Dissociable structural and molecular pathways of age-related change in sustained attention

Sustained attention, the capacity to maintain goal-directed attention over extended periods, declines with age but with substantial individual variability across cognitively unimpaired (CU) older adults. The neurobiological mechanisms driving both the decline and its variability across CU remain poorly understood. Two candidate processes may contribute: microstructural deterioration of the superior longitudinal fasciculus (SLF), the principal white-matter tract coupling prefrontal and parietal nodes of the dorsal attention network, and subclinical accumulation of Alzheimer's disease (AD)-related pathology, which may erode attentional function through disruption of neuromodulatory systems and progressive involvement of frontoparietal cortical substrates. We combined (a) diffusion MRI tractography, quantifying SLF fractional anisotropy (FA) and mean diffusivity (MD) alongside two control tracts, the corticospinal tract (CST) and cingulum (CGC), with (b) a plasma panel indexing AD-related pathology (pTau-181, pTau-217), neuroaxonal injury (NfL), and astrocytic reactivity (GFAP) in 162 CU older adults drawn from two Stanford cohorts (plasma subsample N = 146). Sustained attention was assessed using the gradual-onset Continuous Performance Task (gradCPT) and indexed by a composite score (Att-Z) derived from discriminability (d') and response-time variability (RTV). Parallel mediation and commonality analyses were used to test whether structural and molecular pathways contribute independently to age-related attentional decline. Older age was associated with lower Att-Z (β = -0.315, p < 0.001). In simultaneous three-tract regression models, only SLF microstructure uniquely predicted Att-Z (FA: β = +0.275, p < 0.001; MD: β = -0.320, p < 0.001). SLF microstructure mediated the age-attention relationship. At the molecular level, plasma pTau-181 (β = -0.212, pFDR < 0.03) and pTau-217 (β = -0.163, pFDR < 0.05) predicted Att-Z and each mediated age-related attentional decline. Yet, neither pTau isoform predicted SLF microstructure, indicating that the molecular pathway operates independently of white-matter integrity. NfL also reached FDR-corrected significance for Att-Z (β = -0.156, pFDR < 0.05) but attenuated to non-significance when modelled jointly with pTau-181 or pTau-217, suggesting that the attentionally relevant component of molecular ageing is specific to AD-related pathology rather than NfL-related neuroaxonal damage. GFAP showed no association with sustained attention in any model. In parallel mediation models, SLF microstructure and plasma pTau carried significant independent indirect effects with negligible shared variance, and both pathways retained significance when modelled jointly. These findings reveal a multi-pathway architecture of attentional ageing in which structural disconnection of the dorsal attention network and accumulation of AD-related pathology operate as dissociable and additive mediators of individual differences in attention and of age-related attentional decline, detectable before clinical impairment. Their mechanistic independence identifies two separable biological targets for preserving attentional capacity in CU older adults, including those in the preclinical phase of AD.