Relationship of sex differences in cortical thickness and memory among cognitively healthy subjects and individuals with mild cognitive impairment and Alzheimer disease

Filippo Cieri,Xiaowei Zhuang,Jeffery Cummings,Jessica Caldwell,Dietmar Cordes,Nikki Kaplan

doi:10.1186/s13195-022-00973-1

Abstract

BackgroundAn aging society has increased rates of late onset Alzheimer disease dementia (ADD), the most common form of age-related dementia. This neurodegenerative disease disproportionately affects women.MethodsWe use data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to examine sex differences in cortical thickness (CT) and memory performance. Analyses of covariance (ANCOVA) models were used to examine effects of sex and diagnosis (DX) on CT and verbal memory. For regions demonstrating significant interaction effects of sex and DX, we tested whether sex moderated cognition-thickness relationships. We used machine learning as a complementary method to explore multivariate CT differences between women and men.ResultsWomen demonstrated greater CT in many brain regions. More specifically, men showed relatively consistent CT declines in all stages, from normal control (NC) to ADD in the bilateral cingulate cortex, bilateral temporal regions, and left precuneus; women had more stable CT in these regions between NC and mild cognitive impairment (MCI) stages, but sharper declines from MCI to ADD. Similarly, for the Rey Auditory Verbal Learning Test (RAVLT), ANCOVA analyses showed that women had significantly better immediate and delayed recall scores than men, at NC and MCI stages, but greater differences, cross-sectionally, from MCI to ADD than men. We found significant sex moderation effects between RAVLT-immediate scores and CT of right isthmus-cingulate for all subjects across DX. Partial correlation analyses revealed that increased CT of right isthmus-cingulate was associated with better verbal learning in women, driven by positron emission tomography defined amyloid positive (Aβ+) subjects. Significant sex-moderation effects in cognition-thickness relationships were further found in the right middle-temporal, left precuneus, and left superior temporal regions in Aβ+ subjects. Using a machine learning approach, we investigated multivariate CT differences between women and men, showing an accuracy in classification of 75% for Aβ+ cognitively NC participants.ConclusionsSex differences in memory and CT can play a key role in the different vulnerability and progression of ADD in women compared to men. Machine learning indicates sex differences in CT are most relevant early in the ADD neurodegeneration.

Highlights

An aging society has increased rates of late onset Alzheimer disease dementia (ADD), the most common form of age-related dementia
Handedness and ApoE genotypes are matched between men and women in normal control (NC), mild cognitive impairment (MCI), and ADD subjects (Table 1)
Men are more highly educated than women, as years of education are significantly higher in men than women in NC (p

Summary

Introduction

An aging society has increased rates of late onset Alzheimer disease dementia (ADD), the most common form of age-related dementia. The investigation of sex differences has a long tradition in neuropsychology and cognitive neuroscience This pursuit is important given different vulnerabilities by sex in incidence, symptomatology, and progression of many neurological and psychiatric diseases. Work by our group and others has shown that cognitively normal women have a verbal memory advantage over men [13, 14] that persists in the presence of brain amyloid [1, 2, 4] and mild to moderate ADD pathological burden such as volume loss and brain hypometabolism [14,15,16] It is unclear whether sex differences in brain structure or atrophy over time account for this pattern of women’s advantage followed by accelerated decline in memory between the MCI and the ADD stages

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