AD-associated CSF biomolecular changes are attenuated in KL-VS heterozygotes

Abstract

Introduction: Dementia as an inevitable aging consequence has been challenged and underscores the need for investigations of the factors that confer resilience. We examine whether the functionally advantageous KL-VS variant of the putative aging suppressor KLOTHO gene attenuates age-related cognitive decline and deleterious biomolecular changes. Methods: Trajectories of change in memory and executive function (N = 360; 2–12 visits) and cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers—amyloid beta (Aβ)42, total tau (t-tau), phosphorylated tau (p-tau) (N = 112; 2–4 samplings)—were compared between KL-VS non-carriers and heterozygotes in middle-aged and older adults from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center studies. Results: Memory and executive function declined (p’s (Formula presented.) 0.001) and CSF t-tau, p-tau, t-tau/Aβ42, and p-tau/Aβ42 levels increased (all p’s (Formula presented.) 0.004) with age. The rate of p-tau accumulation was attenuated for KL-VS heterozygotes (p = 0.03). Discussion: KL-VS heterozygosity may confer resilience to AD-associated biomolecular changes.