Having one copy of the Klotho (KL) gene with two missense variants (KL-VS) reduced the risk of Alzheimer’s disease (AD) in older adults who also carried APOE4, an analysis showed.
Klotho is a transmembrane protein hormone thought to promote longevity and a resilient nervous system. Two amino acid substitutions in the KL gene, F352V (V) and C370S (S), segregate together as KL-VS and alter cellular klotho secretion.
Heterozygosity for KL-VS in persons over 60 who were cognitively normal conferred an odds ratio for developing AD of 0.75 (95% CI 0.67-0.84, P = 7.4 × 10−7) compared with persons with any makeup other than KL-VS heterozygosity, including KL-VS homozygosity.
Cerebrospinal fluid (CSF) and PET imaging measure of amyloid beta (Aβ) burden also showed favorable trends in those with APOE4 who had one KL-VS copy.
“Molecular pathways associated with KL merit exploration for novel AD drug targets,” Michael Belloy, PhD, of Stanford University and coauthors wrote in JAMA Neurology. “The KL-VS genotype should be considered in conjunction with the APOE genotype to refine AD prediction models used in clinical trial enrichment and personalized genetic counseling.”
Mice deficient in klotho show premature aging. In humans, klotho levels decline from birth. The KL-VS variant, present in about 20% of humans, is thought to alter trafficking and activity of klotho and contribute to variability in human age-related phenotypes. Having one KL-VS copy increases circulating klotho protein levels, while two copies decreases it.
Prior work established an association between KL-VS and human right dorsolateral prefrontal cortex volume. Higher klotho levels have also been associated with greater functional connectivity in areas affected by AD degeneration in aging human adults.
Other results have been mixed though, showing survival and white matter disadvantages for heterozygotes, though a favorable cognitive trajectory and greater right frontal lobe volumes were also demonstrated.
The e4 allele of APOE confers a dose-dependent increased risk of late-onset AD. It is associated with Aβ accumulation in the brain, but decreased levels in CSF, particularly between the ages of 60 and 80 when Alzheimer’s risk is highest.
The concept of an Alzheimer’s-protective effect in KL-VS heterozygous persons who were cognitively normal has been studied in two smaller cohort studies. One found reduced Aβ burden in heterozygotes with APOE 4; the other that heterozygosity did not protect against cognitive decline regardless of APOE genotype.
Belloy and colleagues explored the question in a larger cohort by combining data from 25 studies. The team analyzed pooled data collected between September 2015 and September 2019 of 20,928 participants in case-control studies, 3,008 in conversion studies, 556 in Aβ CSF regression analyses, and 251 in Aβ PET regression analyses.
The reduction in AD risk for those with APOE4 and one copy of KL-VS was more prominent at ages 60 to 80 years (OR 0.69, 95% CI 0.61-0.79; P=3.6 × 10−8).
Heterozygotes for KL-VS with APOE4 were also at reduced risk for the combined outcome of converting to mild cognitive impairment (MCI) or Alzheimer’s disease (HR 0.64, 95% CI 0.44-0.94; P=0.02).
PET scans showed Aβ burden in the brain was reduced in people with APOE4 and KL-VS heterozygosity (β −0.04, 95% CI −0.07 to −0.00; P=0.04), while CSF showed higher Aβ levels (β 0.06, 95% CI 0.01-0.10; P=0.03).
In persons over age 80, no significant effects were seen. Age-at-onset analyses showed that KL-VS heterozygosity was associated with reduced risk of conversion to MCI or Alzheimer’s beginning around age 77 years in those carrying APOE4.
While the findings could reflect fundamental underlying biology, the authors noted that “null findings in the groups 80 years and older may, however, also be attributable to limited sample sizes in this age stratum.”
In an accompanying editorial, Dena Dubal, MD, PhD, and Jennifer Yokoyama, PhD, both of the University of California, San Francisco, wrote that “the Belloy et al meta-analysis provides strong evidence that individuals who carry APOE4 are not uniformly fated to develop AD and specifically establishes a protective role of KL-VS heterozygosity in the APOE4-AD risk.”
“This work is important because it carries several implications for neurology, clinical trials, and translational research,” they continued. They noted applications in personalized genomics (including Klotho when counseling patients with APOE4), clinical trial research (selecting APOE4 carriers without KL-VS to define a population more likely to convert to AD), and translational research (understanding how klotho affects APOE4 may lead to progress in Alzheimer’s treatment).
“When and how the benefits of KL-VS heterozygosity counter lifelong risks associated with APOE4 remain to be determined,” Dubal and Yokoyama observed. If klotho levels do turn out to matter, “we may outwit our genetics through exercise, which increases klotho, and decreased chronic stress, which decreases it,” they added.
Limitations include variability in age and diagnosis ascertainment across cohorts. In addition, inclusion of only northwestern Europeans (to avoid population confounding) limits generalizability of the results. Klotho levels were not measured in serum or CSF.
- Heterozygosity for Klotho (KL) gene with two missense variants (KL-VS) reduced the risk of Alzheimer’s disease in adults 60 to 80 years old who carried the high-risk APOE4 allele.
- Having one copy of KL-VS increases the level of klotho protein, but two copies reduce it.
Paul Smyth, MD, Contributing Writer, BreakingMED™
Funding for this study was provided by the Iqbal Farrukh & Asad Jamal Center for Cognitive Health in Aging, The South Palm Beach County Foundation, and the NIH.
Researchers were part of the Alzheimer’s Disease Neuroimaging Initiative (ADNI).
Dubal has consulted for Unity Biotechnology and reports funding for her research from the National Institutes of Health, the American Federation for Aging Research, Glenn Medical Foundation, Unity Biotechnology, and philanthropic support for translational research from the Bakar, Coulter-Weeks, Bradley, and Godsoe families; in addition, she holds a patent for Methods for Improving Cognition that includes the subject matter of klotho filed by the Regents of the University of California and issued.
Yokoyama reports funding for her research from the National Institutes of Health, the Department of Defense, the Rainwater Charitable Foundation, the French Foundation, and philanthropic support for clinical research from the Slavik family and an anonymous donor (as part of the Parkinson’s Spectrum Disorders Center).
Cat ID: 130
Topic ID: 82,130,404,494,730,130,33,361,192,925
Belloy ME, Napolioni V, Han SS, Le Guen Y, Greicius MD, for the Alzheimer’s Disease Neuroimaging Initiative “Association of Klotho-VS heterozygosity with risk of Alzheimer disease in individuals who carry APOE4″ JAMA Neurol 2020; Published online April 13 DOI: 10.1001/jamaneurol.2020.0414.
Dubal DB, Yokoyama JS “Longevity gene KLOTHO and Alzheimer disease—A better fate for individuals who carry APOE ε4″ JAMA Neurol 2020; Published online April 13 DOI: 10.1001/jamaneurol.2020.0112.