Updated 23 July 2005
By Dennis Selkoe, Brigham and Women's Hospital, Boston, MA.
The following precis on the amyloid hypothesis was originallly presented by Dennis
Selkoe in his plenary lecture at the Fifth International Conference on Alzheimer's
Disease in Osaka, Japan, in 1996. The summary slide view of the Amyloid Cascade
Hypothesis has subsequently been updated, with the most recent version (2005) currently
on display. Dr. Selkoe was kind enough to respond to questions through January 1997.
The seminar is now closed to new questions. To view the questions and answers, proceed to Q&A. View Live
Debate between Steven Younkin and Dennis Selkoe.
A major theme in many of the speakers is that cognitive impairment in Alzheimer's
disease is referable to loss of specific populations of projection neurons and the
breakdown of highly vulnerable neural systems, especially those involved in memory
formation. There is general consensus among these speakers that these neuronal alterations
occur largely independent of amyloid deposition.
Central Questions in AD Research
- What are the necessary steps in AD pathogenesis that, if inhibited, would slow or
prevent the dementia?
Which of these necessary steps are most amenable to therapeutic inhibition?
AD is a clinicopathological syndrome in which different gene defects can lead—directly
or indirectly—to altered APP expression or proteolytic processing or to changes
in Aβ stability or aggregation. These result in a chronic imbalance between
Aβ production and clearance. Gradual accumulation of aggregated Aβ initiates
a complex, multistep cascade that includes gliosis, inflammatory changes, neuritic/synaptic
change, tangles and transmitter loss.
Amyloid Cascade Hypothesis Diagram
Updated Sequence: 23 May 2005
Amyloid Cascade Hypothesis Diagram )
Amyloid Cascade Hypothesis Diagram )
[Click image to enlarge}
Ten Key Observations that Support β-amyloid as the Common Initiating Factor
- All AD patients have many amyloid plaques containing degenerating nerve endings;
their plaque count far exceeds that found in normal aging.
Blessed G, Tomlinson BE, Roth M. The association between quantitative measures of
dementia and of senile change in the cerebral grey matter of elderly subjects. Br
J Psychiatry. 1968 Jul;114(512):797-811. No abstract available.
Perry EK, Tomlinson BE, Blessed G, Bergmann K, Gibson PH, Perry RH. Correlation
of cholinergic abnormalities with senile plaques and mental test scores in senile
dementia. Br Med J. 1978 Nov 25;2(6150):1457-9.
- The amount of amyloid plaques in "thinking" regions of the brain correlates with
the degree of mental impairment. See:
Cummings BJ, Cotman CW. Image analysis of beta-amyloid load in Alzheimer's disease
and relation to dementia severity. Lancet. 1995 Dec 9;346(8989):1524-8.
- All 4 genes now known to cause AD have been shown to increase Aβ production
(APP, PS1, PS2) or Aß deposition (ApoE4).
- For APP see:
Citron M, Oltersdorf T, Haass C, McConlogue L, Hung AY, Seubert P, Vigo-Pelfrey
C, Lieberburg I, Selkoe DJ. Mutation of the beta-amyloid precursor protein in familial
Alzheimer's disease increases beta-protein production. Nature. 1992 Dec 17;360(6405):672-4.
Cai XD, Golde TE, Younkin SG. Release of excess amyloid beta protein from a mutant
amyloid beta protein precursor. Science. 1993 Jan 22;259(5094):514-6.
Haass C, Hung AY, Selkoe DJ, Teplow DB. Mutations associated with a locus for familial
Alzheimer's disease result in alternative processing of amyloid beta-protein precursor.
J Biol Chem. 1994 Jul 1;269(26):17741-8. Abstract
Suzuki N, Cheung TT, Cai XD, Odaka A, Otvos L Jr, Eckman C, Golde TE, Younkin SG.
An increased percentage of long amyloid beta protein secreted by familial amyloid
beta protein precursor (beta APP717) mutants. Science. 1994 May 27;264(5163):1336-40.
Citron M, Vigo-Pelfrey C, Teplow DB, Miller C, Schenk D, Johnston J, Winblad B,
Venizelos N, Lannfelt L, Selkoe DJ. Excessive production of amyloid beta-protein
by peripheral cells of symptomatic and presymptomatic patients carrying the Swedish
familial Alzheimer disease mutation. Proc Natl Acad Sci U S A. 1994 Dec 6;91(25):11993-7.
