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Objective  To evaluate poly( GP ), a dipeptide repeat protein, and neurofilament light chain (NfL) as biomarkers in presymptomatic  C9orf72  repeat expansion carriers and patients with  C9orf72‐ associated frontotemporal dementia. Additionally, to investigate the relationship of poly( GP ) with indicators of neurodegeneration as measured by NfL and grey matter volume.    Methods  We measured poly( GP ) and NfL levels in cerebrospinal fluid ( CSF ) from 25 presymptomatic  C9orf72  expansion carriers, 64 symptomatic expansion carriers with dementia, and 12 noncarriers. We explored associations with grey matter volumes using region of interest and voxel‐wise analyses.    Results  Poly( GP ) was present in  C9orf72  expansion carriers and absent in noncarriers (specificity 100%, sensitivity 97%). Presymptomatic carriers had lower poly( GP ) levels than symptomatic carriers. NfL levels were higher in symptomatic carriers than in presymptomatic carriers and healthy noncarriers. NfL was highest in patients with concomitant motor neuron disease, and correlated with disease severity and survival. Associations between poly( GP ) levels and small grey matter regions emerged but did not survive multiple comparison correction, while higher NfL levels were associated with atrophy in frontotemporoparietal cortices and the thalamus.    Interpretation  This study of  C9orf72  expansion carriers reveals that: (1) poly( GP ) levels discriminate presymptomatic and symptomatic expansion carriers from noncarriers, but are not associated with indicators of neurodegeneration; and (2) NfL levels are associated with grey matter atrophy, disease severity, and shorter survival. Together, poly( GP ) and NfL show promise as complementary biomarkers for clinical trials for  C9orf72‐ associated frontotemporal dementia, with poly( GP ) as a potential marker for target engagement and NfL as a marker of disease activity and progression.

Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers