Can locus coeruleus structural and functional changes serve as a biomarker for Alzheimer’s disease: a systematic review and meta-analysis

Background

The locus coeruleus (LC), the brain’s principal noradrenergic nucleus, is implicated early in Alzheimer’s disease (AD) pathophysiology. Growing evidence from animal models, human post-mortem studies, and in vivo neuroimaging suggests that LC structural and functional alterations may reflect AD-related neurodegeneration and could serve as a biomarker across the AD continuum.We aimed to systematically evaluate LC degeneration in AD and to compare group differences using meta-analysis based on LC neuroimaging outcomes.

Objectives

This systematic review aims to evaluate whether LC structural and functional changes can serve as a biomarker for AD, including diagnostic differentiation among AD, mild cognitive impairment (MCI), and healthy controls (HC).

Methods

We systematically reviewed the literature in accordance with PRISMA guidelines. Eligible studies included: (1) animal studies evaluating LC-related AD pathology; (2) human post-mortem studies assessing LC degeneration and AD pathology; and (3) human neuroimaging studies examining LC structural and/or functional alterations in AD, MCI, and HC. Observational designs (cross-sectional, cohort, longitudinal) and randomized controlled trials involving LC-related interventions were eligible. Meta-analysis was conducted only for neuroimaging studies reporting quantitative LC measures (neuromelanin-sensitive MRI signal/contrast, LC volume, diffusion metrics, resting-state functional connectivity, PET-related indices), pooling standardized effect sizes under a random-effects model. Two reviewers independently screened records, extracted data, and resolved discrepancies by consensus. Risk of bias was assessed using appropriate tools based on study design.

Results

A total of 234 studies were included (animal: 83; post-mortem: 83; neuroimaging: 68). The neuroimaging meta-analysis comprised 24 studies. Across animal and post-mortem studies, convergent evidence supports LC vulnerability in AD, including LC-related pathological burden and degeneration with accompanying noradrenergic alterations. In neuroimaging meta-analysis, LC measures were substantially reduced in AD compared with HC (pooled SMD = −1.21; high heterogeneity), with the largest and most consistent effects observed for neuromelanin-sensitive MRI contrast/signal indices. In contrast, the pooled difference between MCI and HC was not significant overall (SMD = −0.08; very high heterogeneity), although some structural metrics (e.g., LC length and, to a lesser extent, volume) suggested potential early-stage change in subset analyses. Publication bias tests indicated possible small-study effects in AD–HC comparisons, while bias signals were not evident for MCI–HC.

Conclusions

This systematic review and meta-analysis integrates evidence from animal models, human post-mortem studies, and in vivo neuroimaging to characterise LC involvement across the AD continuum. Experimental models consistently link noradrenergic dysfunction, including neuronal loss, disrupted projections, tau pathology, and pharmacological manipulation, to AD-related neuropathology and behavioural changes. Post-mortem studies corroborate substantial LC neuronal loss and tau burden, particularly in rostral and mid regions, with clear associations with cognitive decline. In vivo imaging demonstrates robust LC degeneration in clinically manifest AD, with large and consistent effect sizes, especially for neuromelanin-sensitive MRI metrics. Findings in MCI remain heterogeneous, likely reflecting methodological and cohort variability. Overall, LC-sensitive imaging shows promise as a marker of noradrenergic degeneration, although its role in early detection requires further longitudinal and standardised investigation.

References

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