Niemann-Pick type C disease (NPC) is a neurovisceral lysosomal storage disorder with a heterogeneous phenotype including ataxia, cognitive impairment, impairment of vertical saccades, and psychiatric symptoms, among many others. Based on clinical, genetic, and biomarker findings, recent guidelines put forward a screening for atypical and oligosymptomatic forms of NPC in clinical niches with an increased risk. Here, we report methods and results of a negative screening study in the niche of a memory clinic. We retrospectively and prospectively identified 83 patients with unclassified cognitive impairment (15 dementia, 46 mild cognitive impairment, and 22 progressive subjective cognitive decline) before 60 years of age (82 patients between 41 and 60 years). We explored the prevalence of clinical features compatible with NPC and measured plasma levels of chitotriosidase and cholestantriol. The NPC suspicion index indicated high probability for NPC in 3 and moderate probability in 16 patients. Prevalent (>5%) neurological and psychiatric features were depression, seizures, ataxia, dysarthria, and psychotic symptoms. Vertical gaze palsy without parkinsonism was observed in one patient. Cholestantriol levels were only abnormal in one patient. Chitotriosidase levels were susceptible to slight elevations that were reproducible in only two of five patients. Our study does not exclude NPC among memory clinic patients. Instead, we suggest conducting prospective screening studies in younger cohorts that include a focused neurological examination. Excluding minor cognitive impairment and discarding depression as an independent disease symptom probably further improve screening effectivity but may delay or miss therapeutic options in early or mild disease.