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bioRxiv · 10.64898/2026.07.16.739039

Brain Structure-Function Association as a Compensatory Factor in Cognitive Aging

Lung, T.-C.·Hoagey, D.·Rodrigue, K.·Rugg, M.·Kennedy, K. M.
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Abstract

Functional activity in response to increasing task difficulty (BOLD-modulation) in regions of the default mode network (DMN/task-negative) and multiple demand network (MDN/task-positive) shows age-related decline, which is associated with reduced cognitive performance. While BOLD-modulation in the DMN begins to decline in middle-age, white matter structural connectivity declines earlier in MDN regions. We conjecture that to maintain executive function (EF) performance with aging, altered BOLD-modulation in DMN during task engagement serves as a compensatory reaction to structural decline in MDN. To test this possibility, functionally-guided tractography was applied in 160 healthy adults aged 20-94 to locate white matter connecting MDN and/or DMN regions that were active during a distance judgement paradigm. Specifically, analyses examined the effects of 1) age on white matter tracts (fractional anisotropy; FA); 2) structure-function association between FA and BOLD-modulation; and 3) age, positive/negative BOLD-modulation, and quadratic FA on EF. Age-related decline was found in one MDN tract (U-shaped tract) and a significant structure-function association was found in inferior fronto-occipital fasciculus (IFOF). Additionally, an interaction effect between quadratic frontal-insular (U-shaped) tract FA, age, and positive/negative BOLD-modulation was found for inhibition performance, supporting the hypothesis of compensatory functional activity effects on executive function for older adults with altered white matter microstructure.

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Lung, T.-C., Hoagey, D., Rodrigue, K., Rugg, M., Kennedy, K. M.. 2026-07-21. Brain Structure-Function Association as a Compensatory Factor in Cognitive Aging. https://doi.org/10.64898/2026.07.16.739039

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