Article Text

First presentation with neuropsychiatric symptoms in autosomal dominant Alzheimer’s disease: the Dominantly Inherited Alzheimer’s Network Study
  1. Antoinette O'Connor1,2,
  2. Helen Rice1,2,
  3. Josephine Barnes1,
  4. Natalie S Ryan1,2,
  5. Kathy Y Liu3,
  6. Ricardo Francisco Allegri4,
  7. Sarah Berman5,
  8. John M Ringman6,
  9. Carlos Cruchaga7,
  10. Martin R Farlow8,
  11. Jason Hassenstab7,
  12. Jae-Hong Lee9,
  13. Richard J Perrin7,10,
  14. Chengjie Xiong11,
  15. Brian Gordon12,
  16. Allan I Levey13,
  17. Alison Goate14,
  18. Neil Graff-Radford15,
  19. Johannes Levin16,17,18,
  20. Mathias Jucker19,20,
  21. Tammie Benzinger12,
  22. Eric McDade7,
  23. Hiroshi Mori21,
  24. James M Noble22,
  25. Peter R Schofield23,24,
  26. Ralph N Martins25,
  27. Stephen Salloway26,
  28. Jasmeer Chhatwal27,
  29. John C Morris7,
  30. Randall Bateman7,
  31. Rob Howard3,
  32. Suzanne Reeves3,
  33. Nick C Fox1,2
  34. for the Dominantly Inherited Alzheimer Network
    1. 1 Dementia Research Centre, UCL Queen Square Institute of Neurology, London, UK
    2. 2 UK Dementia Research Institute at UCL, London, UK
    3. 3 Division of Psychiatry, University College London, London, UK
    4. 4 Cognitive Neurology, Neurological Research Institute FLENI, Buenos Aires (Argentina), Buenos Aires, Argentina
    5. 5 Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
    6. 6 Department of Neurology, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA
    7. 7 Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA
    8. 8 Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana, USA
    9. 9 Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea (the Republic of)
    10. 10 Department of Pathology and Immunology, Washington University in St Louis MO, St Louis, Missouri, USA
    11. 11 Division of Biostatistics, Washington University in St Louis MO, St Louis, Missouri, USA
    12. 12 Department of Radiology, Washington University School of Medicine, Saint Louis, Missouri, USA
    13. 13 Department of Neurology, Emory University School of Medicine Atlanta, Atlanta, Georgia, USA
    14. 14 Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA
    15. 15 Department of Neurology, Mayo Clinic Jacksonville, Jacksonville, Florida, USA
    16. 16 German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
    17. 17 Munich Cluster for Systems Neurology, (SyNergy), Munich, Germany
    18. 18 Department of Neurology, Ludwig-Maximilians Universität München, Munich, Germany
    19. 19 German Center for Neurodegenerative Diseases, Tübingen, Germany
    20. 20 Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
    21. 21 Osaka City University, Osaka, Japan
    22. 22 Department of Neurology and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, USA
    23. 23 Neuroscience Research Australia, Sydney, New South Wales, Australia
    24. 24 School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia
    25. 25 Sir James McCusker Alzheimer's Disease Research Unit, Edith Cowan University, Perth, Western Australia, Australia
    26. 26 Department of Neurology, Butler Hospital & Alpert Medical School of Brown University, Providence, Rhode Island, USA
    27. 27 Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA
    1. Correspondence to Dr Antoinette O'Connor, Dementia Research Centre, London WC1N 3BG, UK; antoinette.o'connor{at}

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    Behavioural changes and neuropsychiatric symptoms (NPS) commonly occur in Alzheimer’s disease (AD) but may not be recognised as AD-related when they are the presenting feature. NPS are important as they are associated with greater functional impairment, poorer quality of life, accelerated cognitive decline and worsened caregiver burden.1

