Sex, amyloid, and APOE ε4 and risk of cognitive decline in preclinical Alzheimer's disease: Findings from three well-characterized cohorts

Rachel F Buckley¹, Elizabeth C Mormino², Rebecca E Amariglio³, Michael J Properzi⁴, Jennifer S Rabin⁵, Yen Ying Lim⁶, Kathryn V Papp³, Heidi I L Jacobs⁷, Samantha Burnham⁸, Bernard J Hanseeuw⁹, Vincent Doré¹⁰, Annette Dobson¹¹, Colin L Masters⁶, Michael Waller¹¹, Christopher C Rowe¹², Paul Maruff¹³, Michael C Donohue¹⁴, Dorene M Rentz³, Dylan Kirn³, Trey Hedden¹⁵, Jasmeer Chhatwal⁴, Aaron P Schultz³, Keith A Johnson¹⁵, Victor L Villemagne¹², Reisa A Sperling³; Alzheimer's Disease Neuroimaging Initiative; Australian Imaging, Biomarker and Lifestyle study of ageing; Harvard Aging Brain Study

Affiliations

¹ The Florey Institute, The University of Melbourne, Victoria, Australia; Melbourne School of Psychological Science, University of Melbourne, Victoria, Australia; Harvard Aging Brain Study, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA. Electronic address: rfbuckley@mgh.harvard.edu.
² Department of Neurology, Stanford University, CA, USA.
³ Harvard Aging Brain Study, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
⁴ Harvard Aging Brain Study, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁵ Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁶ The Florey Institute, The University of Melbourne, Victoria, Australia.
⁷ Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA; Faculty of Health, Medicine and Life Sciences, School for Mental Health and Neuroscience, Alzheimer Centre Limburg, Maastricht University, Maastricht, The Netherlands.
⁸ The Australian eHealth Research Centre, CSIRO Health & Biosecurity, Victoria, Australia.
⁹ Harvard Aging Brain Study, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA; Department of Neurology, Cliniques Universitaires Saint-Luc, Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium.
¹⁰ The Australian eHealth Research Centre, CSIRO Health & Biosecurity, Queensland, Australia.
¹¹ The University of Queensland, School of Public Health, Faculty of Medicine, Queensland, Australia.
¹² Department of Nuclear Medicine and Centre for PET, Austin Health, Victoria, Australia; Department of Medicine, Austin Health, The University of Melbourne, Victoria, Australia.
¹³ Cogstate, Ltd., Australia.
¹⁴ Department of Neurology, University of Southern California, San Diego, CA, USA.
¹⁵ Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.

PMID: 29803541
PMCID: PMC6131023
DOI: 10.1016/j.jalz.2018.04.010

Sex, amyloid, and APOE ε4 and risk of cognitive decline in preclinical Alzheimer's disease: Findings from three well-characterized cohorts

Rachel F Buckley et al. Alzheimers Dement. 2018 Sep.

. 2018 Sep;14(9):1193-1203.

doi: 10.1016/j.jalz.2018.04.010. Epub 2018 May 24.

Authors

Affiliations

¹ The Florey Institute, The University of Melbourne, Victoria, Australia; Melbourne School of Psychological Science, University of Melbourne, Victoria, Australia; Harvard Aging Brain Study, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA. Electronic address: rfbuckley@mgh.harvard.edu.
² Department of Neurology, Stanford University, CA, USA.
³ Harvard Aging Brain Study, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
⁴ Harvard Aging Brain Study, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁵ Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁶ The Florey Institute, The University of Melbourne, Victoria, Australia.
⁷ Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA; Faculty of Health, Medicine and Life Sciences, School for Mental Health and Neuroscience, Alzheimer Centre Limburg, Maastricht University, Maastricht, The Netherlands.
⁸ The Australian eHealth Research Centre, CSIRO Health & Biosecurity, Victoria, Australia.
⁹ Harvard Aging Brain Study, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA; Department of Neurology, Cliniques Universitaires Saint-Luc, Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium.
¹⁰ The Australian eHealth Research Centre, CSIRO Health & Biosecurity, Queensland, Australia.
¹¹ The University of Queensland, School of Public Health, Faculty of Medicine, Queensland, Australia.
¹² Department of Nuclear Medicine and Centre for PET, Austin Health, Victoria, Australia; Department of Medicine, Austin Health, The University of Melbourne, Victoria, Australia.
¹³ Cogstate, Ltd., Australia.
¹⁴ Department of Neurology, University of Southern California, San Diego, CA, USA.
¹⁵ Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.

PMID: 29803541
PMCID: PMC6131023
DOI: 10.1016/j.jalz.2018.04.010

Abstract

Introduction: Our objective was to investigate the effect of sex on cognitive decline within the context of amyloid β (Aβ) burden and apolipoprotein E genotype.

Methods: We analyzed sex-specific effects on Aβ-positron emission tomography, apolipoprotein, and rates of change on the Preclinical Alzheimer Cognitive Composite-5 across three cohorts, such as the Alzheimer's Disease Neuroimaging Initiative, Australian Imaging, Biomarker and Lifestyle, and Harvard Aging Brain Study (n = 755; clinical dementia rating = 0; age (standard deviation) = 73.6 (6.5); female = 55%). Mixed-effects models of cognitive change by sex, Aβ-positron emission tomography, and apolipoprotein ε4 were examined with quadratic time effects over a median of 4 years of follow-up.

Results: Apolipoprotein ε4 prevalence and Aβ burden did not differ by sex. Sex did not directly influence cognitive decline. Females with higher Aβ exhibited faster decline than males. Post hoc contrasts suggested that females who were Aβ and apolipoprotein ε4 positive declined faster than their male counterparts.

Discussion: Although Aβ did not differ by sex, cognitive decline was greater in females with higher Aβ. Our findings suggest that sex may play a modifying role on risk of Alzheimer's disease-related cognitive decline.

Keywords: APOE; Amyloid; Cognitive decline; Gender; Preclinical Alzheimer's disease; Sex.

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Figures

**Figure 1**
(A) Females and males display equal proportions of *APOEε*4 carrier status and (B) Aβ burden. (C) Represents decline in global cognition (as measured by the PACC-5) by Aβ and sex. These are model estimates from a *continuous* model of Aβ; high and low Aβ are represented by the first quartile (on the left) and third quartile (on the right) of Aβ along the continuous spectrum. Each line extends to the longest follow-up period within that group.

**Figure 2**
Decline in global cognition (as measured by the PACC-5) by Aβ and sex across the age span (females = pink, males = blue). These are model estimates from a *continuous* model of Aβ; high and low Aβ is represented by the first quartile (on the top) and third quartiles (on the bottom) of Aβ along the continuous spectrum. Age is also treated continuously in the model, with this visualization showing model estimates at the following ages: 65, 70, 75, 80, 85 years. Each line extends to the longest follow-up period within that group.

**Figure 3**
Decline in global cognition (as measured by the PACC-5) by *APOEε*4 status, sex and Aβ status (see legend for colours). These are model estimates from a factorial model with Aβ status represented by cut-off 1.082. Each line extends to the longest follow-up period within that group.

See this image and copyright information in PMC

References

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Sex, amyloid, and APOE ε4 and risk of cognitive decline in preclinical Alzheimer's disease: Findings from three well-characterized cohorts

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Sex, amyloid, and APOE ε4 and risk of cognitive decline in preclinical Alzheimer's disease: Findings from three well-characterized cohorts

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