What alternatives are there to the amyloid hypothesis?
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 &beta;-Amyoid)

[References to the information given below may be found in Price &amp; 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 &beta;-Amyloid (A&beta;),  or A4-protein.  


The A&beta;, whose tertiary structure is that of a &beta;-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 A&beta; are known which contain between 36 and 43 amino acids, the most common of which are  A&beta;40 and A&beta;42. 
The Amyloid Precursor protein (APP) is a very large protein (&ge; 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 &amp; 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?)  A&beta; formation. 
One of the cleavages which produces the A&beta;, that catalyzed by &gamma;-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  A&beta; 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 &amp; 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 &amp; 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 A&beta; 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 (&epsilon;4 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 &gamma;-secretase protease complex involved in A&beta; 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). 


References


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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. &amp; 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. &amp; 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.
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