    Autosomal dominant AD (ADAD), although <1% of total AD cases, provides a valuable opportunity to study the clinical heterogeneity of AD. The young age at onset reduces the prevalence of age-related comorbid pathologies and the near 100% penetrance of pathogenic mutations reduces the likelihood of misdiagnosis.2

    Anxiety and depression commonly occur in ADAD family members, with increased levels of depression having been found among predementia female mutation carriers.3 Subsequent studies, however, have shown that anxiety and/or depression are common regardless of mutation status, occurring in almost one in three at-risk individuals, with one study reporting a higher rate of depression in non-carriers (17%) than asymptomatic carriers (5%).4 5 Despite the high frequency of NPS in ADAD families, relatively little is known about the proportion of ADAD cases who present with predominantly behavioural symptoms.

    Our aims were to assess the first reported clinical change in symptomatic ADAD, to compare presentations across genotypes, and to compare cognitive performance between behavioural and cognitive-led presentations.


    Data from the first symptomatic visit of ADAD participants were obtained from Data Freeze 14 of the Dominantly Inherited Alzheimer Network (DIAN), an international multisite study of ADAD family members who are affected by, or at 50% risk of inheriting, pathogenic presenilin (PSEN) 1/2, or amyloid precursor protein (APP) mutations.6

    For symptomatic participants, clinicians categorised the first predominant symptom as cognitive, behavioural, motor or unknown. For all symptomatic participants (regardless of presenting symptom domain), the first predominant behavioural symptom was identified. Cognitive function was assessed using a standardised neuropsychological test battery.6 ADAD mutation status was determined using Sanger sequencing.

    Baseline demographics were compared using independent samples t-tests or Mann-Whitney U tests for continuous variables and χ2 or Fisher’s exact tests for categorical variables. Linear regression models with robust SEs that allowed for clustering within families compared cognitive performance (letter fluency, word list recall) between cognitive-led and behavioural-led presentations, adjusting for age, sex, disease duration and years of education. Binary logistic regression, where the outcome of interest was cognitive versus behavioural onset, was performed. Prespecified comparisons of interest were: (1) PSEN1 versus APP and (2) PSEN1 pre-codon200 versus PSEN1 post-codon200 carriers; each analysis allowed for clustering within families. Proportions of first predominant behavioural symptom across genotypes and mutation subgroups were calculated.

    Further details on study procedures and analyses are provided in online supplemental material.

    Supplemental material


    The dataset included 136 (23 APP, 113 PSEN1/2) carriers of whom 112 (82%) had predominantly cognitive onsets while 19 (14%) had behavioural-led presentations. Demographic details online supplemental table 1; demographics of genetic subgroups online supplemental tables 2 and 3).

    There was no significant difference in age at onset between behavioural-led and cognitive-led presentations across all carriers (p=0.51) or across PSEN1 carriers (p=0.80) but PSEN1 precodon200 carriers were significantly younger than postcodon200 carriers (p=0.001) .

    Linear regression models, adjusted for age, gender, disease duration and years of education, found no significant difference in cognitive performance between cognitive-led and behavioural-led presentations: beta coefficient β_word immediate recall −0.06 (95% CI=−0.97 to 0.84, p=0.90), β_average verbal fluency −0.08 (95% CI −0.35 to 0.19, p=0.55).

    Behavioural onset was more common among PSEN1 pre-codon200 carriers (n=8; 26%) than among pre-codon200 non-carriers (n=8;10%) (OR 3.14, 95% CI 1.08 to 9.11, p=0.036).There was no significant difference between APP and PSEN1 carriers (OR 0.08, 95% CI 0.41 to 2.86, p=0.88).

    The most commonly occurring first predominant behavioural symptom among all symptomatic carriers was depression, followed by apathy and irritability (figure 1).

    Figure 1

    First predominant behavioural symptom reported. (A) displays data from all symptomatic mutation carriers, (B) symptomatic PSEN1 carriers and (C) symptomatic APP carriers. There was no significant difference in the proportion of PSEN1 and APP patients with depression as the first predominant behavioural symptom (p=0.80). APP, amyloid precursor protein; PSEN, presenilin.


