Neuropsychiatric symptoms as early clinical indicators and functional biomarkers of cognitive decline in mild cognitive impairment and early Alzheimer's disease

Abstract

Neuropsychiatric symptoms (NPS) have historically been considered secondary or late-stage features of Alzheimer's disease (AD), yet emerging evidence indicates that apathy, depression, anxiety, irritability, agitation, sleep disturbance, and psychosis frequently arise during prodromal phases, including mild cognitive impairment (MCI), and may precede measurable cognitive decline. This narrative review evaluates NPS as early clinical indicators and potential functional biomarkers of cognitive decline in MCI and early AD, emphasizing neurobiological mechanisms, prognostic significance, and translational relevance. A synthesis of epidemiological, longitudinal, neuroimaging, and biomarker studies published between 2012 and 2025 was conducted across major databases, integrating findings within the mild behavioral impairment (MBI) construct and the AT(N) biomarker framework. Across studies, NPS were found to affect approximately 43–80% of individuals with MCI and 75–90% with early AD, with lifetime prevalence approaching 97% across the disease course. Apathy, depression, anxiety, and irritability are particularly common in early stages and independently predict accelerated cognitive and functional decline, increased caregiver burden, and earlier institutionalization. NPS are associated with early tau pathology, neurotransmitter system dysfunction, and fronto-limbic network degeneration. Disparities in symptom burden, diagnostic access, and clinical outcomes are evident across racial, ethnic, sex-related, and cultural groups. Recognizing NPS as core features of early AD supports their integration into MBI- and AT(N)-informed diagnostic and intervention models to enhance early detection, personalize care, and reduce health inequities.