Blood biomarkers for Alzheimer's disease are correlated with measures of agitation and cognition in a randomized trial assessing the effects of escitalopram on agitation

Abstract INTRODUCTION Escitalopram for Agitation in Alzheimer's Disease (S‐CitAD) is a National Institutes of Health–funded randomized controlled trial that randomized 173 participants with clinically diagnosed Alzheimer's disease (AD) and agitation to escitalopram or placebo for 12 weeks, assessing efficacy and safety. There was no advantage for escitalopram in treating agitation, potentially attributed to including participants at various stages of AD brain pathology, reflected in levels of blood biomarkers. Here, we (1) estimated the fraction of participants meeting blood biomarker criteria for AD pathology, (2) examined associations between baseline blood biomarkers and agitation severity or cognitive functioning, and (3) evaluated whether baseline blood biomarkers predicted treatment response. METHODS Eighty‐two randomized participants provided blood for biomarker measurement prior to randomization. Plasma amyloid beta (Aβ)42, Aβ40, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and phosphorylated tau (p‐tau)217 were measured using standard methods. We examined associations of baseline blood biomarkers and clinical measures at baseline and follow‐up with (1) agitation severity (Neuropsychiatric Inventory Clinical Rating of the agitation and aggression domains [NPI‐C‐A+A]), (2) cognitive status (Mini‐Mental State Examination [MMSE]), and (3) escitalopram treatment. RESULTS Seventy‐seven out of 82 (94%) scored above threshold for p‐tau217, supporting the clinical diagnosis of AD. Baseline higher p‐tau217 predicted higher NPI‐C‐A+A scores at weeks 6 (beta = 3.26, p < 0.001) and 12 (beta = 2.86, p = 0.01) after randomization. Baseline higher levels of GFAP (beta = −0.02, p = 0.0002) and p‐tau217 (beta = −2.68, p = 0.003) were associated with lower baseline MMSE scores. After adjusting for treatment, higher baseline p‐tau217 was associated with greater odds of worsening NPI‐C‐A+A scores at weeks 6 (odds ratio [OR] = 2.79, p = 0.02) and 12 (OR = 2.55, p = 0.02). DISCUSSION In this clinical trial cohort, elevated plasma p‐tau217 confirmed AD pathology in 94% of participants and forecast greater agitation severity and worse cognitive functioning, underscoring its practical value for stratifying and monitoring patients in neuropsychiatric intervention studies. Highlights We examined whether Alzheimer's disease (AD) blood biomarkers predicted severity of agitation and cognitive impairment and/or treatment response in the 12‐week Escitalopram for Agitation in Alzheimer's Disease (S‐CitAD) randomized controlled trial. Blood phosphorylated tau (p‐tau)217 confirmed the presence of significant AD brain amyloid pathology in 94% of these clinically diagnosed participants. Independent of treatment assignment, higher baseline p‐tau217 predicted lower baseline and future Mini‐Mental State Examination (MMSE) scores and worse agitation overtime. Independent of treatment assignment, higher baseline levels of glial fibrillary acidic protein were associated with lower baseline and follow‐up MMSE scores.