Longevity Gene Linked to Reduced AD Risk in APOE4 Carriers

April 20, 2020

A certain form of the longevity gene, klotho, is associated with a protective effect against cognitive impairments and Alzheimer's disease (AD) in individuals carrying the APOE4 gene that predisposes to a higher AD risk, a new study has found.

"These results are very exciting and suggest a new pathway for Alzheimer's research," lead author Michael E. Belloy, PhD, Stanford University, California, told Medscape Medical News

"In the short term, these results will help with counseling people who are known to be carrying the APOE4 gene and assessing their future risk of developing Alzheimer's, but there could also be therapeutic possibilities based on boosting pathways related to klotho," he added. 

The study was published online April 13 in JAMA Neurology.

The klotho gene, named after the mythological Greek goddess of fate, who spins the "thread of life," is known to be associated with longer life and enhanced cognition. 

Belloy explained that individuals who are heterozygous for a particular klotho genotype 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 zero or two klotho-VS alleles.

But until now it has remained unclear if heterozygous klotho-VS status also provides protection against aging-associated neurodegenerative disorders, such as Alzheimer's disease.

In 2019, a study was reported in individuals carrying the APOE4 gene in which those who had heterozygous klotho-VS status had less amyloid in the brain.

"There is still so much we don't know about the genetics of Alzheimer's, including why some people with the APOE4 gene never develop Alzheimer's. There may be something else protecting these individuals and we wondered whether this could be the klotho-VS gene," Belloy said.  

To try and answer this question, he and his team analyzed 25 datasets of individuals with genetic information available on the APOE4 and klotho genotypes.

"Our main finding is heterozygous klotho-VS status reduced the risk of developing cognitive impairments and Alzheimer's disease in those who were carrying the APOE4 gene but did not have any effect in those who did not have the APOE4 gene," Belloy reported.  

He said it was not understood why there was a different effect of klotho-VS on those positive and negative for APOE4, but he offered some possibilities

"The most pathological effect of APOE4 is to increase beta-amyloid in the brain and as klotho-VS gene has been shown to reduce beta-amyloid in the brain it would be reasonable to assume it would be particularly effective in the APOE4 patients," he suggested.  

"There is also the idea that the increased lifespan associated with the klotho-VS gene counterbalances the reduction in lifespan linked to APOE4," he added. 

He said the next step will be to replicate these findings in other datasets and learn more about how the APOE4 and klotho-VS genotypes are interacting.

For the current study, the researchers analyzed data from 25 independent 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.

However, klotho-VS status had no association with outcome in individuals who did not carry APOE4 .

"Overall, our findings suggest that heterozygous klotho-VS status, possibly by increasing systemic klotho levels, is associated with a protective outcome against Alzheimer's disease that manifests in participants who carry APOE4 and are cognitively normal between the ages of 60 and 80 years," the researchers conclude.

"Our work paves the way for biological validation studies to elucidate the molecular pathways by which klotho-VS and APOE interact. Information on klotho-VS status should also prove useful in further refinement of genetic risk profiles for both clinical trial enrichment and personalized genetic counseling," they add.

In an accompanying editorial, Dena B. Dubal, MD, and Jennifer S. Yokoyama, PhD, University of California, San Francisco, note that the APOE4 allele is the strongest genetic risk factor for Alzheimer's disease, and occurs in approximately 23% of the US population.  

One copy of the allele increases risk of developing Alzheimer's by threefold; two copies increases it by more than 12-fold. APOE4 also increases the likelihood of cognitive decline in patients with other neurologic disorders, elderly people who are clinically normal, and even patients with head trauma as putatively mild as heading a ball in soccer, they report.

The editorialists say the current study "provides strong evidence that individuals who carry APOE4 are not uniformly fated to develop Alzheimer's disease and specifically establishes a protective role of klotho-VS heterozygosity in the APOE4-Alzheimer's disease risk."

"This work is important because it carries several implications for neurology, clinical trials, and translational research," they state.

"Monumental Progress"

Dubal and Yokoyama suggest that individual's klotho genotype could be considered when counseling individuals who carry APOE4 about their prognosis for Alzheimer's; in clinical trials, selection of individuals who carry APOE4 without klotho-VS could define a population more likely to convert to Alzheimer's and thus increase detection of a therapeutic benefit; and understanding how klotho itself or its biological pathways may counter APOE4 could lead to "monumental progress" in the future treatment of Alzheimer's.

"Furthermore, if levels of the klotho hormone matter, we may outwit our genetics through exercise, which increases klotho, and decreased chronic stress, which decreases it," they propose. "The klotho hormone itself could represent a new treatment. Applying our growing knowledge of klotho to APOE4 and Alzheimer's disease could ultimately pave the path to novel therapeutics for individuals who carry APOE4."

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 National Institutes of Health. Belloy has disclosed no relevant financial relationships. Dubal holds a patent for "Methods for Improving Cognition" that includes the subject matter of klotho. 

JAMA Neurol. Published online April 13, 2020. Abstract, Editorial

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