Objective The rising prevalence of mild cognitive impairment (MCI) has spurred interest in innovative cognitive rehabilitation approaches, including serious games. This review summarizes randomized clinical trials (RCTs) exploring the impact of serious games on MCI patients.Methods We conducted a comprehensive data search using key terms such as “gamification,” “digital therapy,” “cognition,” “mild cognitive impairment,” and “Alzheimer’s disease.” We exclusively considered published RCTs, excluding animal studies and basic research.Results We identified eight RCTs. Four RCTs examined the effects of serious games using cognitive training for MCI patients. Notably, one study found that non-specific training (Nintendo Wii) significantly enhanced cognitive function and quality of life compared to cognition-specific computer training (CoTras). Among the remaining three RCTs, one specifically demonstrated that personalized serious game-based cognitive training yielded superior cognitive outcomes and reduced depressive symptoms. One RCT focused on serious games incorporating physical exercise, highlighting the effectiveness of kinetic-based exergaming in enhancing overall cognition. Three RCT focused on combined cognitive training and physical exercise. A double-blind RCT revealed that progressive resistance training or standalone physical exercise outperformed the combined approach in improving executive function and global cognition. Two additional RCTs reported positive outcomes, including improvements in cognitive function and electroencephalogram patterns associated with game-based interventions.Conclusion Serious games, whether focusing on cognitive training, physical exercise, or a combination of both, have potential to improve cognitive and functional outcomes in individuals with MCI. Further research and standardization of protocols are needed to better understand the full potential of serious games in MCI.

Recent studies have demonstrated the pivotal role of locus coeruleus (LC) and salience network (SN) resting state functional connectivity (rsFC) changes in the early stage of Alzheimer’s disease (AD). Moreover, sex has been a crucial point of discussion in understanding AD pathology. We aimed to demonstrate the sex-related disparities in the functional connectivity (FC) of the SN and LC in preclinical AD. A total of 89 cognitively normal patients with evidence of amyloid beta (Aβ) accumulation ([18F] flutemetamol +) were recruited in the study. A seed-to-voxel analysis was conducted to measure the LC and SN rsFC differences between sexes. In addition, sex by Aβ interactive effects on FC values were analyzed with a general linear model. There were statistically significant sex by regional standardized uptake value ratio (SUVR) interactions in the LC FC with the parietal, frontal, and occipital cortices. Moreover, there was a significant sex by global SUVR interaction in the SN FC with the temporal cortex. The findings suggest that there are differential patterns of LC FC and SN FC in males and females with preclinical AD, which interact with regional Aβ deposition.

Brain atrophy may precede symptoms in Alzheimer's disease (AD), but it remains unclear whether atrophy in this preclinical stage falls within a distinct brain network or is associated with transitional cognitive changes. We investigated cortical thickness in cognitively unimpaired older adults with varying amyloid-β accumulation and estimated the connectivity of each individual’s atrophy pattern using a large normative connectome (n = 1000). A distinct network was connected to atrophy patterns in amyloid-β-positive (n = 1242) versus negative (n = 536) participants. This preclinical AD network was similar to a previously published atrophy network associated with AD dementia (r = 0.8284, p = 0.016). In leave-one-out cross-validation, atrophy patterns connected to the preclinical AD network were associated with lower cognitive performance (p = 0.0018), greater subjective cognitive decline (p < 0.001), and amyloid-β levels (p < 0.001). Atrophy in preclinical AD maps to a network similar to AD dementia that is associated with amyloid-β and cognition, demonstrating an atrophy-related network across the continuum of AD.

Brain atrophy may precede cognitive and functional impairment in Alzheimer's disease (AD), but at this "preclinical" stage, it remains unclear whether atrophy localizes to specific brain networks and whether such localization is associated with clinical outcomes. We investigated cortical thickness in 1778 cognitively unimpaired (CU) older adults with amyloid-β (Aβ) PET from the A4 (Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease) and LEARN (Longitudinal Evaluation of Amyloid Risk and Neurodegeneration) studies, with a subset (N = 445) with tau PET. We estimated the networks disrupted by each individual's cortical thinning using a large normative connectome database (N = 1000), and tested whether this preclinical AD atrophy network is associated with clinical manifestations and longitudinal cognitive (PACC) and functional (CDR) trajectories. Distinct networks connected to atrophy patterns were associated with Aβ and regional tau in CU older adults. These networks were similar to a previously published atrophy network for AD dementia (Aβ: r = 0.817, P = 0.006; tau: r = 0.712, P = 0.046). Atrophy connectivity to this preclinical AD network was associated with higher Aβ and tau, independent of total cortical atrophy, and cross-sectionally with lower cognition, greater subjective cognitive decline, and increased anxiety; longitudinally, it predicted faster cognitive and functional decline over ~5 years. After tau adjustment, the functional-decline effect was preserved while the cognitive-slope effect was largely attenuated. Atrophy in preclinical AD localizes to a network resembling AD dementia, and is independently associated with AD pathologies, clinical outcomes, and longitudinal decline. Network-level neurodegeneration is detectable and clinically informative in preclinical AD, supporting future network-based research and therapeutic development.