Given the recent failure of the Bapi clinical trial, there is a lot of questions that have arised from he amyloid hypothesis. However, I can't really think of many other mechanisms that don't involved plaque formation via protein aggregation.

What are the other dominant proposed mechanisms for the biochemistry of Alzheimers?

Reference: Alzheimer’s Drug Fails Its First Big Clinical Trial. Unfortunately, the results of the study have yet to be presented at a medical conference but will be in September.

  • 2
    $\begingroup$ Could you link to the relevant studies for those who are not familiar with them? $\endgroup$
    – nico
    Aug 17, 2012 at 21:53
  • $\begingroup$ Well, I am sorry but I fail to understand how that would refute the amyloid hypothesis... it just tells us that a monoclonal Ab against amyloid is not a good cure for Alzheimer's. $\endgroup$
    – nico
    Aug 20, 2012 at 6:23
  • $\begingroup$ @nico, strongly agree but I also get the idea that many alzheimer's researchers are beginning to back off on the mechanism and looking for alternative pathways to attack. $\endgroup$
    – bobthejoe
    Aug 20, 2012 at 8:47
  • $\begingroup$ I am not really in that field, so I cannot really comment. However, I would not expect anyone to really say that amyloid plaques are not an important mark of Alzheimer's. They are possibly not the good target for a cure. $\endgroup$
    – nico
    Aug 20, 2012 at 14:17
  • $\begingroup$ Hi all. See this article in Nature - very interesting. $\endgroup$
    – Luke
    Sep 6, 2012 at 9:44

3 Answers 3


Alzheimer's disease is a very complex field, and I am going to restrict my answer to two particular areas: the neuritic plaques and the neurofibrillary tangles. This area is also of interest to me, hence the protracted answer.

The two pathological hallmarks of Alzheimer's disease, first described by Alois Alzheimer in about 1906, are the extracellular neuritic plaques and the intracellular neurofibrillary tangles which occur (exclusively) in the brain of humans with this disease.

The Neuritic Plaques (Amyloid Precursor Protein and β-Amyoid)

[References to the information given below may be found in Price & Sisodia (1998) and in Lowery et al. (1991)]

The major component of the extracellular neuritic plaques is a small, appromimately 4 kDa protein known as the β-Amyloid (Aβ), or A4-protein.

  • The Aβ, whose tertiary structure is that of a β-pleated sheet, is itself derived by proteolysis (see below) from a much larger protein known as the Amyloid Precursor Protein (APP).

    A number of isoforms of Aβ are known which contain between 36 and 43 amino acids, the most common of which are Aβ40 and Aβ42.

  • The Amyloid Precursor protein (APP) is a very large protein (≥ 695 amino acids) of unknown function which is a normal component of brain. It is predicted to have a single transmembrane span.

    A number of isoforms of this protein are also known, which contain 695, 714, 751 & 770 amino acids.

    The AA751 and AA770 isoforms contain a domain (Kunitz domain) homologous to a class of protease inhibitors, strongly suggesting the proteolysis plays a key role in normal function, and perhaps in (abberant?) Aβ formation.

  • One of the cleavages which produces the Aβ, that catalyzed by γ-secretase, occurs within the transmembrane-spanning domain of APP. How the protease has access to its substrate within the lipid bilayer is a major source of interest.

Researchers who believe that neuritic plaques and Aβ hold the key to Alzheimer's disease are known as baptists. Their counterparts, who believe that the neurofibrillary tangles are key, are known as tauists, for reasons that will become obvious (see also here).

For the past number of years, baptists have been to the forefront. In my view, the tauist story is even more interesting, and must surely be important in any final understanding of Alzheimer's disease.

Neurofibrillary Tangles, Paired Helical Filaments and Tau Protein

Examination of the neurofibrillary tangles under the electron microscope revealed that they had a twisted ribbon-like structure which was called the paired helical filament (PHF) (Kidd, 1964; Wisniewksi et al., 1984).

PHFs are practically insoluble and for a long time this impared progress. However, extraction using the detergent sarkosyl, followed by sequence analysis and immunological investigations, produced a major surprise:

A component of the paired helical filament is the microtubule-associated protein tau (Goedert et al., 1988; Wischik et al., 1988), a most unusual and interesting soluble protein which had already been purified to homogeneity and extensively characterized by Kirschner & co-workers (Weingarten et al., 1975; Cleveland et al., 1977a, 1977b).

