Subjective Cognitive Concerns and Cognitive Trajectories in Parkinson's Disease: Biomarker Impact

ABSTRACT Objective To examine the relationship of subjective cognitive concerns (SCC) with biomarkers of Alzheimer's disease (AD), neurodegeneration, and Parkinson's disease (PD) and domain‐specific cognitive trajectories among cognitively unimpaired persons with de novo PD. Method Cognitively unimpaired participants with SCC ( n = 294) and without SCC ( n = 857) from the Parkinson's Progression Markers Initiative underwent neuropsychological testing, lumbar puncture, and dopamine transporter (DaT) single‐photon emission computed tomography (SPECT). Multiple regression analyses examined SCC associations with biomarkers of AD (CSF phosphorylated‐tau181/amyloid‐beta42 [p‐tau181/Aβ42]), neurodegeneration (CSF neurofilament light [NfL]), and PD (DaT‐SPECT in contralateral putamen). Linear mixed effects models examined 5‐year cognitive trajectories (working memory, category fluency, learning and memory, visuospatial functioning, processing speed) by SCC status and the extent to which biomarkers of AD, neurodegeneration, and PD moderated these associations. Result At baseline, the SCC group had higher p‐tau181/Aβ42 (FDR‐adjusted p = 0.004) than the No SCC group, while NfL and DaT‐SPECT did not differ. Relative to the No SCC group, the SCC group exhibited faster decline in learning (FDR‐adjusted p = 0.016), delayed recall (FDR‐adjusted p = 0.016) and working memory (FDR‐adjusted p = 0.016). AD and PD‐related biomarkers moderated cognitive trajectories: SCC in combination with (1) higher CSF p‐tau181/Aβ42 was related to steeper declines in working memory (FDR‐adjusted p = 0.032); and (2) lower DaT‐SPECT was related to steeper declines in delayed recall (FDR‐adjusted p = 0.032). Interpretation SCC is related to AD biomarkers and accelerated cognitive decline in the earliest stages of PD. SCC may serve as an early marker of cognitive risk, especially among persons with greater AD‐ or PD‐related burden.