Sex Differences in Cognitive Decline Among US Adults

Levine, Deborah A.; Gross, Alden L.; Briceño, Emily M.; Tilton, Nicholas; Giordani, Bruno; Sussman, Jeremy B.; Hayward, Rodney A.; Burke, James F.; Hingtgen, Stephanie; Elkind, Mitchell S.V.; Manly, Jennifer J.; Gottesman, Rebecca F.; Gaskin, Darrell J.; Sidney, Stephen; Sacco, Ralph L.; Tom, Sarah E.; Wright, Clinton B.; Yaffe, Kristine; Gałecki, Andrzej T.

doi:10.1001/jamanetworkopen.2021.0169

Cited by 193 publications

(172 citation statements)

References 67 publications

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“…For example, 14/17 old females exhibited VHIPP IL-6 levels that exceeded the mean value measured in old males. These data are in line with other studies indicating that neuroinflammation accumulates in the aged female hippocampus to a greater extent than males [ 57 ] and highlights a potential mechanism whereby females display faster age-related cognitive decline than men [ 81 ] and higher rates of Alzheimer’s disease [ 82 ]. It will be of interest to future studies to understand the basis for these augmented female responses.…”

Section: Discussionsupporting

confidence: 91%

Aging triggers an upregulation of a multitude of cytokines in the male and especially the female rodent hippocampus but more discrete changes in other brain regions

Porcher

Bruckmeier

Burbano

et al. 2021

J Neuroinflammation

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Background Despite widespread acceptance that neuroinflammation contributes to age-related cognitive decline, studies comparing protein expression of cytokines in the young versus old brains are surprisingly limited in terms of the number of cytokines and brain regions studied. Complicating matters, discrepancies abound—particularly for interleukin 6 (IL-6)—possibly due to differences in sex, species/strain, and/or the brain regions studied. Methods As such, we clarified how cytokine expression changes with age by using a Bioplex and Western blot to measure multiple cytokines across several brain regions of both sexes, using 2 mouse strains bred in-house as well as rats obtained from NIA. Parametric and nonparametric statistical tests were used as appropriate. Results In the ventral hippocampus of C57BL/6J mice, we found age-related increases in IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-6, IL-9, IL-10, IL-12p40, IL-12p70, IL-13, IL-17, eotaxin, G-CSF, interfeuron δ, KC, MIP-1a, MIP-1b, rantes, and TNFα that are generally more pronounced in females, but no age-related change in IL-5, MCP-1, or GM-CSF. We also find aging is uniquely associated with the emergence of a module (a.k.a. network) of 11 strongly intercorrelated cytokines, as well as an age-related shift from glycosylated to unglycosylated isoforms of IL-10 and IL-1β in the ventral hippocampus. Interestingly, age-related increases in extra-hippocampal cytokine expression are more discreet, with the prefrontal cortex, striatum, and cerebellum of male and female C57BL/6J mice demonstrating robust age-related increase in IL-6 expression but not IL-1β. Importantly, we found this widespread age-related increase in IL-6 also occurs in BALB/cJ mice and Brown Norway rats, demonstrating conservation across species and rearing environments. Conclusions Thus, age-related increases in cytokines are more pronounced in the hippocampus compared to other brain regions and can be more pronounced in females versus males depending on the brain region, genetic background, and cytokine examined.

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Section: Discussionsupporting

confidence: 91%

Aging triggers an upregulation of a multitude of cytokines in the male and especially the female rodent hippocampus but more discrete changes in other brain regions

Porcher

Bruckmeier

Burbano

et al. 2021

J Neuroinflammation

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“…These factors lead to a higher vascular risk and could be directly related to higher dementia cases in women in the long run (Zhong et al, 2015). Lastly, the sex differences noted in dementia are not really prominent until after the age of 80, and that is only consistent in studies done in the United States (Podcasy and Epperson, 2016;Levine et al, 2021). Other studies in Europe show a sex difference in VaD early on, indicating that the occurrence of VaD can be influenced by external factors (Hasselgren et al, 2020).…”

Section: Sex-specific Differences In Vadmentioning

confidence: 96%

Vascular Dementia and Underlying Sex Differences

Akhter

Persaud

Zaokari

et al. 2021

Front. Aging Neurosci.

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Vascular dementia (VaD) is the second most common form of dementia after Alzheimer’s disease (AD); where Alzheimer’s accounts for 60–70% of cases of dementia and VaD accounts for 20% of all dementia cases. VaD is defined as a reduced or lack of blood flow to the brain that causes dementia. VaD is also known occasionally as vascular contributions to cognitive impairment and dementia (VCID) or multi-infarct dementia (MID). VCID is the condition arising from stroke and other vascular brain injuries that cause significant changes to memory, thinking, and behavior, and VaD is the most severe stage while MID is produced by the synergistic effects caused by multiple mini strokes in the brain irrespective of specific location or volume. There are also subtle differences in the presentation of VaD in males and females, but they are often overlooked. Since 1672 when the first case of VaD was reported until now, sex and gender differences have had little to no research done when it comes to the umbrella term of dementia in general. This review summarizes the fundamentals of VaD followed by a focus on the differences between sex and gender when an individual is diagnosed. In addition, we provide critical evidence concerning sex and gender differences with a few of the main risk factors of VaD including pre-existing health conditions and family history, gene variants, aging, hormone fluctuations, and environmental risk factors. Additionally, the pharmaceutical treatments and possible mitigation of risk factors is explored.

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“…It is noteworthy that agerelated changes in cognition also differ by sex. For instance, a recent study has observed that while women had significantly higher baseline global memory, executive function, and memory performance than men, they showed significantly faster declines in the global memory and executive function (Levine et al, 2021). Another study found that older men had steeper rates of decline on measures of perceptuomotor speed and integration as well as visuospatial abilities (McCarrey et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Age- and Sex-Related Topological Organization of Human Brain Functional Networks and Their Relationship to Cognition

Foo

Thalamuthu

Jiang

et al. 2021

Front. Aging Neurosci.

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Age and sex associated with changes in the functional brain network topology and cognition in large population of older adults have been poorly understood. We explored this question further by examining differences in 11 resting-state graph theory measures with respect to age, sex, and their relationships with cognitive performance in 17,127 United Kingdom Biobank participants (mean = 62.83 ± 7.41 years). Age was associated with an overall decrease in the effectiveness of network communication (i.e., integration) and loss of functional specialization (i.e., segregation) of specific brain regions. Sex differences were also observed, with women showing more efficient networks, which were less segregated than in men (FDR adjusted p < 0.05). The age-related changes were also more apparent in men than in women, which suggests that men may be more vulnerable to cognitive decline with age. Interestingly, while network segregation and strength of limbic network were only nominally associated with cognitive performance, the network measures collectively were significantly associated with cognition (FDR adjusted p ≤ 0.002). This may imply that individual measures may be inadequate to capture much of the variance in the neural activity or its output and need further refinement. The complexity of the organization of the functional brain may be shaped by the age and sex of an individual, which ultimately may influence the cognitive performance of older adults. Age and sex stratification may be used to inform clinical neuroscience research to identify older adults at risk of cognitive dysfunction.

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Sex Differences in Cognitive Decline Among US Adults

Cited by 193 publications

References 67 publications

Aging triggers an upregulation of a multitude of cytokines in the male and especially the female rodent hippocampus but more discrete changes in other brain regions

Aging triggers an upregulation of a multitude of cytokines in the male and especially the female rodent hippocampus but more discrete changes in other brain regions

Vascular Dementia and Underlying Sex Differences

Age- and Sex-Related Topological Organization of Human Brain Functional Networks and Their Relationship to Cognition

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