**Author details**

of dementia and AD with the early onset or sporadic forms with the late start. The genes encoding APP, BACE-1, PS1/2 and *APOE-ε4* thus play a crucial role in the pathogenesis of AD. Besides these genes, it is also worth noting the role of neprilysin and the insulindegrading enzyme. Both neprilysin and the insulin-degrading enzyme are involved in the elimination of Aβ. The levels of both enzymes are decreased in the brains of patients with AD. Further biochemical, behavioral and clinical studies in this area are, however, necessary in order to develop an effective treatment, whether symptomatic or such that alters the course of the disease or hopefully even heal the disease. BACE-1 is an enzyme that initiates the proteolytic cleavage of APP into smaller fragments of Aβ. According to preclinical and clinical data, BACE-1 is a convenient therapeutic target for the treatment of AD. BACE-1 (−/−) knockout mice are viable but they exhibit a range of neurological symptoms which points to the fact that BACE-1 inhibitors may have serious side effects that are associated with the physiological function of this enzyme. In particular, development of new BACE-1 inhibitors represents a major challenge for the future since only a limited number of these drugs successfully entered clinical trials. From this perspective, the most promising compounds are MK-8931 or E2609 which have been promoted to the II/III phase, while the others are between I and II phases. All the drugs consistently induce a large decrease in spinal cord levels of Aβ, up to 90%. They are usually well tolerated; only testing of two inhibitors of BACE-1 was terminated because of serious side effects. The most discussed question remains to what extent it is beneficial to modulate the activity of BACE-1, and in what phase of the AD it is best to start the treatment [17]. Theoretical knowledge on the mutation of Ala673Thr further shows that 50% of BACE-1 inhibition results in a 20% reduction of the Aβ level. But it still remains unclear to what extent it is necessary to inhibit the activity of BACE-1 if the amyloid plaques are already formed. The amyloid plaques themselves can form many years before the clinical manifestation of the symptoms of dementia. However, in recent years, new theories have emerged posing Aβ on the crossroad [43]. Indeed, in some patients, the presence of Aβ in AD brain does not necessarily mean dementia will break out. Postmortem biopsy showed that older persons can have extensive amyloid burden without any signs of cognitive impairment. Note that it also remains unclear whether these individuals would have developed AD if they had lived longer. Be that as it may, it was proved that the presence of Aβ in cognitively normal persons was prone more rapidly to develop symptoms related to AD [44, 45]. Last but not least, it is not fully understood what the relationship between the quantity of the Aβ deposit and cognitive distortions really is. Nonetheless, everything should be more or less elucidated by the results of ongoing clinical trials, especially those on γ-secretase, which seems to be the most perspective

This work has been supported by the MH CZ-DRO (University Hospital Hradec Kralove, No. 00179906) and by the grant of the Grant Agency of the Czech Republic No. 16-08554S).

biological target for therapy of AD.

14 Alzheimer's Disease - The 21st Century Challenge

**Acknowledgements**

Jan Korabecny, Katarina Spilovska, Ondrej Soukup, Rafael Dolezal and Kamil Kuca\*

\*Address all correspondence to: kamil.kuca@uhk.cz

Biomedical Research Centre, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic
