Amyloid pathology drives cognitive decline in Alzheimer’s Disease through impairing neurovascular coupling: An ¹⁸F-Florbetapir PET/MRI Study

Neurovascular coupling (NVC) impairment is implicated in Alzheimer’s disease (AD), but its relationship with amyloid-β (Aβ) pathology and diagnostic value remain unclear. We examined Aβ-related NVC changes and their mediating role in cognitive decline. Using ¹⁸F-florbetapir PET/MRI, we assessed Aβ deposition, neural activity, and cerebral blood flow (CBF) in 96 participants (24 Aβ-negative mild cognitive impairment MCI⁻, 30 Aβ-positive MCI MCI⁺, and 42 Aβ-positive AD AD⁺). Neural activity was quantified using amplitude of low-frequency fluctuation (ALFF), fractional ALFF (fALFF), and degree centrality (DC). Multidimensional NVC was derived from spatial correlations between CBF and these neural activity metrics. Global NVC progressively decreased (MCI⁻ > MCI⁺ > AD⁺). Compared to MCI⁻, the MCI⁺ group exhibited reduced NVC in default mode network hubs, including posterior cingulate gyrus, angular gyrus, and precuneus. These regional metrics demonstrated good diagnostic performance in distinguishing MCI⁺ from MCI⁻, with the combined model achieving an AUC of 0.935 and robust internal validation. The AD⁺ group showed extended impairment to frontal, visual, limbic, and subcortical areas compared to MCI⁺. Mediation analysis identified CBF-DC coupling in left posterior cingulate gyrus as a key mediator between Aβ burden and cognitive impairment for MMSE (β = -1.893, 95% CI: -4.237, -0.253) and MoCA (β = -2.614, 95% CI: -5.472, -0.472). NVC impairment links Aβ pathology to cognitive decline, with the left posterior cingulate gyrus as a key region. This supports AD’s neurovascular hypothesis in vivo and highlights NVC as a potential biomarker and target for early diagnosis and intervention. • Aβ deposition impairs global and regional neurovascular coupling (NVC) strength • Aβ-driven NVC impairment begins in the default mode network and expands brain-wide • Regional NVC effectively discriminate Aβ-positive and Aβ-negative mild cognitive impairment patients • Left posterior cingulate gyrus CBF-DC coupling mediates Aβ-induced cognitive decline