Sex, education and race/ethnicity have distinct effects on amyloid and tau‐PET status

Abstract Background Sex, education and race/ethnicity are all associated with risk of Alzheimer's disease dementia. Here, we assess the effects of self‐reported sex, educational attainment and race/ethnicity on amyloid‐positivity, and tau‐PET‐positivity in 12,048 (7,394 cognitively unimpaired [CU], 2,177 MCI, and 2,477 dementia) individuals from 42 cohorts worldwide. Method Logistic generalized estimating equations were used to estimate frequency of amyloid‐positivity (using cohort‐specific thresholds for amyloid‐PET [84%] or CSF) and tau‐PET‐positivity (cohort‐specific thresholds of 2SD above mean temporal uptake in amyloid‐negative controls). We assessed: i) sex and APOEε4 ( N = 10,098) associations, to complement earlier findings of a higher frequency of tau‐positivity in females, ii) effects of lower/higher education ( N = 10,970; cohort‐specific median‐split), and iii) effects of race/ethnicity (non‐Hispanic White [hereafter: White], N = 4880; Asian, N = 116; Black or African‐American [hereafter: Black], N = 353; Hispanic, N = 356, only from Northern‐American cohorts). Outcomes were frequency of amyloid‐positivity in CU individuals only, and tau‐PET‐positivity in both amyloid‐positive (AB+) CU and cognitively impaired (CI, i.e. MCI and dementia) individuals. Interaction effects on the relationship between age and amyloid/tau‐positivity were assessed and only retained in the models when significant. Result Female sex was associated with an APOEε4 ‐independent increased frequency of amyloid‐positivity (β=0.51[0.22], p = 0.02) in CU and increase of tau‐positivity in both AB+CU (β=0.27[0.08]) and AB+CI (β=0.37[0.08], both p <0.01). Remarkably, tau‐positivity frequencies of female APOEε4 non‐carriers were equivalent to male APOEε4 carriers in AB+CI (Figure 1). No significant sex* APOE interactions were observed. In CU, higher education was associated with lower amyloid‐positivity frequency (β=‐0.12[0.05], p = 0.02). In contrast, among AB+CU, there was an age*education interaction effect that indicated more pronounced age effects on tau‐positivity in individuals with higher education (age*education:β interaction =0.03[0.01], p <0.01). There were no education effects in AB+CI (Figure 2). In CU, an age*race/ethnicity interaction effect was observed across all non‐White groups compared to White (Hispanic:β interaction =‐0.05[0.01], p <0.01; Black:‐0.04[0.01], p <0.01; Asian:‐0.02[0.01], p = 0.04). This suggests that the impact of age on amyloid‐positivity was less pronounced in non‐White groups. Furthermore, in AB+CI, Hispanic ethnicity was related to higher tau‐positivity frequency than White (β=0.51[0.22], p = 0.02; Figure 3). Conclusion In this multi‐center initiative comprised of clinical and community‐based cohorts, we observed that self‐reported sex, educational attainment and race/ethnicity were related to positivity‐frequencies of Alzheimer's disease pathology.

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Journal
Alzheimer s & Dementia
Published
2025-12-01
DOI
https://doi.org/10.1002/alz70856_105387
Primary Topic
Dementia and Cognitive Impairment Research
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article
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article

Sex, education and race/ethnicity have distinct effects on amyloid and tau‐PET status

I. Skoog, Xiaoxie Mao, Theresa Harrison, José A. Luchsinger et al.
Alzheimer s & Dementia
Dementia and Cognitive Impairment Research
article

Sex, education and race/ethnicity have distinct effects on amyloid and tau‐PET status

I. Skoog, Xiaoxie Mao, Theresa Harrison, José A. Luchsinger, Nesrine Rahmouni, Michel Bottlaender, Yuna Gu, Emma M. Coomans, Valentina Garibotto, Beth C. Mormino, Koen J. Van Laere, Azadeh Feizpour, William Coath, Ian Kennedy, Michael J. Pontecorvo, Suzanne L. Baker, Débora Elisa Peretti, Michael Schöll, Willemijn J. Jansen, H Barthel, Christina B. Young, James Rowe, Mahnaz Shekari, Colin Groot, Oskar H. Hansson, William Charles Kreisl, Elena Jäger, Sang Won Seo, Gérard Bischof, Judes Poirier, Laure Spruyt, Ming Lu, Anouk den Braber, David M Cash, Michael Rullmann, Niklas Mattsson‐Carlgren, Rik Vandenberghe, Adam Brickman, Sid E. O'Bryant, Matthias Brendel, Liana G. Apostolova, Jennifer J. Manly, Carolina Minguillón, Joseph Therriault, Erik Stomrud, Reisa A. Sperling, Elsmarieke van de Giessen, Wiesje M. van der Flier, Maria C. Carrillo, Howard J. Rosen, Yolande A.L. Pijnenburg, Christopher C. Rowe, Gil D. Rabinovici, Shannon Risacher, Johannes Gnörich, Fang Xie, Alexander Drzezga, Susan M. Landau, Pedro Rosa‐Neto, Konstantin Messerschmidt, Juan Domingo Gispert, Silke Kern, Julien Lagarde, Tammie L.S. Benzinger, Jun Pyo Kim, Sebastian Palmqvist, Giovanni B Frisoni, Andrew J. Saykin, William J. Jagust, Samantha C. Burnham, Patrick J. Lao, Ruben Smith, Pieter Jelle Visser, Marie Sarazin, Keith A. Johnson, Yihui Guan, Bradley T Christian, ADNI, ADNI‐DOD, A‐Study, MCSA, Prevent‐AD, Jonathan M Schott, Sterling C. Johnson, Nicolai Franzmeier, Yasmine Salman, Clifford R. Jack, Hillary Vossler, Renaud La Joie, Brad C. Dickerson, Rik Ossenkoppele
article en

