title: The interactive effect of demographic and clinical factors on hippocampal volume: A multicohort study on 1958 cognitively normal individuals.
abstract: Alzheimer's disease is characterized by hippocampal atrophy. Other factors also influence the hippocampal volume, but their interactive effect has not been investigated before in cognitively healthy individuals. The aim of this study is to evaluate the interactive effect of key demographic and clinical factors on hippocampal volume, in contrast to previous studies frequently investigating these factors in a separate manner. Also, to investigate how comparable the control groups from ADNI, AIBL, and AddNeuroMed are with five population-based cohorts. In this study, 1958 participants were included (100 AddNeuroMed, 226 ADNI, 155 AIBL, 59 BRC, 295 GENIC, 279 BioFiNDER, 398 PIVUS, and 446 SNAC-K). ANOVA and random forest were used for testing between-cohort differences in demographic-clinical variables. Multiple regression was used to study the influence of demographic-clinical variables on hippocampal volume. ANCOVA was used to analyze whether between-cohort differences in demographic-clinical variables explained between-cohort differences in hippocampal volume. Age and global brain atrophy were the most important variables in explaining variability in hippocampal volume. These variables were not only important themselves but also in interaction with gender, education, MMSE, and total intracranial volume. AddNeuroMed, ADNI, and AIBL differed from the population-based cohorts in several demographic-clinical variables that had a significant effect on hippocampal volume. Variability in hippocampal volume in individuals with normal cognition is high. Differences that previously tended to be related to disease mechanisms could also be partly explained by demographic and clinical factors independent from the disease. Furthermore, cognitively normal individuals especially from ADNI and AIBL are not representative of the general population. These findings may have important implications for future research and clinical trials, translating imaging biomarkers to the general population, and validating current diagnostic criteria for Alzheimer's disease and predementia stages.
authors.affiliation: Division of Clinical Geriatrics, Centre for Alzheimer Research, Department of Neurobiology Care Sciences and Society, Karolinska Institutet, Stockholm, 14157, Sweden.
authors.forename: Daniel
authors.identifier: 0000-0001-9522-4338
authors.initials: D
authors.lastname: Ferreira
authors.affiliation: Department of Clinical Sciences, Clinical Memory Research Unit, Lund University, Malmö, 20502, Sweden.
authors.forename: Oskar
authors.initials: O
authors.lastname: Hansson
authors.affiliation: Department of Clinical Psychology, Psychobiology and Methodology, University of La Laguna, La Laguna, 38071, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Barroso
authors.affiliation: Department of Clinical Psychology, Psychobiology and Methodology, University of La Laguna, La Laguna, 38071, Spain.|Faculty of Health Sciences, University Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain.
authors.forename: Yaiza
authors.initials: Y
authors.lastname: Molina
authors.affiliation: Department of Clinical Psychology, Psychobiology and Methodology, University of La Laguna, La Laguna, 38071, Spain.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Machado
authors.affiliation: Department of Clinical Psychology, Psychobiology and Methodology, University of La Laguna, La Laguna, 38071, Spain.
authors.forename: Juan Andrés
authors.initials: JA
authors.lastname: Hernández-Cabrera
authors.affiliation: Division of Clinical Geriatrics, Centre for Alzheimer Research, Department of Neurobiology Care Sciences and Society, Karolinska Institutet, Stockholm, 14157, Sweden.
authors.forename: J-Sebastian
authors.initials: JS
authors.lastname: Muehlboeck
authors.affiliation: Department of Clinical Sciences, Clinical Memory Research Unit, Lund University, Malmö, 20502, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Stomrud
authors.affiliation: Department of Clinical Sciences, Clinical Memory Research Unit, Lund University, Malmö, 20502, Sweden.
authors.forename: Katarina
authors.initials: K
authors.lastname: Nägga
authors.affiliation: Division of Clinical Geriatrics, Centre for Alzheimer Research, Department of Neurobiology Care Sciences and Society, Karolinska Institutet, Stockholm, 14157, Sweden.|Department of Clinical Sciences, Clinical Memory Research Unit, Lund University, Malmö, 20502, Sweden.
