Abstract Body (Do not enter title and authors here): Background: There are sex differences in the effect of age at onset (AO) of hypertension onbrain structural changes later in life. This may differentially affect long-term cognition through cerebral smallvessel disease (CSVD) in females and males. However, whether and how the association between age ofhypertension diagnosis contributes to sex differences in cognitive decline related to CVSD later in life remainsunclear.
Objective: Our objective was to examine sex differences in cognition in relation to brain structural changesexacerbated by CSVD caused by younger AO of hypertension.
Methods: We used data from the UK Biobank to select participants with a known age of hypertensiondiagnosis who also had neuropsychological test scores for cognitive functions affected by CSVD i.e., memoryand executive function (n= 6095). We stratified data by sex and AO at baseline (2006-2010). Controlparticipants who did not have hypertension were chosen at random using propensity score matching. Principalcomponents analysis (PCA) was used to reduce the number of CSVD related cognitive function tests(measured at 2014 follow-up). We selected participants >65 years of age at the time of cognitive function teststo determine cognitive function later in life. This was followed by a sex disaggregated regression analysis totest for the effect of AO on cognitive functions identified from the PCA in females and males.
Results: Our main outcomes were cognitive function tests in the domains of memory (working and visual-spatial) and executive function/processing speed. When compared to normotensive controls, cognitiveoutcomes differed by sex and age of hypertension diagnosis. Whereas females diagnosed at middle age (45-54 years) had worse outcomes in the working memory domain compared to controls, males diagnosed at olderage (>65 years) had worse outcomes compared to controls. Only females diagnosed with hypertension ateither younger age (< 35 years) or older age (>65 years) had worse outcomes in the executive visualdeclarative memory domain. We did not see any differences in the processing speed/executive functiondomain in either males or females.
Conclusions: This study demonstrates distinctive characteristics of CSVD-related cognitive decline in malesand females based on the age of hypertension onset. Therefore, CSVD is a critical pathophysiologicalmechanism for sex differences in cognitive decline and may aid in identification of novel sex-specific therapy.