Modeling heterogeneity in cognitive trajectories in the Framingham Heart Study

Yuan Fang^1*Jiachen Chen²Jesse Mez^3,4,5Claudia L Satizabal^4,5,6Michael L Alosco^3,7,8Wei Qiao (Wendy) Qiu^10,3,9Margaret F Doyle¹¹Joanne M Murabito^12,13,5Kathryn L Lunetta²

• ¹Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Binghamton University, Binghamton, United States
• ²Department of Biostatistics, School of Public Health, Boston University, Boston, Massachusetts, United States
• ³Alzheimer’s Disease Research Center and CTE Center, Boston University Chobanian and Avedisian School of Medicine, Boston University, Boston, United States
• ⁴Department of Neurology, School of Medicine, Boston University, Boston, Massachusetts, United States
• ⁵Framingham Heart Study, National Heart, Lung, and Blood Institute and Boston University Chobanian and Avedisian School of Medicine, Framingham, United States
• ⁶Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, Joe R. & Teresa Lozano Long School of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
• ⁷Department of Anatomy and Neurobiology, Chobanian & Avedisian School of Medicine, Boston University, Boston, Massachusetts, United States
• ⁸Department of Neurology, Boston Medical Center, Boston, United States
• ⁹Department of Psychiatry, School of Medicine, Boston University, Boston, Massachusetts, United States
• ¹⁰Department of Pharmacology and Experimental Therapeutics, School of Medicine, Boston University, Boston, Massachusetts, United States
• ¹¹Department of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, Vermont, United States
• ¹²Department of Medicine, Chobanian and Avedisian School of Medicine, Boston University, Boston, United States
• ¹³Section of General Internal Medicine, Boston Medical Center, Boston, United States

The prevalence of cognitive impairment in the population is growing; however, there is substantial heterogeneity in the rate of decline across different cognitive domains. Harmonized factor scores measuring memory, executive function, and language domains have been created in the Framingham Heart Study (FHS). This work identified FHS participants with two or more repeated factor scores after age 60 and fitted latent class mixed models (LCMM) to cluster cognitive trajectories within each domain. Non-linear shapes of trajectories were modeled piecewise linearly, followed by stepwise selections to select cluster-specific change points. We identified different latent classes of participants with early cognitive decline, compared to late decliners, for each domain. Ten-fold cross-validation yielded stable subgroupings. Our findings show latent-class-related differential patterns in cognitive aging in the FHS. We also investigated the association between identified latent classes with existing protein biomarkers of cognitive aging in a subsample of the study and found elevated levels of CD40L and CD14 were associated with a higher risk of early decline in memory and executive function domain, respectively. In summary, our study advances the understanding of cognitive decline heterogeneity among FHS participants and sets the stage for further investigations into early intervention strategies and personalized approaches to mitigate cognitive aging risks.