The Interaction between Ventricle to Brain Ratio and Serum Klotho on Cognition in Older Adults at Risk for Alzheimer’s Disease

Background Ventricle to brain volume ratio (VBR) may be associated with Alzheimer’s disease (AD) progression and is a robust correlate of cognition in AD. Klotho is a circulating protein positively associated with cognition. The purpose of this study was to evaluate whether serum klotho attenuates the adverse effect of higher VBR on cognition in older adults at risk for AD. Method This study included 359 cognitively unimpaired participants from the Wisconsin Alzheimer’s Disease Research Center and Wisconsin Registry for Alzheimer’s Prevention (mean age = 61.8 ± 6.5, 67% female). VBR was calculated from structural T1 MRI scans as the ratio of total ventricle volume to the sum of grey and white matter. Fasting venipuncture was conducted and analyzed for serum klotho. Neuropsychological examination was conducted for global cognition (PACC3) and composite scores were calculated for executive function, immediate learning, and delayed recall. Linear regression models were performed to assess the effect of VBR on cognition, accounting for APOE, gender, age, and time difference between MRI and serum klotho measurements. Next, models were fitted with an interaction for VBR x klotho. Follow‐up analyses, stratified by median age (63.2 years), assessed age‐specific effects. Result Higher VBR predicted poorer delayed recall (β(SE)=‐6.3(3.1); p=.043), but not global cognition (β(SE)=‐4.9(3.0); p=.101), executive function (β(SE)=‐4.4(3.3); p=.178), or immediate learning (β(SE)=‐4.4(3.3); p=.185). Significant VBR x klotho interactions existed for global cognition (p=.024) and executive function (p=.009) whereby higher serum klotho attenuated the adverse effect of VBR. This effect was absent for immediate learning (p=.162) and delayed recall (p=.267). Among older participants, VBR predicted worse global cognition (β=‐7.4; p=.055), executive function (B=‐8.8; p=.048), and nearly delayed recall (β=‐8.1; p=.061), but not for immediate learning (p=.521). There were no effects among younger individuals (all p’s ≥ .203). Lastly, the VBR x klotho interaction on executive function was significant among older participants (p=.037). Conclusion Serum klotho may protect against the adverse effect of high VBR on cognition, particularly among older individuals.