| 1. |
- Driscoll, Ira, et al.
(author)
-
AD-associated CSF biomolecular changes are attenuated in KL-VS heterozygotes.
- 2022
-
In: Alzheimer's & dementia (Amsterdam, Netherlands). - : Wiley. - 2352-8729. ; 14:1
-
Journal article (peer-reviewed)abstract
- 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.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.Memory and executive function declined (p's ≤ 0.001) and CSF t-tau, p-tau, t-tau/Aβ42, and p-tau/Aβ42 levels increased (all p's ≤ 0.004) with age. The rate of p-tau accumulation was attenuated for KL-VS heterozygotes (p = 0.03).KL-VS heterozygosity may confer resilience to AD-associated biomolecular changes.
|
|
| 3. |
- Driscoll, Ira Frahmand, et al.
(author)
-
KLOTHO KL-VS heterozygosity is associated with diminished age-related neuroinflammation, neurodegeneration, and synaptic dysfunction in older cognitively unimpaired adults
- 2024
-
In: ALZHEIMERS & DEMENTIA. - 1552-5260 .- 1552-5279.
-
Journal article (peer-reviewed)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 alpha-synuclein [alpha-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 alpha-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.
|
|
