**6. Conclusion**

412 Neuroscience – Dealing with Frontiers

earliest reports from human trials suggest that, despite reducing amyloid load, these strategies have no effect on cognitive function (Rinne *et al.,* 2010). Furthermore trials determining the efficacy and safety of the -secretase inhibitor, semagacestat, had to be

These results have been seen by some as serious threats to the validity of the amyloid cascade hypothesis in sporadic AD, although proponents have countered these criticisms by arguing that A therapy is failing because it is instituted too late in the disease process (Gandy, 2011; Golde *et al.*, 2011). They maintain that A therapy needs to be instituted as a prophylaxis and this, of course, means the preclinical identification of future AD patients and the treatment, or at least testing, of individuals without symptoms (Golde *et al.,* 2011). According to Golde, Schneider and Koo, and based on the findings from imaging and CSF biomarker studies described above, individuals destined to have AD show detectable A deposition at least 10 years earlier. Furthermore amyloid plaques visualized by radioligand imaging and low CSF A1-42 can be monitored throughout potential trials of A therapies. It is not clear how an original cohort might be selected but aged *APOE* 4 carriers were suggested for screening (Golde *et al.,* 2011). This hypothesized approach raises some very interesting ethical questions, not to mention changes required to regulatory criteria that are

Epidemiological studies were instrumental in establishing the connection between serum lipid levels, particularly high cholesterol, and coronary heart disease. Proponents of prophylactic A immunotherapy might argue that their proposal is similar to the current use of statins in reducing blood cholesterol. However epidemiological studies have been relatively unsuccessful in finding factors that modify the risk for AD, meaning that any

The statins story is an interesting one because individuals in the initial trials for heart disease appeared to have a reduced incidence of AD (Jick *et al.,* 2000; Wolozin *et al.,* 2000). This led to considerable research into cardiovascular risk factors in AD including hypertension, elevated serum cholesterol, smoking middle age obesity and type II diabetes.

Remaining physically and mentally active does seem to be relatively effective but it is likely that a cognitive reserve allows individuals to starve off the effects of AD pathology rather than decreasing the pathology itself. Of course this would still be an effective method to

Despite all the research, the current situation in AD could still be summarised by the following paragraph from a recent commentary in the Journal supplement, Nature Outlook: *"A big part of the problem is that researchers don't know enough about the biology of Alzheimer's disease to identify the right targets. The disease is the result of a long chain of events, but some of the links in that chain are still a mystery — nobody is certain which link to cut to stop disease* 

Interesting only type II diabetes survives meta-analyses (Sutherland *et al.*, 2011b).

terminated due to actual cognitive decline (Cummings, 2010).

proposed preventative strategies remain speculative at best.

currently based on clinical symptoms.

reduce the societal burden of AD.

*progression" (Gravitz, 2011).* 

**5.4 Preventive health** 

Given the passage above the reader may become overly pessimistic about the possibilities for a cure of Alzheimer's in the immediate future. In its general use the term 'cure' implies that there is a readily identifiable agent that causes AD and that this agent can be attenuated or even removed without any serious deleterious effects to the sufferer.

All AD research to date suggests that there is no clear single aetiology for the majority of sufferers. The major pathogenic hypothesis is that in susceptible individuals, on a background of ageing, there is an increased production or decreased clearance (Mawuenyega *et al.,* 2010) of a normal 'degradative' product called A whose build up in the brain becomes neurotoxic.

An alternative or adjunctive interpretation is that A has a physiological role in the brain, perhaps synaptic pruning or inhibiting excitatory activity and that A metabolism itself becomes dysregulated in response to an unknown aetiological factor. The individuals who develop AD may have a greater propensity to deposit A or are less resistance to its downstream effects. In the latter scenario, monogenic forms of AD could still explained by a greater propensity to oligomerisation and deposition. The caveat is that prophylactic A immunotherapy may prove to have more serious side effects than if A is just a degradative product.

The amyloid cascade hypothesis is a very good one that no doubt encapsulates important aspects of the pathogenesis of sporadic AD. However technological advances such as GWAs suggests that A-independent mechanisms are (also) important in AD while RNA-Seq is only now offering a methodology where the transcriptome of the human brain can actually be comprehensively examined. It therefore seems too premature to place all our therapeutic eggs in the A cascade basket.
