The clinical manifestations of sporadic amyotrophic lateral sclerosis (ALS) are highly variable, implying existence of subgroups in pathophysiology. We studied a group of patients with sporadic ALS and an ALS mouse model having superoxide dismutase 1 (SOD1)/G93A transgenes using chemical precipitation followed by enzyme-linked immunosorbent assay analysis for measurement of plasma misfolded protein levels and by a nerve excitability test (NET) to investigate axonal membrane properties. Six of 19 patients (31.6%) with sporadic ALS had elevated plasma misfolded SOD1 protein levels. In sporadic ALS patients, only participants with elevated misfolded SOD1 protein level showed increased inward rectification of the current-threshold (I/V) curve and increased threshold reduction of the hyperpolarizing threshold electrotonus (TE) in NET study. Two familial ALS patients with SOD1 mutation also showed above electrophysiological patterns of NET. The computer simulation demonstrated that the above axonal excitability changes is likely associated with an increase of hyperpolarization-activated cyclic nucleotide-gated (HCN) current. In SOD1/G93A mice, the NET also showed increased inward rectification of I/V curve, which could be reversed by single injection of an HCN channel blocker, ZD7288. Daily treatment with ZD7288 in SOD1/G93A mice partially prevented early motor functional decline and spinal motor neuron death. In summary, sporadic ALS patients with elevated plasma misfolded SOD1 presented with similar patterns of motor axonal excitability changes as familial ALS patients and ALS mice with mutant SOD1 genes, indicating existence of SOD1-associated sporadic ALS.