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Genetic Influences on Atrophy Patterns in Familial Alzheimer's Disease: A Comparison of APP and PSEN1 Mutations

Article type: Research Article

Authors: Scahill, Rachael I.a; * | Ridgway, Gerard R.a; b | Bartlett, Jonathan W.c | Barnes, Josephinea | Ryan, Natalie S.a | Mead, Simond | Beck, Jonathand | Clarkson, Matthew J.a; e | Crutch, Sebastian J.a | Schott, Jonathan M.a | Ourselin, Sebastiena; e | Warren, Jason D.a | Hardy, Johnf | Rossor, Martin N.a | Fox, Nick C.a

Affiliations: [a] Dementia Research Centre, Department of Neurodegeneration, UCL Institute of Neurology, London, UK | [b] Wellcome Trust Centre for Neuroimaging, UCL Institute of Neurology, London, UK | [c] Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK | [d] MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK | [e] Centre for Medical Image Computing, University College London, London, UK | [f] Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK

Correspondence: [*] Correspondence to: Dr. Rachael Scahill, Box 104, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK. Tel.: +44 207 242 0038; E-mail: [email protected].

Keywords: Alzheimer's disease, APP, atrophy, autosomal dominant, magnetic resonance imaging, PSEN1

DOI: 10.3233/JAD-121255

Journal: Journal of Alzheimer's Disease, vol. 35, no. 1, pp. 199-212, 2013

Accepted 14 January 2013
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Published: 29 March 2013
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Supplementary Materials:

Supplementary Materials.

Abstract

Mutations in the presenilin1 (PSEN1) and amyloid β-protein precursor (APP) genes account for the majority of cases of autosomal dominantly inherited Alzheimer's disease (AD). We wished to assess and compare the patterns of cerebral loss produced by these two groups of mutations. Volumetric magnetic resonance imaging and neuropsychological assessments were performed in individuals with clinical AD carrying mutations in the APP (n = 10) and PSEN1 (n = 18) genes and in healthy controls (n = 18). Voxel-based morphometry (VBM), cortical thickness, and region of interest analyses were performed. Mini-Mental State Examination scores were similar in the two disease groups suggesting similar levels of disease severity. There was evidence that APP subjects have smaller hippocampal volume compared with PSEN1 subjects (p = 0.007), and weak evidence that they have larger whole-brain and grey matter volumes (both p = 0.07). Although there was no evidence of statistically significant differences between APP and PSEN1 in VBM or cortical thickness analyses, effect-maps were suggestive of APP subjects having more medial temporal lobe atrophy and conversely PSEN1 subjects showing more neocortical loss. Neuropsychological data were consistent with these regional differences and suggested greater memory deficits in the APP patients and greater impairment in non-memory domains in the PSEN1 group, although these differences were not statistically significant. We conclude that the mechanisms by which APP and PSEN1 mutations cause neuronal loss may differ which furthers our understanding of the neuropathology underlying AD and may inform future therapeutic strategies and trial designs.

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