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April 24, 2020 – The klotho gene is named after the fanciful Greek goddess of destiny Clotho who turns the string of life known to be related with longer life and improved cognizance. In modern biology, allelic variants of the klotho gene in fact have been associated with long life span. Klotho seems also related to a defensive capacity against psychological debilitations and Alzheimer’s disease (AD) in people conveying variants of the APOE4 gene that predispose individuals to a higher risk for the development of AD, a recent study from Stanford University, published online April 13 in JAMA. Neurology, has found.
Individuals who are heterozygous (i.e., they are carrying one copy out of two) for a particular klotho allelic variant known as klotho-VS, estimated to be about 25% of the population, produce increased serum levels of the klotho protein, which is associated with protective effects on healthy aging and longevity compared with those with no or two (i.e., being homozygous for this variant) klotho-VS alleles. Previous observational studies indicated that patients carrying certain forms of the APOE4 gene were at heightened genetic susceptibility for development of dementia along with heightened susceptibility to the detrimental effects of various lifestyle-related risk factors, mostly because of varying degrees of amyloid bild-up in the brain (i.e., cerebrum). As recently as 2019 it was found that people carrying the APOE4 gene who had a heterozygous klotho-VS status had less amyloid in the cerebrum.
These observations led to the questions if patients with a heterozygous klotho-VS status could be protected from developing neurodegenerative diseases, such as AD, for example, and whether patients who are known to carr the APOE4 gene could be candidates for remedy of their future danger of development of AD by boosting pathways identified to dependent of klotho.
In an attempt to answer at least some of the aspects of these questions, the authors of the present study investigated 25 datasets of people with hereditary data accessible on the APOE4 and klotho genotypes. Thus, the researchers analyzed these independent datasets from case-control, family-based, and longitudinal Alzheimer’s cohorts. The risk of developing mild cognitive impairment or Alzheimer’s was evaluated through competing risks regression under a case-control design. Associations with beta-amyloid, measured from cerebrospinal fluid (CSF) or brain positron emission tomography (PET), were evaluated using linear regression and mixed-effects modeling.
Participants were men and women aged 60 years and older who were non-Hispanic and of Northwestern European ancestry and had been diagnosed as being cognitively normal or having mild cognitive impairment or Alzheimer’s. The sample included 20,928 participants in case-control studies, 3008 in conversion studies, 556 in beta-amyloid CSF regression analyses, and 251 in PET regression analyses. Results showed that individuals who were heterozygous for the klotho-VS gene had a reduced risk for Alzheimer’s in those carrying APOE4 (odds ratio [OR], 0.75; 95% confidence interval [CI], 0.67 – 0.84) among the whole population aged over 60 years. This was more prominent in those aged 60 to 80 years (OR, 0.69; 95% CI, 0.61 – 0.79). In addition, control participants carrying APOE4 with klotho-VS heterozygosity were at reduced risk of converting to mild cognitive impairment or Alzheimer’s (hazard ratio, 0.64; 95% CI, 0.44 – 0.94). Further, in control participants who carried APOE4 and were aged 60 to 80 years, klotho-VS heterozygosity was associated with higher beta-amyloid in CSF (correlating to lower levels in the brain) and lower beta-amyloid on PET scans.
In contrast, however, klotho-VS status had no association with outcome in individuals who did not carry APOE4 .
The outcomes of this research are intriguing and propose new pathways for Alzheimer’s exploration. For the moment, these outcomes will help with guiding individuals who are known to carry the APOE4 gene in therapeutic approaches. The research also opens new questions as to why a few people with the APOE4 gene never develop AD and whether heterozygosity in klotho-VS status could be the crucial determent in these clinical phenotype.
See a short sequence on some molecular events around amyloid in AD-affected brains which may be influenced by klotho-VS status: