Cholinergic hypothesis
It has been found that patients with AD have deficits in cholinergic neurons, particularly in the nucleus basalis magnocellularis (a.k.a. basal nucleus of Meynert). The suggestion that a cholinergic deficit can impair memory has been backed up by other evidence: anticholinergics in young people can impair memory, and cholinergic stimulation can improve memory. Further research suggested that perhaps it's actually not so much memory that's affected, but instead selective attention. Nevertheless, enhancing selective attention may be helpful too.
Current therapies
Acetylcholinesterase inhibitors (AChEI)
Acetylcholinesterase inhibitors, as their name suggests, inhibit acetylcholinesterase (AChE). AChE normally breaks down ACh in the synapse, so when it is inhibited, there is more ACh bouncing around. The main AChEIs used are donepezil, galantamine and rivastigmine. (The very first AChEI to be used, tacrine, is no longer used due to safety concerns.) Despite being widely used, they are not particularly effective (at least not as effective as we would like them to be!) and can have adverse effects such as confusion, hallucinations, sudden changes in behaviour, nausea, and stomach pain.
Some AChEIs ("dual-binding AChEIs") can actually work through a second mechanism in which they bind to the peripheral anionic site (PAS) of AChE. Beta-amyloid can normally interact with the PAS, increasing aggregation of beta-amyloid. Therefore, blocking PAS also blocks aggregation of beta-amyloid.
Glutamate NMDA receptor inhibitors
Beta-amyloid can do some damage by binding to NMDA receptors (which normally bind glutamate), so if NMDA receptors are blocked, beta-amyloid can't do as much damage. Memantine is an NMDA-antagonist which is currently used to treat AD.
Combination treatments
Current combination treatments for AD include an AChEI and memantine. It is indicated for patients with moderate-to-severe AD.
Future potential treatments
CB1 receptors
CB1 receptors are cannabinoid receptors in the central nervous system. (CB2 receptors are mainly found in the peripheral nervous system.) CB1-receptor agonists have been found to impair memory, so CB1 antagonists such as rimonabant might help to improve it. Rat studies have found this to be the case, but I don't know whether or not this has also been found in humans.
Anti-inflammatories and anticholesterol drugs
AD lesions are often associated with activated microglia, suggesting inflammation. Beta-amyloid also activates the complement system. Furthermore, patients who regularly consume anti-inflammatory medication were less likely to develop AD. From this, it seems likely that targeting inflammation might help. Indeed, studies have found that NSAID use might have a somewhat protective effect.
As for cholesterol, studies in cells and animals have suggested that high cholesterol may increase levels of beta-amyloid. Hence, it seems like it would be a good idea to target cholesterol with drugs such as statins. Unfortunately, there is no evidence to show that this works.
Amyloid targeting treatments
Since amyloid plaques are a main feature of AD, γ-secretase and BACE1 (β-amyloid precursor protein cleaving enzyme 1) have also been suggested as potential targets. Unfortunately, targeting these enzymes may have some nasty side effects. Interestingly enough, it has been suggested that targeting both might actually be safe and effective.
Tau centred therapies
Since hyperphosphorylated tau is one of the hallmarks of AD, it makes sense to target it, right? The possibility of creating a vaccine against tau has been suggested, but while a potential vaccine (AADvac1) succeeded in a safety trial, it still needs to be tested further to establish safety and efficacy. It's likely that the blood-brain barrier will be an issue.
Another possible method of targeting tau is to use a tau aggregation inhibitor. Methylene blue (a.k.a. methylthion-inium chloride, or MTC) is a dye that can also inhibit the aggregation of tau. A new reduced form of methylene blue called LMTX has been tested in clinical trials, but has failed to show efficacy. Sigh...
Antioxidants
Various antioxidants have been trialled in the treatment of AD. Unfortunately, very few have shown any degree of success.
Phosphodiesterase inhibitors
Sildenafil (Viagra), which is a phosphodiesterase 5 inhibitor, can also enhance phosphorylation of CREB, which is involved in memory. In mice, Viagra improves synaptic function and memory by improving CREB phosphorylation. It was also associated with a long-lasting reduction in beta-amyloid levels. Sounds good, right? Unfortunately, of all of the trials done on Viagra to treat AD, the only study with published data shows no difference in AD symptoms. Ugh, back to the drawing board...
PPARγ agonists (Thiazolidinedione drugs)
In animals, thiazolidinediones (TZDs) have been shown to reduce neurodegeneration, improve cognition, inhibit neuroinflammation, facilitate beta-amyloid clearance, enhance mitochondrial function, improve synaptic plasticity and attenuate tau hyperphosphorylation. (Phew! That was a lot...) The two main TZDs that have been trialled are rosiglitazone and pioglitazone. Pioglitazone passed phase I safety, but no further data appears to have been published. Rosiglitazone has also been tested, but no data appears to have been published.
Nerve growth factors
In animals, nerve growth factor (NGF) and brain-derived nerve factor (BDNF) can stimulate cholinergic function and improve memory. Additionally, there may be other complex interactions between BDNF and beta-amyloid. NGF did okay in a phase I study, but results from phase II and III studies don't appear to have been published. As for BDNF, no clinical trials appear to have been done.
5-HT6 receptor antagonists
The rationale behind using drugs that target 5-HT6 (serotonin receptor, subtype 6) is still unclear. Studies in animals have found that 5-HT6 agonists and antagonists can improve learning and memory, which seems really contradictory. Patients with AD have been found to have reductions in 5-HT6 receptor density, but this seems unrelated to cognitive status. Another thing that has been found that 5-HT6 receptor blockade induces acetylcholine release. All in all, our knowledge of this receptor is still a bit hazy and unclear. There have been trials of 5-HT6 receptor antagonists in humans (such as SUVN-502), but no data as of yet.
α7 nicotine receptor agonists
Only one has been developed (EVP-6124), but no data.
tl;dr: the last 5 drugs that I talked about have little to no data to show for them.
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