Table 2 Challenges for non-invasive therapies in AD treatment

PBM

• No agreement on the parameters of PBM therapy in the clinical application [96]

• There are still have conflicting data doubting whether it is the primary acceptor or target of PBM therapy [148, 149]

• The precise mechanisms of PBM treatment, especially the exact mechanisms of pulsed-wave PBM therapy in AD, remain elusive [69, 70]

• The effects and mechanisms of indirect or remote PBM therapy remain to be understood [150, 151]

rTMS

• Evidence regarding long-term efficacy and exact underlying mechanisms is still limited [153]

• More advanced clinical trials are still needed to find the therapeutic window [153]

• No agreement on the parameters and protocols of rTMS therapy at which a medication appeared to be effective in the clinical application of AD [153]

• More studies on the regulation of mitochondria and glial cells’ transformation are needed

• The safety of rTMS treatment needs to be clarified [234]

tDCS

• No standard protocols regarding the clinical use of tDCS [278]

• Finds ways to extend the after-effect of the tDCS [247]

• The effect of anodal and cathodal tDCS needs to be clarified [234]

• More studies are required to investigate the specific target of tDCS

Exercise

• No agreement on the optimal dosages, the best types of exercise, and the optimal timing of initiation of physical exercise for prevention or slowing down AD

• The effects of exercise in different types of memory tasks are variable [9, 44, 282, 342]

• The gender difference is one of the major factors that need to be considered [343]

• More animal and human studies are still required to elucidate the underlying molecular mechanism of physical activity in AD (for instance, the effectiveness of exercise on BBB) [310, 344]