authors.forename: Olof
authors.initials: O
authors.lastname: Lindberg
authors.affiliation: National Ageing Research Institute, Parkville, Victoria, 3050, Australia.|University of Melbourne Academic Unit for Psychiatry of Old Age, St George's Hospital, Kew, Victoria, 3101, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Ames
authors.affiliation: Aging Research Center (ARC), Department of Neurobiology, Care Sciences and Society, Karolinska Institutet and Stockholm University, 113 30, Stockholm, Sweden.
authors.forename: Grégoria
authors.initials: G
authors.lastname: Kalpouzos
authors.affiliation: Aging Research Center (ARC), Department of Neurobiology, Care Sciences and Society, Karolinska Institutet and Stockholm University, 113 30, Stockholm, Sweden.|Stockholm Gerontology Research Centre, Stockholm, 11330, Sweden.
authors.forename: Laura
authors.initials: L
authors.lastname: Fratiglioni
authors.affiliation: Aging Research Center (ARC), Department of Neurobiology, Care Sciences and Society, Karolinska Institutet and Stockholm University, 113 30, Stockholm, Sweden.|Stockholm Gerontology Research Centre, Stockholm, 11330, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Bäckman
authors.affiliation: Division of Neurogeriatrics, Department of Neurobiology Care Sciences and Society, Centre for Alzheimer Research, Karolinska Institutet, Stockholm, 14157, Sweden.|Department of Geriatric Medicine, Karolinska University Hospital Huddinge, Stockholm, 14186, Sweden.
authors.forename: Caroline
authors.initials: C
authors.lastname: Graff
authors.affiliation: Institute of Gerontology and Geriatrics, University of Perugia, Perugia, 06100, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Mecocci
authors.affiliation: INSERM U 558, University of Toulouse, Toulouse, 31024, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Vellas
authors.affiliation: 3rd Department of Neurology, Aristoteleion Panepistimeion Thessalonikis, Thessaloniki, 54124, Greece.
authors.forename: Magda
authors.initials: M
authors.lastname: Tsolaki
authors.affiliation: Medical University of Lodz, Lodz, 92216, Poland.
authors.forename: Iwona
authors.initials: I
authors.lastname: Kłoszewska
authors.affiliation: University of Eastern Finland and Kuopio University Hospital, Kuopio, 70211, Finland.
authors.forename: Hilkka
authors.initials: H
authors.lastname: Soininen
authors.affiliation: Department of Psychiatry, Warneford Hospital University of Oxford, Oxford, OX37JX, United Kingdom.
authors.forename: Simon
authors.initials: S
authors.lastname: Lovestone
authors.affiliation: Department of Surgical Sciences, Radiology, Uppsala University, Uppsala, 75185, Sweden.
authors.forename: Håkan
authors.initials: H
authors.lastname: Ahlström
authors.affiliation: Department of Medical Sciences, Uppsala University, Uppsala, 75185, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Lind
authors.affiliation: Department of Surgical Sciences, Radiology, Uppsala University, Uppsala, 75185, Sweden.
authors.forename: Elna-Marie
authors.initials: EM
authors.lastname: Larsson
authors.affiliation: Division of Clinical Geriatrics, Centre for Alzheimer Research, Department of Neurobiology Care Sciences and Society, Karolinska Institutet, Stockholm, 14157, Sweden.
authors.forename: Lars-Olof
authors.initials: LO
authors.lastname: Wahlund
authors.affiliation: Division of Clinical Geriatrics, Centre for Alzheimer Research, Department of Neurobiology Care Sciences and Society, Karolinska Institutet, Stockholm, 14157, Sweden.|NIHR Biomedical Research Centre for Mental Health, London, SE58AF, United Kingdom.|NIHR Biomedical Research Unit for Dementia, London, SE58AF, United Kingdom.|Institute of Psychiatry, King's College London, London, SE58AF, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Simmons
authors.affiliation: Division of Clinical Geriatrics, Centre for Alzheimer Research, Department of Neurobiology Care Sciences and Society, Karolinska Institutet, Stockholm, 14157, Sweden.|Institute of Psychiatry, King's College London, London, SE58AF, United Kingdom.
authors.forename: Eric
authors.initials: E
authors.lastname: Westman
mesh_terms: D015331:Cohort Studies; D006624:Hippocampus / Q000033:anatomy & histology*; D006801:Humans; D009929:Organ Size
keywords: Alzheimer's disease; aging; hippocampal volume; magnetic resonance imaging; multicohort