Plasma biomarker levels and cognitive decline in a heterogenous community-based cohort with multiple comorbidities

INTRODUCTION

Knowledge about how Alzheimer’s disease (AD) and AD-related dementia (AD/ADRD) plasma biomarkers relate to global and domain-specific cognitive functioning across diagnostic groups remains limited, particularly in heterogeneous, community-dwelling populations with multiple comorbidities.

METHODS

We evaluated associations between baseline plasma biomarker levels (Aβ42/40, p-tau181, p-tau217, NfL, GFAP) and cognitive performance at baseline and longitudinally (up to 7 years). Participants (n=590) enrolled in the Wake Forest Alzheimer’s Disease Research Center Clinical Core (314 cognitively unimpaired [CU]; 206 mild cognitive impairment [MCI]; and 70 dementia) completed annual cognitive assessments including the Uniform Data Set (UDSv3; NACC). Domain-specific cognitive composites including memory, executive function, attention, language, visuospatial ability, and phonemic fluency, as well as a modified Preclinical Alzheimer’s Cognitive Composite (PACC5), were evaluated. General linear and mixed-effects models were adjusted for demographics (age, sex, race, education), APOE-ε4 status, comorbidities (estimated glomerular filtration rate; BMI), and cardiometabolic health factors (hypertension, diabetes). Effect modification by cognitive diagnosis was evaluated.

RESULTS

Baseline plasma biomarkers, particularly p-tau217, were associated with poorer baseline cognitive performance and greater longitudinal decline on the PACC5 and all cognitive domains assessed, except phonemic fluency (strongest for memory). Post-hoc analyses indicated associations between plasma biomarker levels and cognition were generally more pronounced in MCI compared with CU participants. Effect modification by baseline cognitive status was limited and attenuated when all biomarkers were modeled simultaneously. Comorbidities and cardiometabolic factors modified select associations.

DISCUSSION

Plasma AD/ADRD biomarkers, particularly p-tau217, were associated with cognitive impairment and decline in a heterogenous community cohort.

HIGHLIGHTS

• The WF ADRC is a clinically heterogeneous, comorbidity-rich community-dwelling cohort

• Plasma AD/ADRD biomarkers were associated with poorer baseline cognition and longitudinal cognitive decline

• Associations were strongest for the PACC5 composite and memory-related cognitive domains

• p-tau217 provided the most robust biomarker signal across models