A perusal of pubmed shows that at this stage interest in tau increased dramatically!

It is now accepted that microtubule-acssociated protein tau in a hyper-phosphorylated state is the major structural component of the paired helical filament (Lee et al., 1991; Kosik & Greenberg, 1994).

Some key properties of tau are the following.

  • Tau was first isolated as a series of closely related proteins (isoforms) which co-purify with porcine tubulin during successive cycles of polymerization/depolymerization (Weingarten et al., 1975). On an SDS gel, one sees (with bovine brain tau) 4 bands quite close together from (say) 58 - 64 kDa.
  • Interaction with tubulin is the only known 'normal' function of tau. It promotes the polymerization of tubulin into microtubules under polymerization conditions, for example (Cleveland et al., 1977a, 1977b).
  • Tau is encoded by a single gene, located on chromosome 17, and differential mRNA splicing gives rise to the brain isoforms (six in humans and four in cow) [Andreadis et al., 1989; Goedert et al., 1989; Himmler, 1989], and a single high molecular weight tau ('big tau') in peripheral tissues (Goedert et al., 1992).
  • Tau contains a series of imperfect amino-acid repeats, located in the C-terminus of the protein. These repeats are thought to be responsible for microtubule binding (see, for example, Lee, 1990).
  • Although tau occurs in a hyper-phosphorylated state in the PHF, and may be phosphorylated in normal brain, phosphorylation is not necessary for formation of paired-helical filaments (Goedert et al., 1996).
  • The tau gene may be knocked out without any visible alteration of phenotype! (experiments done in mice) (Harada et al., 1994).
  • Mutations in the tau gene are not known to cause Alzheimer's disease, but are associated with very rare 'taupathies', such as an inherited dementia called frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17; possibly identical with Pick's disease) [Hutton et al., 1994].
  • The crystal structure of tau has not been obtained to date. Current thinking is that the soluble form of tau is mainly a random coil (see von Bergen et al., 2006).

The fact that tau can be knocked without serious consequence, together with the lack of mutations causing Alzheimer's, has led to much criticism of the tauist story.

However it still is the major structural component of the paired helical filament (neurofibrillary tangles), and must surely be a key player in the understanding of Alzheimer's disease.

This is not to imply that Aβ and tau are the only shows in town. As stated above, the field of Alzheimer's disease is very complex

An allele of Apolipoprotein E (ε4 allele) is genetically associated with an increased risk in late-onset Alzheimer's, for example (Corder et al., 1993).

Mutations in the presenilin genes are also associated with the disease (Sherrington et al., 1995). Presenilins form part of the γ-secretase protease complex involved in Aβ formation (see Takeo et al., 2012).

I do not know enough about these fields to comment any further (although this does not usually stop me).

It should be emphasized, however, that most cases of Alzheimer's disease are sporadic, and only a small subset has a genetic component. It is a disease of the brain, and of aging. There is no known cure, no known cause and no reliable (biochemical) pre-mortem test (although a clinic diagnosis may of course be made).


  • Andreadis, A., Brown, W. M. & Kosik, K. S. (1992) Structure and novel exons of the human tau gene. Biochemistry, 31, 10626-10633.

  • von Bergen, M, Barghorn, S, Jeganathan, S, Mandelkow, E.M., Mandelkow, E. (2006) Spectroscopic approaches to the conformation of tau protein in solution and in paired helical filaments. Neurodegener. Dis. 3, 197-206.

  • Cleveland, D. W., Hwo, S.-Y. & Kirschner, M. W. (1977a) Purification of tau, a microtubule associated protein that induces assembly of microtubules from purified tubulin. J. Mol. Biol. 116, 207-225

  • Cleveland, D. W., Hwo, S.-Y. & Kirschner, M. W. (1977b) Physical and chemical properties of purified tau factor and the role of tau in microtubule assembly. J. Mol. Biol. 116, 227-247.

  • Corder, E.H., Saunders, A.M., Strittmatter, W.J., Schmechel, D.E., Gaskell, P.C. Small, G.W. Roses, A.D., Haines, J. L. & Pericak-Vance, M.A. (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261, 921-923.

