Cognitive impairment and p-tau217 are high in a vascular patient cohort

Scott R French¹, Juan C Arias¹, Summan Zahra¹, Madeline Ally², Cris Escareno¹, Emma Heitkamp¹, Franchell Vazquez¹, Madison Hillis¹, Haley Wiskoski^{1

3}, Karthik Ainapurapu¹, Gavin Culwell¹, Caronae Howell¹, Kevin Johnson³, Cody Kraemer^{1

4}, John Pacanowski^{1

4}, Luis Leon^{1

4}, Scott Berman^{1

4}, Federico Yanquez^{1

4}, Joshua Balderman^{1

4}, Joseph Sabat^{1

4}, Olivia Hung⁵, Layla Lucas^{1

4}, Francesca Vitali^{6

7}, Edward J Bedrick⁸, Raza Mushtaq⁹, Maria Altbach³, Theodore P Trouard^{3

10

11

12}, Fanny M Elahi¹³, Nicholas J Ashton^{14

15

16}, Jeffrey L Dage¹⁷, Eric M Reiman¹⁶, Gene E Alexander^{2

18}, Craig C Weinkauf¹

Affiliations

¹ The Division of Vascular Surgery, University of Arizona, Tucson, Arizona, USA.
² Department of Psychology, University of Arizona, Tucson, Arizona, USA.
³ Department of Medical Imaging, University of Arizona, Tucson, Arizona, USA.
⁴ Pima Heart and Vascular, Tucson, Arizona, USA.
⁵ Department of Cardiovascular Medicine, Sarver Heart Center, University of Arizona College of Medicine, Tucson, Arizona, USA.
⁶ Department of Neurology, University of Arizona, Tucson, Arizona, USA.
⁷ Center for Innovation in Brain Science, University of Arizona, Tucson, Arizona, USA.
⁸ Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona Health Sciences Center, Tucson, Arizona, USA.
⁹ Department of Neuroradiology, Barrow Neurological Institute, Phoenix, Arizona, USA.
¹⁰ Department of Biomedical Engineering, University of Arizona, Tucson, Arizona, USA.
¹¹ BIO5 Research Institute, University of Arizona, Tucson, Arizona, USA.
¹² Evelyn F. McKnight Brain Institute, University of Arizona, Tucson, Arizona, USA.
¹³ Department of Neurology and Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁴ Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, the Sahlgrenska Academy at the University of Gothenburg, Göteborg, Sweden.
¹⁵ Banner Sun Health Research Institute, Sun City, Arizona, USA.
¹⁶ Banner Alzheimer's Institute, Phoenix, Arizona, USA.
¹⁷ Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
¹⁸ Evelyn F. McKnight Brain Institute, Department of Psychiatry, Neuroscience and Physiological Sciences Graduate Interdisciplinary Programs and BIO5 Institute, University of Arizona and Arizona Alzheimer's Disease Consortium, Tucson, Arizona, USA.

PMID: 40772428
PMCID: PMC12329572
DOI: 10.1002/alz.70565

Cognitive impairment and p-tau217 are high in a vascular patient cohort

Scott R French et al. Alzheimers Dement. 2025 Aug.

. 2025 Aug;21(8):e70565.

doi: 10.1002/alz.70565.

Authors

Affiliations

¹ The Division of Vascular Surgery, University of Arizona, Tucson, Arizona, USA.
² Department of Psychology, University of Arizona, Tucson, Arizona, USA.
³ Department of Medical Imaging, University of Arizona, Tucson, Arizona, USA.
⁴ Pima Heart and Vascular, Tucson, Arizona, USA.
⁵ Department of Cardiovascular Medicine, Sarver Heart Center, University of Arizona College of Medicine, Tucson, Arizona, USA.
⁶ Department of Neurology, University of Arizona, Tucson, Arizona, USA.
⁷ Center for Innovation in Brain Science, University of Arizona, Tucson, Arizona, USA.
⁸ Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona Health Sciences Center, Tucson, Arizona, USA.
⁹ Department of Neuroradiology, Barrow Neurological Institute, Phoenix, Arizona, USA.
¹⁰ Department of Biomedical Engineering, University of Arizona, Tucson, Arizona, USA.
¹¹ BIO5 Research Institute, University of Arizona, Tucson, Arizona, USA.
¹² Evelyn F. McKnight Brain Institute, University of Arizona, Tucson, Arizona, USA.
¹³ Department of Neurology and Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁴ Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, the Sahlgrenska Academy at the University of Gothenburg, Göteborg, Sweden.
¹⁵ Banner Sun Health Research Institute, Sun City, Arizona, USA.
¹⁶ Banner Alzheimer's Institute, Phoenix, Arizona, USA.
¹⁷ Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
¹⁸ Evelyn F. McKnight Brain Institute, Department of Psychiatry, Neuroscience and Physiological Sciences Graduate Interdisciplinary Programs and BIO5 Institute, University of Arizona and Arizona Alzheimer's Disease Consortium, Tucson, Arizona, USA.

PMID: 40772428
PMCID: PMC12329572
DOI: 10.1002/alz.70565

Abstract

Introduction: Vascular comorbidities are modifiable contributors to cognitive impairment and Alzheimer's disease (AD), yet brain health outcomes are rarely evaluated in cardiovascular patients.

Methods: This study prospectively evaluated cognition and AD pathology in 162 community-dwelling adults with asymptomatic cardiovascular disease who did not have a clinical diagnosis of dementia or cognitive impairment.

