Biomarkers

The Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) study is a national Canadian observational study of participants clinically diagnosed with various forms of dementia and cognitive complaints. Here, we utilize plasma biomarkers including amyloid beta (Aβ42/40), phosphorylated tau-181 (p-tau-181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP), to estimate the prevalence of Alzheimer's disease (AD) pathology in COMPASS-ND. This enables us to assess concordance between clinical presentation and underlying pathogenesis in participants.

Biomarkers were analysed in COMPASS-ND plasma samples (n = 936) using the Quanterix Simoa HD-X analyzer with Neurology 4-plex E and p-tau-181 assays. A sub-cohort (n = 150) of participants with cerebrospinal fluid (CSF) Aβ42, p-tau-181 and total tau (Roche Elecsys assays) were utilized to determine plasma biomarker cut-offs. Area under the receiver operating curve (AUROC) analysis was conducted. Cut-offs, determined at the Youden's index, were then applied to the remaining COMPASS-ND participants to estimate the percentage of biomarker positive individuals in each clinically determined diagnostic group.

Of the COMPASS-ND participants with CSF, 80% (n = 120) were on the AD continuum. AUROC analysis revealed an area of 0.768 for Aβ42/40, 0.638 for p-tau-181, 0.559 for NfL, and 0.689 for GFAP. Cut-offs for plasma biomarkers to be considered on the AD continuum were Aβ42/40 <0.068 pg/mL, p-tau-181 >2.7 pg/mL, NfL >18.6 pg/mL, and GFAP >134.9 pg/mL. A multi-biomarker cut-off based on having positive results for 2 out of 3 from Aβ42/40, p-tau-181, and GFAP, yielded a sensitivity of 64% and specificity of 83%. In the remaining n = 786 COMPASS-ND participants, the multi-marker panel estimated that AD pathology would be present in 30% (n = 28/93) of cognitively normal, 25% (n = 27/106) of subjective cognitive impairment, 52% (n = 167/321) of mild cognitive impairment, 83% (n = 96/116) of AD, 73% (n = 16/22) of Lewy body dementia, 45% (n = 13/29) of frontal temporal dementia, and 34% (n = 34/99) of Parkinson's disease participants.

The plasma biomarkers assays tested have high specificity for detecting AD pathology, enabling their use to estimate AD pathology in a larger cohort. Based on the low sensitivity of the plasma biomarkers tested, we assume that these results underestimate the prevalence of AD pathology in the COMPASS-ND cohort.