KL∗VS heterozygosity reduces brain amyloid in asymptomatic at-risk APOE∗4 carriers

Michael E Belloy¹, Sarah J Eger², Yann Le Guen², Valerio Napolioni², Kacie D Deters², Hyun-Sik Yang³, Marzia A Scelsi⁴, Tenielle Porter⁵, Sarah-Naomi James⁶, Andrew Wong⁶, Jonathan M Schott⁷, Reisa A Sperling³, Simon M Laws⁵, Elisabeth C Mormino², Zihuai He⁸, Summer S Han⁹, Andre Altmann⁴, Michael D Greicius²; A4 Study Team; Insight 46 Study Team; Australian Imaging Biomarkers and Lifestyle (AIBL) Study; Alzheimer's Disease Neuroimaging Initiative

Affiliations

¹ Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA. Electronic address: mbelloy@stanford.edu.
² Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
³ Department of Neurology, Brigham and Women's Hospital, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁴ Centre for Medical Image Computing (CMIC), University College London, London, UK.
⁵ Collaborative Genomics and Translation Group, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, Australia; School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin University, Bentley, Western Australia, Australia.
⁶ Medical Research Council Unit for Lifelong Health and Ageing, University College London, London, UK.
⁷ Dementia Research Centre, University College London Queen Square Institute of Neurology, University College London, London, UK; UK Dementia Research Institute, University College London, London, UK.
⁸ Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA; Department of Medicine, Quantitative Sciences Unit, Stanford University, Stanford, CA, USA.
⁹ Department of Medicine, Quantitative Sciences Unit, Stanford University, Stanford, CA, USA; Department of Neurosurgery, Stanford University, Stanford, CA, USA.

PMID: 33610961
PMCID: PMC8122023
DOI: 10.1016/j.neurobiolaging.2021.01.008

Meta-Analysis

KL∗VS heterozygosity reduces brain amyloid in asymptomatic at-risk APOE∗4 carriers

Michael E Belloy et al. Neurobiol Aging. 2021 May.

. 2021 May:101:123-129.

doi: 10.1016/j.neurobiolaging.2021.01.008. Epub 2021 Jan 23.

Authors

Affiliations

¹ Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA. Electronic address: mbelloy@stanford.edu.
² Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
³ Department of Neurology, Brigham and Women's Hospital, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁴ Centre for Medical Image Computing (CMIC), University College London, London, UK.
⁵ Collaborative Genomics and Translation Group, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, Australia; School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin University, Bentley, Western Australia, Australia.
⁶ Medical Research Council Unit for Lifelong Health and Ageing, University College London, London, UK.
⁷ Dementia Research Centre, University College London Queen Square Institute of Neurology, University College London, London, UK; UK Dementia Research Institute, University College London, London, UK.
⁸ Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA; Department of Medicine, Quantitative Sciences Unit, Stanford University, Stanford, CA, USA.
⁹ Department of Medicine, Quantitative Sciences Unit, Stanford University, Stanford, CA, USA; Department of Neurosurgery, Stanford University, Stanford, CA, USA.

PMID: 33610961
PMCID: PMC8122023
DOI: 10.1016/j.neurobiolaging.2021.01.008

Abstract

KLOTHO∗VS heterozygosity (KL∗VS^HET+) was recently shown to be associated with reduced risk of Alzheimer's disease (AD) in APOE∗4 carriers. Additional studies suggest that KL∗VS^HET+ protects against amyloid burden in cognitively normal older subjects, but sample sizes were too small to draw definitive conclusions. We performed a well-powered meta-analysis across 5 independent studies, comprising 3581 pre-clinical participants ages 60-80, to investigate whether KL∗VS^HET+ reduces the risk of having an amyloid-positive positron emission tomography scan. Analyses were stratified by APOE∗4 status. KL∗VS^HET+ reduced the risk of amyloid positivity in APOE∗4 carriers (odds ratio = 0.67 [0.52-0.88]; p = 3.5 × 10^-3), but not in APOE∗4 non-carriers (odds ratio = 0.94 [0.73-1.21]; p = 0.63). The combination of APOE∗4 and KL∗VS genotypes should help enrich AD clinical trials for pre-symptomatic subjects at increased risk of developing amyloid aggregation and AD. KL-related pathways may help elucidate protective mechanisms against amyloid accumulation and merit exploration for novel AD drug targets. Future investigation of the biological mechanisms by which KL interacts with APOE∗4 and AD are warranted.

Keywords: APOE4; Alzheimer's disease; Amyloid; Heterozygosity; KLOTHO; PET; Pre-clinical.

PubMed Disclaimer

Conflict of interest statement

Disclosure statement

The authors report no conflicts of interest.

References

1. Arking DE, Krebsova A, Macek M, Macek M, Arking A, Mian IS, Fried L, Hamosh A, Dey S, McIntosh I, Dietz HC, 2002. Association of human aging with a functional variant of klotho. Proc. Natl. Acad. Sci. U S A 99, 856–861. - PMC - PubMed
1. Ballard C, Atri A, Boneva N, Cummings JL, Frölich L, Molinuevo JL, Tariot PN, Raket LL, 2019. Enrichment factors for clinical trials in mild-to-moderate Alzheimer’s disease. Alzheimers Dement. 5, 164–174. - PMC - PubMed
1. Bejanin A, Schonhaut DR, Joie R. La, Kramer JH, Baker SL, Sosa N, Ayakta N, Cantwell A, Janabi M, Lauriola M, Neil JPO, Gorno-tempini ML, Miller ZA, Rosen HJ, Miller BL, Jagust WJ, Rabinovici GD, 2017. Tau pathology and neurodegeneration contribute to cognitive impairment in Alzheimer’s disease. Brain 140, 3286–3300. - PMC - PubMed
1. Belloy ME, Napolioni V, Greicius MD, 2019. A quarter century of APOE and Alzheimer’s disease: progress to date and the path forward. Neuron 101, 820–838. - PMC - PubMed
1. Belloy ME, Napolioni V, Han SS, Guen Y. Le, Greicius MD, Initiative, for the A.D.N., 2020. Association of klotho-VS heterozygosity with risk of Alzheimer disease in individuals who carry APOE4. JAMA Neurol. E1–E14. - PMC - PubMed

Publication types

Actions
Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

KL∗VS heterozygosity reduces brain amyloid in asymptomatic at-risk APOE∗4 carriers

Affiliations

KL∗VS heterozygosity reduces brain amyloid in asymptomatic at-risk APOE∗4 carriers

Authors

Affiliations

Abstract

Conflict of interest statement

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical