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Background <p>Non-linear alterations in brain network connectivity may represent early neural signatures of Alzheimer’s disease (AD) pathology in cognitively normal older adults. Understanding these changes and their cognitive relevance may help clarify early network vulnerability associated with AD pathology. Most prior studies recruited participants from memory clinics, often with subjective memory concerns, limiting generalizability.</p> Methods <p>We examined 14 large-scale functional brain networks in 968 cognitively normal older adults recruited from the community using resting-state functional MRI, cerebrospinal fluid (CSF) biomarkers (amyloid-β 1–42 [Aβ], total tau, phosphorylated tau 181), and neuropsychological assessments. Functional networks were identified using group independent component analysis.</p> Results <p>Inverted U-shaped associations between CSF Aβ and functional connectivity were observed in the precuneus network and ventral default mode network (DMN), but not in the dorsal DMN, indicating network-specific vulnerability to early amyloid pathology. Higher connectivity in Aβ-related networks, including dorsal and ventral DMN, precuneus, and posterior salience networks, was associated with better visual memory, visuospatial, and executive performance. No significant relationships were observed between CSF tau and functional connectivity.</p> Conclusions <p>Using a large, community-based cohort, we demonstrate that non-linear alterations in functional connectivity occur in specific networks even during the asymptomatic phase of AD. Moreover, Aβ-related network connectivity is cognitively relevant, highlighting early network vulnerability and its functional consequences in amyloid pathology.</p>

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Non-linear associations of amyloid-β with resting-state functional networks and their cognitive relevance in a large community-based cohort of cognitively normal older adults

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月12日

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  • Junjie Wu,
  • Benjamin B. Risk,
  • Taylor A. James,
  • Nicholas T. Seyfried,
  • David W. Loring,
  • Felicia C. Goldstein,
  • Allan I. Levey,
  • James J. Lah,
  • Deqiang Qiu

摘要

Background

Non-linear alterations in brain network connectivity may represent early neural signatures of Alzheimer’s disease (AD) pathology in cognitively normal older adults. Understanding these changes and their cognitive relevance may help clarify early network vulnerability associated with AD pathology. Most prior studies recruited participants from memory clinics, often with subjective memory concerns, limiting generalizability.

Methods

We examined 14 large-scale functional brain networks in 968 cognitively normal older adults recruited from the community using resting-state functional MRI, cerebrospinal fluid (CSF) biomarkers (amyloid-β 1–42 [Aβ], total tau, phosphorylated tau 181), and neuropsychological assessments. Functional networks were identified using group independent component analysis.

Results

Inverted U-shaped associations between CSF Aβ and functional connectivity were observed in the precuneus network and ventral default mode network (DMN), but not in the dorsal DMN, indicating network-specific vulnerability to early amyloid pathology. Higher connectivity in Aβ-related networks, including dorsal and ventral DMN, precuneus, and posterior salience networks, was associated with better visual memory, visuospatial, and executive performance. No significant relationships were observed between CSF tau and functional connectivity.

Conclusions

Using a large, community-based cohort, we demonstrate that non-linear alterations in functional connectivity occur in specific networks even during the asymptomatic phase of AD. Moreover, Aβ-related network connectivity is cognitively relevant, highlighting early network vulnerability and its functional consequences in amyloid pathology.