Meta-Analysis

. 2021 May:101:123-129.

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

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.

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Conflict of interest statement

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The authors report no conflicts of interest.

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

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

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