(1) Background: The convergence of digital twin technology, artificial intelligence, and multimodal biomarkers heralds a transformative era in neuropsychological assessment and intervention. Digital twin cognition represents an emerging paradigm that creates dynamic, personalized virtual models of individual cognitive systems, enabling continuous monitoring, predictive modeling, and precision interventions. This systematic review comprehensively examines the integration of AI-driven biomarkers within biomimetic neuropsychological frameworks to advance personalized cognitive health. (2) Methods: Following PRISMA 2020 guidelines, we conducted a systematic search across six major databases spanning medical, neuroscience, and computer science disciplines for literature published between 2014 and 2024. The review synthesized evidence addressing five research questions examining framework integration, predictive accuracy, clinical translation, algorithm effectiveness, and neuropsychological validity. (3) Results: Analysis revealed that multimodal integration approaches combining neuroimaging, physiological, behavioral, and digital phenotyping data substantially outperformed single-modality assessments. Deep learning architectures demonstrated superior pattern recognition capabilities, while traditional machine learning maintained advantages in interpretability and clinical implementation. Successful frameworks, particularly for neurodegenerative diseases and multiple sclerosis, achieved earlier detection, improved treatment personalization, and enhanced patient outcomes. However, significant challenges persist in algorithm interpretability, population generalizability, and the integration of healthcare systems. Critical analysis reveals that high-accuracy claims (85–95%) predominantly derive from small, homogeneous cohorts with limited external validation. Real-world performance in diverse clinical settings likely ranges 10–15% lower, emphasizing the need for large-scale, multi-site validation studies before clinical deployment. (4) Conclusions: Digital twin cognition establishes a new frontier in personalized neuropsychology, offering unprecedented opportunities for early detection, continuous monitoring, and adaptive interventions while requiring continued advancement in standardization, validation, and ethical frameworks.
Gkintoni et al. (Tue,) studied this question.