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Review
. 2024 Aug;20(8):5695-5719.
doi: 10.1002/alz.13844. Epub 2024 Jul 5.

Sex and gender differences in cognitive resilience to aging and Alzheimer's disease

Eider M Arenaza-Urquijo  1   2 , Rory Boyle  3 , Kaitlin Casaletto  4 , Kaarin J Anstey  5   6   7 , Clara Vila-Castelar  3 , Aaron Colverson  8 , Eleni Palpatzis  1   2 , Jaclyn M Eissman  9   10 , Ted Kheng Siang Ng  11 , Sheelakumari Raghavan  12 , Muge Akinci  1   2 , Jet M J Vonk  4 , Luiza S Machado  13 , Preeti P Zanwar  14   15 , Hom L Shrestha  16 , Maude Wagner  17 , Stefano Tamburin  18 , Hamid R Sohrabi  19   20 , Samantha Loi  21   22 , David Bartrés-Faz  23   24   25 , Dena B Dubal  26   27 , Prashanthi Vemuri  12 , Ozioma Okonkwo  28 , Timothy J Hohman  9   10 , Michael Ewers  29   30 , Rachel F Buckley  3 ; Reserve, Resilience and Protective Factors Professional Interest Area, Sex and Gender Professional Interest area and the ADDRESS! Special Interest Group
Affiliations
Review

Sex and gender differences in cognitive resilience to aging and Alzheimer's disease

Eider M Arenaza-Urquijo et al. Alzheimers Dement. 2024 Aug.

Abstract

Sex and gender-biological and social constructs-significantly impact the prevalence of protective and risk factors, influencing the burden of Alzheimer's disease (AD; amyloid beta and tau) and other pathologies (e.g., cerebrovascular disease) which ultimately shape cognitive trajectories. Understanding the interplay of these factors is central to understanding resilience and resistance mechanisms explaining maintained cognitive function and reduced pathology accumulation in aging and AD. In this narrative review, the ADDRESS! Special Interest Group (Alzheimer's Association) adopted a multidisciplinary approach to provide the foundations and recommendations for future research into sex- and gender-specific drivers of resilience, including a sex/gender-oriented review of risk factors, genetics, AD and non-AD pathologies, brain structure and function, and animal research. We urge the field to adopt a sex/gender-aware approach to resilience to advance our understanding of the intricate interplay of biological and social determinants and consider sex/gender-specific resilience throughout disease stages. HIGHLIGHTS: Sex differences in resilience to cognitive decline vary by age and cognitive status. Initial evidence supports sex-specific distinctions in brain pathology. Findings suggest sex differences in the impact of pathology on cognition. There is a sex-specific change in resilience in the transition to clinical stages. Gender and sex factors warrant study: modifiable, immune, inflammatory, and vascular.

Keywords: TDP43; brain maintenance; cardiovascular; cognitive decline; cognitive reserve; education; genetics; inequalities; lifestyle.

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Conflict of interest statement

E.M.A.U. has nothing to disclose. R.B has nothing to disclose. K.C. has nothing to disclose. M.A. has nothing to disclose. E.P. has nothing to disclose. M.E. has nothing to disclose. C.V.‐C. has nothing to disclose. M.W. has nothing to disclose. L.M. has nothing to disclose. J.M.J.V. has nothing to disclose. S.K. has nothing to disclose. T.K.S.N. has nothing to disclose. J.M.E. has nothing to disclose. H.S. has nothing to disclose. P.V. has nothing to disclose. S.T. has nothing to disclose. L.S.Z. has nothing to disclose. K.A. received honorarium from Roche for a lecture and funding from the National Health and Medical Research Council and the Australian Research Council. T.J.H. sits on the scientific advisory board for Vivid Genomics and is a senior associate editor for Alzheimer's & Dementia. O.O. has received consulting fees from Mayo Clinic Rochester and IUPUI and holds a fiduciary role in the International Neuropsychological Society (Board Member). S.L. has received honorarium from Otsuka and Lundbeck. D.B.‐F. serves as a member of the Scientific Advisory Council for Linus Health. D.B.D. is an associate editor for JAMA Neurology, serves on the Board of the Glenn Foundation for Medical Research, and has consulted for Unity Biotechnology and SV Health Investors. H.Sohrabi is a non‐executive Director of SMarT Minds WA, Australia. He has been or is receiving personal reimbursements or research support from the Australian Alzheimer's Research Foundation and Pharmaceutical and Nutraceutical companies including Alector, Alnylam Pharmaceuticals, CWEK PTY LTD (WA, Australia), and Biogen pharmaceuticals. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
Illustration of resilience and resistance frameworks considering sex and gender effects and associated factors. Sex‐ and gender‐related protective factors may act through increasing resistance and resilience to ultimately impact cognitive resilience. We are providing examples of sex‐ and gender‐related factors shown to have an impact on pathologies, brain structure and function, or cognitive decline. APOE, apolipoprotein; TDP43, Tar DNA‐binding protein; WMH, white matter hyperintensities
FIGURE 2
FIGURE 2
Hypothetical models explaining sex differences in memory throughout aging and disease. A, Initial memory advance provides cognitive resilience through aging (differences in level but not slope). B, Sex differences in memory may vary at different stages of the aging process. The discontinuous line in the 60s to 80s period for men illustrates the conflicting findings. C, The initial memory advantage in women diminishes over time: women cope with AD pathology for longer until they experience a faster decline (differences in level and slope). D, Diagnosis bias due to the differences in baseline memory performance. The red line in C and D illustrates the onset of AD pathology.
FIGURE 3
FIGURE 3
Illustration of the hypothesized sex differences in cognitive and brain resilience to amyloid burden and brain atrophy. A, Cognitive resilience to hippocampal atrophy: women show better memory function and maintained memory performance despite hippocampal atrophy, until a certain threshold is reached, beyond which women show accelerated cognitive decline compared to men. B, Cognitive resilience to amyloid: women show greater cognitive resilience to initial amyloid accumulation evidenced by superior memory performance compared to men at similar levels of amyloid deposition. However, this advantage fades away at higher amyloid levels leading to faster cognitive decline in women. C, There is greater brain resilience to amyloid burden in women evidenced by a smaller effect of amyloid on hippocampal volume compared to men at lower levels of amyloid. This trend reverses at higher levels of amyloid burden, leading to a greater effect on hippocampal volume in women. The red background in the despicted scatterplots indicates higher levels of hippocampal atrophy or amyloid burden.
FIGURE 4
FIGURE 4
Illustration of the effects of APOE ε4 on the amyloid cascade. Sex effects are observed downstream amyloid. Illustration of the available evidence showing no sex‐specific genetic drivers of amyloidosis but different effects of APOE ε4 in tau (lowering resistance in women) and cognition (lowering cognitive resilience in women compared to men). The magnitudes of the arrows are indicative of effect sizes, with larger arrows representing larger effects. APOE: apolipoprotein E
FIGURE 5
FIGURE 5
Illustration of how non‐AD pathologies may diminish brain resilience. Non‐AD pathologies are considered together with AD pathologies and risk factors (left box, red) as variables that may have a negative impact on brain resilience, while protective factors may have a positive effect (left box, green). The figure considers that sex/gender may have an effect on each box and in the relation between them. AD, Alzheimer's disease; CVD, cardiovascular disease; HS, hippocampal sclerosis; LBD, Lewy body disease; TDP43, Tar DNA‐binding protein 43
See this image and copyright information in PMC

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