Dissecting IWG-2 typical and atypical Alzheimer's disease: insights from cerebrospinal fluid analysis

Pathobiological factors underlying phenotypic diversity in Alzheimer's disease (AD) are incompletely understood. We used an extended cerebrospinal fluid (CSF) panel to explore differences between "typical" with "atypical" AD and between amnestic, posterior cortical atrophy, logopenic aphasia and frontal variants. We included 97 subjects fulfilling International Working Group-2 research criteria for AD of whom 61 had "typical" AD and 36 "atypical" syndromes, and 30 controls. CSF biomarkers included total tau (T-tau), phosphorylated tau (P-tau), amyloid β1-42, amyloid βX-38/40/42, YKL-40, neurofilament light (NFL), and amyloid precursor proteins α and β. The typical and atypical groups were matched for age, sex, severity and rate of cognitive decline and had similar biomarker profiles, with the exception of NFL which was higher in the atypical group (p = 0.03). Sub-classifying the atypical group into its constituent clinical syndromes, posterior cortical atrophy was associated with the lowest T-tau [604.4 (436.8-675.8) pg/mL], P-tau (79.8 ± 21.8 pg/L), T-tau/Aβ1-42 ratio [2.3 (1.4-2.6)], AβX-40/X-42 ratio (22.1 ± 5.8) and rate of cognitive decline [1.9 (0.75-4.25) MMSE points/year]. Conversely, the frontal variant group had the highest levels of T-tau [1185.4 (591.7-1329.3) pg/mL], P-tau (116.4 ± 45.4 pg/L), T-tau/Aβ1-42 ratio [5.2 (3.3-6.9)] and AβX-40/X-42 ratio (27.9 ± 7.5), and rate of cognitive decline. Whilst on a group level IWG-2 "typical" and "atypical" AD share similar CSF profiles, which are very different from controls, atypical AD is a heterogeneous entity with evidence for subtle differences in amyloid processing and neurodegeneration between different clinical syndromes. These findings also have practical implications for the interpretation of clinical CSF biomarker results.