There are many potential mechanisms by which Aβ42 may lead to downstream neurodegeneration. These include direct neurotoxicity [2, 3], direct vascular endothelial dysfunction  and neuroinflammation . The direct neurotoxic affects of Aβ42 oligomers [2, 3] include reductions in glutamatergic synaptic transmission and plasticity and attenuation of excitatory synaptic transmission by decreasing the number of surface AMPA and NMDA receptors associated with a collapse of glutamatergic dendritic spines.
At present, it does not seem possible to detemine the relative neurotoxicities of the various effects of Aβ42 and their relative contributions could differ depending on the stage of disease. However, even if statin therapy does not decrease sAPPβ and Aβ42 in non- PSEN1 subjects, there remains the possibility that increases in α-secretase activity activate a pathway that substantially reduces the neurotoxicity of Aβ42
There is a possible relationship between our findings and recent work on a connection between cellular prion protein (PrPc) and Aβ42 metabolism [37, 38]. For example, PrPc has been reported to mediate the impairment of synaptic plasticity by Aβ oligomers . According to these authors, the blockade of long-term potentiation may be rescued by anti-PrP antibodies that prevent Aβ oligomers from binding to PrPc . These studies [37, 38] conclude that PrPc is a mediator of Aβ oligomer-induced synaptic dysfunction and that PrPc-specific pharmacologic interventions may have therapeutic potential for the treatment of AD. Moreover, studies of memory impairment in a mouse model of AD have found that the deletion of PrPc expression dissociated Aβ accumulation from behavioral impairment in mice, suggesting that the cognitive deficit normally resulting from some aspect of the Aβ42 cascade selectively requires PrPc .
However, even more recently, three groups [40–42] studying different model systems from those utilized by the above authors, although confirming the high avidity of Aβ42 for PrPc, failed to confirm any reduction in the neurotoxicity of Aβ42 in the absence of its binding to PrPc. Clearly, it would be of great interest if it could be determined whether the original results apply to humans. Moreover, α-secretase has been reported to be responsible for the physiological processing of PrPc in the middle of its toxic sequence [43–45]. Thus, Cisse and Mucke  suggest that one way to prevent both Aβ production and the downstream mediation of PrPc might be to increase α-secretase activity. We suggest the possibility that a statin-induced increase in α-secretase activity could, assuming that the Aβ42-PrPc link for the neurotoxicity of Aβ42 applies in humans, lead to the reduction of the neurotoxicity of Aβ42 even if its concentration was not reduced. Thus, our recent findings preceding publications about the proposed link between Aβ42 oligomers and PrPc (together with their cleavage by α-secretase) may take on added significance, at least for the reduction of AD risk in non- PSEN1 subjects, depending upon the outcome of the Aβ42-PrPc controversy.
Moreover, other agents increase the production of α-secretase, at least in cell lines. For example, both testosterone  and estradiol  increase the secretion of the non-amyloidogenic APP fragment, sAPPα, and decrease the secretion of Aβ peptides. It would be of great interest to know whether testosterone and estradiol have similar actions in human males and females, respectively, for carriers of PSEN1 mutations as well as for carriers of ApoEε4 alleles.
It is also well established that mid-life serum total cholesterol levels are associated with an increased risk of both AD and vascular dementia . Clearly, dementia risk factors are best addressed well before disease symptoms appear. While there is strong evidence that these conclusions apply to non- PSEN1 subjects, it is important to know whether or not they apply to PSEN1 subjects as well.
Although this review has focused on the relationship of putative statin therapy with excess Aβ42 assumed to be part of the cascade that leads to neurodegenerative factors, pleiotropic effects of statins must be considered. For example, others have suggested that the putative beneficial effects of statins might be through the production of nitric oxide at the microvascular endothelial level . Moreover, a recent study suggests that mutations in PSEN1 genes may produce defective lysosomal proteolysis, which could itself represent a basis for pathologic protein accumulations in neuronal cell death leading to the identification of novel therapeutic targets .