Plasma Klotho and Cognitive Decline in Older Adults: Findings From the InCHIANTI Study

Background: The hormone klotho, encoded by the gene klotho, is primarily expressed in the kidney and choroid plexus of the brain. Higher klotho concentrations and certain genetic variants of klotho have been linked to better cognition; however, it is unknown whether klotho relates prospectively to slower cognitive decline in older adults. Methods: Plasma klotho was measured in 833 participants aged 55 or older without dementia enrolled in InCHIANTI, a prospective cohort study comprising Italian adults. Cognition was measured by Mini-Mental State Examination (MMSE) and Trail-Making Tests A and B (Trails A and Trails B) at enrollment and at 3 and 6 years after enrollment. We assessed whether klotho concentrations measured at the 3-year visit related to cognition and cognitive decline. Results: Each additional natural logarithm of klotho (pg/mL) was associated with 35% lower risk of meaningful decline in MMSE, defined as decline exceeding three points (relative risk = 0.65; 95% confidence interval 0.45, 0.95; p value = .02), and 0.75-point smaller average 3-year decline (baseline to 3-year visit) in MMSE (95% confidence interval 0.02, 1.48; p value = .04). No statistically significant associations were found between klotho and declining Trails A (relative risk = 0.99; 95% confidence interval 0.75, 1.32; p value = .97) and B (relative risk = 1.02; 95% confidence interval 0.84, 1.24; p value = .82). Conclusions: Higher plasma klotho concentrations were associated with lower risk of meaningful decline and smaller average decline in MMSE. We did not observe such findings with Trails A and B, perhaps because they test executive function and motor skills, whereas MMSE measures global cognition. Future studies should investigate mechanisms through which klotho may affect domain-specific cognitive changes.