Purpose The role of glymphatic dysfunction in Alzheimer's disease (AD), as measured by diffusion tensor imaging along perivascular spaces (DTI-ALPS) indexing of perivascular function, its progression, and its interaction with amyloid-β (Aβ) and tau proteins, remains controversial. To investigate whether the DTI-ALPS index mediates AD-related cognitive decline through Aβ/tau-dependent pathways using tri-tracer PET/MRI. Methods This retrospective study (2021–2024) analyzed 140 participants (median age 69.00 [61.00, 74.00] years; 84 women), including 99 with AD (37 early-onset [EOAD], 62 late-onset [LOAD]), 35 with mild cognitive impairment (MCI), and 6 with subjective cognitive decline (SCD). All participants underwent simultaneous [1⁸F] Florbetapir (Aβ), [1⁸F] PI-2620(tau), and [1⁸F] FDG PET/MRI with DTI-ALPS indexing for glymphatic function quantification. Causal mediation analysis was used to assess the relationships between biomarkers (P < 0.05). Results The ALPS index progressively decreased across clinical stages (SCD: 1.51 ± 0.08 vs. MCI: 1.37 ± 0.13 vs. AD: 1.32 ± 0.14; P = 0.001), correlating with higher Aβ-PET (r = − 0.31, P < 0.001), tau-PET (ρ = − 0.18, P = 0.035), and FDG-PET scores (ρ = − 0.22, P = 0.008). Aβ-PET fully mediated the ALPS effects on FDG-PET (β = − 0.14, P = 0.002) and cognition (β = 0.12 ~ 0.14, P < 0.01), independent of tau (P > 0.05). The Aβ-negative subgroups showed correlations with ALPS-age (r = − 0.48, P = 0.007), ALPS-education (r = 0.39, P = 0.035), and ALPS-cognition (MoCA: r = 0.62, P < 0.001). The Aβ-positive subgroups revealed inverse ALPS-Aβ associations (ρ = − 0.27, P = 0.010; age/education-adjusted ρ = − 0.24, P = 0.022) alongside positive adjusted correlations with cognition (MMSE: ρ = 0.28, P = 0.009). EOAD exhibited distinct ALPS-cognition relationships compared to LOAD (MMSE: r = − 0.39, P = 0.016 vs. ρ = − 0.06, P = 0.620). Conclusion DTI-ALPS quantifies glymphatic dysfunction driving AD progression predominantly through Aβ-dependent pathways, with EOAD demonstrating distinct neuroimaging-cognition relationships compared to LOAD.

DTI-ALPS index-assessed glymphatic dysfunction mediates Alzheimer’s cognitive decline via amyloid-β-dependent pathways: multimodal PET/MRI study

期刊论文
发表日期：

2025年7月18日

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Yan Zhang,
Gan Huang,
Jieli Geng,
Xia Li,
Mei Xin,
Peizhe Yuan,
Yue Wang,
Qun Xu,
Gang Wang,
Gang Huang,
Jianjun Liu,
Chenpeng Zhang

摘要

Purpose

The role of glymphatic dysfunction in Alzheimer's disease (AD), as measured by diffusion tensor imaging along perivascular spaces (DTI-ALPS) indexing of perivascular function, its progression, and its interaction with amyloid-β (Aβ) and tau proteins, remains controversial. To investigate whether the DTI-ALPS index mediates AD-related cognitive decline through Aβ/tau-dependent pathways using tri-tracer PET/MRI.

Methods

This retrospective study (2021–2024) analyzed 140 participants (median age 69.00 [61.00, 74.00] years; 84 women), including 99 with AD (37 early-onset [EOAD], 62 late-onset [LOAD]), 35 with mild cognitive impairment (MCI), and 6 with subjective cognitive decline (SCD). All participants underwent simultaneous [¹⁸F] Florbetapir (Aβ), [¹⁸F] PI-2620(tau), and [¹⁸F] FDG PET/MRI with DTI-ALPS indexing for glymphatic function quantification. Causal mediation analysis was used to assess the relationships between biomarkers (P < 0.05).

Results

The ALPS index progressively decreased across clinical stages (SCD: 1.51 ± 0.08 vs. MCI: 1.37 ± 0.13 vs. AD: 1.32 ± 0.14; P = 0.001), correlating with higher Aβ-PET (r = − 0.31, P < 0.001), tau-PET (ρ = − 0.18, P = 0.035), and FDG-PET scores (ρ = − 0.22, P = 0.008). Aβ-PET fully mediated the ALPS effects on FDG-PET (β = − 0.14, P = 0.002) and cognition (β = 0.12 ~ 0.14, P < 0.01), independent of tau (P > 0.05). The Aβ-negative subgroups showed correlations with ALPS-age (r = − 0.48, P = 0.007), ALPS-education (r = 0.39, P = 0.035), and ALPS-cognition (MoCA: r = 0.62, P < 0.001). The Aβ-positive subgroups revealed inverse ALPS-Aβ associations (ρ = − 0.27, P = 0.010; age/education-adjusted ρ = − 0.24, P = 0.022) alongside positive adjusted correlations with cognition (MMSE: ρ = 0.28, P = 0.009). EOAD exhibited distinct ALPS-cognition relationships compared to LOAD (MMSE: r = − 0.39, P = 0.016 vs. ρ = − 0.06, P = 0.620).

Conclusion

DTI-ALPS quantifies glymphatic dysfunction driving AD progression predominantly through Aβ-dependent pathways, with EOAD demonstrating distinct neuroimaging-cognition relationships compared to LOAD.