The current study aimed to evaluate the impact of anodal-tDCS on cognitive performance and functional segregation and integration parameters in MCI patients, according to the presence of Aβ deposits and the APOE ε4-allele.We evaluated the effect of interactions between anodal-tDCS application and AD risk factors on changes in cognitive function and intrinsic brain activity and explored differences in changes in cognitive function and spontaneous brain activity parameters between MCI patients with and without AD risk factors after multiple sequential anodal-tDCS sessions. With regard to cognitive performance, we found that there was a statistical trend toward an interaction between anodal-tDCS and Aβ deposition, which might be attributable to increased MMSE-K score after tDCS application in patients with MCI without Aβ accumulation. However, the impact of tDCS was not significant for changes in cognitive performance, including the MMSE-K score, in the current study.
Similarly, some prior studies have demonstrated improvement of semantic word-retrieval performance after a single-session anodal-tDCS application over the left ventral inferior frontal gyrus of MCI patients . On the other hand, in another study that conducted a nine-session clinical trial for 3 weeks in MCI patients, there was no improvement in the objective neuropsychological test score . In previous studies that performed anodal-tDCS on AD patients, they reported improved MMSE scores , recognition memory , and global functioning as compared to the sham group . Additionally, in a meta-analysis of administering tDCS in patients with mild to moderate AD, repeated-session tDCS was not significantly more effective than single-session tDCS . Moreover, stimulation of the temporal cortex significantly improved cognitive function, as compared to other areas, although the left DLPFC was the most frequently stimulated area . The tDCS protocol of the present study did not contain factors that show beneficial effects identified in the meta-analysis, which could contribute to the restricted improvement in cognitive function. However, this meta-analysis targeted only seven studies, and the sample size was small, and thus results should be interpreted cautiously.
Additionally, although there have been no human studies on the effect of tDCS on cognitive functional changes according to Aβ deposits, an AD rat model, generated by injection of Aβ1−40 in the bilateral hippocampus, showed worse memory performance than control rats after repetitive anodal-tDCS . We found a negative association between baseline Aβ accumulation and change in word recognition scores. Aβ deposits might inhibit cognitive improvement induced by tDCS, which modulates cortical excitability. However, given that this was only a statistical trend, it is necessary to conduct additional research with larger sample sizes.
With regard to changes in brain functional segregation parameters, this study found a statistical trend toward an interaction between tDCS and high AD risk factors, including the presence of Aβ deposits and the APOE ε4-allele, in the left temporal pole. This interaction could contribute to increased temporal pole fALFF after anodal-tDCS application in MCI patients with Aβ deposition or the APOE ε4-allele. The left temporal pole is part of the DMPFC subsystem of the DMN, which is vulnerable to AD pathology . The DC of the left temporal lobe is lower in patients with MCI than in cognitively intact older adults . Additionally, the temporal pole was associated with an abnormal insula network in MCI patients, and decreased functional connectivity in this network is related to cognitive decline in MCI patients . Furthermore, the APOE ε4-allele reduces connectivity of the hippocampal network, which includes the temporal pole in healthy older adults . Although the present study showed a relative lack of evidence for functional integration changes, application of anodal-tDCS in prodromal AD patients with high-risk factors appears to restore the local intrinsic change in the temporal pole found in the MCI stage. This observation might support the hypothesis that tDCS-induced improvement is related to restoration, rather than compensation, of brain activity patterns .
In this study, the index reflecting the global functional integration of aMPFC also showed a similar pattern to the interaction found in the functional segregation parameter of the temporal pole. These results might be attributed to increased functional integration after anodal-tDCS application in MCI patients with the APOE ε4 genotype. The aMPFC is an anterior core set of hubs in the DMN and shows global connectivity with other areas that constitute a DMN subsystem . Additionally, the anterior DMN shows increased connectivity during AD and cognitive decline progression, and this change in the anterior hubs may be a compensatory response to AD pathology . Furthermore, in the current study, the higher the baseline Aβ deposits level, the greater the changes in functional segregation parameters of the temporal pole and functional integration parameters of the aMPFC. These findings could support the concept of compensatory response to AD pathology after tDCS. However, it is possible that these results may underestimate Aβ-mediated hyperactivation in the early stages of AD . Therefore, it is important to bear in mind the possible bias in these responses.
Another important finding was that a decreased change in DC of hippocampal formation was exhibited in the higher baseline Aβ deposits. This result might reflect decoupling of the hippocampal formation from posterior DMN nodes at the prodromal AD stage , and it is estimated that the tDCS application does not significantly affect pathologic functional changes in the hippocampal formation.
Lastly, in the present study, differences were observed in changing functional segregation and integration patterns after anodal-tDCS application, depending on the APOE ε4-allele or Aβ deposits by whole-brain voxel-based analysis in MCI patients. In terms of functional segregation parameters after anodal-tDCS application, our MCI patients with APOE ε4-allele displayed increased local intrinsic brain activity in DMN hub regions and AD compensatory regions, in which previous studies have shown a decreasing trend of fALFF across the AD spectrum . However, MCI patients without the APOE ε4-allele showed increased fALFF after repetitive anodal-tDCS administration in different brain regions, such as the inferior occipital gyrus, calcarine fissure, and surrounding cortex. The inferior occipital gyrus has been documented to be vulnerable during the MCI stage and is connected with deep brain structures related to MCI pathology . Additionally, the fALFF of the calcarine fissure and surrounding cortex showed a decreasing trend during the AD course . However, the lack of information on the APOE genotype in previous reports adds further caution regarding the interpretation of these findings. In MCI patients in the present study, regional intrinsic activity of the inferior temporal gyrus was increased both with and without Aβ deposits, and this region has shown lower local integrity in the MCI group than in the normal group in our previous study . Furthermore, the cerebellum, in which regional intrinsic brain activity increased after tDCS in MCI patients with Aβ deposits, was also the area in which fALFF tended to decrease with AD progression in a previous study . Therefore, these findings might indicate that increased fALFF in functionally deteriorated regions might be induced by sequential anodal-tDCS during the prodromal AD stage. Additionally, MCI patients without Aβ deposits showed increased intrinsic brain activity at various locations in the frontal gyrus, unlike those with Aβ deposition after multiple sessions of anodal-tDCS. In a prior study, the frontal cortex showed hypermetabolism in MCI patients without Aβ accumulation, and MCI patients with cortical hypermetabolism did not convert to AD during the follow-up period . Hence, it could conceivably be hypothesised that sequential anodal-tDCS may restore spontaneous brain activity in MCI patients with Aβ deposits but play a compensatory role in those without Aβ deposition. Future studies on the current topic are therefore recommended.
Regarding the functional integration parameter evaluated by whole-brain voxel-based analysis, we found that MCI patients with AD risk factors showed increased DC in the cerebellum after anodal-tDCS, similar to the pattern of functional segregation parameter changes. Another finding was that MCI patients with the APOE ε4-allele showed increased temporal pole DC after anodal-tDCS, in which a fALFF increase was observed in ROI-based analysis. According to these data, it might be assumed that the intensity at which a region locally activated by anodal-tDCS is integrated with other regions increases simultaneously in MCI patients with high-risk factors of AD.
A significant limitation of the current study is that the sample size was relatively small, and no comparisons with a sham group were made. Consequently, there is a relative lack of statistical robustness for the interaction between anodal-tDCS application and AD risk factors for changes in cognitive function and brain functional segregation and integration. Lastly, considering the after-effects of tDCS  and the important role of stimulation frequency for outcomes in MCI and AD patients , further research, applying tDCS for a longer duration, is needed.