- For presenilins see:
Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, Bird TD, Hardy J, Hutton
M, Kukull W, Larson E, Levy-Lahad E, Viitanen M, Peskind E, Poorkaj P, Schellenberg
G, Tanzi R, Wasco W, Lannfelt L, Selkoe D, Younkin S. Secreted amyloid beta-protein
similar to that in the senile plaques of Alzheimer's disease is increased in vivo
by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease.
Nat Med. 1996 Aug;2(8):864-70. Abstract
Thinakaran G, Borchelt DR, Lee MK, Slunt HH, Spitzer L, Kim G, Ratovitsky T, Davenport
F, Nordstedt C, Seeger M, Hardy J, Levey AI, Gandy SE, Jenkins NA, Copeland NG,
Price DL, Sisodia SS. Endoproteolysis of presenilin 1 and accumulation of processed
derivatives in vivo. Neuron. 1996 Jul;17(1):181-90.
Citron M, Westaway D, Xia W, Carlson G, Diehl T, Levesque G, Johnson-Wood K, Lee
M, Seubert P, Davis A, Kholodenko D, Motter R, Sherrington R, Perry B, Yao H, Strome
R, Lieberburg I, Rommens J, Kim S, Schenk D, Fraser P, St George Hyslop P, Selkoe
DJ. Mutant presenilins of Alzheimer's disease increase production of 42-residue
amyloid beta-protein in both transfected cells and transgenic mice. Nat Med. 1997
Duff K, Eckman C, Zehr C, Yu X, Prada CM, Perez-tur J, Hutton M, Buee L, Harigaya
Y, Yager D, Morgan D, Gordon MN, Holcomb L, Refolo L, Zenk B, Hardy J, Younkin S.
Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature.
1996 Oct 24;383(6602):710-3. Abstract
- For ApoE4 see:
Schmechel DE, Saunders AM, Strittmatter WJ, Crain BJ, Hulette CM, Joo SH, Pericak-Vance
MA, Goldgaber D, Roses AD. Increased amyloid beta-peptide deposition in cerebral
cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease.
Proc Natl Acad Sci U S A. 1993 Oct 15;90(20):9649-53.
Rebeck GW, Reiter JS, Strickland DK, Hyman BT. Apolipoprotein E in sporadic Alzheimer's
disease: allelic variation and receptor interactions. Neuron. 1993 Oct;11(4):575-80.
Hyman BT, West HL, Rebeck GW, Buldyrev SV, Mantegna RN, Ukleja M, Havlin S, Stanley
HE. Quantitative analysis of senile plaques in Alzheimer disease: observation of
log-normal size distribution and molecular epidemiology of differences associated
with apolipoprotein E genotype and trisomy 21 (Down syndrome). Proc Natl Acad Sci
U S A. 1995 Apr 11;92(8):3586-90. Abstract
Greenberg SM, Rebeck GW, Vonsattel JP, Gomez-Isla T, Hyman BT. Apolipoprotein E
epsilon 4 and cerebral hemorrhage associated with amyloid angiopathy. Ann Neurol.
1995 Aug;38(2):254-9. Abstract
- Down syndrome patients, who invariably develop classical AD pathology by age 50,
produce too much Aß from birth and begin to get amyloid plaques as early as age
12, long before they get tangles and other AD lesions. See:
Lemere CA, Blusztajn JK, Yamaguchi H, Wisniewski T, Saido TC, Selkoe DJ. Sequence
of deposition of heterogeneous amyloid beta-peptides and APO E in Down syndrome:
implications for initial events in amyloid plaque formation. Neurobiol Dis. 1996
Querfurth HW, Wijsman EM, St George-Hyslop PH, Selkoe DJ. Beta APP mRNA transcription
is increased in cultured fibroblasts from the familial Alzheimer's disease-1 family.
Brain Res Mol Brain Res. 1995 Feb;28(2):319-37.
- ApoE4, the major genetic risk factor for AD, leads to excess amyloid buildup in
the brain before AD symptoms arise. Thus, Aß deposition precedes clinical AD. See:
Polvikoski T, Sulkava R, Haltia M, Kainulainen K, Vuorio A, Verkkoniemi A, Niinisto
L, Halonen P, Kontula K. Apolipoprotein E, dementia, and cortical deposition of
beta-amyloid protein. N Engl J Med. 1995 Nov 9;333(19):1242-7.
