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 (τT and τP-181), and
amyloid beta with 42 and 40
amino acids (Aβ42 and Aβ40) are
biomarkers of AD pathology. The primary aim of this study was to compare the diagnostic accuracy of Aβ42 to Aβ42/Aβ40 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 (Aβ42/Aβ40; τT/τP-181; τT/Aβ42; τP-181/Aβ42) and composite markers (t-tau: τT/(Aβ42/Aβ40); p-tau: τP-181/(Aβ42/Aβ40) were calculated. ROC curve analysis was performed to compare AUCs of Aβ42 and Aβ42/Aβ40 ratio and relevant composite markers between ADD and FTD, as defined clinically. BIOMARKAPD/ABSI criteria (abnormal τT, τP-181 Aβ42, and Aβ42/Aβ40 ratio) were used to re-classify all patients into AD pathology vs. non-AD pathologies, and ROC curve analysis was repeated to compare Aβ42 and Aβ42/Aβ40; Results: Aβ42 did not differ from Aβ42/Aβ40 ratio in the differentiation of ADD from FTD (AUCs 0.752 and 0.788 respectively; p = 0.212). The τT/Aβ42 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. Aβ42/Aβ40 ratio was superior to Aβ42 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: Aβ42/Aβ40 ratio is superior to Aβ42 in identifying AD pathology, irrespective of the clinical phenotype. CSF
biomarker ratios and composite markers provide higher diagnostic accuracy compared to single CSF
biomarkers.