Age-Related Tau Burden and Cognitive Deficits Are Attenuated in KLOTHO KL-VS Heterozygotes.

Background Identification of new genetic variants that modify Alzheimer's disease (AD) risk will elucidate novel targets for curbing the disease progression or delaying symptom onset. Objective To examine whether the functionally advantageous KLOTHO gene KL-VS variant attenuates age-related alteration in cerebrospinal fluid (CSF) biomarkers or cognitive function in middle-aged and older adults enriched for AD risk. Methods Sample included non-demented adults (N = 225, mean age = 63±8, 68% women) from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center who were genotyped for KL-VS, underwent CSF sampling and had neuropsychological testing data available proximal to CSF draw. Covariate-adjusted multivariate regression examined relationships between age group (Younger versus Older; mean split at 63 years), AD biomarkers, and neuropsychological performance tapping memory and executive function, and whether these relationships differed between KL-VS non-carriers (KL-VSNC) and heterozygote (KL-VSHET). Results In the pooled analyses, older age was associated with higher levels of total tau (tTau), phosphorylated tau (pTau), and their respective ratios to amyloid-β (Aβ)42 (ps ≤ 0.002), and with poorer performance on neuropsychological tests (ps ≤ 0.001). In the stratified analyses, KL-VSNC exhibited this age-related pattern of associations with CSF biomarkers (all ps ≤ 0.001), and memory and executive function (ps ≤ 0.003), which were attenuated in KL-VSHET (ps≥0.14). Conclusion Worse memory and executive function, and higher tau burden with age were attenuated in carriers of a functionally advantageous KLOTHO variant. KL-VS heterozygosity seems to be protective against age-related cognitive and biomolecular alterations that confer risk for AD.