    Behavioural-led presentations, although less frequent than cognitive led, are relatively common in ADAD with 14% of cases presenting in this way. There were no significant differences in age at onset or cognitive performance between these two groups.

    NPS occurred in over 60% of symptomatic carriers, with depression, apathy and irritability being especially common. Smaller DIAN series (n=58 and n=107 symptomatic carriers) previously found a reasonably similar frequency of behavioural/personality change.4 7 This is greater than the prevalence reported (approximately 40%) in the wider literature.7 This may be attributable to DIAN being a prospective study with active screening for these symptoms, which may have been under-reported in retrospective series.

    The frequency (14%) of behavioural symptom onset is also higher than that reported in a large retrospective ADAD series (8%; n=17/213).2 Additionally, over 30% of cases reported here had a first predominant behavioural symptom of depression, followed by apathy (17%) and irritability (14%). Interpreting the clinical significance of these symptoms in ADAD is challenging: asymptomatic carriers were previously found to be less likely than non-carriers to experience behavioural changes.4 Nonetheless the high frequency of behavioural onset and NPS reported here suggests that these symptoms should be screened for as they may herald clinical onset.

    There was no difference in the likelihood of behavioural predominant presentations between APP and PSEN1 carriers, however pre-codon 200 PSEN1 carriers were over three times more likely to have behavioural onset compared with post-codon 200 carriers. This is somewhat surprising given atypical cognitive presentations have been found to occur more commonly in post-codon 200 carriers.2 This result should be interpreted cautiously given the small numbers.

    A limitation of this study is the reliance on clinician judgement of retrospective caregiver and participant reports to determine initial symptoms. However, recall bias is minimised by the prospective nature of this study as well as the performance of annual study visits for symptomatic participants. Individuals with NPS may be less likely to participate in multimodal observational research. However, this would, if anything, strengthen our findings regarding the high prevalence of non-cognitive symptoms/presentations. Finally, the relative rarity of ADAD resulted in small numbers being included in subgroup analysis.


    This paper shows the relatively high frequency of behavioural predominant presentations in ADAD, and describes the earliest NPS in this ‘genetically pure’ form of AD. Behavioural change and NPS are important, common and potentially under-recognised and undertreated features of ADAD, which may herald cognitive decline.

    Supplemental material

    Ethics statements

    Patient consent for publication

    Ethics approval

    This study involves human participants and was approved by NHS National Research Ethics Service, REC number 09/H0505/73. Participants gave informed consent to participate in the study before taking part.


    Supplementary materials

    • Supplementary Data

      This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.


