Alzheimer’s Research & Therapy (May 2023)

Phenotype and imaging features associated with APP duplications

  • Lou Grangeon,
  • Camille Charbonnier,
  • Aline Zarea,
  • Stephane Rousseau,
  • Anne Rovelet-Lecrux,
  • David Bendetowicz,
  • Marion Lemaitre,
  • Cécile Malrain,
  • Muriel Quillard-Muraine,
  • Kevin Cassinari,
  • David Maltete,
  • Jeremie Pariente,
  • Olivier Moreaud,
  • Eloi Magnin,
  • Benjamin Cretin,
  • Marie-Anne Mackowiak,
  • Adeline Rollin Sillaire,
  • Martine Vercelletto,
  • Elsa Dionet,
  • Olivier Felician,
  • Pauline Rod-Olivieri,
  • Catherine Thomas-Antérion,
  • Gaelle Godeneche,
  • Mathilde Sauvée,
  • Leslie Cartz-Piver,
  • Isabelle Le Ber,
  • Valérie Chauvire,
  • Therèse Jonveaux,
  • Anna-Chloé Balageas,
  • Annie Laquerriere,
  • Charles Duyckaerts,
  • Anne Vital,
  • Andre Maues de Paula,
  • David Meyronet,
  • Lucie Guyant-Marechal,
  • Didier Hannequin,
  • Elisabeth Tournier-Lasserve,
  • Dominique Campion,
  • CNR-MAJ collaborators,
  • Gaël Nicolas,
  • David Wallon

DOI
https://doi.org/10.1186/s13195-023-01172-2
Journal volume & issue
Vol. 15, no. 1
pp. 1 – 12

Abstract

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Abstract Background APP duplication is a rare genetic cause of Alzheimer disease and cerebral amyloid angiopathy (CAA). We aimed to evaluate the phenotypes of APP duplications carriers. Methods Clinical, radiological, and neuropathological features of 43 APP duplication carriers from 24 French families were retrospectively analyzed, and MRI features and cerebrospinal fluid (CSF) biomarkers were compared to 40 APP-negative CAA controls. Results Major neurocognitive disorders were found in 90.2% symptomatic APP duplication carriers, with prominent behavioral impairment in 9.7%. Symptomatic intracerebral hemorrhages were reported in 29.2% and seizures in 51.2%. CSF Aβ42 levels were abnormal in 18/19 patients and 14/19 patients fulfilled MRI radiological criteria for CAA, while only 5 displayed no hemorrhagic features. We found no correlation between CAA radiological signs and duplication size. Compared to CAA controls, APP duplication carriers showed less disseminated cortical superficial siderosis (0% vs 37.5%, p = 0.004 adjusted for the delay between symptoms onset and MRI). Deep microbleeds were found in two APP duplication carriers. In addition to neurofibrillary tangles and senile plaques, CAA was diffuse and severe with thickening of leptomeningeal vessels in all 9 autopsies. Lewy bodies were found in substantia nigra, locus coeruleus, and cortical structures of 2/9 patients, and one presented vascular amyloid deposits in basal ganglia. Discussion Phenotypes associated with APP duplications were heterogeneous with different clinical presentations including dementia, hemorrhage, and seizure and different radiological presentations, even within families. No apparent correlation with duplication size was found. Amyloid burden was severe and widely extended to cerebral vessels as suggested by hemorrhagic features on MRI and neuropathological data, making APP duplication an interesting model of CAA.

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