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Familial Alzheimer’s disease associated with heterozygous NPC1 mutation
  1. Diego Lopergolo1,2,
  2. Silvia Bianchi1,2,
  3. Gian Nicola Gallus1,2,
  4. Sara Locci1,2,
  5. Barbara Pucci1,3,
  6. Valerio Leoni4,
  7. Daniele Gasparini1,2,
  8. Elisa Tardelli5,
  9. Andrea Chincarini6,
  10. Stelvio Sestini5,
  11. Filippo Maria Santorelli7,
  12. Henrik Zetterberg8,9,10,11,12,
  13. Nicola De Stefano1,2,
  14. Andrea Mignarri1,2
  1. 1Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
  2. 2UOC Neurologia e Malattie Neurometaboliche, Azienda Ospedaliero-Universitaria Senese, Siena, Italy
  3. 3UOC Neurologia e Neurofisiologia Clinica, Azienda Ospedaliero-Universitaria Senese, Siena, Italy
  4. 4Laboratory of Clinical Chemistry, Hospital of Desio, ASST Brianza, School of Medicine and Surgery, University of Milano Bicocca, Milan, Italy
  5. 5Unit of Nuclear Medicine, Department of Diagnostic Imaging, PO - S. Stefano, Azienda U.S.L. Toscana Centro, Prato, italy
  6. 6National Institute of Nuclear Physics ((INFN), Genoa, Italy
  7. 7Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Stella Maris Foundation, Calambrone, Italy
  8. 8Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
  9. 9Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
  10. 10UK Dementia Research Institute at UCL, London, UK
  11. 11Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK
  12. 12Hong Kong Center for Neurodegenerative Diseases, Hong Kong Special Administrative Region, People's Republic of China
  1. Correspondence to Andrea Mignarri, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, 53100, Italy; andrea.mignarri{at}


Introduction NPC1 mutations are responsible for Niemann-Pick disease type C (NPC), a rare autosomal recessive neurodegenerative disease. Patients harbouring heterozygous NPC1 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 NPC1 mutation.

Methods 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.

Results We detected the novel heterozygous c.3034G>T (p.Gly1012Cys) mutation in NPC1, shared by all the siblings. No other point mutations or deletions in NPC1 or NPC2 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.

Discussion We describe a novel NPC1 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 NPC1 mutation. Our work, illustrating clinical and biochemical disease hallmarks associated with NPC1 heterozygosity in patients affected by AD, provides relevant insights into the pathogenetic mechanisms underlying this possible novel association.

  • brain diseases, metabolic
  • central nervous system diseases
  • neurodegenerative diseases
  • dementia

Data availability statement

Data are available on reasonable request.

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  • Contributors DL and AM contributed to the conception and design of the study. AM is responsible for the overall content as the guarantor. DL, SB, GNG, SL, BP, VL, DG, ET, AC, FMS, SS and AM contributed to acquisition and analysis of data. DL, NDS, HZ and AM contributed to drafting the text.

  • Funding FMS is supported in part by the Italian Ministry of Health Grant RC2023 and RC 5×1000. HZ is a Wallenberg Scholar supported by grants from the European Research Council (#681712 and #101053962), Swedish State Support for Clinical Research (#ALFGBG-71320), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF-21-831376-C, #ADSF-21-831381-C and #ADSF-21-831377-C), the Bluefield Project, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2022-0270), the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no 860197 (MIRIADE), the European Union Joint Programme—Neurodegenerative Disease Research (JPND2021-00694) and the UK Dementia Research Institute at UCL (UKDRI-1003).

  • Competing interests HZ has served at scientific advisory boards and/or as a consultant for AbbVie, Acumen, Alector, ALZ Path, Annexon, Apellis, Artery Therapeutics, AZ Therapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Passage Bio, Pinteon Therapeutics, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen and Roche and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Programme (outside submitted work). None of the other authors have a conflict of interest to disclose.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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