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

Michael E Belloy; Sarah J Eger; Yann Le Guen; Valerio Napolioni; Kacie D Deters; Hyun-Sik Yang; Marzia A Scelsi; Tenielle Porter; Sarah-Naomi James; Andrew Wong; Jonathan M Schott; Reisa A Sperling; Simon M Laws; Elisabeth C Mormino; Zihuai He; Summer S Han; Andre Altmann; Michael D Greicius; A4 Study Team; Insight 46 Study Team; Australian Imaging Biomarkers and Lifestyle (AIBL) Study; Alzheimer's Disease Neuroimaging Initiative

doi:10.1016/j.neurobiolaging.2021.01.008

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

Neurobiol Aging. 2021 May:101:123-129. doi: 10.1016/j.neurobiolaging.2021.01.008. Epub 2021 Jan 23.

Authors

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: [email protected].
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.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Aged
Aged, 80 and over
Alzheimer Disease / diagnostic imaging
Alzheimer Disease / genetics*
Amyloidogenic Proteins / metabolism*
Apolipoprotein E4 / genetics*
Brain / metabolism*
Carrier State*
Female
Glucuronidase / genetics*
Heterozygote*
Humans
Klotho Proteins
Male
Middle Aged
Positron-Emission Tomography
Risk

Substances

Amyloidogenic Proteins
Apolipoprotein E4
Glucuronidase
Klotho Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding