Extracellular deposits of Aβ peptides as senile plaques, intraneuronal neurofibrillary tangles (NFTs), and large-scale neuronal loss were the main pathological features of AD. Thus, Aβ peptides have long been viewed as a potential target for AD which dominated new drug research during the past twenty years [
2]. The most direct strategy in anti-Aβ therapy is to reduce Aβ production by targeting β- and γ-secretase [
3]. Safety issues are the overriding problem. For targeting γ-secretase, undesirable side effects are inevitable due to its physiological substrates, eg. the Notch signaling protein [
4‐
7], which is essential in normal biological process. Similarily, targeting β-secretase is also challenged for the side effects such as blindness and the large catalytic pocket [
8]. More importantly, in sporadic AD cases, the majority of AD patients do not necessarily have over-producted amyloid precursor protein. Besides, Aβ isoforms could also serve as endogenous positive regulators for neurotransmitter release at hippocampal synapses [
9]. Thus, inhibiting Aβ production may encounter many challenges.
Aβ clearance by immunotherapy is the alternative choice. For active Aβ-immunotherapy, although the first active AD vaccine (AN1792) developed by ELAN showed some beneficial effects such as less cognitive decline, it was suspended owing to serious side effect, or meningoencephalitis [
10‐
12]. Also, the passive immunotherapy did not do much better than active immunotherapy. Several antibodies targeting Aβ have failed in clinical trials, including bapineuzumab (Pfizer/Johnson & Johnson) [
13,
14], Crenezumab (Genentech) [
15,
16], solanezumab (Eli Lilly) [
16‐
18] and ponezumab (Johnson & Johnson /Pfizer) [
19‐
21]. In addition, although passive immunotherapy could overcome some problems of active immunotherapy, there were still inevitable side effects such as amyloid-related imaging abnormalities [
22]. Likewise, the small molecule Aβ binder scyllo-inositol [
23] and tramiprosate [
24‐
26] also failed in clinical trials. These failures even cast more doubts on the Aβ theory [
27]. Actually, the strategy of targeting only a single functional subregion of Aβ may partly account for these failures [
27,
28]. Furthermore, immunotherapy may influence the human immune system, which might cause beneficial or detrimental consequence (such as side effects). However, every cloud has a silver lining. A phase Ib trial of aducanumab (Biogen) showed a positive correlation between brain Aβ levels and disease exacerbation as measured by Clinical Dementia Rating [
29‐
31]. Even the failed phase III EXPEDITION3 trial of solanezumab (Eli Lilly) still demonstrated better performance in Clinical Dementia Rating Sum of Boxes and beneficial impacts on Mini-Mental State Examination and Activities of Daily Living [
17,
18,
32,
33]. Thus, despite all kinds of problems, immunotherapy may still be the better approach to modify the extent of neurodegeneration in AD currently [
34].
In fact, the original amyloid cascade hypothesis was that “Aβ is the causative agent in Alzheimer’s Disease pathology, and that neurofibrillary tangles, cell loss, vascular damage, and dementia follow as a direct result of this deposition” [
35]. After decades of research, although the bulk of data still supports a role for Aβ as the primary initiator of the complex pathogenic cascade in AD, more and more evidences indicate that Aβ acts as a trigger in the early disease process and appears to be necessary but not sufficient in the late stage of AD [
36]. Especially, recent rapid progresses in understanding on toxic amyloid assembly and Aβ metabolism associated systemic abnormalities will provide fresh impetus and new opportunities for this interesting approach [
37].