Klotho protein levels linked to Alzheimer's, cognitive decline, amyloid and tau burden

Klotho protein levels in cerebrospinal fluid and plasma were associated with clinical stages of Alzheimer’s disease, cognitive decline, and amyloid and tau burden, independent of KL-VS heterozygosity status, according to research.

Heterozygosity of the KL-VS haplotype has been associated with reduced amyloid and tau burden, but whether this association is mediated by the Klotho protein was not known, Gøril Rolfseng Grøntvedt, MD, of the University Hospital of Trondheim in Norway, and colleagues wrote in JAMA Network Open.

Grøntvedt and colleagues sought to assess concentrations of Klotho protein in CSF and plasma in patients with AD and healthy controls and understand the link between KL-VS heterozygosity status and amyloid and tau burden.

They conducted a case-control study that included 243 participants, of whom 117 were controls (38.5% men; median age, 65 years), 102 had mild cognitive impairment from AD (57.8% men; median age, 66 years), and 24 had AD-related dementia (50% men; median age, 64.5 years). Researchers measured Klotho levels in CSF and plasma and determined KL-VS heterozygosity status and amyloid-beta 42, total tau and phosphorylated tau levels.

According to results, median Klotho levels in CSF were higher in controls (1236.4 pg/mL; beta = 0.103; 95% CI, 0.023-0.183) and in patients with mild cognitive impairment (1188.1 pg/mL; beta = 0.095; 95% CI, 0.018-0.172) compared with patients with dementia (1073.3 pg/mL).

In addition, higher levels of CSF Klotho were linked to lower amyloid-beta 42 (beta = 0.519; 95% CI, 0.201-0.836) and tau burdens (total tau levels: beta = –0.884; 95% CI, 0.223 to –0.395; phosphorylated tau: beta = –0.672; 95% CI, –1.022 to –0.321). These findings were independent of clinical status, KL-VS heterozygosity or APOE4 status.

“The findings of this case-control study suggest that Klotho protein levels were associated with clinical stages of AD, cognitive decline, and amyloid and tau burden and that these outcomes were more clearly mediated by the protein directly rather than the KL-VS heterozygosity variant,” Grøntvedt and colleagues wrote. “When selecting individuals at risk for clinical trials, the Klotho protein level and not only the genetic profile should be considered.”