteoporosis, loss of muscle control and strength, poor balance, slower reaction time, and weakening visual acuity. None of these by themselves cause hip fracture, but they set the stage for an event that does, such as a fall. Is something similar going on in the aging brain? Herrup hypothesizes three steps that ultimately lead to AD: an initial injury, an ensuing chronic inflammatory response, and a change in cellular state that affects most of the brain. The initial injury could be a head trauma or a cardiovascular failure, such as a micro-stroke. The change in state could be an attempted re-entry into the cell cycle—a no-no for post-mitotic neurons—or an irreversible activation of microglia. These events would, in turn, set the stage for accumulation of Aβ and for neurodegeneration.

What does this view mean for the study, prevention, and treatment of Alzheimer’s? Herrup suggests that if the initial injuries can be identified, then it may be possible to intervene early to delay disease onset. A refocus on aging as the major risk factor might spur new therapeutic approaches that capitalize on recent insights into the aging process. And the realization that cells are changing could lead to a re-evaluation of the molecular biology surrounding Aβ, tau, autophagy, and other key players and processes that have been implicated in pathology. To understand Herrup’s perspective beyond these brief excerpts, Read his article in the Journal of Neuroscience, and then bring your comments to the table.


  1. I agree with Dr. Herrup that Alzheimer’s disease pathogenesis should be examined in the context of age as the strongest risk factor. The point I want to make is that inflammation, too, has to be looked at from the perspective of aging. A major flaw in the view of inflammation and Alzheimer’s disease is that most of the evidence supporting a deleterious role of microglia comes from: 1) studies in fetal microglia cultures, and 2) studies in mouse models where plaques develop at a relative young age. None of these approaches recapitulate the inflammatory reactions of an old brain. A second flaw is that conclusions are based upon correlative observations such as the increase of inflammatory mediators in fluids or in the brain, of the “activation” of microglia according to morphology. None of these data support a causal role of microglia in Alzheimer’s pathogenesis, and we should dispel once and for all the notion that morphological changes are a telltale of function, for all the spectrum of microglia phenotypes is accompanied by a characteristic shortening of processes. Yet a third flaw is the inattention to astrocytes and how these cells, which control energy homeostasis, neurovascular coupling, and antioxidant protection, are affected by aging.

    My view is that age renders astrocytes and microglia dysfunctional. Astrocytes neglect their support roles, thereby contributing to hypometabolism, hypoperfusion, and oxidative stress. Microglia, in turn, do not mount an optimal inflammatory response that includes amyloid-β phagocytosis and tissue repair. This implies that appropriate activation of microglia may have therapeutic benefits. In this vein, note that administration of allegedly bad pro-inflammatory cytokines like IL1, IL6, or TNFα, or increasing noradrenaline levels in the brain, result in microglia activation and reduced plaque deposition. Finally, returning to Dr. Herrup´s contribution, he contends that the epidemiological evidence describing protection by NSAIDs should be taken as a proof that inflammation serves as a cause of Alzheimer’s disease. I want to draw attention to the epidemiological observation that NSAIDs afford protection only in ApoE4 carriers. This suggests that the long-elusive molecular target of these drugs is the lipoprotein, and not the canonical cyclo-oxygenases.

  2. Enticed by the topic and the title of this well-timed Alzforum Webinar, I would like to briefly present here a novel, unifying scenario on the nature of AD, PD, HD, ALS, FTLD-U, CJD, and other related devastating neurodegenerative disorders (1,2). Similar to Herrup’s, and the work of many other AD researchers, this new scenario bypasses the amyloid cascade hypothesis in rationalizing AD etiology. However, unlike these efforts, which ‘throw the baby out with the bath water,’ this scenario places APP/Aβ at the center of AD etiology, albeit from a radical new perspective.

