Journal of Neurology

, Volume 266, Issue 12, pp 2920–2928 | Cite as

Cognitive function and neuropathological outcomes: a forward-looking approach

  • Elizabeth MunozEmail author
  • Teresa FilshteinEmail author
  • Brianne M. Bettcher
  • Donald McLaren
  • Trey Hedden
  • Doug Tommet
  • Dan Mungas
  • Terry Therneau
Original Communication



To evaluate the risk of Alzheimer’s disease-related neuropathology burden at autopsy given older adults’ current cognitive state.


Participants included 1,303 individuals who enrolled in the Religious Orders Study (ROS) and 1,789 who enrolled in the Rush Memory and Aging Project (MAP). Cognitive status was evaluated via standardized assessments of global cognition and episodic memory. At the time of analyses, about 50% of participants were deceased with the remaining numbers right censored. Using multi-state Cox proportional hazard models, we compared the cognitive status of all subjects alive at a given age and estimated future risk of dying with different AD-related neuropathologies. Endpoints considered were Braak Stages (0–2, 3–4, 5–6), CERAD (0, 1, 2, 3), and TDP-43 (0, 1, 2, 3) level.


For all three pathological groupings (Braak, CERAD, TDP-43), we found that a cognitive test score one standard deviation below average put individuals at up to three times the risk for being diagnosed with late stage AD at autopsy according to pathological designations. The effect remained significant after adjusting for sex, APOE-e4 status, smoking status, education level, and vascular health scores.


Applying multi-state modeling techniques, we were able to identify those at risk of exhibiting specific levels of neuropathology based on current cognitive test performance. This approach presents new and approachable possibilities in clinical settings for diagnosis and treatment development programs.


Alzheimer’s disease Neuropathology Cognition Multi-state model 


Author contributions

All authors developed the study concept. EM drafted the manuscript. TF performed the data analysis. TF and EM interpreted the results under the supervision of TT, BB, TH, DM, DT, TT, and DM provided comprehensive and critical revisions. All authors approved the final version of the manuscript submission.


Research reported in this publication was supported by the National Institute on Aging of the National Institutes of Health under Award Numbers: P30AG010161, R01AG015819, R01AG017917 and R01AG042210 to Rush Alzheimer’s Disease Center. We thank Dr. David Bennett and Rush Alzheimer’s Disease Center for data access. ROSMAP data can be requested at This manuscript was a joint effort from the 2015 Friday Harbor Advanced Psychometrics Workshop (R13AG030995). This research was also supported in part by K01AG040197 (Hedden), F32AG042228 (McLaren), and F32AG056134 (Munoz). The content is solely the responsibility of the authors and does not necessarily represents the official views of the National Institutes of Health.

Compliance with ethical standards

Conflicts of interest

The authors have no relevant conflict of interest to report.

Ethical standards

The studies reported in this manuscript were approved by the Institutional Review Board of Rush—Presbyterian—St. Luke’s Medical Center and the Institutional Review Board of Rush University Medical Center.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Human Development and Family SciencesUniversity of Texas at AustinAustinUSA
  2. 2.Department of Epidemiology and BiostatisticsUniversity of CaliforniaSan FranciscoUSA
  3. 3.Rocky Mountain Alzheimer’s Disease Center, Department of NeurologyUniversity of Colorado Anschutz Medical CampusAuroraUSA
  4. 4.Biospective Inc.MontréalCanada
  5. 5.Department of NeurologyIcahn School of Medicine At Mount SinaiNew YorkUSA
  6. 6.Department of Psychiatry and Human Behavior, Alpert Medical SchoolBrown UniversityProvidenceUSA
  7. 7.Department of NeurologyUniversity of CaliforniaDavisUSA
  8. 8.Division of Biomedical Statistics and InformaticsMayo ClinicRochesterUSA
  9. 9.University of CaliforniaRiversideUSA

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