Miglustat in Alzheimer's Disease Associated With Heterozygous NPC1 Mutation: Exploratory Case Series and Preliminary Findings

Introduction: Several studies have previously demonstrated an increased risk of dementia and brain amyloid deposition in individuals with heterozygous NPC1 mutations. Moreover, in a recent study, we identified the first family with autosomal dominant late-onset Alzheimer's disease (AD) caused by a heterozygous NPC1 mutation. Unfortunately, there are currently no effective treatments available for this condition. Miglustat, which impacts the metabolism of oxysterols, has been shown to exert an anti-amyloidogenic effect in a human cellular model of AD. Methods: In our exploratory uncontrolled study, three patients from the previously published family were orally treated with miglustat for 12 months. They underwent monthly clinical evaluations and routine blood tests. Additionally, neuropsychological evaluations, brain amyloid-PET imaging, and biochemical analyses on plasma and CSF were performed. Results: All three patients achieved clinical stability, showed a sustained reduction in serum oxysterol levels, and experienced a marked decrease in brain amyloid burden. Discussion: Based on our preliminary observations and hypothesis-generating findings, along with the growing evidence suggesting AD as a lipid disorder, miglustat should be further tested in a larger cohort of heterozygous NPC1 mutated patients and probably evaluated as a potential disease-modifying treatment for AD.