KLOTHO heterozygosity attenuates APOE4 -related amyloid burden in preclinical AD

Abstract

ObjectiveTo examine whether the KLOTHO gene variant KL-VS attenuates APOE4-associated β-amyloid (Aβ) accumulation in a late-middle-aged cohort enriched with Alzheimer disease (AD) risk factors.MethodsThree hundred nine late-middle-aged adults from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center were genotyped to determine KL-VS and APOE4 status and underwent CSF sampling (n = 238) and/or 11C-Pittsburgh compound B (PiB)-PET imaging (n = 183). Covariate-adjusted regression analyses were used to investigate whether APOE4 exerted expected effects on Aβ burden. Follow-up regression analyses stratified by KL-VS genotype (i.e., noncarrier vs heterozygous; there were no homozygous individuals) evaluated whether the influence of APOE4 on Aβ was different among KL-VS heterozygotes compared to noncarriers.ResultsAPOE4 carriers exhibited greater Aβ burden than APOE4-negative participants. This effect was stronger in CSF (t = −5.12, p < 0.001) compared with PiB-PET (t = 3.93, p < 0.001). In the stratified analyses, this APOE4 effect on Aβ load was recapitulated among KL-VS noncarriers (CSF: t = −5.09, p < 0.001; PiB-PET: t = 3.77, p < 0 .001). In contrast, among KL-VS heterozygotes, APOE4-positive individuals did not exhibit higher Aβ burden than APOE4-negative individuals (CSF: t = −1.03, p = 0.308; PiB-PET: t = 0.92, p = 0.363). These differential APOE4 effects remained after KL-VS heterozygotes and noncarriers were matched on age and sex.ConclusionIn a cohort of at-risk late-middle-aged adults, KL-VS heterozygosity was associated with an abatement of APOE4-associated Aβ aggregation, suggesting KL-VS heterozygosity confers protections against APOE4-linked pathways to disease onset in AD.

Deregulated expression of a longevity gene, Klotho, in the C9orf72 deletion mice with impaired synaptic plasticity and adult hippocampal neurogenesis

“…Thus, it is conceivable that ablation of C9orf72 alters the Klotho expression and affects Klotho-mediated regulation on synaptic plasticity. Importantly, polymorphisms in the KLOTHO gene (known as KL-VS variant) have been identified to associate with a longer lifespan [2], better cognition in human [12], and is protective for the APOE4 carriers in Alzheimer's disease [3,13]. In the context of ALS, overexpressing Klotho was beneficial in protecting neuronal loss in a SOD1 mouse model [42].…”

Variation at the Klotho gene locus does not affect cognitive function in up to 335,074 British Caucasians in the UK Biobank

“…In particular, the participants are generally healthier than average (21). There is evidence to suggest that the effect of KL variants on cognitive function/decline may be as a result of affecting the severity of a pre-existing psychopathology (22,23) and individuals suffering from early dementia, etc. would be either unlikely or even unable to volunteer to participate.…”

Association of a single nucleotide polymorphism combination pattern of the Klotho gene with non-cardiovascular death in patients with chronic kidney disease

“…According to the National Centre for Biotechnology Information, Klotho contains >11 000 SNPs [ 27 ]. Most of the genetic studies on Klotho have focused on the KL-VS polymorphisms located in exon 2 (name due to the F352V change of rs9536314 and C370S from rs9527025), which are related to human longevity [ 28 ], cognition [ 29 ], neuroprotection [ 30 ] and occult coronary artery disease [ 31 ]. The rs1207568 (G395A) SNP located at the promoter region has also been widely studied and has been associated with coronary artery disease [ 32 ], metabolic syndrome [ 33 ], kidney stones [ 34 ], mortality in dialysis [ 35 ] and immunoglobulin A nephropathy [ 36 ].…”