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Background <p>The medial temporal lobe is organized into two memory-critical networks: the anterior–temporal and posterior–medial systems. While these systems show selective vulnerability to aging and Alzheimer’s disease, the underlying structural and molecular determinants of this susceptibility remain unclear. We aimed to characterize the specific white matter pathways supporting these networks, investigate how amyloid-β and neuroinflammation interact to impact their integrity, and determine if structural changes relate to functional connectivity alterations.</p> Methods <p>In 88 cognitively unimpaired (CU) older adults (≥ 65&#xa0;years) from the Age-Well cohort (NCT02977819), we combined longitudinal diffusion MRI tractography, resting-state fMRI, amyloid-β PET (Florbetapir), and plasma glial fibrillary acidic protein (GFAP). We reconstructed fiber pathways of the perirhinal (anterior-temporal system hub) and parahippocampal (posterior–medial system hub) cortices and quantified their microstructural integrity, network connectivity, and relationships to pathology.</p> Results <p>The anterior–temporal and posterior–medial systems relied on partly distinct structural pathways. Both involved the inferior longitudinal and cingulum bundles, but the anterior–temporal system was specifically associated to their inferior portions, as well as thalamic radiations, and callosal fibers, whereas the posterior–medial system relied more on their superior portions and the inferior fronto-occipital fasciculus. We identified a non-linear, inverted U-shaped association between pathway integrity and amyloid-β burden, suggesting dynamic structural changes across early pathological stages. Crucially, plasma GFAP moderated this relationship for the posterior-medial pathway: the negative impact of amyloid-β on structural integrity was exacerbated in individuals with higher astroglial reactivity, highlighting a synergistic pathological effect. Finally, in high amyloid-β individuals, increased anterior-temporal functional connectivity correlated with lower anterior-temporal pathway integrity, suggesting that network higher FC may represent a maladaptive response to early amyloid-β deposition leading to white matter integrity loss.</p> Conclusions <p>Together, our findings reveal distinct mechanisms of vulnerability within medial temporal networks: while the posterior-medial system is primarily sensitive to the synergistic effects of amyloid-β and astroglial reactivity, the anterior-temporal system shows lower structural integrity linked to higher FC in the presence of amyloid. By providing a mechanistic framework for these early disruptions, this study advances the understanding of preclinical Alzheimer’s disease and identifies specific structural–functional signatures that could serve as sensitive biomarkers for targeted interventions.</p>

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Structural and molecular determinants of medial temporal lobe network vulnerability in aging and Alzheimer’s disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月27日

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  • Elise Saul,
  • Léa Chauveau,
  • Brigitte Landeau,
  • Jade Lasserve,
  • Blandine Montagne,
  • Emilie Foyard,
  • Géraldine Poisnel,
  • Gaël Chételat,
  • Robin de Flores

摘要

Background

The medial temporal lobe is organized into two memory-critical networks: the anterior–temporal and posterior–medial systems. While these systems show selective vulnerability to aging and Alzheimer’s disease, the underlying structural and molecular determinants of this susceptibility remain unclear. We aimed to characterize the specific white matter pathways supporting these networks, investigate how amyloid-β and neuroinflammation interact to impact their integrity, and determine if structural changes relate to functional connectivity alterations.

Methods

In 88 cognitively unimpaired (CU) older adults (≥ 65 years) from the Age-Well cohort (NCT02977819), we combined longitudinal diffusion MRI tractography, resting-state fMRI, amyloid-β PET (Florbetapir), and plasma glial fibrillary acidic protein (GFAP). We reconstructed fiber pathways of the perirhinal (anterior-temporal system hub) and parahippocampal (posterior–medial system hub) cortices and quantified their microstructural integrity, network connectivity, and relationships to pathology.

Results

The anterior–temporal and posterior–medial systems relied on partly distinct structural pathways. Both involved the inferior longitudinal and cingulum bundles, but the anterior–temporal system was specifically associated to their inferior portions, as well as thalamic radiations, and callosal fibers, whereas the posterior–medial system relied more on their superior portions and the inferior fronto-occipital fasciculus. We identified a non-linear, inverted U-shaped association between pathway integrity and amyloid-β burden, suggesting dynamic structural changes across early pathological stages. Crucially, plasma GFAP moderated this relationship for the posterior-medial pathway: the negative impact of amyloid-β on structural integrity was exacerbated in individuals with higher astroglial reactivity, highlighting a synergistic pathological effect. Finally, in high amyloid-β individuals, increased anterior-temporal functional connectivity correlated with lower anterior-temporal pathway integrity, suggesting that network higher FC may represent a maladaptive response to early amyloid-β deposition leading to white matter integrity loss.

Conclusions

Together, our findings reveal distinct mechanisms of vulnerability within medial temporal networks: while the posterior-medial system is primarily sensitive to the synergistic effects of amyloid-β and astroglial reactivity, the anterior-temporal system shows lower structural integrity linked to higher FC in the presence of amyloid. By providing a mechanistic framework for these early disruptions, this study advances the understanding of preclinical Alzheimer’s disease and identifies specific structural–functional signatures that could serve as sensitive biomarkers for targeted interventions.