- The earliest Aβ deposits ("diffuse plaques") are analogous to fatty streaks
of cholesterol, while mature Aβ deposits ("senile plaques") are analogous to
advanced atherosclerotic plaques.
- Aβ fibrils reproducibly damage cultured neurons and activate brain inflammatory
cells (microglia). Blocking Aß fibril formation prevents this toxicity. See for
Pike CJ, Burdick D, Walencewicz AJ, Glabe CG, Cotman CW. Neurodegeneration induced
by beta-amyloid peptides in vitro: the role of peptide assembly state. J Neurosci.
1993 Apr;13(4):1676-87. Abstract
Lorenzo A, Yankner BA. Beta-amyloid neurotoxicity requires fibril formation and
is inhibited by congo red. Proc Natl Acad Sci U S A. 1994 Dec 6;91(25):12243-7.
Meda L, Cassatella MA, Szendrei GI, Otvos L Jr, Baron P, Villalba M, Ferrari D,
Rossi F. Activation of microglial cells by beta-amyloid protein and interferon-gamma.
Nature. 1995 Apr 13;374(6523):647-50. Abstract
El Khoury J, Hickman SE, Thomas CA, Cao L, Silverstein SC, Loike JD. Scavenger receptor-mediated
adhesion of microglia to beta-amyloid fibrils. Nature. 1996 Aug 22;382(6593):716-9.
- Transgenic mice solely expressing a mutant human APP gene develop first diffuse
and then fibrillar Aß plaques, associated with neuronal and microglial damage. This
mouse model reproduces the major features of AD. See:
Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T,
Clemens J, Donaldson T, Gillespie F, et al. Alzheimer-type neuropathology in transgenic
mice overexpressing V717F beta-amyloid precursor protein. Nature. 1995 Feb 9;373(6514):523-7.
D. Games, et al., Soc. Neurosci. Abstr. 21(1): 258 (1995); Masliah E, Sisk A, Mallory
M, Mucke L, Schenk D, Games D. Comparison of neurodegenerative pathology in transgenic
mice overexpressing V717F beta-amyloid precursor protein and Alzheimer's disease.
J Neurosci. 1996 Sep 15;16(18):5795-811. Abstract
Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G. Correlative
memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science.
1996 Oct 4;274(5284):99-102. Abstract
- Humans get other amyloid diseases (e.g., in the kidney). Blocking the production
of the responsible amyloid protein can successfully treat these diseases. See:
Amyloid and Amyloidosis 1993: The VIIth International Symposium on Amyloidosis,
Kingston, Ontario. Kissilevsky, et al., eds. (Parthenon Publishing, New York, NY,
Rigorous evidence for an alternate basis for AD (virus, toxin,loss of trophic factor,
etc) has not emerged during > 20 years of intensive research on AD.
Data Supporting Early Endosomes as the Principal Site of Aβ Generation
- Deleting βAPP cytoplasmic domain (GYENPTY) lowers Aβ production
- Mild alkalinization lowers Aβ production
- Altering vesicular H+ transport lowers Aβ production
- Late endosome/lysosome fractions do not contain Aβ
- Endocytosis of surface-labeled βAPP molecules leads directly to release of
- Kinetics of labeled Aβ release are slightly slower than those of APPs and consistent
with those of recycling endosomes
Depleting cellular K+ inhibits clathrin-mediated endocytosis and lowers Aβ
Some Future Directions for AD Research
- Identify and characterize β- and γ-secretases and screen for inhibitors.
- Establish the detailed mechanism of Aβ42 (and Aβ40) aggregation (including
non-fibrillar aggregates) and screen for inhibitors.
- Elucidate how apoE4 promotes the aggregation and/or deposition of Aβ or retards
its clearance under physiologic conditions.
- Detect and quantitate soluble and insoluble Aβ aggregates that precede the
formation of diffuse plaques. Correlate their levels with early markers of glial
activation and neuronal toxicity.
- Identify proteases that normally degrade monomeric or polymeric Aβ in brain
and determine their regulation and how they can be activated.
Further define the role of proteoglycans and other vascular basement membrane components
in Aβ deposition and the contributions of CSF and plasma Aβ to the deposition
- Determine whether microglial activation and astrocytosis precede local neuritic/neuronal
changes in AD, using young Down's syndrome brains and transgenic mcie as models.
