A meta-analysis of 22 cohorts seems to leave little doubt that variants of the longevity gene klotho protect against dementia—at least in people unfortunate enough to have inherited an ApoE4 allele. Researchers led by Michael Belloy, Stanford University, calculated that cognitively normal APOE4 carriers who are heterozygous for the F352V/C370S klotho haplotype are 35 percent less likely to develop mild cognitive impairment or AD. Published April 13 in JAMA Neurology, the study also supports the idea that Klotho VS slows accumulation of Aβ in the brain. “[The] meta-analysis provides strong evidence that individuals who carry APOE4 are not uniformly fated to develop AD,” noted Dena Dubal and Jennifer Yokoyama, University of California, San Francisco, in an accompanying editorial.
- Analysis of more than 20,000 people says Klotho protects ApoE4 carriers.
- The gene’s VS haplotype docks their risk of AD by up to a third.
- Klotho VS associated with less amyloid burden in the brain.
APOE4 is the strongest genetic risk factor for sporadic, late-onset AD. Just recently, a separate paper in JAMA Neurology once again reinforced that ApoE4 genotype and family history of dementia were the principal determinants of amyloid pathology in healthy older people.
Klotho is named for the Greek goddesses who spins the threads of mythological life. The gene has puzzled scientists since it revealed itself to be involved in longevity in 1997. Its protein regulates biology in multiple organs, including the brain, where it seems to enhance learning and memory (May 2014 news). Klotho levels fall with age and in AD (Semba et al., 2014). Curiously, people who carry a single copy of the VS variant live longer than those with no or two copies (Arking et al., 2002). This is likely because heterozygotes have more klotho in their circulation. Higher levels have been tied not only to longevity but also to large cerebral cortex volume, strong functional connectivity, and better cognition (Yokoyama et al., 2015; Yokoyama et al., 2016; Dubal et al., 2014).
Last year, Dubal and colleagues reported that the VS haplotype associated with lower amyloid burden among 127 healthy ApoE4 carriers in a cohort of 309 middle-aged adults in Wisconsin (Erickson et al., 2019). In Michael Greicius’ lab at Stanford, Belloy and colleagues use big-data approaches to learn what protects ApoE4 carriers against dementia. They wondered if this klotho/AD association would hold up in a larger sample.
Belloy examined data from 22 cohorts comprising 36,530 research volunteers in observational aging and AD cohorts. Of those, 22,748 fit the inclusion criteria. They came from Alzheimer’s disease centers, ADNI, NIA, Mayo Clinic, ROSMAP, and Washington University studies, to name a few. Belloy ran case-control comparisons and correlated longitudinal outcomes with klotho genotype.
In the case-control analysis, 26 percent of 11,576 ApoE4-negative volunteers carried one copy of the klotho VS haplotype. This percentage was the same regardless of AD diagnosis, suggesting the klotho haplotype had no bearing on the AD risk of people without the E4 allele.
Among the 9,240 ApoE4 carriers, however, it was a different story. Twenty-nine percent of the cognitively normal among them carried the VS allele versus 25.3 percent of those diagnosed with AD. This worked out to a risk ratio of 0.75 for AD among ApoE4-positive klotho VS carriers. This association was mainly driven by people between age 60 and 80, for whom the odds ratio was 0.69.
To test how klotho might push back dementia, Belloy and colleagues examined longitudinal data from the ADC, ADNI, and ROSMAP cohorts. Among 1,997 cognitively normal APOE4 carriers, klotho VS heterozygotes had a hazard ratio of 0.64 for developing mild cognitive impairment or AD over a period of three years compared with klotho homozygotes. Over five years, their HR was 0.6. Comparing hazard ratios by age suggested that the protection begins to kick in around age 77 (see figure above).
In people who already had MCI, klotho VS seemed less protective. The hazard ratio for incident AD among those with MCI was 0.8 over three years, and 0.75 over five years. “This suggests that the protective nature of KL-VS HET+ status is stronger in control participants and diminishes in affected individuals who have already developed MCI,” the authors wrote.
How does the klotho variant protect? And why only in ApoE4 carriers? Belloy thinks this all ties in with amyloid burden. Similar to Dubal before, Belloy found that klotho VS came with higher CSF Aβ42, and lower uptake of amyloid PET tracers in accumulating regions, including parietal, temporal, frontal, and cingulate cortices. Belloy said klotho might protect ApoE4 carriers only because they are most at risk for amyloid deposition.
