**6. Can Aβ clarify all aspects of the onset and progression of AD?**

Autosomal dominant mutations in and around the Aβ region of the *APP* gene, which accel‐ erate proteolytic processing, are responsible for hereditary early-onset AD [3]. The human *APP* gene is located on the long arm of chromosome 21 [53], an extra copy of which is present in individuals with Down's syndrome (trisomy 21). Patients with Down's syndrome develop AD by 40 years of age, most likely due to this gene dosage effect [4]. In addition, both PS1 and PS2, which are catalytic components of the γ-secretase complex, were identi‐ fied by genetic linkage analyses as the genes responsible for FAD [5-7]. In many cases, fami‐ lial diseases can provide an understanding of the sporadic ones. Therefore, both APP itself and its proteolytic processing may be responsible for the onset and progression of not only FAD but also sporadic AD.

As mentioned above, Aβ is the main constituent of amyloid plaque, which is thought to play a major role in the pathogenesis of AD; its presence is a hallmark of the AD brain. Thus, the amyloid hypothesis is generally accepted as the mechanism of the onset and progression of AD. Although an alternative hypothesis has also been proposed, which suggests that solu‐ ble Aβ oligomers rather than insoluble amyloid plaques are responsible for the onset and progression of AD because the soluble form of the Aβ oligomer is toxic for neurons [100, 101], Aβ still plays a central role in this idea.

However, several doubts have recently been raised regarding the amyloid hypothesis that Aβ plays a central role in the onset and progression of AD. One of the most critical argu‐ ments against this hypothesis is the presence of high levels of Aβ deposition in many nondemented elderly people [102], suggesting that Aβ amyloid plaques are not toxic. Indeed, transgenic mice overproducing Aβ show amyloid deposition mimicking that seen in the AD brain but do not show neurodegeneration [61]. Furthermore, several anti-Aβ drugs and vac‐ cines have failed to show efficacy in phase III clinical trials [103]. Surprisingly, long-term fol‐ low-up studies showed unexpected problems [104]. Immunization of AD patients with the anti-Aβ vaccine, AN-1792, cleared Aβ amyloid plaques. Actually, patients with high titers of antibody against Aβ showed virtually complete plaque removal. However, there was no evidence of improvement in survival and/or cognitive function, even in patients with high titers of anti-Aβ antibody [104]. Although several interpretation for this lack of improve‐ ment have been proposed, these results lead to the idea that both soluble and insoluble forms of Aβ may not be involved in the onset and progression of AD.

Based on these observations, it has been suggested that AD may be caused by an APP-de‐ rived fragment, just not necessarily Aβ [105]. As both extracellular fragments and AICD are generated at the same time as Aβ, acceleration of proteolytic processing leads to overpro‐ duction of not only Aβ but also of both the extracellular fragments and AICD. Therefore, it is likely that the extracellular fragments and/or AICD are responsible for the onset and pro‐ gression of AD. Indeed, AICD has been shown to induce neuron-specific apoptosis, which leads to AD pathology, as mentioned above.

In addition, it has also been proposed that APP is a ligand of Death receptor 6 (DR6) [106], which mediates cell death and is expressed at high levels in the human brain regions most affected by AD. APP is cleaved by β-secretase, releasing the extracellular domain (sAPPβ), which is further cleaved by an as yet unknown mechanism to release a 35 kDa N-terminal fragment (N-APP). This N-APP fragment binds DR6 to trigger neurodegeneration through caspase 6 in axons and caspase 3 in cell bodies [106]. These results suggest that N-APP may also be involved in the onset and progression of AD.
