Work

Associations between plasma biomarkers and longitudinal neuropsychiatric symptoms across the cognitive spectrum in older adults: findings from the Massachusetts Alzheimer's Disease Research Center

Year: 2025

Type: article

Abstract: Background Neuropsychiatric symptoms (NPS) are common in the preclinical and prodromal stages of Alzheimer's Disease and Related Dementias (ADRD) and are associated with cognitive and functional decline. However, the neurobiology of these symptoms and prognostic markers of their emergence are not well understood. We sought to examine the associations between established baseline plasma biomarkers of ADRD and the longitudinal trajectory of NPS in older adults. Method Participants were from the Massachusetts Alzheimer's Disease Research Center longitudinal research cohort. A subset, spanning consensus diagnoses of cognitively normal (CN)( n = 282, age:68±10) years) to mild cognitive impairment (MCI)( n = 331, age:74±8 years), had baseline plasma samples assayed for phospho‐tau 217 ( p ‐tau 217 ), neurofilament‐light (NfL) and glial fibrillary acidic protein (GFAP) (Table 1). Average follow‐up was 8.6±4.2 years (CN) and 7.2±4.1 years (MCI). NPS were measured annually using the self‐reported Geriatric Depression Scale (GDS‐15) and the study‐partner‐reported Neuropsychiatric Inventory Questionnaire (NPI‐Q). Plasma biomarkers were log‐transformed and z‐scores were derived using baseline values of the study sample. In longitudinal linear mixed‐effects models, we examined the NPS measures as the dependent variable in relation to individual plasma biomarkers, time, and the plasma biomarker × time interaction, controlling for age and sex. Result In CN participants, plasma NfL and GFAP were associated with change in GDS (NfL x time: β=0.02, CI=0.01‐0.03 p = 0.007); GFAP x time: β=0.02, CI=0.01‐0.04, p = 0.002) but not with NPI‐Q ( p >0.05 for all); (Figure 1). In MCI participants, p ‐tau 217 and NfL were associated with change in GDS ( p ‐tau 217 : β=0.02, CI=0‐0.04, p = 0.04; NfL: β=0.02, CI=0‐0.04, p = 0.02) whereas all three biomarkers predicted increasing NPI‐Q score over time ( p ‐tau 217 : β=0.09 CI=0.07‐0.12, p <0.001; NfL: β=0.03, CI=0‐0.06 p = 0.025; GFAP: β=0.07, CI=0.04‐0.10, p <0.001) (Figure 2). In exploratory NPI‐Q analyses, when NfL and GFAP were individually added as predictors alongside p ‐ tau 217 , only p ‐tau 217 remained significant. Conclusion Findings suggest differential plasma biomarker‐NPS associations across the early ADRD spectrum, with a central role of p ‐tau 217 at the stage of MCI. Results also support biomarker signatures of affective vs. overall NPS. Further dissecting plasma biomarker signatures of specific NPS domains will provide insight into the prognostic value of plasma measures in predicting NPS trajectories over the course of ADRD.

Source: Alzheimer s & Dementia

DOI: 10.1002/alz70857_103645