Sex Differences in Dementia and Mild Cognitive Impairment in Nondialysis CKD

KEY POINTS: In Systolic Blood Pressure Intervention Trial Memory and Cognition in Decreased Hypertension, men with CKD had a higher risk of dementia than women, whereas no sex differences were observed among participants without CKD. In the physiologic study, men with CKD exhibited greater cerebrovascular stiffness, slower processing speed, and worse executive function versus women. Men with nondialysis CKD may have higher dementia risk than women, potentially associated with greater cerebrovascular stiffness. BACKGROUND: Women face higher risk of dementia than men in the general population, with some studies also reporting female sex is associated with higher dementia risk in patients receiving hemodialysis. However, it is unclear whether this sex-specific pattern extends to nondialysis CKD, in whom the pathophysiology of cognitive impairment may differ due to the absence of dialysis-related factors. Accordingly, we examined sex differences in older adults with and without nondialysis CKD, who participated in Systolic Blood Pressure Intervention Trial Memory and Cognition in Decreased Hypertension (SPRINT MIND). Using pooled data from our clinical studies, we further explored mechanisms underlying sex-specific cognitive decline by cross-sectionally comparing cerebrovascular and cognitive measures between sexes, separately for adults with and without nondialysis CKD. METHODS: SPRINT MIND analyses used Cox proportional hazard models to compare sex differences in the risk of cognitive outcomes (probable dementia [PD], mild cognitive impairment, and their composite) in men and propensity score-matched women, separately for CKD and non-CKD. A total of 681 men with CKD were propensity score-matched to 681 women with CKD and 1253 men without CKD to 1253 women without CKD. In physiologic clinical study, including participants with CKD (81 men, 34 women) and without CKD (35 men, 64 women), we compared middle cerebral artery pulsatility index (MCA PI; measure of cerebrovascular stiffness assessed by transcranial Doppler) and cognitive function (trails A and B times) by sex, separately for CKD and non-CKD. RESULTS: In SPRINT MIND, men with CKD had higher risk of PD/mild cognitive impairment composite (hazard ratio, 1.49; 95% confidence interval, 1.10 to 2.02) and PD alone (hazard ratio, 1.98; 95% confidence interval, 1.23 to 3.17) than women, with no sex differences in non-CKD. In the physiologic clinical study, men with CKD exhibited higher MCA PI and slower trails A and B times than women, with no sex differences in non-CKD. Across all participants, lower eGFR was associated with greater MCA PI more strongly in men ( r =-0.34; P < 0.001) than women ( r =-0.23; P = 0.03) and with slower trails B time ( r =-0.22; P = 0.02) in men only. CONCLUSIONS: Men with nondialysis CKD may have higher dementia risk than women, potentially associated with greater cerebrovascular stiffness. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: NCT04040959 .