From Single-Modal to Multi-Modal Artificial Intelligence in Alzheimer's Disease: A Systematic Review of Databases, Modalities, Diagnostic Performance, and Clinical Translation Challenges.

Alzheimer's disease (AD) is the leading cause of dementia and a major cause of death worldwide, making early detection a critical clinical priority. Because pathological changes may begin 15-20 years before symptom onset, artificial intelligence (AI) has emerged as a promising tool for identifying and characterizing AD. In particular, multi-modal approaches that integrate cognitive, biological, and sensor-based data have attracted growing interest. This systematic review compares single- and multi-modal AI strategies for AD detection, covering machine learning and deep learning methods, feature representations, validation strategies, and classification tasks. Searches of major databases identified 568 studies published between 2016 and early 2026; 278 met the inclusion criteria according to PRISMA guidelines. Multi-modal approaches generally achieved higher performance than single-modal strategies, particularly for challenging tasks such as predicting progression between closely related disease stages, although direct comparisons under identical conditions remain scarce. Critically, only about 4% of studies evaluated their models on a genuinely independent external cohort, raising substantial concerns about model generalizability. Overall, current AI systems remain highly dependent on existing datasets and heterogeneous evaluation protocols, which limit generalizability and clinical applicability. Future research should prioritize representative multimodal datasets, rigorous external validation, and clinically interpretable AI systems.