title: Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer's disease: a case series.
abstract: BACKGROUND
  The causes of phenotypic heterogeneity in familial Alzheimer's disease with autosomal dominant inheritance are not well understood. We aimed to characterise clinical phenotypes and genetic associations with APP and PSEN1 mutations in symptomatic autosomal dominant familial Alzheimer's disease (ADAD).
  
  
  METHODS
  We retrospectively analysed genotypic and phenotypic data (age at symptom onset, initial cognitive or behavioural symptoms, and presence of myoclonus, seizures, pyramidal signs, extrapyramidal signs, and cerebellar signs) from all individuals with ADAD due to APP or PSEN1 mutations seen at the Dementia Research Centre in London, UK. We examined the frequency of presenting symptoms and additional neurological features, investigated associations with age at symptom onset, APOE genotype, and mutation position, and explored phenotypic differences between APP and PSEN1 mutation carriers. The proportion of individuals presenting with various symptoms was analysed with descriptive statistics, stratified by mutation type.
  
  
  RESULTS
  Between July 1, 1987, and Oct 31, 2015, age at onset was recorded for 213 patients (168 with PSEN1 mutations and 45 with APP mutations), with detailed history and neurological examination findings available for 121 (85 with PSEN1 mutations and 36 with APP mutations). We identified 38 different PSEN1 mutations (four novel) and six APP mutations (one novel). Age at onset differed by mutation, with a younger onset for individuals with PSEN1 mutations than for those with APP mutations (mean age 43·6 years [SD 7·2] vs 50·4 years [SD 5·2], respectively, p<0·0001); within the PSEN1 group, 72% of age at onset variance was explained by the specific mutation. A cluster of five mutations with particularly early onset (mean age at onset <40 years) involving PSEN1's first hydrophilic loop suggests critical functional importance of this region. 71 (84%) individuals with PSEN1 mutations and 35 (97%) with APP mutations presented with amnestic symptoms, making atypical cognitive presentations significantly more common in PSEN1 mutation carriers (n=14; p=0·037). Myoclonus and seizures were the most common additional neurological features; individuals with myoclonus (40 [47%] with PSEN1 mutations and 12 [33%] with APP mutations) were significantly more likely to develop seizures (p=0·001 for PSEN1; p=0·036 for APP), which affected around a quarter of the patients in each group (20 [24%] and nine [25%], respectively). A number of patients with PSEN1 mutations had pyramidal (21 [25%]), extrapyramidal (12 [14%]), or cerebellar (three [4%]) signs.
  
  
  CONCLUSIONS
  ADAD phenotypes are heterogeneous, with both age at onset and clinical features being influenced by mutation position as well as causative gene. This highlights the importance of considering genetic testing in young patients with dementia and additional neurological features in order to appropriately diagnose and treat their symptoms, and of examining different mutation types separately in future research.
  
  
  BACKGROUND
  Medical Research Council and National Institute for Health Research.
authors: Dementia Research Centre, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, UK. Electronic address: natalie.ryan@ucl.ac.uk.
authors: Natalie S
authors: NS
authors: Ryan
authors: Dementia Research Centre, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, UK; Medical Statistics Unit, Department of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, UK.
authors: Jennifer M
authors: JM
authors: Nicholas
authors: Dementia Research Centre, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, UK.
authors: Philip S J
authors: PSJ
authors: Weston
authors: Dementia Research Centre, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, UK.
authors: Yuying
authors: Y
authors: Liang
authors: Queen Square Brain Bank, University College London Institute of Neurology, London, UK.
authors: Tammaryn
authors: T
authors: Lashley
authors: Department of Molecular Neuroscience, University College London Institute of Neurology, London, UK; Department of Medical Sciences, Institute of Biomedicine iBiMED, University of Aveiro, Aveiro Portugal.
authors: Rita
authors: R
authors: Guerreiro
authors: Medical Research Council Prion Unit, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, UK.
authors: Gary
authors: G
authors: Adamson
authors: Medical Research Council Prion Unit, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, UK.
authors: Janna
authors: J
authors: Kenny
authors: Medical Research Council Prion Unit, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, UK.
authors: Jon
authors: J
authors: Beck
authors: VIB Center for the Biology of Disease, Leuven, Belgium; Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases, University of Leuven, Leuven, Belgium.
authors: Lucia
authors: L
authors: Chavez-Gutierrez
authors: Department of Molecular Neuroscience, University College London Institute of Neurology, London, UK; VIB Center for the Biology of Disease, Leuven, Belgium; Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases, University of Leuven, Leuven, Belgium.
authors: Bart
authors: B
authors: de Strooper
authors: Queen Square Brain Bank, University College London Institute of Neurology, London, UK.
authors: Tamas
authors: T
authors: Revesz
authors: Queen Square Brain Bank, University College London Institute of Neurology, London, UK.
authors: Janice
authors: J
authors: Holton
authors: Medical Research Council Prion Unit, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, UK.
authors: Simon
authors: S
authors: Mead
authors: Dementia Research Centre, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, UK.
authors: Martin N
authors: MN
authors: Rossor
authors: Dementia Research Centre, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, UK.
authors: Nick C
authors: NC
authors: Fox
mesh_terms: D000328:Adult; D017668:Age of Onset; D000544:Alzheimer Disease / Q000145:classification / Q000235:genetics* / Q000503:physiopathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D053764:Presenilin-1 / Q000235:genetics*; D012189:Retrospective Studies
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; C508853:PSEN1 protein, human; D053764:Presenilin-1