    According to this unifying scenario, APP/Aβ, α-synuclein, tau, huntingtin, TDP-43, and prion protein are members of the innate immune system, and their primary function is to block the life cycle of various pathogens, such as viruses, either directly by interacting with their components, or indirectly by inducing the death of the host cells by various mechanisms, including apoptosis (discussed in 1,2). Moreover, some of these innate immunity proteins exercise their protective function in other types of injuries that mimic those produced by infectious pathogens, including physical, biochemical, and age related injuries.

    Similar to other components of the immune system, the genes coding for APP/Aβ, α-synuclein, tau, huntingtin, TDP-43, and prion protein were evolutionarily selected against autoimmune diseases; however, like many other immune components, they run a fine line between protection and pathogenicity. Due to mutations or other factors, these innate immunity proteins inadvertently assemble into oligomeric species, or aberrant ‘pathogen-like immune complexes’ (PICs) that structurally or functionally resemble components or activities of foreign infectious pathogens. From a biochemical, functional, and evolutionary perspective, the propensity of this group of proteins to form oligomeric complexes is related to their innate immune mechanisms (for example, in the case of Aβ the formation of pores or other complexes that interfere with viral replication at internal membrane sites, such as the mitochondrial membranes); for some of these proteins, such as the prion protein, this feature is also related to their viral evolutionary origin (1).

    The native APP/Aβ, α-synuclein, tau, huntingtin, TDP-43, and prion protein recognize PICs) as foreign infectious agents (i.e. as ‘non-self’) which leads to their immune response. Unfortunately, during their immune response, these proteins form additional aberrant PICs, leading to a vicious autoimmune cycle (VAC) and to cellular death (in the context of this model, in addition to PICs, these innate immunity proteins form numerous benign amyloid-like complexes, which accumulate as plaques or tangles). Furthermore, once the PICs are formed, they circulate among cells, tissues, and (more rarely) among individuals, leading to an expanded VAC, to massive cellular death, and to a wide spectrum of clinical diseases.

    The overall strength of this unifying scenario is that it is consistent with, and it integrates and explains much of the existing data and observations, and makes biological and evolutionary sense (reviewed in 1). For example, APP/Aβ, α-synuclein, tau, huntingtin, TDP-43, and prion protein are expressed primarily in tissues that are not under normal adaptive immune surveillance, such as the brain and germ-line tissues, and at portals for the entry and circulation of infectious agents. Additionally, as expected, deleting or silencing the genes coding for these proteins in animal models have no observable phenotypic effects under normal experimental conditions that keep these animals isolated from infectious agents.

    Most importantly, though, this new scenario links the biological function of APP/Aβ, α-synuclein, tau, huntingtin, TDP-43 and prion protein to the pathogenic mechanisms, which is a complete departure from the current paradigms, including the perspective presented in Herrup’s paper. More specifically, according to this radical scenario, the formation of PICs and the pathogenic mechanisms leading to cellular death are basically the same intrinsic properties and mechanisms that these proteins normally use during their protective functions.

    Although this new unifying scenario is consistent with the current observations and experimental data (see, e.g., Refs 3-9 for data on antiviral/antimicrobial activity of some of these putative innate immunity proteins), and it integrates many of the current ideas and hypotheses, including some of the tenets presented in Herrup’s hypothesis, obviously, it needs further evaluation and full experimental validation. It would be an understatement to say that understanding the function of APP/Aβ, α-synuclein, tau, huntingtin, TDP-43, and prion protein, and the etiology of these neurodegenerative disorders, would help with the development of prevention and therapeutic approaches, which are urgently needed.

    References: See also Bandea C. Comment to paper by Sandberg et al. Prion propagation and toxicity in vivo occur in two distinct mechanistic phases, Nature 2011; 470:450-452.


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  3. I have much respect for Dr. Herrup and for his scholarly review article. I agree that dementia comes from many different diseases, and aging no doubt plays a role in some dementia subtypes.

    Focusing on non-AD processes linked to aging is laudable and important. In particular, treatment of conditions such as hypertension and diabetes—which affect the brain adversely and increase in prevalence in advanced age—has a high likelihood of improving clinical outcomes.

