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.

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  1. This is an interesting study by Belloy and colleagues, which reports an association between Klotho-VS heterozygosity (KL-VS HET+) and apolipoprotein 4 (APOE4) allele carriage, with risk for conversion to Alzheimer’s disease (AD) and β-amyloid (Aβ) pathology. Specifically, they report that in APOE4 carriers, those who were KL-VS HET+ showed a reduced risk of converting to AD, higher CSF Aβ, and lower PET Aβ when compared to KL-VS HET-. The results presented in this study add to the growing literature supporting the hypothesis that multiple gene variants are likely to interact to influence disease outcomes in AD.

    The main strength of this study is the size and quality of the sample, with participant data available from a number of large longitudinal cohort studies. As discussed by Belloy et al., we have previously investigated whether the interaction between APOE4 and KL-VS is associated with cognitive decline in the Australian Imaging, Biomarker, and Lifestyle (AIBL) study (Porter et al., 2019). We observed no difference in cognitive decline over 7.5 years between KL-VS HET+/HET- in cognitively normal APOE4 carriers and regardless of PET Aβ burden. However, as calculated by Belloy et al., in our sample there is an association between KL-VS, APOE4, and PET Aβ burden in cognitively normal APOE4 carriers, with odds ratios observed similar to those of the current study. Whilst our initial study, referenced here, did not report any influence of KL-VS on cognitive decline, our subsequent studies assessing it in combination with an increased number of genetic variants do report an effect of KL-VS. In our published genetic risk profile (Porter et al., 2018) and episodic memory weighted genetic risk scores (Porter et al., 2018), KL-VS status significantly contributed to the prediction of cognitive performance.

    Overall, Belloy and colleagues’ study is an important one that adds to the growing literature indicating that genetic influence over progression to Alzheimer’s disease is more than just APOE4 alone. Lastly, we strongly agree with the authors’ suggestion that KL-VS genotype be seriously considered in the selection of participants in prevention trials, to increase the likelihood the cohort will convert to AD, and further, as additional genetic variants are assessed in this way that they be similarly considered.

    References:

    Porter T, Burnham SC, Milicic L, Savage G, Maruff P, Lim YY, Ames D, Masters CL, Martins RN, Rainey-Smith S, Rowe CC, Salvado O, Groth D, Verdile G, Villemagne VL, Laws SM. Klotho allele status is not associated with Aβ and APOE ε4-related cognitive decline in preclinical Alzheimer's disease. Neurobiol Aging. 2019 Apr;76:162-165. Epub 2019 Jan 6 PubMed.

    Porter T, Villemagne V, Savage G, Milicic L, Lim YY, Maruff P, Masters CL, Ames D, Bush AI, Rainey-Smith S, Rowe CC, Groth D, Martins RN, Verdile G, Burnham SC, Laws SM, for the AIBL research group. Cognitive gene risk profile for the prediction of cognitive decline in presymptomatic Alzheimer’s disease. Personalized Medicine in Psychiatry, March–April 2018

    Porter T, Burnham SC, Savage G, Lim YY, Maruff P, Milicic L, Peretti M, Ames D, Masters CL, Martins RN, Rainey-Smith S, Rowe CC, Salvado O, Taddei K, Groth D, Verdile G, Villemagne VL, Laws SM. A Polygenic Risk Score Derived From Episodic Memory Weighted Genetic Variants Is Associated With Cognitive Decline in Preclinical Alzheimer's Disease. Front Aging Neurosci. 2018;10:423. Epub 2018 Dec 19 PubMed.

    View all comments by Simon Laws

  2. This is a very extensive meta-analysis of over 20,000 individuals, aimed at elucidating whether an interaction between APOE4 and a polymorphism in the coding region of the klotho gene, known as KL-VS, affects AD outcome. The genotype KL-VSHET+ was associated with reduced risk for AD in individuals carrying APOE4 who were 60 years old or older; control participants carrying APOE4 with KL-VS heterozygosity were at reduced risk of converting to MCI or AD and in control participants who carried APOE4 and were aged 60 to 80 years, KL-VS heterozygosity was associated with higher Aβ in CSF and lower Aβ on PET scans.

    These are very interesting findings which serve as additional validation for the previously published work on the neuroprotective role of klotho. In the past we showed that klotho levels decrease as a function of age in the healthy brain (Duce et al., 2008). We then provided evidence for its protective functions in the CNS and reported possible mechanisms of protection: a reduction in oxidative stress (Zeldich et al., 2014), increased oligodendrocyte differentiation and myelination in vitro and in vivo (Chen et al., 2013; Zeldich, 2015), improved cognition and LTP in an APP model overexpressing klotho (Dubal et al., 2015), and reduced cell death and neuroinflammation in an ALS mouse model (Zeldich et al., 2019). In other words, klotho functions against the common age-related changes that occur in the brain during normal aging and neurodegeneration: it is anti-oxidative, anti-inflammatory, and promotes myelination.

