Cognitively normal carriers of the apolipoprotein E epsilon-4 (APOE4) allele aged 60 years and older who also showed heterozygosity for the Klotho-VS allele had a significantly reduced risk of developing Alzheimer’s disease, according to data from 22 research groups including more than 20,000 adults.
The transmembrane protein known as klotho (KL) is part of a functional haplotype known as KL-VS. “Specifically, heterozygosity for KL-VS (KL-VSHET+ status) has been shown to increase serum levels of KL and exert protective effects on healthy aging and longevity when compared with individuals who are homozygotes for the major or minor alleles (KL-VSHET−),” wrote Michael E. Belloy, PhD, of Stanford (Calif.) University and colleagues. However, the possible role of KL-VS in protecting against neurodegenerative disorders such as Alzheimer’s disease (AD) remains unclear, they said.
In a study published in JAMA Neurology, the researchers reviewed data from 20,928 participants in case-control studies, as well as 3,008 participants in conversion studies, 556 in amyloid-beta (a-beta) cerebrospinal fluid regression analyses, and 251 in brain amyloid PET regression analyses. The participants were aged 60-80 years, and of non-Hispanic northern European ancestry and were identified as cognitively normal or having mild cognitive impairment (MCI) or AD.
Overall, individuals with the APOE4 allele who were cognitively normal and heterozygous for KL-VS had a significantly reduced risk for developing AD (odds ratio, 0.75).
In addition, cognitively normal carriers of APOE4 with KL-VS heterozygosity had significantly lower risk of developing either MCI or AD (hazard ratio, 0.64). Also, those persons with APOE4 and positive KL-VS heterozygosity had higher a-beta in cerebrospinal fluid (P = .03) and lower a-beta on PET scans (P = .04). However, no association with cognitive outcomes were noted among APOE4 noncarriers, the researchers noted.
“This suggests that KL-VS interacts with aspects of AD pathology that are more pronounced in those who carry APOE4, such as a-beta accumulation during the presymptomatic phases of the disease,” they said.
The study findings were limited by the variable age and diagnoses across the multiple cohorts, but strengthened by the meta- and mega-analyses and sensitivity analyses that yielded consistent results, the researchers noted.
“Our work paves the way for biological validation studies to elucidate the molecular pathways by which KL-VS and APOE interact,” they said.
“The specificity of KL-VS benefits on AD in individuals who carry APOE4 is striking and suggests a yet-unstudied interaction between biological pathways of the klotho and APOE4 proteins,” wrote Dena B. Dubal, MD, and Jennifer S. Yokoyama, PhD, of the University of California, San Francisco, in an accompanying editorial. Despite limitations, the study findings have implications for clinical neurology, as well as clinical and translational research, they said.
“For personalized genomics, KL-VS status should integrate into knowledge that both lifestyle and genetics can negate or at least mitigate harmful influences of APOE4,” they noted. “In light of this, we might consider an individual’s KLOTHO genotype when counseling individuals who carry APOE4 about their prognosis for AD. In clinical trials using APOE4 for trial enrichment, further selection of individuals who carry APOE4 without KL-VS could define a population more likely to convert to AD and thus increase detection of a therapeutic benefit. In translational research, understanding how klotho itself or its biological pathways may counter APOE4 could lead to monumental progress in the future treatment of AD,” they added.
“Applying our growing knowledge of klotho to APOE4 and AD could ultimately pave the path to novel therapeutics for individuals who carry APOE4,” they concluded.
The study was supported by the Iqbal Farrukh & Asad Jamal Center for Cognitive Health in Aging, the South Palm Beach County Foundation, and the National Institutes of Health. The researchers had no financial conflicts to disclose. Dr. Dubal disclosed holding a patent for Methods for Improving Cognition that includes klotho, as well as consulting for Unity Biotechnology and receiving research funding from the National Institutes of Health, the American Federation for Aging Research, Glenn Medical Foundation, Unity Biotechnology, and other philanthropic support for translational research. Dr. Yokoyama disclosed research funding from the National Institutes of Health, the Department of Defense, and other foundations and philanthropic donors.
SOURCE: Belloy ME et al. JAMA Neurol. 2020 Apr 13. doi: 10.1001/jamaneurol.2020.0414.