Computational and physiological markers of neuropsychiatric symptom vulnerability relevant to early Alzheimer’s disease

INTRODUCTION

Neuropsychiatric symptoms (NPS) are common in early Alzheimer’s disease (AD) and are associated with faster disease progression and poorer quality of life, but they are often under-recognised.

The locus coeruleus-noradrenaline (LC-NA) system, which is involved in arousal, motivation, reward processing, and cognitive effort, is affected early in AD.

Aim: To determine whether pupillary and behavioural markers of LC-NA function during effort, reward, and feedback processing are associated with NPS vulnerability in older adults with intact or mildly impaired cognition.

METHODS

Participants completed a numerical Stroop task embedded within an effort–reward decision paradigm. On each trial, participants chose whether to accept or reject an offer requiring a specified level of cognitive effort in exchange for reward. Task difficulty was individually calibrated to equate performance across participants.

Continuous pupil diameter was recorded throughout. Baseline pupil activity was measured during a 1.5-second pre-trial period. Mean pupil diameter across the entire trial was subsequently calculated, and a baseline-to-full-trial ratio was computed to quantify baseline pupil activity relative to task-evoked pupil responses.

NPS vulnerability was assessed using validated questionnaires for apathy, depression, anhedonia, irritability, neuroticism, and mild behavioural impairment (MBI). Cognition was measured using the modified Telephone Interview for Cognitive Status (TICS-m).

Analysis: Computational modelling was used to estimate reward and effort sensitivity. Behavioural and pupillary measures were related to NPS and cognition scores.

Participants showed robust Stroop interference. Cognitive impairment was associated with slower responses but not reduced task accuracy.

RESULTS

Apathy was associated with: