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

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: see text] 0.001) and CSF t‐tau, p‐tau, t‐tau/Aβ42, and p‐tau/Aβ42 levels increased (all p’s [Formula: see text] 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.