  • Goedert, M., Wischik, C. M., Crowther, R. A., Walker, J. E. & Klug, A. (1988) Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of alzheimer disease: Identification as the microtubule associated protein tau. Proc. Natl. Acad. Sci. USA 85, 4051-4055. [pdf]

  • Goedert, M., Spillantini, M. G., Jakes, R., Rutherford, D. & Crowther, R. A. (1989) Multiple isoforms of human microtubule associated protein tau: sequences and localization in neurofibrillary tangles of alzheimer's disease Neuron 3, 519-526.

  • Goedert, M., Spillantini, M. G. & Crowther, R. A. (1992) Cloning of a big tau microtubule associated protein characteristic of the peripheral nervous system. Proc. Natl. Acad. Sci. USA 89, 1983-1987. [pdf]

  • Goedert, M., Jakes, R., Spillantini, M. G, Hasegawa, M., Smith, M.J. & Crowther, R. A. (1996) Assembly of microtubule-associated protein tau into Alzheimer-like filaments induced by sulphated glycosaminoglycans. Nature, 83, 550-553.

  • Harada, A., Oguchi, K., Okabe, S., Kuno, J., Terada, S., Ohshima, T., Sato-Yoshitake, R., Takei, Y., Noda, T. & Hirokawa, N. (1994). Altered microtubule organization in small-calibre axons of mice lacking tau protein. Nature 369, 488-491

  • Himmler, A. (1989) Structure of the bovine tau gene: alternatively spliced transcripts generate a protein family. Molec. Cell. Biol. 9, 1389-1396.[pdf]

  • Hutton, M., Lendon, C. L., Rizzu, P., Baker, M., Froelich, S., et al. (1998) Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393, 702-705.

  • Kidd, M. (1964) Alzheimer's disease - an electron microscopical study. Brain 87, 307-320.

  • Kosik, K. S. & Greenberg, S. M. (1994) Tau protein and alzheimer disease. In Alzheimer Disease. Terry, R. D., Katzmann, R. & Bick, K. L., eds. pp 335-344. Raven k. Press, New York.

  • Lee, G. (1990) Tau protein: an update on structure and function. Cell Motil. Cytoskel. 15, 199-203

  • Lee, V. M.-Y., Balin, B. J., Otvos, L. & Trojanowski, J. Q. (1991) A68: A major subunit of paired helical filaments and derivatized forms of normal tau. Science 251, 675-678.

  • Lowery, D.E., Pasternackj, J.M., Gonzalez-DeWhitt, P.A., Zurcher-Neely, H. Tomich, C-S. C., Altman, R.A., Fairbanks, M. B., Heinrikson, R. L. Younkin, S. G. & Greenberg, B. D. (1991) Alzheimer’s Amyloid Precursor Protein Produced by Recombinant Baculovirus Expression. Proteolytic Processing And Protease Inhibitory Properties. J. Biol. Chem. 266, 19842-19850. pdf

  • Price, D. L. & Sisodia, S. S. (1998) Mutant genes in familial alzhiemer's disease and transgenic models. Annu. Rev. Neurosci. 21, 479-505.

  • Sherrington, R, Rogaev, E.I, Liang, Y, Rogaeva, E.A, Levesque, G, Ikeda, M, Chi, H, Lin, C, Li, G, Holman, K, Tsuda T, Mar, L, Foncin, J.F, Bruni, AC, Montes, M.P, Sorbi, S, Rainero, I, Pinessi, L, Nee, L, Chumakov, I, Pollen, D, Brookes, A, Sanseau, P, Polinsky, RJ, Wasco, W, Da Silva, H.A, Haines, J.L, Perkicak-Vance, M.A, Tanzi, RE, Roses, A.D, Fraser, PE, Rommens, J.M, St George-Hyslop, P.H. (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature, 375, 754-760.

