Enhancing diagnostic precision in Alzheimer's disease: Impact of comorbidities on blood biomarkers for clinical integration.

INTRODUCTION: Comorbidities may influence Alzheimer's disease (AD) plasma biomarkers. This study aimed to investigate how medical conditions impact AD plasma biomarkers and whether comorbidity-adjusted models enhance their diagnostic performance. METHODS: We analyzed key AD plasma biomarkers in 311 memory clinic patients (mean age 59 years, 57% female) at Karolinska University Hospital, Sweden. Biomarkers were measured using single molecular array (SIMOA) and Lumipulse assay. Multivariate linear regressions and receiver operating characteristic/area under the curves (ROC/AUCs) were calculated using clinical diagnosis and cerebrospinal fluid biomarkers as gold standards. RESULTS: Plasma biomarkers were associated with comorbidities and metabolites such as estimated glomerular filtration rate, homocysteine, and high-density lipoprotein. Phosphorylated tau (p-tau)/amyloid beta (Aβ)42 and p-tau217 had excellent performances in AD pathology classification (AUCs > 0.938). Adjusting for comorbidity measures significantly improved the diagnostic accuracy of Aβ42/40. DISCUSSION: In conclusion, plasma biomarkers performed robustly despite comorbidity associations, with p-tau217 emerging as the strongest discriminator. These findings support their potential as diagnostic tools in clinical settings. HIGHLIGHTS: Plasma biomarkers for Alzheimer's disease (AD) were assessed in a real-world memory clinic population. Kidney dysfunction and cardiovascular risk factors influenced plasma biomarker levels. Phosphorylated tau (p-tau)217 and p-tau217/amyloid beta (Aβ)42 ratio showed strongest association with AD pathology. Aβ42/40 ratio's accuracy was improved by including comorbidities into the diagnostic algorithms.