Unfortunately, there are many hypothesis but nothing written on the wall. I study motoneuron disease, which is ~90% sporadic, and we have the same problem. I think it is changes in synaptic transmision (excitatoty/inhibitory) imbalance and intrinsic membrane properties leadiing to hyperexcitability and hyperexcitation, which ultimately increases metabolic demand to unsustainable levels. The cells become too depolarized for too long and loading of Na and Ca ions, subsequently activating resident microglia and immune system to target the neurons one by one. By the time you notice the symptoms a significant amount of neurons >25% are gone, and the process of cell death get fasters as the remaining cells have to work harder to make up for the loss. You cant bring the dead cells back with current technology, but may be possible in the future. I think currently best option to do will be to reduce excitability in predisposed subjects from earlier age, prior to significant symptoms appear. This may be achived by using blockers of Na channels such as riluzole, or openers of K channels such as retigabine. If you want to get some more detail please download my recent review available in RG on this subject.

cheers,

Refik

We must keep in mind that Alzheimer's Disease is a disease with no defined etiology. If we can not define with is the cause, we will have no success in solve this problem. It would be similar to a flu...you can take medicine to cure the sneeze, but if don't take care with the virus, its only a paliative response.

In AD is very similar... we know the signs and symptoms, but if we do not understand how it starts, all the treatment will be paliative.

We have three well acepted theories for the AD development: The cholinergic hypothesis, the amyloidal hypothesis and the inflamatory hypothesis... but there's another one that is more complex... one that mix all of those, when each one is cause and effect of each other. Genetical alterations in some proteins would stimulate the production of amiloid 42 could cause inflamation on brain. Inflamatory process in brain could cause alteration in TAU protein, which  would interrupt the flux of vesicles... without neurotransmitters, we can not send info along the axons... and etc. 

The cholinergic theory is the most weak among all of those. It's based on the fact that we use choline mimetic in clinics... but there are other better explanations to memory alterations, like hipocampal neurodegeneration.

I have a paper explaning the details of memory... maybe we could read it, and other, and try to create another possibility, maybe...

Cheers,

Eduardo

Recently due to its neuroprotective and antioxydative properties is used Minocycline - the second generation semisintethic antibiotic which penetrates blood-brain barrier

The minimal effect of  treatment basing on cholinergic , amyloid hypothesis for moderate-late AD convince me that we only know tiny fraction of AD and other neurodegenerative disorders.  Imagine fanaticism once we came across an idea which may suggest that it  will possibly open a new avenue, however, we are still stepping on the same ground after many years of trial and error-- it is really ironical.   Sometimes I ponder over whether the current in research in neurodegeneration is a type of Alchemy which lead us to nowhere.