    On the other hand, it may not be accurate to say that “aging is the greatest risk factor for AD.” Approximately 70 percent of an individual’s risk for AD comes through his/her genetic repertoire (1,2), and not all aged folks get AD (either according to clinical or pathological diagnostic criteria).

    Data from a variety of sources indicate that there is an important and particular disease characterized pathologically by plaques and tangles that has not been proven to be linked to aging any more than other conditions such as genetic prion, FTLD, metabolic, or mitochondrial diseases that affect older individuals. This disease (AD) may best respond to therapies that target particular pathways that are aberrantly regulated, probably linked to APP and MAPT. For people interested in the data that could support these ideas, see Ref. 3 below.


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  4. I fully agree with Karl Herrup’s diagnosis that the early detection of risk factors, and their elimination could lead to novel therapeutic and preventive strategies in Alzheimer’s disease. I would also go further and suggest that many of these risk factors are already known, and that many can perhaps be prevented. There are hundreds of genetic risk factors and dozens of environmental risk factors thought to contribute to Alzheimer’s disease, some of which are indexed at Polygenic Pathways.

    β amyloid deposition can be produced by several of the environmental risk factors in animal models, without the aid of any particular gene variant. Those able to do so include herpes simplex (1-3) or Chlamydia pneumoniae infection (4;5), Borrelia burgdorferi spirochete infection (6), hypercholesterolemia (which also causes cholinergic neuronal loss and memory deficits in rats [7-10]), hyperhomocysteinemia (an effect reversed by folate and vitamin-B12 [11]), NGF deprivation (12), reduced cerebral perfusion (hypoxia, cerebral ischemia or carotid artery occlusion [13-16]), as well as experimental diabetes and streptozotocin (17,18), estrogen depletion (19) or vitamin A deficiency, which also reduces choline acetyltransferase activity in the forebrain (20).

    The risk factors in Alzheimer’s disease include herpes simplex infection (21,22), C. pneumoniae (23,24) Helicobacter pylori or Borrelia infection (25-27), hypercholesterolemia (28), atherosclerosis of the carotid arteries, leptomeningeal arteries or the circle of Willis, and stroke leading to cerebral hypoperfusion (29-32), hyperhomocysteinemia (33), low folate levels in carriers of a certain MTHFR genotype (34), type 2 diabetes and modified insulin metabolism (35), age-related loss of sex steroid hormones in both women and men (36,37), low levels of cerebral NGF (38) and vitamin A deficiency (39).

    Many of the various risk factors that predominate in Alzheimer’s disease could thus be causative agents, at least in terms of being able to generate β amyloid deposition. In many cases, subsets of Alzheimer’s disease susceptibility genes can also be related to these various risk factors, suggesting that genes and risk factors are likely to condition each other’s effects (40) (see full text in press).

    Vitamin and folate deficiencies can be monitored and corrected, advice on cholesterol- and homocysteine-friendly diets can be given, pathogens can be detected and in some cases eliminated. The eradication of Helicobacter pylori has recently been reported to increase the lifespan and cognitive abilities of Alzheimer’s disease patients (41,42). Many of these β amyloid-generating risk factors are thus detectable and preventable, and their regular monitoring and correction in the aging population could perhaps have a marked effect on the incidence, severity, and progression of Alzheimer’s disease.


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  5. I found quite informative the paper by Karl Herrup describing a novel hypothesis for the initiation and progression of AD. I have nevertheless some criticisms to his hypothesis.

    The initiation step formulated under this hypothesis seems to be primarily of stochastic nature. This concept is in contradiction with the known spatial progression of the pathological hallmarks of the disease. Braak and Braak (1991) described that the first AD stages affect the transentorhinal layer Pre-α; then, in subsequent stages, layer Pre-α in both transentorhinal region and proper entorhinal cortex are observed to be affected. This is followed by the effects on the first Ammon's horn sector. Finally, virtually all isocortical association areas were severely affected. I think this reproducible pattern cannot be simply explained by stochastic injuries of different nature in the aged brain. Therefore, specific factors, participating in the initial step of the disease, should have been taken into consideration in this hypothesis.

    One putative factor initiating this stereotyped pattern could be the presence of the common neurotrophin receptor p75 and its ligand proNGF in the basal forebrain. These molecules are activated under stress conditions, they become upregulated in aged brain, and they trigger cell cycle reentry/tetraploidization of neurons (Morillo et al., 2010).

    We have recently proposed a model for the initiation and progression of AD based on p75 (Frade and López-Sánchez, 2010). Our model coincides in many aspects with Herrup’s proposal, as we also consider the existence of an amyloid deposition cycle that could propagate the disease throughout the different structures of the brain, as described by Braak and Braak (1991). Moreover, we considered in our hypothesis that the change-of-state affecting tetraploid neurons (step 3 of Herrup’s hypothesis) is due to the morphological and the associated functional alterations expected to occur in neurons undergoing tetraploidy (see Morillo et al., 2010; Yamagishi et al., 2011). Maybe our hypothesis could be integrated in the more general view described by Herrup in his article.


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    . DNA endoreplication in the brain neurons during body growth of an adult slug. J Neurosci. 2011 Apr 13;31(15):5596-604. PubMed.

  6. If history is any guide, we won't really have an understanding of the "cause" of Alzheimer's disease until we have a treatment that blocks or reduces its progression. In any event, from the clinical point of view, a "cause" is of little value if we can't interrupt its effects.

    Having experience leading to the development of the main drug currently used to treat AD, I believe the approved products are not there yet.

    We've believed that cellular damage was an important part of AD and shown that various types of cellular "damage" replicate many of the biochemical changes associated with AD. Our company, Senex Biotechnology, Inc., has discovered an entirely new class of drug that blocks all of the damage-induced biochemical changes associated with Alzheimer's disease that we've looked at so far, including APP synthesis, tau synthesis and hyperphosphorylation, cytokine production, and entry into the cell cycle. These compounds could provide a test of the hypothesis that AD is the result of accumulated cellular damage. They could also be effective, disease-modifying treatments if accumulated cellular damage is an important cause of AD.

    We are focused mainly on using these agents for treatment of other diseases, but they might be useful for assessing the validity of this model of AD. If anyone is interested in trying this, please let me know.

  7. I think Prof. Herrup’s proposal is a very valuable contribution to the debate about mechanism. I would like to comment on the proposal of an amyloid expression/deposition cycle driven by inflammation. There is another possibility for a driver of this cycle, and it is low oxygen/oxidative stress.

    Oxygen supply to the brain is dependent, of course, on the condition of the vasculature. Insufficient oxygen supply causes mitochondria to generate larger amounts of reactive oxygen species (oxidative stress). We also know that the vasculature is particularly sensitive to reactive oxygen species (ROS). Therefore, under conditions where oxygen supply to the brain becomes limited and the brain’s ability to neutralize reactive oxygen species is surpassed, we can imagine a damaging positive feedback occurring where increased oxidative stress damages the vasculature and so causes more oxidative stress. A number of papers show that genes central to Alzheimer’s disease—such as the presenilins, APP, and BACE1—are upregulated under oxidative stress, and that this leads to upregulation of Aβ production (e.g., see papers from Tabaton’s laboratory and others).

    My laboratory has looked at this in zebrafish and found that the regulatory responses of these genes to low oxygen are conserved over 400 million years of evolution (manuscript submitted)—suggesting that upregulation of these genes (and, presumably, Aβ production) under low oxygen/oxidative stress is selectively advantageous (and presumably protective). There are also papers suggesting that Aβ has antioxidant properties (e.g., Nadal et al., 2008 and Baruch-Suchodolsky and Fischer, 2009). Put this together with the work from Schon’s laboratory showing that most γ-secretase activity, much of APP, most PSEN1, and, apparently, all PSEN2 are concentrated in the mitochondrial-associated membranes (MAM) of the ER that communicate intimately with mitochondria (and that are themselves a source of considerable hydrogen peroxide), and you have a situation where BACE1, the presenilins, and APP act to regulate reactive oxygen species and that part of this mechanism involves production of Aβ. Of course, mutations that alter Aβ production (leading either to overexpression or underexpression of Aβ peptides) would lead to dysregulation of ROS, and, presumably, damage to microvasculature (which might also then affect Aβ clearance).

