Cognition Mediates the Association Between Cerebrospinal Fluid Biomarkers of Amyloid and P-Tau and Neuropsychiatric Symptoms

Article type: Research Article

Authors: Frank, Brandon^{a; b; c} | Walsh, Michael^b | Hurley, Landon^a | Groh, Jenna^b | Blennow, Kaj^{d; e} | Zetterberg, Henrik^{d; e; f; g; h; i} | Tripodis, Yorghos^{b; j} | Budson, Andrew E.^{a; b; c} | O’Connor, Maureen K.^{b; c; k} | Martin, Brett^{b; l} | Weller, Jason^{b; c} | McKee, Ann^{b; c; l; m} | Qiu, Wendy^{b; n; o} | Stein, Thor D.^{b; c; l; m} | Stern, Robert A.^{b; c; p; q} | Mez, Jesse^{b; c; r} | Henson, Rachel^s | Long, Justin^s | Aschenbrenner, Andrew J.^s | Babulal, Ganesh M.^s | Morris, John C.^s | Schindler, Suzanne^s | Alosco, Michael L.^{b; c; *}

Affiliations: [a] U.S. Department of Veteran Affairs, VA Boston Healthcare System, Boston, MA, USA | [b] Boston University Alzheimer’s Disease Research Center and CTE Center, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA | [c] Department of Neurology, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA | [d] Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden | [e] Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden | [f] Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK | [g] UK Dementia Research Institute at UCL, London, UK | [h] Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China | [i] Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA | [j] Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA | [k] VA Bedford Healthcare System, U.S. Department of Veteran Affairs, Bedford, MA, USA | [l] Biostatistics and Epidemiology Data Analytics Center, Boston University School of Public Health, Boston, MA, USA | [m] Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA | [n] Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA | [o] Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA | [p] Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA, USA | [q] Department of Neurosurgery, Boston University School of Medicine, Boston, MA, USA | [r] Framingham Heart Study, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA | [s] Knight Alzheimer Disease Research Center (ADRC), Washington University, St. Louis, MO, USA

Correspondence: [*] Correspondence to: Michael L. Alosco, PhD, 72 E. Concord Street, Instructional Building, L-5, Boston, MA 02118, USA. Tel.: +1 617 358 6029; E-mail: malosco@bu.edu.

Abstract: Background:Neuropsychiatric symptoms (NPS) can be an early manifestation of Alzheimer’s disease (AD). However, the associations among NPS, cognition, and AD biomarkers across the disease spectrum are unclear. Objective:We analyzed cross-sectional mediation pathways between cerebrospinal fluid (CSF) biomarkers of AD (Aβ1-42, p-tau181), cognitive function, and NPS. Methods:Primary models included 781 participants from the National Alzheimer’s Coordinating Center (NACC) data set who had CSF analyzed for AD biomarkers using Lumipulse. NPS were assessed with the Neuropsychiatric Inventory Questionnaire (NPI-Q). We assessed cognition with the harmonized MMSE/MoCA, as well as neuropsychological tests sensitive to AD pathology: story recall, naming, animal fluency, and Trails B. The Clinical Dementia Rating (CDR®) scale assessed dementia severity. Mediation models were estimated with Kemeny metric covariance in a structural equation model framework, controlling for age, education, sex, and APOE ɛ4. Results:The sample was older adults (M = 73.85, SD = 6.68; 49.9% male, 390; 27.9% dementia, 218) who were predominantly white (n = 688, 88.1%). Higher p-tau181/Aβ1-42 ratio predicted higher NPI-Q, which was partially mediated by the MMSE/MoCA and, in a second model, story recall. No other pathway was statistically significant. Both the MMSE/MoCA and NPI-Q independently mediated the association between p-tau181/Aβ1-42 ratio and CDR global impairment. With dementia excluded, p-tau181/Aβ1-42 ratio was no longer associated with the NPI-Q. Conclusions:NPS may be secondary to cognitive impairment and AD pathology through direct and indirect pathways. NPS independently predict dementia severity in AD. However, AD pathology likely plays less of a role in NPS in samples without dementia.

Keywords: Alzheimer’s disease, amyloid, biomarkers, cerebrospinal fluid, cognition, neuropsychiatric symptoms, p-tau

DOI: 10.3233/JAD-240125

Journal: Journal of Alzheimer's Disease, vol. 100, no. 3, pp. 1055-1073, 2024