Emerging evidence suggested a converging mechanism in neurodegenerative brain diseases (NBD) involving early neuronal
network dysfunctions and alterations in the homeostasis of neuronal fring as culprits of neurodegeneration. In this study,
we used paired-end short-read and direct long-read whole genome sequencing to investigate an unresolved autosomal
dominant dementia family signifcantly linked to 7q36. We identifed and validated a chromosomal inversion of ca. 4 Mb,
segregating on the disease haplotype and disrupting the coding sequence of dipeptidyl-peptidase 6 gene (DPP6). DPP6
resequencing identifed signifcantly more rare variants—nonsense, frameshift, and missense—in early-onset Alzheimer’s
disease (EOAD, p value=0.03, OR=2.21 95% CI 1.05–4.82) and frontotemporal dementia (FTD, p=0.006, OR=2.59, 95%
CI 1.28–5.49) patient cohorts. DPP6 is a type II transmembrane protein with a highly structured extracellular domain and
is mainly expressed in brain, where it binds to the potassium channel Kv4.2 enhancing its expression, regulating its gating
properties and controlling the dendritic excitability of hippocampal neurons. Using in vitro modeling, we showed that the
missense variants found in patients destabilize DPP6 and reduce its membrane expression (p<0.001 and p<0.0001) leading
to a loss of protein. Reduced DPP6 and/or Kv4.2 expression was also detected in brain tissue of missense variant carriers.
Loss of DPP6 is known to caus