  • Takeo, K, Watanabe, N, Tomita, T, Iwatsubo, T. (2012) Contribution of the γ-Secretase Subunits to the Formation of Catalytic Pore of Presenilin 1 Protein. J. Biol. Chem. 287, 25834-25843

  • Weingarten, M. D., Lockwood, A. H., Hwo, S.-Y. & Kirschner, M. W. (1975) A protein factor essential for microtubule assembly. Proc. Natl. Acad. Sci. USA 72, 1858-1862. [pdf]

  • Wischik, C. M., Novak, M., Edwards, P. C., Klug, A., Tichelaar, W. & Crowther, R. A. (1988) Structural characterization of the core of the paired helical filament of alzheimer disease. Proc. Natl. Acad. Sci. USA, 85, 4884-32768. [pdf]

  • Wisniewski, H. M., Merz, P. A. & Iqbal, K. (1984) Ultrastructure of paired helical filaments of Alzheimer's neurofibrillary tangle. J. Neuropathol. Exper. Neurol., 43, 643-656.


Alzheimer is also considered a tauopathy due to abnormal aggregation of the tau protein. There has been succesful research in that direction, recently, which was a bit neglected, presumably because of vested interests in the amyloid hypothesis.


However, another alternative to amyloid (and tau) is the hypothesis that Alzheimer is caused or enhanced by Herpes Simplex virus (HSV-1). One landmark paper found HSV DNA in amyloid plaques and another hint is the association of a lysin-poor/arginine-rich diet with Alzheimer risk (the connection being that HSV thrives in Arg-rich tissue). Also, a cohort study found a direct association.

N. Zilka, Z. Kazmerova, S. Jadhav, P. Neradil, A. Madari, D. Obetkova, O. Bugos, M. Novak: Who fans the flames of Alzheimer's disease brains? Misfolded tau on the crossroad of neurodegenerative and inflammatory pathways. In: Journal of neuroinflammation. Vol.9, 2012, p. 47 doi:10.1186/1742-2094-9-47. PMID 22397366. PMC 3334709. (Review).

A. M. Geppert: [Alzheimer's disease and HSV-1 infection]. In: Neurologia i neurochirurgia polska. 40, 1, 2006 Jan-Feb, 57–61. PMID 16463223. (Review).

M. A. Wozniak, A. P. Mee, R. F. Itzhaki: Herpes simplex virus type 1 DNA is located within Alzheimer's disease amyloid plaques. In: The Journal of pathology. 217, 1, Jan 2009, 131–138. doi:10.1002/path.2449. PMID 18973185.

Letenneur, L; Pérès, K, Fleury, H, Garrigue, I, Barberger-Gateau, P, Helmer, C, Orgogozo, JM, Gauthier, S, Dartigues, JF (2008): Seropositivity to herpes simplex virus antibodies and risk of Alzheimer's disease: a population-based cohort study." In: PLoS ONE 3 (11): e3637. doi:10.1371/journal.pone.0003637. PMC 2572852. PMID 18982063.


Whilst there are several competing ideas for the cause of Alzheimer's, it seems to me that the deposition of β-amyloid (Aβ) is key to the understanding of the disease progression. In many of the papers I will go on to cite, they suggest that prevention of Alzheimer's may be the only cure, as neurons (once damaged) cannot be replaced.

During aging there is a progressive increase in the systemic pro-inflammatory state (sometimes called 'inflammaging'). This is also true for the brain (commonly known as neuroinflammation), and is known to contribute to neurodegenerative diseases by promoting the destruction of local tissues (i.e. neurons) [ref].

Under normal circumstances microglia (resident macrophages of the brain) clear any excess protein depositions (plaques), such as Aβ, in much the same way as macrophages respond to carotid plaques (as can occur during cardiovascular disease). With age, the immune system becomes less functional - a process known as immunosenescence - which contributes to the pro-inflammatory state of aging [ref].

As the immune system becomes less functional, the clearance of Aβ deposits is reduced, possibly contributing to the increased plaque deposition [ref.1][ref.2]. There is also discussion on whether it is the decreased effectiveness of the blood-brain barrier that allows peripheral (from the blood) immune cells to infiltrate the central nervous system, possibly kick-starting the degeneration [ref].

There are many more factors than this, but this is certainly one that interests me as I can see that individuals will have different responses and predispositions to plaques formation in the first place (i.e. the ApoE risk allele, exposure to certain pathogens over the lifetime).

I therefore don't think the study rules out the amyloid hypothesis, in that removal Aβ does not restore the lost neurons (did they really expect it to?). What it does show is that the emphasis should be on prevention, not cure, as 'early-warning' signs, such as biomarkers of Aβ deposits, will be the best way to prevent the loss of neurons.


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