ADNI data reveals multifactorial mechanisms driving Alzheimer's disease progression over two decades

Understanding the complex and heterogeneous progression of Alzheimer's disease (AD) remains a significant challenge, hindering effective diagnostic and therapeutic strategies. Current approaches often focus on single biomarkers like amyloid-beta or tau, yet AD involves a cascade of interconnected pathologies. There's a critical need for comprehensive, longitudinal datasets that integrate multimodal assessments to unravel these intricate mechanisms. The Alzheimer's Disease Neuroimaging Initiative (ADNI) addresses this gap by providing an open-access resource of imaging, fluid biomarkers, genetics, and clinical data, enabling researchers to explore the multifactorial nature of AD progression.

This targeted review synthesized 122 high-impact studies published from 2023 to mid-2025 that utilized data or biospecimens from the Alzheimer's Disease Neuroimaging Initiative (ADNI). The authors aimed to clarify the diverse mechanisms underlying Alzheimer's disease progression by examining recent research outputs. The review systematically categorized findings across various biological domains, integrating insights from multimodal imaging, fluid biomarker analysis, genetics, and clinical assessments to provide a holistic view of AD pathology.

The review identified several key mechanisms contributing to AD progression, including impaired glymphatic clearance and the impact of cerebral small vessel disease. Studies detailed distinct trajectories of amyloid beta and tau deposition, alongside significant roles for inflammation, metabolic disturbances, synaptic dysfunction, and neurodegeneration. These factors collectively lead to cognitive impairment and neuropsychiatric symptoms. The analysis also highlighted multifactorial contributions from genetic and epigenetic influences, various co-pathologies, and comorbidities that modulate disease progression. Furthermore, the review underscored the substantial heterogeneity in clinical presentation and disease course, emphasizing the intricate interplay of these contributing factors. This comprehensive integration of diverse data types from ADNI provides a robust framework for understanding the disease's complexity.

Studies describe impairment of glymphatic clearance and the impact of cerebral small vessel disease, trajectories of amyloid beta and tau deposition, inflammation, metabolic disturbances, synaptic dysfunction, and neurodegeneration, leading to cognitive impairment and neuropsychiatric symptoms.