Association Between Cerebrospinal Fluid Biomarkers of Amyloid and Tau and Neuropsychiatric Symptoms Among Participants from the National Alzheimer’s Coordinating Center Uniform Data Set
Michael Walsh 1, Brandon Frank 2, Landon Hurley 3, Kaj Blennow4, Henrik Zetterberg4, Yorghos Tripodis 2, Brett Martin2, Jason Weller5, Wendy Qui2, Ann McKee6, Thor Stein7, Robert Stern2, Jesse Mez2, Michael Alosco2
1Neurology, Boston University Chobanian & Avedisian School of Medicine, 2Boston University Chobanian & Avedisian School of Medicine, 3Yale University, 4Gothenburg University, 5Boston VA Healthcare System, 6VA Boston, 7VA Boston Healthcare System
Objective:
To investigate the associations between cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD) (Aβ1-42, p-tau181), neuropsychiatric symptoms (NPS), and cognitive function across the disease spectrum.
Background:
Neuropsychiatric symptoms are often an early manifestation of AD. Previous research using CSF Aβ and p-tau suggests the effects of AD pathology on NPS are mediated by cognitive impairment. The causes of NPS across the disease continuum are poorly understood.
Design/Methods:
This sample included 1772 participants from the National Alzheimer’s Coordinating Center (NACC) who had available CSF biomarker data. There is lack of standardization of CSF analysis in NACC. CSF Aβ1-42, p-tau181, and t-tau were measured using ELISA (n=276), Luminex (n=680), and Lumipulse (n=816). NPS were measured using the Neuropsychiatric Inventory Questionnaire (NPI-Q). Factor analysis reduced NPI-Q items into a single factor. The MMSE estimated global cognition. Mediation models were estimated using the Kemeny covariance matrix in a structural equation model framework, controlling for age, education, sex, APOE ε4, and CSF assay method. Models were done in the entire sample and excluding dementia.
Results:
The sample included older adults (M=71.6, SD=8.98; 896, 50.6% females; 590, 33% dementia) who were predominantly white (n=1600, 90.3%). Lower CSF Aβ1-42 predicted higher NPI-Q scores, βz=-0.242, 95% CI:-0.312,-0.172, which was partially mediated by MMSE scores, standardized indirect effect (IEz)=-0.098, 95% CI:-0.123,-0.073. Higher CSF p-tau181 predicted higher NPI-Q scores, βz=0.127, 95% CI:0.044,0.210, which was partially mediated by MMSE scores, IEz=0.041, 95% CI:0.021,0.061. CSF t-tau did not predict NPI-Q or MMSE scores. Among those without dementia, effects were diminished and only CSF Aβ1-42 predicted higher NPI-Q scores, βz=-0.130, 95% CI:-0.248,-0.013, which was partially mediated by MMSE scores, IEz=-0.022, 95% CI:-0.036,-0.007.
Conclusions:
NPS are likely secondary to both AD pathology and cognitive impairment. However, AD pathology likely plays less of a role in the manifestation of NPS in early disease stages.