Associations between reproductive history, hormone use, APOE ε4 genotype and cognition in middle- to older-aged women from the UK Biobank

Linn R S Lindseth; Ann-Marie G de Lange; Dennis van der Meer; Ingrid Agartz; Lars T Westlye; Christian K Tamnes; Claudia Barth

doi:10.3389/fnagi.2022.1014605

Associations between reproductive history, hormone use, APOE ε4 genotype and cognition in middle- to older-aged women from the UK Biobank

Front Aging Neurosci. 2023 Jan 19:14:1014605. doi: 10.3389/fnagi.2022.1014605. eCollection 2022.

Authors

Linn R S Lindseth¹, Ann-Marie G de Lange^{2

3

4}, Dennis van der Meer^{1

5}, Ingrid Agartz^{1

6

7}, Lars T Westlye^{3

8}, Christian K Tamnes^{6

8

9}, Claudia Barth^{1

6}

Affiliations

¹ NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
² LREN, Department of Clinical Neurosciences, Centre for Research in Neurosciences, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland.
³ Department of Psychology, University of Oslo, Oslo, Norway.
⁴ Department of Psychiatry, University of Oxford, Oxford, United Kingdom.
⁵ School of Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, Netherlands.
⁶ Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway.
⁷ Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm Health Care Services, Karolinska Institute, Stockholm County Council, Stockholm, Sweden.
⁸ NORMENT, Division of Mental Health and Addiction, Oslo University Hospital, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁹ Department of Psychology, PROMENTA Research Center, University of Oslo, Oslo, Norway.

Abstract

Introduction: Relative to men, women are at a higher risk of developing age-related neurocognitive disorders including Alzheimer's disease. While women's health has historically been understudied, emerging evidence suggests that reproductive life events such as pregnancy and hormone use may influence women's cognition later in life.

Methods: We investigated the associations between reproductive history, exogenous hormone use, apolipoprotein (APOE) ε4 genotype and cognition in 221,124 middle- to older-aged (mean age 56.2 ± 8.0 years) women from the UK Biobank. Performance on six cognitive tasks was assessed, covering four cognitive domains: episodic visual memory, numeric working memory, processing speed, and executive function.

Results: A longer reproductive span, older age at menopause, older age at first and last birth, and use of hormonal contraceptives were positively associated with cognitive performance later in life. Number of live births, hysterectomy without oophorectomy and use of hormone therapy showed mixed findings, with task-specific positive and negative associations. Effect sizes were generally small (Cohen's d < 0.1). While APOE ε4 genotype was associated with reduced processing speed and executive functioning, in a dose-dependent manner, it did not influence the observed associations between female-specific factors and cognition.

Discussion: Our findings support previous evidence of associations between a broad range of female-specific factors and cognition. The positive association between a history of hormonal contraceptive use and cognition later in life showed the largest effect sizes (max. d = 0.1). More research targeting the long-term effects of female-specific factors on cognition and age-related neurocognitive disorders including Alzheimer's disease is crucial for a better understanding of women's brain health and to support women's health care.

Keywords: big data; cognition; hormonal contraceptives; hormone therapy; population-based; pregnancy; women’s health.

Grants and funding

MC_PC_17228/MRC_/Medical Research Council/United Kingdom