Predicting Future Cognitive Decline Using Novel fMRI-Based Biomarkers in Preclinical Alzheimer's Disease

Objective: Despite significant advances in biomarker-based detection of preclinical Alzheimer’s disease (AD), the prediction of future cognitive decline in at-risk individuals still remains challenging. Recent research has demonstrated the diagnostic potential of fMRI-based single-value scores— Functional Activity Deviation during Encoding (FADE) and Similarity of Activations during Memory Encoding (SAME)—which reflect deviations from or similarities to prototypical activation patterns observed in young, healthy adults. These scores were previously associated with disease stage (healthy controls [HC], subjective cognitive decline [SCD], mild cognitive impairment [MCI], early AD dementia) and biochemical risk factors (CSF Aβ ratio, ApoE genotype).

Methods: The present study investigates the prognostic utility of FADE and SAME scores by examining their relationship with neuropsychological test performance over three years. Data from the DZNE’s multi-center DELCODE study, which includes individuals across the AD risk spectrum, were used to assess the association of these scores at baseline with changes in the PACC5, a composite measure of cognitive performance, from baseline to follow-up visits 1, 2, and 3.

Results: Preliminary canonical correlation analysis identified SAME-memory and FADE-novelty as the strongest predictors of cognitive performance during follow-up. Regression analyses using contrast coding for the timepoints baseline to follow ups revealed that SAME-memory scores were linked to both cognitive performance and cognitive decline three years after baseline, particularly in individuals with MCI, and indicated that this relationship varied between Aβ-positive and Aβ-negative individuals as determined by the Aβ1-42/1-40 ratio in plasma. FADE-novelty scores showed a similar, though weaker, pattern for cognitive performance, but not for performance change.

Conclusion: These findings suggest that fMRI-based single-value scores could serve as valuable prognostic markers for predicting disease progression in individuals at risk for AD. The association between baseline scores and cognitive decline up to three years later indicates that an individual’s similarity to memory-related brain activity in healthy young adults may reflect neurocognitive reserve in older adults.

Publication History

Article published online:
30 April 2025