    • Twitter @ccrugom, @BrianGordon81, @Suzanne04823062

    • Collaborators Sarah Adams, Ricardo Allegri, Aki Araki, Nicolas Barthelemy, Randall Bateman, Jacob Bechara, Tammie Benzinger, Sarah Berman, Courtney Bodge, Susan Brandon, William (Bill) Brooks, Jared Brosch, Jill Buck, Virginia Buckles, Kathleen Carter, Lisa Cash, Charlie Chen, Jasmeer Chhatwal, Patricio Chrem, Jasmin Chua, Helena Chui, Carlos Cruchaga, Gregory S Day, Chrismary De La Cruz, Darcy Denner, Anna Diffenbacher, Aylin Dincer, Tamara Donahue, Jane Douglas, Duc Duong, Noelia Egido, Bianca Esposito, Anne Fagan, Marty Farlow, Becca Feldman, Colleen Fitzpatrick, Shaney Flores, Nick Fox, Erin Franklin, Nelly Friedrichsen, Hisako Fujii, Samantha Gardener, Bernardino Ghetti, Alison Goate, Sarah Goldberg, Jill Goldman, Alyssa Gonzalez, Brian Gordon, Susanne Gräber-Sultan, Neill Graff-Radford, Morgan Graham, Julia Gray, Emily Gremminger, Miguel Grilo, Alex Groves, Christian Haass, Lisa Häsler, Jason Hassenstab, Cortaiga Hellm, Elizabeth Herries, Laura Hoechst-Swisher, Anna Hofmann, David Holtzman, Russ Hornbeck, Yakushev Igor, Ryoko Ihara, Takeshi Ikeuchi, Snezana Ikonomovic, Kenji Ishii, Clifford Jack, Gina Jerome, Erik Johnson, Mathias Jucker, Celeste Karch, Stephan Käser, Kensaku Kasuga, Sarah Keefe, William (Bill) Klunk, Robert Koeppe, Deb Koudelis, Elke Kuder-Buletta, Christoph Laske, Allan Levey, Johannes Levin, Yan Li, Oscar Lopez, Jacob Marsh, Rita Martinez, Ralph Martins, Neal Scott Mason, Colin Masters, Kwasi Mawuenyega, Austin McCullough, Eric McDade, Arlene Mejia, Estrella Morenas-Rodriguez, John Morris, James MountzMD, Cath Mummery, Neelesh Nadkarni, Akemi Nagamatsu, Katie Neimeyer, Yoshiki Niimi, James Noble, Joanne Norton, Brigitte Nuscher, Antoinette O'Connor, Ulricke Obermüller, Riddhi Patira, Richard Perrin, Lingyan Ping, Oliver Preische, Alan Renton, John Ringman, Stephen Salloway, Peter Schofield, Michio Senda, Nick Seyfried, Kristine Shady, Hiroyuki Shimada, Wendy Sigurdson, Jennifer Smith, Lori Smith, Beth Snitz, Hamid Sohrabi, Sochenda Stephens, Kevin Taddei, Sarah Thompson, Jonathan Vöglein, Peter Wang, Qing Wang, Elise Weamer, Chengjie Xiong, Jinbin Xu, Xiong Xu.

    • Contributors AO'C, SR, NCF did the literature search. AO'C, SR, HR, JB and NCF designed the study. AO'C and SR carried out the statistical analysis. AO created the figures. All authors were involved in the interpretation of results and writing the report.

    • Funding Data collection and sharing for this project was supported by The Dominantly Inherited Alzheimer Network (DIAN, U19AG032438) funded by the National Institute on Ageing (NIA),the Alzheimer’s Association (SG-20–6 90 363-DIAN), the German Centre for Neurodegenerative Diseases (DZNE), Raul Carrea Institute for Neurological Research (FLENI), Partial support by the Research and Development Grants for Dementia from Japan Agency for Medical Research and Development, AMED, and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), Spanish Institute of Health Carlos III (ISCIII), Canadian Institutes of Health Research (CIHR), Canadian Consortium of Neurodegeneration and Ageing, Brain Canada Foundation, and Fonds de Recherche du Québec – Santé. This manuscript has been reviewed by DIAN Study investigators for scientific content and consistency of data interpretation with previous DIAN Study publications. We acknowledge the altruism of the participants and their families and contributions of the DIAN research and support staff at each of the participating sites for their contributions to this study. AO'C acknowledges support from an Alzheimer’s Society clinical research training fellowship (AS-CTF18-001) and from the Rosetrees Trust (M668). NSR is supported by a University of London Chadburn Academic Clinical Lectureship. KYL is supported by the UK Medical Research Council (MRC) (MR/S021418/1). This work was supported by the NIHR UCLH/UCL Biomedical Research Centre, the Rosetrees Trust, the MRC Dementia Platform UK and the UK Dementia Research Institute at UCL which receives its funding from UK DRI (UKDRI-1001), funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. NCF has served on advisory boards or as a consultant for Biogen, Ionis, Lilly, and Roche (all payments to UCL) and has served on a data safety monitoring board for Biogen.

    • Competing interests None declared.

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

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.