Abstract
AbstractBackgroundWomen have higher prevalence and risk for developing Alzheimer’s disease (AD) than men. The reason(s) underlying this sex difference in AD has not been definitively established but has been theorized to reflect sex‐specific patterns in age‐related depletion of sex steroid hormones, primarily the loss of estrogens in women. Not well considered is the possible role of developmental actions of sex steroids, which drive sexual differentiation of the brain. We investigated the hypothesis that early life differences in sex hormone exposure yield a female brain that is inherently more vulnerable to AD and related dementias.MethodRelative group differences in prenatal sex steroid hormone exposure were indirectly assessed by the ratio of the index (2nd digit) and ring (4th digit) fingers (2D:4D). The subjects were a community sample of non‐demented and demented men (N=66; 31 non‐demented, 35 demented) and women (N=73; 39 non‐demented, 34 demented) aged >65 years. Subjects’ right hands were scanned, finger length determined by caliper measurement, and 2D:4D calculated. Data were analyzed by two‐way ANOVA with sex and dementia status as the variables.ResultThere were no significant differences in age between men (age range: 65‐97 years; mean age=82.8 years) and women (age range: 65‐104 years; mean age=84.5). Men had a significantly lower mean 2D:4D than women (0.948 versus 0.964; p=0.006), which is expected since relatively higher androgen exposure in utero has been linked with lower 2D:4D. Among men, there was no significant difference in 2D:4D between non‐demented and demented subjects (0.954 versus 0.943; p=0.57). Importantly, women with dementia showed a significantly higher 2D:4D than non‐demented women (0.979 versus 0.951; p=0.005).ConclusionThe data demonstrate a higher (more feminine) 2D:4D in women with dementia in comparison to non‐demented women. Similar effects were not observed in men. These results suggest that developmental events that yield relatively more feminine phenotypes increase vulnerability of women to dementia. The findings support the hypothesis that the female bias in AD risk is due in part to developmental sex differences. (Support: RF1AG058068 [NIH] and SAGA‐17‐419408 [Alzheimer’s Association].)
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