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. 2025 Jul 7;82(8):848-858.
doi: 10.1001/jamaneurol.2025.1801. Online ahead of print.

Higher Educational Attainment and Accelerated Tau Accumulation in Alzheimer Disease

Yue Cai  1 , Lili Fang  1 , Jie Yang  1   2 , Xin Zhou  1   3 , Lin Liu  1 , Anqi Li  1   4 , Pan Sun  1 , Guoyu Lan  1 , Zhengbo He  1   5 , Yalin Zhu  1   4 , Laihong Zhang  1   6 , Mingxing Jiang  1   7 , Xianfeng Yu  8 , Zhen Liu  1 , Tengfei Guo  1   9   10 ; Alzheimer’s Disease Neuroimaging Initiative Group
Collaborators, Affiliations

Higher Educational Attainment and Accelerated Tau Accumulation in Alzheimer Disease

Yue Cai et al. JAMA Neurol. .

Abstract

Importance: The impact of educational attainment (EA) on longitudinal tau accumulation remains largely underexplored.

Objective: To investigate the association of EA with tau accumulation in Alzheimer disease (AD).

Design, setting, and participants: This cohort study used 3 independent samples: the Alzheimer's Disease Neuroimaging Initiative (ADNI; October 2015-July 2022, mean follow-up: 3.0 years), Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease study (A4; 2014-2022, mean follow-up: 4.7 years), and Greater-Bay-Area Healthy Aging Brain Study (GHABS; July 2021-August 2024, mean interval from plasma collection to tau positron emission tomography [PET]: 1.0 years). The ADNI and GHABS represent Northern American and Southern Chinese populations, respectively. A4 is a multicenter trial. Participants with amyloid β (Aβ) and subsequent tau PET were included from ADNI, A4, and GHABS, and a subset had plasma phosphorylated tau (p-tau) 217 (p-tau217) and resting-state functional magnetic resonance imaging (RS-fMRI) data. Data were analyzed from July 2022 to January 2025.

Exposures: EA, Aβ-PET, tau-PET, plasma p-tau217, and RS-fMRI.

Main outcomes and measures: Participants were classified as high EA and low EA based on median years of EA. Longitudinal tau changes were compared across Aβ-PET positivity and EA groups. Interactions of EA status with Aβ burden, entorhinal tau, and plasma p-tau217 on tau accumulation were investigated in Aβ-positive (Aβ+) individuals. Connectivity-associated tau spread was compared across different Aβ/EA groups. Whether or not Aβ-targeting treatment attenuated tau accumulation in Aβ+ high-EA individuals was also evaluated.

Results: This study included 887 participants: 377 from ADNI (mean [SD] age, 73.3 [7.2] years; 191 female [50.7%]), 395 from A4 (mean [SD] age, 71.9 [4.8] years; 223 female [56.5%]), and 115 from GHABS (mean [SD] years, 66.0 [7.4] years; 76 female [66.1%]). In the Aβ-negative group, high-EA individuals exhibited slower tau accumulation than low-EA individuals (right middle temporal gyrus: estimate = -0.002; 95% CI, -0.003 to -0.0002; P = .03). Conversely, higher EA in the Aβ+ group was correlated with accelerated tau accumulation (left middle temporal gyrus: estimate = 0.003; 95% CI, 0.0003-0.005; P = .03) and stronger Aβ-associated (left visual region: estimate = 0.38; 95% CI, 0.11-0.65; P = .006), entorhinal tau-associated (left middle temporal gyrus: estimate = 0.35; 95% CI, 0.08-0.63; P = .01), and plasma p-tau217-associated tau accumulation (left inferior temporal gyrus: estimate = 0.46; 95% CI, 0.02-0.90; P = .04), as well as increased connectivity-associated tau spread compared with lower EA (estimate = 0.33; 95% CI, 0.003-0.67; P = .048). Aβ-targeting treatment appeared to mitigate plasma p-tau217-associated tau accumulation in patients with AD and higher EA (estimate = -0.52; 95% CI, -0.80 to -0.24; P < .001).

Conclusions and relevance: Results of this cohort study suggest that higher EA was associated with faster tau accumulation and spread in Aβ+ individuals, highlighting the importance of Aβ clearance in mitigating tau progression in patients with AD and higher EA.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Guo reported receiving Alzheimer’s Association International Conference (AAIC) travel fees for the AAIC 2023 conference and serving on the editor board of Alzheimer’s & Dementia. No other disclosures were reported.

References

    1. van der Kant R, Goldstein LSB, Ossenkoppele R. Amyloid-β–independent regulators of tau pathology in Alzheimer disease. Nat Rev Neurosci. 2020;21(1):21-35. doi: 10.1038/s41583-019-0240-3 - DOI - PubMed
    1. Guo T, Dukart J, Brendel M, Rominger A, Grimmer T, Yakushev I; Alzheimer’s Disease Neuroimaging Initiative . Rate of β-amyloid accumulation varies with baseline amyloid burden: Implications for antiamyloid drug trials. Alzheimers Dement. 2018;14(11):1387-1396. doi: 10.1016/j.jalz.2018.05.013 - DOI - PubMed
    1. La Joie R, Ayakta N, Seeley WW, et al. Multisite study of the relationships between antemortem [11C]PIB-PET Centiloid values and postmortem measures of Alzheimer disease neuropathology. Alzheimers Dement. 2019;15(2):205-216. doi: 10.1016/j.jalz.2018.09.001 - DOI - PMC - PubMed
    1. Fleisher AS, Pontecorvo MJ, Devous MD Sr, et al. ; A16 Study Investigators . Positron emission tomography imaging with [18F]flortaucipir and postmortem assessment of alzheimer disease neuropathologic changes. JAMA Neurol. 2020;77(7):829-839. doi: 10.1001/jamaneurol.2020.0528 - DOI - PMC - PubMed
    1. Malpetti M, Kievit RA, Passamonti L, et al. Microglial activation and tau burden predict cognitive decline in Alzheimer disease. Brain. 2020;143(5):1588-1602. doi: 10.1093/brain/awaa088 - DOI - PMC - PubMed

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