This would agree with newly published screening data from the A4 AD prevention trial. Writing in the April 6 JAMA Neurology, researchers led by Reisa Sperling at Brigham and Women’s Hospital, Boston, reported that among 4,486 volunteers aged 65 to 85, only ApoE4 genotype and a family history of dementia distinguished amyloid-positive from amyloid-negative participants. None of the other factors examined that are often associated with AD had any bearing on whether a person had amyloid in his or her brain. They included sex, level of education, marital status, and a range of lifestyle factors such as body mass index, physical activity, hours of sleep, alcohol and caffeine consumption, and tobacco use. “These risk factors for AD dementia may play a role in the vulnerability/resilience to cognitive decline in the setting of elevated Aβ rather than serving as a risk factor for Aβ accumulation itself,” Sperling and colleagues write.
Another reason why klotho VS may only protect ApoE4 carriers is because the latter is an anti-aging factor. “If you have ApoE4 you will likely not live as long,” said Belloy. He thinks klotho, being a longevity factor, might counteract that.
Both the aging and amyloid hypotheses need to be functionally validated, he said.
One approach would be to correlate Aβ and dementia with blood levels of klotho. Belloy said this was beyond the scope of the current study, something Dubal and Yokoyama lamented. “The lack of measurements of the klotho hormone itself from the serum or cerebrospinal fluid of individuals restricts interpretation of the findings, particularly since klotho levels might represent a higher resolution biomarker in assessing the APOE4-AD risk,” they write. Belloy has serum tests in his sights. “If klotho levels do correlate, that would bring us a new biomarker and potentially a new therapeutic target for AD,” he said.—Tom Fagan
- Semba RD, Moghekar AR, Hu J, Sun K, Turner R, Ferrucci L, O'Brien R. Klotho in the cerebrospinal fluid of adults with and without Alzheimer's disease. Neurosci Lett. 2014 Jan 13;558:37-40. Epub 2013 Nov 7 PubMed.
- Arking DE, Krebsova A, Macek M Sr, Macek M Jr, Arking A, Mian IS, Fried L, Hamosh A, Dey S, McIntosh I, Dietz HC. Association of human aging with a functional variant of klotho. Proc Natl Acad Sci U S A. 2002 Jan 22;99(2):856-61. Epub 2002 Jan 15 PubMed.
- Yokoyama JS, Sturm VE, Bonham LW, Klein E, Arfanakis K, Yu L, Coppola G, Kramer JH, Bennett DA, Miller BL, Dubal DB. Variation in longevity gene KLOTHO is associated with greater cortical volumes. Ann Clin Transl Neurol. 2015 Mar;2(3):215-30. Epub 2015 Jan 26 PubMed.
- Yokoyama JS, Marx G, Brown JA, Bonham LW, Wang D, Coppola G, Seeley WW, Rosen HJ, Miller BL, Kramer JH, Dubal DB. Systemic klotho is associated with KLOTHO variation and predicts intrinsic cortical connectivity in healthy human aging. Brain Imaging Behav. 2016 Oct 6; PubMed.
- Dubal DB, Yokoyama JS, Zhu L, Broestl L, Worden K, Wang D, Sturm VE, Kim D, Klein E, Yu GQ, Ho K, Eilertson KE, Yu L, Kuro-o M, De Jager PL, Coppola G, Small GW, Bennett DA, Kramer JH, Abraham CR, Miller BL, Mucke L. Life extension factor klotho enhances cognition. Cell Rep. 2014 May 22;7(4):1065-76. Epub 2014 May 10 PubMed.
- Erickson CM, Schultz SA, Oh JM, Darst BF, Ma Y, Norton D, Betthauser T, Gallagher CL, Carlsson CM, Bendlin BB, Asthana S, Hermann BP, Sager MA, Blennow K, Zetterberg H, Engelman CD, Christian BT, Johnson SC, Dubal DB, Okonkwo OC. KLOTHO heterozygosity attenuates APOE4-related amyloid burden in preclinical AD. Neurology. 2019 Apr 16;92(16):e1878-e1889. Epub 2019 Mar 13 PubMed.
No Available Further Reading
- Belloy ME, Napolioni V, Han SS, Le Guen Y, Greicius MD, Alzheimer’s Disease Neuroimaging Initiative. Association of Klotho-VS Heterozygosity With Risk of Alzheimer Disease in Individuals Who Carry APOE4. JAMA Neurol. 2020 Jul 1;77(7):849-862. PubMed.
- Sperling RA, Donohue MC, Raman R, Sun CK, Yaari R, Holdridge K, Siemers E, Johnson KA, Aisen PS, A4 Study Team. Association of Factors With Elevated Amyloid Burden in Clinically Normal Older Individuals. JAMA Neurol. 2020 Jun 1;77(6):735-745. PubMed.