Abstract

Abstract Background Sex, education and race/ethnicity are all associated with risk of Alzheimer's disease dementia. Here, we assess the effects of self‐reported sex, educational attainment and race/ethnicity on amyloid‐positivity, and tau‐PET‐positivity in 12,048 (7,394 cognitively unimpaired [CU], 2,177 MCI, and 2,477 dementia) individuals from 42 cohorts worldwide. Method Logistic generalized estimating equations were used to estimate frequency of amyloid‐positivity (using cohort‐specific thresholds for amyloid‐PET [84%] or CSF) and tau‐PET‐positivity (cohort‐specific thresholds of 2SD above mean temporal uptake in amyloid‐negative controls). We assessed: i) sex and APOEε4 ( N = 10,098) associations, to complement earlier findings of a higher frequency of tau‐positivity in females, ii) effects of lower/higher education ( N = 10,970; cohort‐specific median‐split), and iii) effects of race/ethnicity (non‐Hispanic White [hereafter: White], N = 4880; Asian, N = 116; Black or African‐American [hereafter: Black], N = 353; Hispanic, N = 356, only from Northern‐American cohorts). Outcomes were frequency of amyloid‐positivity in CU individuals only, and tau‐PET‐positivity in both amyloid‐positive (AB+) CU and cognitively impaired (CI, i.e. MCI and dementia) individuals. Interaction effects on the relationship between age and amyloid/tau‐positivity were assessed and only retained in the models when significant. Result Female sex was associated with an APOEε4 ‐independent increased frequency of amyloid‐positivity (β=0.51[0.22], p = 0.02) in CU and increase of tau‐positivity in both AB+CU (β=0.27[0.08]) and AB+CI (β=0.37[0.08], both p <0.01). Remarkably, tau‐positivity frequencies of female APOEε4 non‐carriers were equivalent to male APOEε4 carriers in AB+CI (Figure 1). No significant sex* APOE interactions were observed. In CU, higher education was associated with lower amyloid‐positivity frequency (β=‐0.12[0.05], p = 0.02). In contrast, among AB+CU, there was an age*education interaction effect that indicated more pronounced age effects on tau‐positivity in individuals with higher education (age*education:β interaction =0.03[0.01], p <0.01). There were no education effects in AB+CI (Figure 2). In CU, an age*race/ethnicity interaction effect was observed across all non‐White groups compared to White (Hispanic:β interaction =‐0.05[0.01], p <0.01; Black:‐0.04[0.01], p <0.01; Asian:‐0.02[0.01], p = 0.04). This suggests that the impact of age on amyloid‐positivity was less pronounced in non‐White groups. Furthermore, in AB+CI, Hispanic ethnicity was related to higher tau‐positivity frequency than White (β=0.51[0.22], p = 0.02; Figure 3). Conclusion In this multi‐center initiative comprised of clinical and community‐based cohorts, we observed that self‐reported sex, educational attainment and race/ethnicity were related to positivity‐frequencies of Alzheimer's disease pathology.

Alzheimer s & DementiaVol. 21(S2)
University of Geneva (CH), University of North Texas (US), Alzheimer's Association (US), Brigham and Women's Hospital (US), Montreal Neurological Institute and Hospital (CA), Commonwealth Scientific and Industrial Research Organisation (AU), Centre National de la Recherche Scientifique (FR), University of Wisconsin–Madison (US), Harvard University (US), Lawrence Berkeley National Laboratory (US), Inserm (FR), University of North Texas Health Science Center (US), The University of Melbourne (AU), Eli Lilly (United States) (US), University of California, San Francisco (US), University of Cologne (DE), Transnational University Limburg (NL), Lund University (SE), Xiamen University (CN), Washington University in St. Louis (US), Université Paris Cité (FR), University of Cambridge (GB), Fudan University (CN), Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR), Université Paris-Saclay (FR), Douglas Mental Health University Institute (CA), Columbia University Irving Medical Center (US), Samsung Medical Center (KR), LMU Klinikum (DE), Maastricht University (NL), Massachusetts General Hospital (US), Sorbonne Paris Cité (FR), Bridge University (SS), University Memory and Aging Center (US), University Hospital of Geneva (CH), Pasqual Maragall Foundation (ES), Amsterdam Neuroscience (NL), Centre Hospitalier Sainte-Anne (FR), Mayo Clinic in Arizona (US), UK Dementia Research Institute (GB), Barcelonaβeta Brain Research Center (ES), CEA Paris-Saclay (FR), University of Wisconsin Health (US), Skåne University Hospital (SE), National Hospital for Neurology and Neurosurgery (GB), Amsterdam University Medical Centers (NL), University Hospital Cologne (DE), Huashan Hospital (CN), Austin Health (AU), Indiana University School of Medicine, University College London (GB), McGill University (CA), Indiana University – Purdue University Indianapolis (US), Geneva College (US), Columbia University (US), Ludwig-Maximilians-Universität München (DE), Vrije Universiteit Amsterdam (NL), University of Gothenburg (SE), Leipzig University (DE), University of California, Berkeley (US), Stanford University (US), KU Leuven (BE)
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