Alzheimer’s and Longevity Genes: Are They Connected?

A lifespan-extending variant of the human KLOTHO gene attenuated beta-amyloid (Aβ) accumulation associated with the APOE4 genotype, researchers found.

Among a group of people at risk for Alzheimer’s disease, those who were APOE4-positive and heterozygous carriers of the KLOTHO KL-VS gene variant showed no higher Aβ burden than those who were APOE4-negative, reported Ozioma Okonkwo, PhD, of the University of Wisconsin School of Medicine and Public Health, Madison, and colleagues, in Neurology.

These findings “may point to a novel pathway by which KLOTHO exerts its influence on age-related disease,” noted Argonde van Harten, MD, PhD, of VU University Medical Center in Amsterdam, in a commentary accompanying the research.

“They show that KL-VS may protect against the detrimental effect of the APOE e4 genotype on in vivo evidence of amyloidosis in cognitively unimpaired persons with an average age of 61 years,” van Harten wrote.

The APOE4 gene confers the greatest genetic risk for developing Alzheimer’s disease. “Alzheimer’s disease is one of our biggest biomedical challenges, currently without effective therapies,” said study co-author Dena Dubal, MD, PhD, of the University of California, San Francisco, who previously studied klotho protein levels in humans and mice.

“These findings are important because they establish a protective genetic link between longevity factor klotho and deleterious factor APOE4, and suggest that klotho could block or attenuate APOE4 toxicity,” Dubal told MedPage Today. “That’s big.”

“Since KL-VS heterozygosity leads to higher levels of circulating klotho in humans, and elevating klotho causes brain enhancement and resilience in animal models of Alzheimer’s, one wonders whether klotho could lead us to an effective treatment for this devastating disease,” she added. “If so, could carriers of APOE4 be treated preventatively with klotho therapy even before Alzheimer’s develops? The implications of this study are far reaching.”

Early research showed that mice who did not have the klotho gene aged and died prematurely; when the gene was over-expressed in mice, they lived longer. In humans, the KLOTHO variant KL-VS is associated with extreme longevity. Recent research by Dubal and colleagues demonstrated that KL-VS elevated klotho levels and was associated with enhanced cognition in humans, and that elevated klotho in mice enhanced normal cognition, independent of age.

In this study, Okonkwo and colleagues studied 309 late-middle-age adults from the Wisconsin Registry for Alzheimer’s Prevention and the Wisconsin Alzheimer’s Disease Research Center who underwent cerebrospinal fluid (CSF) sampling (n=238) and/or 11C-Pittsburgh compound B (PiB)-PET imaging (n=183).

The group had an average age of about 61, and 69% were women. About 41% of participants were APOE4 carriers, and 73% had a parental history of dementia. No participants were KL-VS homozygotes (as expected, considering the allele frequency), and KL-VS heterozygotes represented 27% of the sample.

Overall, APOE4 carriers showed a greater Aβ burden than APOE4-negative participants, and this effect was stronger in CSF (t = −5.12, P<0.001) than PiB-PET (t = 3.93, P<0.001). In stratified analyses, this APOE4 effect on Aβ load was seen in KL-VS non-carriers (CSF: t = −5.09, P<0.001; PiB-PET: t = 3.77, P<0.001).

Among KL-VS heterozygotes, however, APOE4-positive individuals did not exhibit higher Aβ burden than APOE4-negative individuals (CSF: t=−1.03, P=0.308; PiB-PET: t=0.92, P=0.363). These APOE4 effects remained after KL-VS heterozygotes and non-carriers were matched on age and sex.

The most important limitation of the study is its small number of KL-VS heterozygotes (62 in the CSF sample and 45 in the PiB-PET sample), observed van Harten.

“In addition, there may be issues of generalizability; the sample consists of a group that is at increased risk of developing Alzheimer’s disease and is largely white. This means that replication of these findings in larger, more diverse cohorts is warranted,” she added, noting that future studies also should look at interactions with sex because KLOTHO may have sex-specific effects.

“Still, the current results are promising,” she said. “They open up the field for myriad other questions, ranging from those related to the reason why KL-VS is able to attenuate the effect of APOE e4 on amyloidosis to those related to the holy grail in Alzheimer’s disease research: could KLOTHO eventually turn out to be a therapeutic target?”