CSF Aβ42 and Aβ42/Aβ40 Ratio in Alzheimer’s Disease and Frontotemporal Dementias

Background: Alzheimer’s disease dementia (ADD) may manifest with atypical phenotypes, resembling behavioral variant frontotemporal dementia (bvFTD) and corticobasal syndrome (CBS), phenotypes which typically have an underlying frontotemporal lobar degeneration with tau proteinopathy (FTLD-tau), such as Pick’s disease, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), or FTLD with TDP-43 proteinopathy (FTLD-TDP). CSF biomarkers total and phosphorylated tau (τ(T) and τ(P-181)), and amyloid beta with 42 and 40 amino acids (Aβ(42) and Aβ(40)) are biomarkers of AD pathology. The primary aim of this study was to compare the diagnostic accuracy of Aβ(42) to Aβ(42)/Aβ(40) ratio in: (a) differentiating ADD vs. frontotemporal dementias; (b) patients with AD pathology vs. non-AD pathologies; (c) compare biomarker ratios and composite markers to single CSF biomarkers in the differentiation of AD from FTD; Methods: In total, 263 subjects were included (ADD: n = 98; bvFTD: n = 49; PSP: n = 50; CBD: n = 45; controls: n = 21). CSF biomarkers were measured by commercially available ELISAs (EUROIMMUN). Multiple biomarker ratios (Aβ(42)/Aβ(40); τ(T)/τ(P-181); τ(T)/Aβ(42); τ(P-181)/Aβ(42)) and composite markers (t-tau: τ(T)/(Aβ(42)/Aβ40); p-tau: τ(P-181)/(Aβ(42)/Aβ(40)) were calculated. ROC curve analysis was performed to compare AUCs of Aβ(42) and Aβ(42)/Aβ(40) ratio and relevant composite markers between ADD and FTD, as defined clinically. BIOMARKAPD/ABSI criteria (abnormal τ(T), τ(P-181) Aβ(42), and Aβ(42)/Aβ(40) ratio) were used to re-classify all patients into AD pathology vs. non-AD pathologies, and ROC curve analysis was repeated to compare Aβ(42) and Aβ(42)/Aβ(40); Results: Aβ(42) did not differ from Aβ(42)/Aβ(40) ratio in the differentiation of ADD from FTD (AUCs 0.752 and 0.788 respectively; p = 0.212). The τ(T)/Aβ(42) ratio provided maximal discrimination between ADD and FTD (AUC:0.893; sensitivity 88.8%, specificity 80%). BIOMARKAPD/ABSI criteria classified 60 patients as having AD pathology and 211 as non-AD. A total of 22 had discrepant results and were excluded. Aβ(42)/Aβ(40) ratio was superior to Aβ(42) in the differentiation of AD pathology from non-AD pathology (AUCs: 0.939 and 0.831, respectively; p < 0.001). In general, biomarker ratios and composite markers were superior to single CSF biomarkers in both analyses. Conclusions: Aβ(42)/Aβ(40) ratio is superior to Aβ(42) in identifying AD pathology, irrespective of the clinical phenotype. CSF biomarker ratios and composite markers provide higher diagnostic accuracy compared to single CSF biomarkers.