Sex‐ and age‐specific associations between cardiometabolic risk and white matter brain age in the UK Biobank cohort

Abstract

Cardiometabolic risk (CMR) factors are associated with accelerated brain aging and increased risk for sex‐dimorphic illnesses such as Alzheimer's disease (AD). Yet, it is unknown how CMRs interact with sex and apolipoprotein E‐ϵ4 (APOE4), a known genetic risk factor for AD, to influence brain age across different life stages. Using age prediction based on multi‐shell diffusion‐weighted imaging data in 21,308 UK Biobank participants, we investigated whether associations between white matter Brain Age Gap (BAG) and body mass index (BMI), waist‐to‐hip ratio (WHR), body fat percentage (BF%), and APOE4 status varied (i) between males and females, (ii) according to age at menopause in females, and (iii) across different age groups in males and females. We report sex differences in associations between BAG and all three CMRs, with stronger positive associations among males compared to females. Independent of APOE4 status, higher BAG (older brain age relative to chronological age) was associated with greater BMI, WHR, and BF% in males, whereas in females, higher BAG was associated with greater WHR, but not BMI and BF%. These divergent associations were most prominent within the oldest group of females (66–81 years), where greater BF% was linked to lower BAG. Earlier menopause transition was associated with higher BAG, but no interactions were found with CMRs. In conclusion, the findings point to sex‐ and age‐specific associations between CMRs and brain age. Incorporating sex as a factor of interest in studies addressing CMR may promote sex‐specific precision medicine, consequently improving health care for both males and females.

Associations between abdominal adipose tissue, reproductive span, and brain characteristics in post-menopausal women

“…The associations between abdominal adipose tissue and brain characteristics are consistent with previous studies linking elevated adipose tissue to older brain age ( Beck et al, 2022 , Subramaniapillai et al, 2022 ), lower brain volume ( Cho et al, 2021 , Debette and Markus, 2010 , Gurholt et al, 2021 , Isaac et al, 2011 , Veit et al, 2014 ), and higher WMH load ( Arnoldussen et al, 2019 , Lampe et al, 2019 , Park et al, 2018 , Vuorinen et al, 2014 ). The relationships were more prominent for WMH volume compared to GM and WM BAG (about 3 standard deviations higher, see Fig.…”

“…Our results further indicated associations between a shorter reproductive span and higher GM/WM BAG and WMH volume independent of abdominal adipose tissue levels. Although these effects were not fully conclusive, the directions of the associations align with previous studies showing beneficial effects of a longer reproductive span on a number of brain health markers ( Georgakis et al, 2016 , Schelbaum et al, 2021 , Subramaniapillai et al, 2022 , Zeydan et al, 2019 ) and dementia risk ( Gong et al, 2022 ). In line with previous studies ( Day et al, 2015 , Day et al, 2017 , Zhao et al, 2021 ) we found an association between polygenic and phenotypic variance in reproductive span, but we found no notable associations between PGS, adipose tissue measures and brain measures, nor did PGS alter the interactions when included as a covariate.…”

“…The relationships between oestrogen exposure, body composition, and brain health in females are complex and largely unexplored. The menopause transition is linked to an accelerated increase of central fat accumulation ( Lizcano and Guzmán, 2014 ), and abdominal adipose tissue has been associated with higher grey matter (GM) and white matter (WM) brain age ( Beck et al, 2022 , Beck et al, 2022 , Subramaniapillai et al, 2022 ), WM hyperintensities (WMH) ( Arnoldussen et al, 2019 , Han et al, 2021 , Lampe et al, 2019 , Pasha et al, 2017 , Park et al, 2018 , Vuorinen et al, 2014 ), and dementia risk ( Kiliaan et al, 2014 , Tang et al, 2021 , Razay et al, 2006 , Whitmer et al, 2008 ). However, in females, adipose tissue also serves as the primary biosynthesis site of oestrogens post-menopause ( Steiner and Berry, 2022 , Bhardwaj et al, 2019 , Kershaw and Flier, 2004 , Siiteri, 1987 , Simpson, 2003 ).…”

“…However, in females, adipose tissue also serves as the primary biosynthesis site of oestrogens post-menopause ( Steiner and Berry, 2022 , Bhardwaj et al, 2019 , Kershaw and Flier, 2004 , Siiteri, 1987 , Simpson, 2003 ). Since oestradiol is consistently found to exert neuroprotective effects on the pre-menopausal female brain across preclinical and clinical studies ( Azcoitia et al, 2019 , Barth et al, 2016 , Galea et al, 2017 , Jacobs and Goldstein, 2018 , Merlo et al, 2017 , Scott et al, 2012 , Zárate et al, 2017 ), changes in adipose tissue distribution could also involve mechanisms that foster a protective source of oestrogens after menopause ( Klosinski et al, 2015 , Subramaniapillai et al, 2022 ). Although the oestrogen levels produced via adipose tissue do not fully compensate for the loss of ovarian oestrogen production ( Steiner and Berry, 2022 ), it is possible that different types of adipose tissue may play diverging roles in female brain health post-menopause.…”

“…In females, levels of oestrogen exposure pre-menopause may influence both brain health and body composition post-menopause, emphasising the complex interactions between neuroendocrine and metabolic processes across the female lifespan. For example, levels of cumulative oestrogen exposure, often assessed by reproductive span (age at menarche to age at menopause; ( Fu et al, 2022 , Gilsanz et al, 2019 , Jett et al, 2022 ), have been linked to larger GM volumes ( Schelbaum et al, 2021 ), lower WM brain age ( Subramaniapillai et al, 2022 ), and lower dementia risk in older-age samples ( Fox et al, 2013 , Gilsanz et al, 2019 , Gong et al, 2022 ), although contrasting results have linked a longer reproductive span to increased risk of Alzheimer’s disease ( Najar et al, 2020 , Geerlings et al, 2001 ). Age at menarche and menopause are also known to have genetic components ( Fernández-Rhodes et al, 2018 , Wang et al, 2019 , Ruth et al, 2021 ), but it is unclear how the genetics underlying reproductive span relate to body composition and brain structure ( Roa-Díaz et al, 2021 ).…”