Using an in-house established liquid chromatography−tandem mass spectrometry (LC–MS/MS) method in multiple reaction monitoring mode (MRM) we measured cerebrospinal fluid (CSF) levels of PENK- and PDYN- derived peptides in patients with HD (n = 47), PD (n = 61), Alzheimer’s disease (n = 11), amyotrophic lateral sclerosis (n = 14) and in 92 control subjects. Here, PENK is linked to early-onset autosomal dominant Alzheimer disease.