    The mechanism suggested above supports the hypothesis that Alzheimer’s disease is, primarily, a disease of the vasculature, which is in line with the similarity of cardiovascular and AD risk factors, and the fact that in a mouse model, AD mutations in PSEN1 expressed only in neurons can cause changes in microvasculature (Gama Sosa et al., 2010), and that AD patients show changes in cerebral blood flow (van Beek et al., 2011), etc.

    It is also interesting that Kallhoff-Munoz et al. showed that the hydrophilic loop of PSEN1 is required for cell cycle events in mouse neurons (Kallhoff-Munoz et al., 2008) and Varvel et al. showed that oligomeric but not monomeric Aβ could induce cell cycle events in such cells (Varvel et al., 2008). (This suggests that oligomeric Aβ somehow feeds back through PSEN1 to induce these events.) The existence or not of amyloid plaques in sporadic AD may have to do with the susceptibility of an individual’s aging neuronal microvasculature to microhemorrhage, since Cullen et al. showed a very significant association of plaques with microvasculature (Cullen et al., 2006) and Stone pointed out in his 2008 paper in Medical Hypotheses (Stone, 2008) that heme is found in all Aβ plaques.


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  8. Yes, aging is the strongest risk factor, but how does age induce Alzheimer's disease?

    We have found that age suppresses excretion of homocysteic acid (HA) into urine, which, we believe, induces Alzheimer's disease (1). We reported that HA is a pathogen of Alzheimer's disease in 3xTg-AD model mice (2). That is, HA showed a strong neurodegenerative effect in mice, and so it is suggested it may have the same effect on the human brain.

    Normally, humans actively excrete HA into urine, but age suppresses this, increasing blood HA. The increased HA disrupts the blood-brain barrier, enters the brain, and consequently compromises brain function, such as cognitive ability.

    This age effect should be considered as a pathogen for Alzheimer's disease.

    See also:
    Abstract accepted in ICAD in Paris on 19 July 2011.


    . Treatment of Alzheimer's disease with anti-homocysteic acid antibody in 3xTg-AD male mice. PLoS One. 2010 Jan 20;5(1):e8593. PubMed.

  9. We recently suggested that dementia-related hyperhomocysteinemia and its attendant hypomethylation reflect B vitamin depletion due to predictable consequences of neuroinflammatory oxidative stress (1).

    Framed within the context of an age-based hypothesis, this can be considered a consequence of the inflammatory response and an important component of the postulated “change of state,” with pathways leading to both tau hyperphosphorylation and amyloid deposition (2,3).


    . Alzheimer's disease, oxidative stress and B-vitamin depletion. Future Neurol. 2007 Sep;2(5):537-47.

    . Protein phosphatase 2A methyltransferase links homocysteine metabolism with tau and amyloid precursor protein regulation. J Neurosci. 2007 Mar 14;27(11):2751-9. PubMed.

    . One-carbon metabolism and Alzheimer's disease: is it all a methylation matter?. Neurobiol Aging. 2011 Jul;32(7):1192-5. PubMed.

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Paper Citations

  1. . Reimagining Alzheimer's disease--an age-based hypothesis. J Neurosci. 2010 Dec 15;30(50):16755-62. PubMed.

External Citations

  1. article in the Journal of Neuroscience
  2. Read the article

Further Reading


  1. . Induction of neurogenesis in the neocortex of adult mice. Nature. 2000 Jun 22;405(6789):951-5. PubMed.
  2. . Self-repair in the brain. Nature. 2000 Jun 22;405(6789):892-3, 895. PubMed.
  3. . Reimagining Alzheimer's disease--an age-based hypothesis. J Neurosci. 2010 Dec 15;30(50):16755-62. PubMed.