- Attempt to define a stepwise inflammatory cascade that follows initial Aβ42
and Aβ40 accumulation and deposition. Determine the temporal order of complement
activation, microgliosis, cytokine release, astrocytosis, acute phase protein release,
etc. Screen for inhibitors of certain steps.
Determine the key intracellular effector pathways that occur downstream of Aβ-induced
microglial and astrocytic activation and screen for inhibitors.
- Determine whether aggregated Aβ induces neurotoxicity directly (i.e., independently
of glial activation/inflammation) in vivo, using Down's syndrome and transgenic
mice brains as models.
- Further define the biochemical pathways through which Aβ (directly or indirectly)
slowly induces altered neuronal structure and function: e.g., via free radical generation,
increased intracellular [Ca++]; EAA toxicity; apoptosis; all of the Aβove;
- Screen for various classes of inhibitors of neurotoxicity that address each of the
pathways implicated in (2).
- Identify the biochemical events inside neurons that precede
the altered phosphorylation/dephosphorylation of tau and determine which other neuronal
proteins also serve as substrates in these reactions.
The following questions were asked via the Alzheimer Research Forum:
Question from James Vickers.
Q: Dear Dr Selkoe - I was intrigued by your flow diagram on the
amyloid cascade hypothesis. A problem has always been concerning the toxicity of
βamyloid. Have you considered the possibility that it may not be toxic at all
- perhaps it acts like other amyloidegenic diseases - the slow formation of βamyloid
deposits may cause slowly evolving structural damage to surrounding axons which
leads to a sprouting response involving cytoskeletal changes that eventually result
in the classical neurofibrillary pathology?
A: My opinion is that the sequence you provide in your question may well
be how Aβ leads to neuronal injury. The gradual cerebral accumulation of Aβ—first
in soluble form and then in insoluble (but not yet fibrillar) form—should
allow the slow formation of amyloid fibrils that, as they accumulate to sufficient
levels, begin to induce local microglial activation, astrocytosis and neuritic changes,
i.e., the evolution of neuritic plaques. It is currently unclear whether high levels
of soluble or insoluble (but not fibrillar) Aβ are themselves locally neuritotoxic
and/or one needs actual amyloid (sizeable masses of fibrils) to get cell injury.
Since neuritic changes in the AD cortex are generally intimately associated with
"mature" (fibrillar) amyloid deposits (not diffuse plaques), my speculation is that
the occurrence of actual amyloid is needed for substantial, progressive cytotoxicity
to occur. It might well be that fibrillar amyloid acts as a reservoir for a more
diffusable form of Aβ that can induce local cell injury, but the fibrillar
amyloid would still need to be there for the disease to progress. I also agree with
your comment that the accumulation of amyloid (and its associated proteins) could
induce—directly or indirectly—sprouting responses and/or degenerative
cytoskeletal changes that are ultimately associated with neurofibrillary changes
in neurities and cell bodies.
Question from John Moore.
Q: What's your best guess on the role of the endocrine system in Aβ
A: I suppose you are referring to the role of the endocrine system in APP
expression and turnover. This is largely unexplored, and I do not have any specific
information. But since we already know that a number of first and second messenger
systems, when activated, can alter APP metabolism, usually to increase soluble APP
secretion from the cell, I would guess that a number of endocrine hormones will
be shown to affect APP proteolytic processing. Indeed, there is published datain
JBC from Samuel Gandy's lab that estrogen receptor stimulation may do just that.
Questions from Weihai Ying
Q: Aging is a major risk factor of all forms of AD, How to explain this observation
based on the amyloid hypothesis of AD?
A: It appears that it takes many years for Aβ to accumulate as first
diffuse deposits and then, to a limited extent, as "mature" neuritic deposits. It
is only when the latter begin to accumulate (associated with microgliosis, astrocytosis
and neuritic dystrophy and tangle formation) in brain areas important for memory
and cognitive fuction that sufficient neuronal dysfunction and loss occur to lead
to symptoms of dementia. I think the best evidence that aging (i.e., the passage
of time) is necessary for AD to develop comes from studies of Down's syndrome. Here,
patients have little or no Aβ deposition in the first decade of life, but by
around 12 years, one begins to see diffuse plaques containing Aβ42 (not Aβ40),
and more and more Down's subjects develop such plaques during the second and third
decade of life ( see e.g., Lemere et al, Neurobiol .Dis. 3: 16-32, 1996). Then,
after the age of 30 years or so, one begins to see amyloid fibril formation in plaques
(i.e., some of them become Congo red- and thioflavin-positive) and there is associated
microgliosis, astrocytosis and some peri-plaque neuritic dystrophy. These lesions
(neuritic plaques) become more prevalent over the next 2 decades (i.e., ages 30-->50)
or so, and Down's subjects often develop symptoms of dementia during this time.
Therefore, I believe time (i.e., aging) is an important factor to allow Abeta to
deposit in the first place and to allow some mature plaques to gradually form and
lead to surrounding cell injury. Of, course, it may well not be the fibrillar Aβ
itself that injures the cells but soluble Aβ species (e.g., oligomers) and/or
some non-Aβ molecules released by microglia and/or astrocytes that actually
cause the cell injury.
Q: It has been found that there is no strong correlation between Aβ
deposition and NFT development, and senile plaques formation does not correlate
well with AD cognitive deterioration. What are your opinions to those observations?
A: I don't agree that there is no correlation. Brian Cummings and Carl Cotman
have published a paper in Lancet in 1996 that does show statistically significant
correlation between total Abeta burden (determined immunocytochemically) and some
measures of cognitive impairment) and this has been confirmed by a study in Japan
(Osaka meeting 8/96). Nf\FT occur in numerous diseases besides AD, and these have
no amyloid. Thus, NFT formation is probably a somewhat non-specific (but still neuropathologically
important) response to a variety of neural insults.
Q: It has been indicated that oxidative stress may contribute to Aβ
deposition, which provides support to the free radical hypothesis of AD. I proposed
the deleterious network hypothesis of AD (Med Hypothees 46:421-428), which seems
to provide certain explanations to the chicken-egg relationships between Aβ
deposition and oxidative damage. Would you give comments to these ideas?
A: I cannot comment in detail on the deleterious network hypothesis here,
but I do feel there is growing evidence that Aβ helps to trigger oxidative
stress locally in AD brain tissue and that free radical activity is playing a role
in Aβ-induced cell injury. This is a complex area which needs to be worked
out in greater detail, particularly using transgenic mouse models of AD. But I still
believe that, at least in genetically caused forms of FAD (APP, PS and ApoE4), it
is the accumulation of Aβ that initiates the cell injury cascade in some way.
Question from Steven W. Barger, Ph.D.
Q: I must admit that the significance of Aβ(1-42) is lost
on me. I realize that it aggregates faster than 1-40 in vitro, but is this sufficient
linkage to the disease process considering all the ancillary factors that could
be involved in plaque genesis/ maturation (alpha-ACT, proteoglycans, ApoE, etc.)?
Indeed, I am most disturbed by the fact that early plaques (specifically plaques
in non-demented individuals) are ALL 1-42. If 1-42 is the bad-guy, why is 1-40 the
form specific to the disease state?
A: My opinion is that Aβ1-42 is produced throughout life and is naturally
more prone to aggregate slowly into oligomers and eventually high MW polymers that
we recognize as diffuse plaques in the brains of elderly humans. It appears that
Abeta1-40, although much more abundantly produced by brain (and other) cells throughout
life, has little or no tendency to aggregate into stable polymers unless Aβ42
aggregates are already there. In other words, we do not seem to see diffuse plaques
composed solely of Aβ40 in normal aged brains, just Aβ42 diffuse plaques.
Now, since we know that APP and presenilin mutations which cause AD can significantly
increase Aβ42 production without increasing Aβ40, we can surmise that
increased Aβ42 levels and thus aggregates are able to initiate the amyloidotic
process. But the build-up of Aβ42 deposits is not sufficient to produce mature
neuritic/glial plaques; the latter appear when aggregated Aβ40 is also found
in the plaque. No doubt, numerous other factors are involved in this maturation
of plaques, as you suggest. So, I agree that Abeta42 is not the sole "bad guy",
but it may be the earliest "bad guy" and is then joined by the Abeta40 bad guy and
many other bad guys to actually begin to alter surrounding neuronal and microglial
and astrocytic cells. We can't really say the one bad guy is worse than the other.
They're both needed to do the dirty work.
