The consensus view on Alzheimer's disease is that the immediate agent of destruction in the disease process is beta amyloid, one of a number of misfolded proteins that aggregate in various organs and tissues in increasing amounts as a person ages. Why some people accumulate this metabolic waste product more rapidly than others, and why amyloid deposition accelerates in later life, is a topic for another day: there is plenty of room for theorizing, as the full details of degeneration and damage in the interaction between metabolism and aging are not yet known.
The Strategies for Engineered Negligible Senescence (SENS) approach to amyloid is to find ways to get rid of it on a periodic basis - such as some form of immune therapy that directs immune cells to attack and destroy amyloid wherever it occurs. If a therapy can clear amyloids such as beta amyloid from tissues, then it doesn't matter why it is building up, or why some people see more of it than others, as treatments will ensure that no-one ever suffers from a pathological level of amyloid. It is probably the case that beta amyloid deposition accelerates in later life due to other forms of damage at the level of cells and tissues. But in the SENS vision that other damage should also be reverted and repaired. This model of repairing all the primary, fundamental differences between old and young tissue is very powerful: it enables researchers to sidestep the enormous costs and time involved in gaining a complete understanding of all of the processes involved.
The mainstream research community tends to focus on obtaining a full understanding before taking action, however: that is very much the scientific process. In recent years great strides have been made in understanding the molecular biology of beta amyloid and the ways in which it harms brain cells. The dominant strategy here is to find some part of this process that is amenable to sabotage: don't try to remove the amyloid, but instead disable the identified ways by which it causes harm. I believe that this is a less robust approach in comparison to removal, and one that will probably prove more costly in the long run: what if there are multiple processes by which amyloid harms tissues, for example? Each requires identification and full understanding in order to have a good shot at sabotaging it. Removal just requires one research and development effort, and through removal researchers can eliminate all other potential harms.
This research is a good example of the full understanding and molecular sabotage approach to developing a therapy for Alzheimer's disease:
Beta-amyloid begins life as a solitary molecule but tends to bunch up - initially into small clusters that are still soluble and can travel freely in the brain, and finally into the plaques that are hallmarks of Alzheimer's. Using an experimental mouse strain that is highly susceptible to the synaptic and cognitive impairments of Alzheimer's disease, [researchers] showed that if these mice lacked a surface protein ordinarily situated very close to synapses, they were resistant to the memory breakdown and synapse loss associated with the disorder. The study demonstrated for the first time that this protein, called PirB, is a high-affinity receptor for beta-amyloid in its "soluble cluster" form, meaning that soluble beta-amyloid clusters stick to PirB quite powerfully. That trips off a cascade of biochemical activities culminating in the destruction of synapses.
[The researchers] wondered whether eliminating PirB from the Alzheimer's mouse strain could restore that flexibility. So [they bred] Alzheimer's-genes-carrying strain with the PirB-lacking strain to create hybrids. Experimentation showed that the brains of young "Alzheimer's mice" in which PirB was absent retained as much synaptic-strength-shifting flexibility as those of normal mice. PirB-lacking Alzheimer's mice also performed as well in adulthood as normal mice did on well-established tests of memory, while their otherwise identical PirB-expressing peers suffered substantial synapse and memory loss. "The PirB-lacking Alzheimer's mice were protected from the beta-amyloid-generating consequences of their mutations." The question now was, why?
In another experiment, [researchers] compared proteins in the brains of PirB-lacking Alzheimer's mice to those in the brains of PirB-expressing Alzheimer's mice. The latter showed significantly increased activity on the part of a few workhorse proteins, notably an enzyme called cofilin. Subsequent studies also found that cofilin activity in the brains of autopsied Alzheimer's patients is substantially higher than in the brains of people without the disorder. Here the plot thickens: Cofilin works by breaking down actin, a building-block protein essential to maintaining synaptic structure. And, as the new study also showed, beta-amyloid's binding to PirB results in biochemical changes to cofilin that revs up its actin-busting, synapse-disassembling activity. "No actin, no synapse."
Beta-amyloid binds to PirB (and, the researchers proved, to its human analog, LilrB2), boosting cofilin activity and busting synapses' structural integrity. Although there may be other avenues of destruction along which synapses are forced to walk, [researchers doubt] there are very many, [and suggest] that drugs that block beta-amyloid's binding to PirB on nerve-cell surfaces - for example, soluble PirB fragments containing portions of the molecule that could act as decoy - might be able to exert a therapeutic effect.