Results: Twenty-nine percent of the cohort had Montreal Cognitive Assessment (MoCA) scores indicative of cognitive impairment or dementia after adjusting for age, sex, and education based on National Alzheimer's Coordinating Center normative data. AD blood biomarker phosphorylated tau217 was elevated in 55% of the cohort, significantly associated with decreased MoCA scores (β = -1.46, 95% confidence interval [CI] -2.53 to -0.39, p < 0.01), and accurately differentiated cognitive impairment (area under the curve 0.94, 95% CI 0.88-0.99).

Discussion: This level of undiagnosed cognitive impairment and AD pathology exceeds what would be expected in the general population and highlights a potential need for screening and future work to better identify treatment options.

Highlights: Brain health outcomes are rarely evaluated in vascular patients. One hundred sixty-two adults with asymptomatic cardiovascular disease but without diagnoses of cognitive impairment or dementia were evaluated. Phosphorylated tau217 accurately differentiated cognitive impairment in patients with cardiovascular disease. High levels of cognitive impairment and Alzheimer's disease pathology are greatly underdiagnosed in the cardiovascular population.

Keywords: Alzheimer's disease; blood biomarkers; cognitive impairment; vascular disease; vascular risk factors.

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Conflict of interest statement

J.L.D. is an inventor on patents or patent applications of Eli Lilly and Company relating to the assays, methods, reagents, and/or compositions of matter for p‐tau assays and Aβ targeting therapeutics. J.L.D. has served as a consultant or on advisory boards for Eisai, Abbvie, Genotix Biotechnologies Inc., Gates Ventures, Gate Neurosciences, Dolby Family Ventures, Karuna Therapeutics, AlzPath Inc., Cognito Therapeutics, Inc., Prevail Therapeutics, and received research support from ADx Neurosciences, Fujirebio, AlzPath Inc., Roche Diagnostics, and Eli Lilly and Company in the past 2 years. J.L.D. has received speaker fees from Eli Lilly and Company and LabCorp. J.L.D. is a founder and advisor for Monument Biosciences. J.L.D. has stock or stock options in Eli Lilly and Company, Genotix Biotechnologies, AlzPath Inc., and Monument Biosciences. E.M.R. is a co‐founder and advisor of ALZpath, and a compensated scientific advisor to Alzheon, Denali, Cognition Therapeutics, Enigma, Retromer Therapeutics, and Vaxxinity. While the Quanterix ALZpath assay was used to characterize pTau217 levels, he was not involved in the analysis of data. None of the other authors declare that they have conflicts of interest. Author disclosures are available in the supporting information.

Figures

**FIGURE 1**
Distribution of NACC‐adjusted MoCA scores within this community‐dwelling vascular cohort. Frequency plot showing the distribution of age‐, sex‐, and education‐adjusted MoCA scores based on NACC normative data within our vascular cohort of 162 individuals. The blue line represents the mean normative MoCA score of the cohort. The red lines represent the –1.5 SD and –2 SD cutoffs, representing cognitive impairment compatible with MCI and dementia. Approximately 70% are below the normative population mean of zero; 30% of the cohort falls below the 1.5 SD threshold; 18.5% of the cohort falls below 2 SD. MCI, mild cognitive impairment; MoCA, Montreal Cognitive Assessment; NACC, National Alzheimer's Coordinating Center; SD, standard deviation.

**FIGURE 2**
Distribution of plasma p‐tau217 and Aβ42/40 in this community‐dwelling vascular cohort. Frequency plots showing the distribution of (A) plasma Aβ42/40 and (B) p‐tau217 within the vascular cohort. The blue lines represent the mean plasma Aβ42/40 and p‐tau217 levels within the cohort. The red lines represent previously published cutoffs based on PET positivity. Applying these cutoffs, 10.9% and 54.5% of the cohort had abnormal levels of plasma Aβ42/40 and p‐tau217, respectively. Six participants were missing p‐tau217 and Aβ42/40 and were excluded from this analysis. One outlier was removed from the p‐tau217 frequency plot for data visualization purposes (p‐tau217 = 4.59) but was included in all statistical analyses. Aβ, amyloid beta; PET, positron emission tomography; p‐tau, phosphorylated tau.

**FIGURE 3**
Plasma p‐tau217, but not Aβ42/40, is associated with worse cognitive performance in this community‐dwelling vascular cohort. A, Forest plot showing a significant relationship between plasma p‐tau217 and MoCA scores after adjusting for age (years), sex, race and ethnicity, education years, *APOE* ε4, and plasma Aβ2/40 using a multivariate linear regression model. No significant effect was observed for Aβ42/40. Each dot represents the beta estimates, with error bars representing the 95% confidence interval. The beta estimates, 95% confidence intervals, and p values are transcribed; p < 0.05 was considered statistically significant. Aβ, amyloid beta; *APOE*, apolipoprotein E; p‐tau, phosphorylated tau.

**FIGURE 4**
Plasma p‐tau217 detects cognitive impairment with high accuracy. Receiver operating characteristic (ROC) plots were generated by partitioning study participants into normal (MoCA ≥ 26), mild (MoCA 18–25), and moderate (MoCA ≤ 17) cognitive status: (A) shows normal versus mild + moderate (n = 156) and (B) shows normal versus moderate (n = 72). p‐tau217 was used as a continuous variable. MoCA scores were adjusted for age, sex, education, and race and ethnicity. AUC, area under the curve; MoCA, Montreal Cognitive Assessment; p‐tau, phosphorylated tau.

See this image and copyright information in PMC

References

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Cognitive impairment and p-tau217 are high in a vascular patient cohort

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Cognitive impairment and p-tau217 are high in a vascular patient cohort

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Conflict of interest statement

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