KLOTHO KL-VS heterozygosity is associated with diminished age-related neuroinflammation, neurodegeneration, and synaptic dysfunction in older cognitively unimpaired adults.

Ira Frahmand Driscoll,Mark A Sager,Sterling C Johnson,Dena Dubal,Henrik Zetterberg,Cynthia Carlsson,Sarah Lose,Sanjay Asthana,Henrik Zetterberg,Kaj Blennow,Cynthia Carlsson,Kaj Blennow,Bruce Hermann,Gwendlyn Kollmorgen,Kaj Blennow,Sterling C Johnson,Barbara B Bendlin,Ozioma C Okonkwo,Henrik Zetterberg,Catherine Gallagher,Henrik Zetterberg,Barbara B Bendlin,Catherine Gallagher,Mark A Sager,Cynthia Carlsson,Yue Ma,Bruce Hermann,Ozioma C Okonkwo,Sanjay Asthana,Henrik Zetterberg,Barbara B Bendlin,Kaj Blennow,Ozioma C Okonkwo,Sanjay Asthana,Clara Quijano‐Rubio,Bruce Hermann

doi:10.1002/alz.13912

Abstract

We examined whether the aging suppressor KLOTHO gene's functionally advantageous KL-VS variant (KL-VS heterozygosity [KL-VSHET]) confers resilience against deleterious effects of aging indexed by cerebrospinal fluid (CSF) biomarkers of neuroinflammation (interleukin-6 [IL-6], S100 calcium-binding protein B [S100B], triggering receptor expressed on myeloid cells [sTREM2], chitinase-3-like protein 1 [YKL-40], glial fibrillary acidic protein [GFAP]), neurodegeneration (total α-synuclein [α-Syn], neurofilament light chain protein), and synaptic dysfunction (neurogranin [Ng]). This Alzheimer disease risk-enriched cohort consisted of 454 cognitively unimpaired adults (Mage=61.5±7.75). Covariate-adjusted multivariate regression examined relationships between age (mean-split[age ≥ 62]) and CSF biomarkers (Roche/NeuroToolKit), and whether they differed between KL-VSHET (N=122) and non-carriers (KL-VSNC; N=332). Older age was associated with a poorer biomarker profile across all analytes (Ps ≤ 0.03). In age-stratified analyses, KL-VSNC exhibited this same pattern (Ps ≤ 0.05) which was not significant for IL-6, S100B, Ng, and α-Syn (Ps ≥ 0.13) in KL-VSHET. Although age-related differences in GFAP, sTREM2, and YKL-40 were evident for both groups (Ps ≤ 0.01), the effect magnitude was markedly stronger for KL-VSNC. Higher levels of neuroinflammation, neurodegeneration, and synaptic dysfunction in older adults were attenuated in KL-VSHET. Older age was associated with poorer profiles across all cerebrospinal fluid biomarkers of neuroinflammation, neurodegeneration, and synaptic dysfunction. KLOTHO KL-VS non-carriers exhibit this same pattern, which is does not significantly differ between younger and older KL-VS heterozygotes for interleukin-6, S100 calcium-binding protein B, neurogranin, and total α-synuclein. Although age-related differences in glial fibrillary acidic protein, triggering receptor expressed on myeloid cells, and chitinase-3-like protein 1 are evident for both KL-VS groups, the magnitude of the effect is markedly stronger for KL-VS non-carriers. Higher levels of neuroinflammation, neurodegeneration, and synaptic dysfunction in older adults are attenuated in KL-VS heterozygotes.

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