Question from Jim Knittweis
Q: Various reports have shown that zinc ions can increase beta
amyloid aggregation. Colin Masters gave oral zinc to some AD patients and their
dementia markedly worsened in a 1991 study. Do you think that zinc chelators, such
as the amino acid l-histidine, might inhibit beta amyloid formation and ameliorate
AD dementia clinically? How important do you view zinc as contributing to Alzheimer
A: I am not sure of the level of importance of zinc in the genesis of AD,
but I suspect that it may play a role. Because we have no evidence that I know of
that there is a primary or secondary elevation of the absolute levels of zinc in
AD brain tissue, I would not think that reducing zinc to subnormal levels in the
brain would be an effective (and safe) way to inhibit beta-amyloid formation and
slow or prevent AD. I believe Ashley Bush at MGH and his colleagues have developed
increasing evidence that zinc and other metallic ions in the brains could help mediate
the toxicity of Aβ on surrounding brain cells, but that would not yet lead
me to believe that removing zinc would arrest the disease process.
Questions from Weihai Ying
Q: Several studies, e.g., the studies of Dr.H.Braak and Dr.E.Braak,
found that initial NFT changes can occur frequently without presence of A-beta deposits.
A: The Braak data are often cited as a major concern for the amyloid hypothesis.
But I can give at least three explanations for this discrepancy. First, Braak is
examining brains of aged individuals to look for very early morphological changes,
and these postmortem brains come from individuals in whom it cannot automatically
be concluded that they would all have developed AD had they survived longer. It
is possible that some of his stage 1 brains might indeed have alterations that are
not due to pre-existing Aβ deposition but represent another age-related neurodegenrative
process in the hippocampus. If one knew for sure that most or all stage 1 brains
came from presymptomatic AD patients, it would be another matter. Second, I don't
know whether the Braaks can exclude the presence of any Aβ deposits in other
brains areas that project to hippocampus in their stage 1 cases. The Aβ would
not necessarily have to be solely in the immediate vicinity of the altered neurons.
Third, the Braak analysis cannot, per force, exclude a toxic effect of any soluble
oligomeric forms of the peptide that have not yet reached the stage of microscopically
visible diffuse plaques. There is suggestive evidence from transgenic mouse studies
that build-up of oligomeric but still soluble forms of Aβ that are microscopically
invisible but biochemically detectable could potentially be cytotoxic. Until these
three points are clarified, I don't believe that the Braak data exclude an initial
role for Abeta accumulation as a critical factor in the genesis of AD.
Q: You and other researchers have reported that PS mutations can lead to
increased Aβ(1-42). The studies by Wolozin et al. (Science 274:1710) and Yamatsuji
et al. (Science 272:1349) have also suggested that PS-2 mutations and APP mutations
may promote AD pathogenesis by enhancing apoptosis. Therefore, PS mutations and
APP mutations might promote AD pathogenesis through more than one pathway.
A: Although PS mutations may enhance apoptosis and thus contribute to neuronal
death, my own opinion is that the Aβ42 elevation that these mutations induce
is more likely to be the initial and critical factor in promoting AD. This is because
APP mutations that clearly can cause AD that is essentially indistinguishable from
the AD caused by PS also increase Abeta 42 and do not have a known effect on apoptosis.
Likewise, Down's syndrome appears to involve an early build-up of Aβ42 (starting
as early as age 12) based on increased APP expression without any known involvement
of enhanced apoptosis as the basis for the development of AD pathology at that age.
Given these similarities in the early role of Abeta42 build up in these three genetically
based forms of the AD syndrome, I would bet that the Aβ42 mechanism of mutant
PS is more likely to be responsible for triggering the AD than the apoptotic effect.
But we'll have to see!
Additional Questions/Commentary—Posted 23 July 2005
1. In the current amyloid hypothesis diagram, the formation of amyloid plaques in
LOAD is attributed to "failure in Aβ clearance." But, what has caused the failure
itself, or what is the initial cause for plaque deposition in LOAD?
2. Why does this clearance failure not happen to many other proteins in the brain
3. Most chronic diseases at old age cannot be traced to a single cause, but result
from multiple factors interactions, and it is hard to say any one of them by itself
is the culprit. How can amyloid hypothesis be compatible with this concept?
Comments from readers are also welcome.
View Live Debate between Steven
Younkin and Dennis Selkoe.