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. 2025 Feb;21(2):e14426.
doi: 10.1002/alz.14426. Epub 2024 Dec 6.

Locus coeruleus tau is linked to successive cortical tau accumulation

Dahyun Yi  1 , Min Soo Byun  2   3 , Joon Hyung Jung  4 , Gijung Jung  1 , Hyejin Ahn  5 , Yoon Young Chang  6 , Musung Keum  7 , Jun-Young Lee  8 , Yun-Sang Lee  9 , Yu Kyeong Kim  10 , Koung Mi Kang  11   12 , Chul-Ho Sohn  11   12 , Shannon L Risacher  13   14   15 , Andrew J Saykin  13   14   15   16 , Dong Young Lee  1   2   3 ; KBASE Research Group
Affiliations

Locus coeruleus tau is linked to successive cortical tau accumulation

Dahyun Yi et al. Alzheimers Dement. 2025 Feb.

Abstract

Introduction: We investigated the hypothesis that tau burden in the locus coeruleus (LC) correlates with tau accumulation in cortical regions according to the Braak stages and examined whether the relationships differed according to cortical amyloid beta (Aβ) deposition.

Methods: One hundred and seventy well-characterized participants from an ongoing cohort were included. High-resolution T1, tau positron emission tomography (PET), and amyloid PET were obtained.

Results: LC tau burden was significantly linked to global tau in neocortical regions, as was tau in both early Braak stage (stage I/II) and later Braak stage areas. This relationship was significant only in Aβ-positive individuals. While LC tau did not directly impact memory, it was indirectly associated with delayed memory through mediation or moderation pathways.

Discussion: The findings from living human brains support the idea that LC tau closely relates to subsequent cortical tau accumulation, particularly among individuals with pathological Aβ accumulation, and identify LC tau burden as a promising indicator of cognitive trajectories of AD.

Highlights: Tau burden in the LC was significantly associated with cortical tau accumulation. Tau burden in SN or PPN showed no association with cortical tau accumulation. LC tau burden was serially associated with Braak stages. The tau-LC and cortical tau relationship was significant only in the Aβ-positive group. Cortical amyloid's impact on memory worsens with higher tau accumulation in the LC.

Keywords: Alzheimer's disease; amyloid beta; cortical tau accumulation; locus coeruleus; tau pathology.

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Conflict of interest statement

Dr. Saykin receives support from multiple NIH grants (P30 AG010133, P30 AG072976, R01 AG019771, R01 AG057739, U19 AG024904, R01 LM013463, R01 AG068193, T32 AG071444, U01 AG068057, U01 AG072177, and U19 AG074879). He has also received support from Avid Radiopharmaceuticals, a subsidiary of Eli Lilly (in kind contribution of PET tracer precursor) and participated in scientific advisory boards (Bayer Oncology, Eisai, Novo Nordisk, and Siemens Medical Solutions USA, Inc.) and an Observational Study Monitoring Board (MESA, NIH NHLBI), as well as external advisory committees for multiple NIA grants. He also serves as editor‐in‐chief of Brain Imaging and Behavior, a Springer‐Nature Journal. D.Y., M.S.B., J‐H.P, J‐W.K, G.J., H.A., J‐Y.L., Y‐S.L., Y.K.K., K.M.K, C‐H.S., S.L., Y‐N.H., D.Y.L., K.N., and KBASE Research Group have nothing to disclose. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
The relationship of tau burden between LC, PPN, and SN with cortical regions. Note: Associations between LC SUVR and cortical tau global mean SUVR (A), Braak I/II ROI tau mean SUVR (B), Braak III/IV ROI tau mean SUVR (C), or Braak V/VI ROI tau mean SUVR (D). The associations between cortical tau levels and PPN tau levels are also shown (E–H). The associations between cortical tau levels and SN tau levels are also shown (I–L). P values were adjusted for multiple comparisons using FDR method. Statistical significance is denoted as p < 0.05. Fitted graphs are partial‐effects plots adjusted for the effects of age and sex. FDR = false discovery rate. LC = locus coeruleus. PPN = pedunculopontine nucleus. SN = substantia nigra. SUVR = standard uptake ratio value.
FIGURE 2
FIGURE 2
Effects of amyloid positivity on relationship between tau levels in LC and cortical regions. Note: Fitted interaction graphs are partial‐effects plots adjusted for effects of age and sex. Interaction effects of amyloid positivity on associations between LC SUVR and cortical tau global mean SUVR (A), Braak I/II ROI tau mean SUVR (B), Braak III/IV ROI tau mean SUVR (C), or Braak V/VI ROI tau mean SUVR (D). (E) Voxel‐wise analysis of tau levels in LC and cortex tau levels among amyloid‐positive group. P values were adjusted for multiple comparisons using FDR method. Statistical significance is denoted as p < 0.05. FDR, false discovery rate; LC, locus coeruleus; SUVR, standard uptake ratio value.
FIGURE 3
FIGURE 3
Mediation analysis of tau in LC and cortical regions. Note: Serial mediation models showing significant paths mediating association of tau in LC with tau in Braak III/IV (A) or Braak V/VI (B) ROIs. Solid lines are part of a significant pathway, whereas dashed lines represent non‐significant pathways. Age and sex are used as covariates. Values are indicated as beta and p values. 95% CIs are bootstrapped with 10,000 replications. CI, confidence interval; LC, locus coeruleus; ROI, region of interest.
FIGURE 4
FIGURE 4
Relationship of LC tau burden and delayed verbal memory. Note: Mediation analyses for likelihood of Braak stage 3 or higher as mediator of relationship between LC tau SUVR and memory (A). Moderation analysis on effects of cortical global Aβ deposition on delayed memory performance by LC tau levels (B). Age, sex, and years of education are used as covariates. Values are indicated as beta and p values. 95% CI are bootstrapped with 10,000 replications. CI = confidence interval. LC = locus coeruleus. SUVR = standard uptake ratio value.
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