Abstract
INTRODUCTION
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]).
METHODS
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).
RESULTS
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
.
DISCUSSION
Higher levels of neuroinflammation, neurodegeneration, and synaptic dysfunction in older adults were attenuated in KL-VSHET.
Highlights
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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This post is Copyright: Ira Frahmand Driscoll,
Sarah Lose,
Yue Ma,
Barbara B. Bendlin,
Catherine Gallagher,
Sterling C. Johnson,
Sanjay Asthana,
Bruce Hermann,
Mark A. Sager,
Kaj Blennow,
Henrik Zetterberg,
Cynthia Carlsson,
Gwendlyn Kollmorgen,
Clara Quijano‐Rubio,
Dena Dubal,
Ozioma C. Okonkwo | June 22, 2024