    We and others also showed that being heterozygous for KL-VS, a double mutation associated with higher levels of klotho, is beneficial for cognition and in a multitude of diseases (Dubal et al., 2014). In addition to the benefits due to the higher level of Klotho, we pointed out a biochemical mechanism specific to KL-VS that may explain its effects (Tucker-Zhou et al., 2013). 

    Among the key questions to consider addressing in the future are:

    1. What functions among those described for klotho may interact differently with APOE4 and APOE3?
    2. Is it the anti-inflammatory action of klotho that may affect microglia behavior into phagocytosing Aβ? APOE was recently shown to affect AD in part through its immunomodulatory function. This function of APOE is likely linked to triggering receptor expressed on myeloid cells 2 (TREM2), which is expressed by microglia in the CNS (Shi and Holzman, 2018). 
    3. Or, is it the anti-oxidative role of klotho which precludes chemical modifications in Aβ? Oxidation would make Aβ more insoluble and resistant to degradation.
    4. Regarding the conversion from MCI to AD, does KL-VS prevent white-matter abnormalities which may affect cognition via some indirect or direct lipid interaction with APOE4?
    5. Why do individuals over 80 not benefit from klotho heterozygocity like those aged 60 to 80? I propose that a potential reason is lower levels of klotho as we described to occur with aging. Perhaps under a certain threshold of klotho levels, it is no longer beneficial.
    6. There is an excellent ELISA kit for measuring human klotho levels in blood or CSF. It would be interesting to quantify klotho levels in a subgroup of control, MCI, and AD individuals with KL-VS with APOE4 and APOE3. If klotho levels are similar in APOE4 and 3 carriers, perhaps the modifications caused by the two amino acid substitutions in KL-VS could explain the intriguing interplay between klotho and APOE4.

    Last but not least, this work emphasizes the importance of identifying compounds that boost klotho levels and might delay or even prevent AD.

    References:

    Duce JA, Podvin S, Hollander W, Kipling D, Rosene DL, Abraham CR. Gene profile analysis implicates Klotho as an important contributor to aging changes in brain white matter of the rhesus monkey. Glia. 2008 Jan 1;56(1):106-17. PubMed.

    Chen CD, Sloane JA, Li H, Aytan N, Giannaris EL, Zeldich E, Hinman JD, Dedeoglu A, Rosene DL, Bansal R, Luebke JI, Kuro-o M, Abraham CR. The antiaging protein Klotho enhances oligodendrocyte maturation and myelination of the CNS. J Neurosci. 2013 Jan 30;33(5):1927-39. PubMed.

    Tucker Zhou TB, King GD, Chen C, Abraham CR. Biochemical and functional characterization of the klotho-VS polymorphism implicated in aging and disease risk. J Biol Chem. 2013 Dec 20;288(51):36302-11. Epub 2013 Nov 11 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.

    Zeldich E, Chen CD, Colvin TA, Bove-Fenderson EA, Liang J, Tucker Zhou TB, Harris DA, Abraham CR. The neuroprotective effect of Klotho is mediated via regulation of members of the redox system. J Biol Chem. 2014 Aug 29;289(35):24700-15. Epub 2014 Jul 18 PubMed.

    Zeldich E, Chen CD, Avila R, Medicetty S, Abraham CR. The Anti-Aging Protein Klotho Enhances Remyelination Following Cuprizone-Induced Demyelination. J Mol Neurosci. 2015 Oct;57(2):185-96. Epub 2015 Jun 12 PubMed.

    Dubal DB, Zhu L, Sanchez PE, Worden K, Broestl L, Johnson E, Ho K, Yu GQ, Kim D, Betourne A, Kuro-O M, Masliah E, Abraham CR, Mucke L. Life extension factor klotho prevents mortality and enhances cognition in hAPP transgenic mice. J Neurosci. 2015 Feb 11;35(6):2358-71. PubMed.

    Shi Y, Holtzman DM. Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight. Nat Rev Immunol. 2018 Dec;18(12):759-772. PubMed.

    Zeldich E, Chen CD, Boden E, Howat B, Nasse JS, Zeldich D, Lambert AG, Yuste A, Cherry JD, Mathias RM, Ma Q, Lau NC, McKee AC, Hatzipetros T, Abraham CR. Klotho Is Neuroprotective in the Superoxide Dismutase (SOD1G93A) Mouse Model of ALS. J Mol Neurosci. 2019 Oct;69(2):264-285. Epub 2019 Jun 27 PubMed.

    View all comments by Carmela Abraham

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  1. Klotho Variant Cuts ApoE4’s Alzheimer Risk by a Third

Mutations

  1. APOE C130R (ApoE4)