Familial Alzheimer's disease associated with heterozygous <i>NPC1</i> mutation.

Abstract

<i>NPC1</i> mutations are responsible for Niemann-Pick disease type C (NPC), a rare autosomal recessive neurodegenerative disease. Patients harbouring heterozygous <i>NPC1</i> mutations may rarely show parkinsonism or dementia. Here, we describe for the first time a large family with an apparently autosomal dominant late-onset Alzheimer's disease (AD) harbouring a novel heterozygous <i>NPC1</i> mutation. All the five living siblings belonging to the family were evaluated. We performed clinical evaluation, neuropsychological tests, assessment of cerebrospinal fluid markers of amyloid deposition, tau pathology and neurodegeneration (ATN), structural neuroimaging and brain amyloid-positron emission tomography. Oxysterol serum levels were also tested. A wide next-generation sequencing panel of genes associated with neurodegenerative diseases and a whole exome sequencing analysis were performed. We detected the novel heterozygous c.3034G>T (p.Gly1012Cys) mutation in <i>NPC1</i>, shared by all the siblings. No other point mutations or deletions in <i>NPC1</i> or <i>NPC2</i> were found. In four siblings, a diagnosis of late-onset AD was defined according to clinical characterisation and ATN biomarkers (A+, T+, N+) and serum oxysterol analysis showed increased 7-ketocholesterol and cholestane-3β,5α,6β-triol. We describe a novel <i>NPC1</i> heterozygous mutation harboured by different members of a family with autosomal dominant late-onset amnesic AD without NPC-associated features. A missense mutation in homozygous state in the same aminoacidic position has been previously reported in a patient with NPC with severe phenotype. The alteration of serum oxysterols in our family corroborates the pathogenic role of our <i>NPC1</i> mutation. Our work, illustrating clinical and biochemical disease hallmarks associated with <i>NPC1</i> heterozygosity in patients affected by AD, provides relevant insights into the pathogenetic mechanisms underlying this possible novel association.