Normative brain-state trajectories reveal deviation from healthy aging in Alzheimer's disease

Abstract

INTRODUCTIONDistinguishing healthy brain aging from early neurodegenerative disruption remains a major challenge in Alzheimers disease. METHODSUsing resting-state fMRI from the Alzheimers Disease Neuroimaging Initiative (357 participants; cognitively normal, mild cognitive impairment, Alzheimers disease), we trained a Hidden Markov Model exclusively on cognitively normal adults to define latent connectivity states. A generalized additive model estimated an age-adjusted reference trajectory of transition entropy, and subject-specific deviations from this trajectory were quantified. RESULTSMild cognitive impairment and Alzheimers disease showed progressively greater deviation from the normative reference, with the strongest disruption in Alzheimers disease. A single absolute-deviation score retained much of the predictive information contained in higher-dimensional dynamic features. DISCUSSIONThese findings suggest Alzheimers disease is associated with measurable departure from healthy dynamic brain aging, providing an interpretable framework for future longitudinal and clinically validated studies.