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Background Slow prion disease characterized by progression from normality to death after three years is uncommon. We report a case of neuropathologically confirmed variably protease sensitive prionopathy (VPSPr); a rare molecular subtype of sporadic prion disease.Methods Case ReportResults A 50-year-old gentleman was referred with a 7-year history of gradual onset slowly progressive cognitive decline, behavioural and personality change. Symptom onset at age 43 years was characterised by social withdrawal, impaired balance and short-term memory concerns. He then developed progressive aphasia, prominent apathy and significant functional decline. At age 52 years the patient was akinetic and mute, requiring full time care.Cerebrospinal fluid Alzheimer disease screen revealed abnormally elevated total tau with a normal Abeta1–42 and P-tau. CSF real-time quaking-induced conversion was negative. MRI brain revealed generalised atrophy with minimal white matter disease. FDG PET revealed bilateral anterior cingulate and left frontal minor hypometabolism. Amyloid PET was negative.Prion gene testing was normal with no OPRI mutations detected.Diagnosis was established through post-mortem pathological examination. Western Blot assay demonstrated PrPSc positivity with a banding pattern consistent with variably protease sensitive prion protein VPSPr. Genomic testing demonstrated homozygosity for methionine (MM) at the polymorphic codon 129.Conclusion Slow prion disease typically manifests as a slowly progressive dementia which is uniformly fatal. It can occur both in genetic and sporadic forms. Variably protease sensitive prionopathy should be considered in slowly progressive dementing syndromes.