Multimodal brain age estimates relate to Alzheimer disease biomarkers and cognition in early stages: a cross-sectional observational study

Abstract

BackgroundEstimates of "brain-predicted age" quantify apparent brain age compared to normative trajectories of neuroimaging features. The brain age gap (BAG) between predicted and chronological age is elevated in symptomatic Alzheimer disease (AD), but has not been well explored in preclinical AD. Prior studies have typically modeled BAG with structural magnetic resonance imaging (MRI), but more recently other modalities, including functional connectivity (FC) and multimodal MRI, have been explored. MethodsWe trained three models to predict age from FC, volumetric (Vol), or multimodal MRI (Vol+FC) in 390 control participants (18-89 years old). In independent samples of 144 older adult controls, 154 preclinical AD participants, and 154 cognitively impaired (CI; CDR > 0) participants, we tested relationships between BAG and AD biomarkers of amyloid, tau, and neurodegeneration, as well as a global cognitive composite. ResultsAll models predicted age in the control training set, with the multimodal model outperforming the unimodal models. All three BAG estimates were significantly elevated in CI compared to controls. FC-BAG and Vol+FC-BAG were marginally reduced in preclinical AD participants compared to controls. In CI participants only, elevated Vol-BAG and Vol+FC-BAG were associated with more advanced AD pathology and lower cognitive performance. ConclusionsBoth FC-BAG and Vol-BAG are elevated in CI participants. However, FC and volumetric MRI also capture complementary signals. Specifically, FC-BAG may capture a unique biphasic response to preclinical AD pathology, while Vol-BAG may capture pathological progression and cognitive decline in the symptomatic stage. A multimodal age-prediction model captures these modality-specific patterns, and further, improves sensitivity to healthy age differences. FundingThis work was supported by the National Institutes of Health (P01-AG026276, P01-AG03991, P30-AG066444, 5-R01-AG052550, 5-R01-AG057680, 1-R01-AG067505, 1S10RR022984-01A1, U19-AG032438), the BrightFocus Foundation (A2022014F), and the Alzheimers Association (SG-20-690363-DIAN).