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

## TL;DR

This study explores miglustat as a potential treatment for Alzheimer's disease linked to a specific NPC1 mutation, showing promising results in reducing amyloid buildup and stabilizing patients.

## Contribution

The study presents preliminary evidence that miglustat may reduce brain amyloid burden in patients with heterozygous NPC1 mutations and Alzheimer's disease.

## Key findings

- Three patients with heterozygous NPC1 mutations showed clinical stability after 12 months of miglustat treatment.
- Miglustat led to a sustained reduction in serum oxysterol levels and a marked decrease in brain amyloid burden.
- The findings suggest miglustat could be a potential disease-modifying treatment for Alzheimer's disease in this patient group.

## Abstract

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.

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.

All three patients achieved clinical stability, showed a sustained reduction in serum oxysterol levels, and experienced a marked decrease in brain amyloid burden.

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.

Three AD patients sharing the same heterozygous NPC1 mutation were orally treated with miglustat for 12 months and underwent monthly clinical and neuropsychological evaluations, brain amyloid‐PET imaging, and biochemical analyses on plasma and CSF. All three patients achieved clinical stability, showed a sustained reduction in serum oxysterol levels, and experienced a marked decrease in brain amyloid burden. Based on our preliminary observations, on the light of 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.