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Hippocampus. 2017 Jun;27(6):653-667. doi: 10.1002/hipo.22721. Epub 2017 Apr 10.

The interactive effect of demographic and clinical factors on hippocampal volume: A multicohort study on 1958 cognitively normal individuals.

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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.
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.
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.
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.
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.
Institute of Gerontology and Geriatrics, University of Perugia, Perugia, 06100, Italy.
INSERM U 558, University of Toulouse, Toulouse, 31024, France.
3rd Department of Neurology, Aristoteleion Panepistimeion Thessalonikis, Thessaloniki, 54124, Greece.
Medical University of Lodz, Lodz, 92216, Poland.
University of Eastern Finland and Kuopio University Hospital, Kuopio, 70211, Finland.
Department of Psychiatry, Warneford Hospital University of Oxford, Oxford, OX37JX, United Kingdom.
Department of Surgical Sciences, Radiology, Uppsala University, Uppsala, 75185, Sweden.
Department of Medical Sciences, Uppsala University, Uppsala, 75185, 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.


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.


Alzheimer's disease; aging; hippocampal volume; magnetic resonance imaging; multicohort

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