APOE4 Carriers With Longevity-Gene Variant Have Lower Alzheimer Risk

The risk of developing Alzheimer disease among people who carry the genetic risk factor apolipoprotein E4 (APOE4) appears to be lower in those who are also heterozygous for the Klotho functional haplotype known as Klotho-VS, according to results from a case-control study.

The Klotho protein is a longevity factor that is thought to reduce aging-associated phenotypes and cognitive decline. Heterozygosity for Klotho-VS increases serum levels of Klotho and exerts protective effects on healthy aging and longevity when compared with homozygosity for the major or minor alleles of Klotho-VS. Whether it also protects against aging-associated neurodegenerative disorders has been unclear.

"Our findings suggest that genetic testing for Klotho-VS will allow better prediction of Alzheimer's disease risk in APOE4-carrying subjects, which in turn will improve genetic risk counseling and help drug companies decide which subjects to recruit in their clinical trials," said Dr. Michael E. Belloy of Stanford University, in California.

"Because Klotho-VS genotype has been reported to correlate with levels of Klotho in serum and cerebrospinal fluid, Klotho levels may also become useable as a biomarker to help clinicians counsel patients at risk for Alzheimer disease," he told Reuters Health by email.

Dr. Belloy and colleagues in the Alzheimer's Disease Neuroimaging Initiative investigated the possible association of Klotho-VS heterozygosity and Alzheimer disease risk in their study of 22 late-onset Alzheimer disease cohorts with genotype data.

Klotho-VS heterozygosity was associated with 25% lower odds of Alzheimer disease in participants who carried APOE4, a significant reduction, but there was no association between Klotho-VS heterozygosity and Alzheimer disease risk in any APOE4-negative group, the researchers report in JAMA Neurology.

Even the association between Klotho-VS heterozygosity and decreased Alzheimer disease risk was apparent only in the group aged 60 to 80 years, with no association in the group 80 years and older.

Klotho-VS heterozygosity in participants who carried APOE4 was also associated with significantly reduced risk of conversion from being cognitively normal to mild cognitive impairment (MCI) or Alzheimer disease. Again, reduced conversion risk was not apparent among participants who were APOE4-negative.

Among participants aged 60 to 80 years, Klotho-VS heterozygosity was associated with significantly lower amyloid-beta burden on PET scan, but only in those who were APOE4-positive.

"When counseling a patient at potential risk for cognitive decline and Alzheimer disease, it is likely relevant to factor in whether they carry APOE4 or not," Dr. Belloy said. "Our findings may help further fine-tune counseling patients about their APOE4-related risk for Alzheimer disease by also taking into account what is their Klotho-VS genotype status."

"Perhaps even, in the long run, investigating Klotho-related pathways may offer new targets to develop drugs for treating patients at risk of Alzheimer disease," he said.

Dr. Dena B. Dubal of the University of California, San Francisco, associate editor of JAMA Neurology, who co-authored a linked editorial, told Reuters Health by email, "Not all individuals that carry APOE4 are doomed for Alzheimer disease. Carrying the longevity gene Klotho variant thwarts the risk of Alzheimer risk in APOE4 carriers. We can also outwit our genetics and genetic risks through a healthy lifestyle that includes proper diet, exercise, and brain engagement."

"Since the 'protective' gene variant of Klotho leads to higher levels of the Klotho hormone in our bodies, and higher Klotho boosts brain health in model organisms, the study carries exciting implications for future therapies," she said. "Could treatment with the Klotho hormone itself, which declines in Alzheimer disease, be a new therapy for individuals that carry APOE4? Maybe Klotho, along with a healthy lifestyle, could be a particularly effective treatment for APOE4 carriers in staving off Alzheimer risk."

"More work down this path is needed; it could be really impactful," Dr. Dubal ventured.

The study had no commercial funding, and the authors report no conflicts of interest.

—Will Boggs MD

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