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

A4 Study Team; Insight 46 Study Team; Australian Imaging Biomarkers and Lifestyle (AIBL) Study; Alzheimer's Disease Neuroimaging Initiative; 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

doi:10.1016/j.neurobiolaging.2021.01.008

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

A4 Study Team, Insight 46 Study Team, Australian Imaging Biomarkers and Lifestyle (AIBL) Study, Alzheimer's Disease Neuroimaging Initiative, 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. HanAndre Altmann, Michael D. Greicius

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

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.

Original language	English
Pages (from-to)	123-129
Number of pages	7
Journal	Neurobiology of Aging
Volume	101
DOIs	https://doi.org/10.1016/j.neurobiolaging.2021.01.008
State	Published - May 2021

Keywords

Alzheimer's disease
Amyloid
APOE4
Heterozygosity
KLOTHO
PET
Pre-clinical

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10.1016/j.neurobiolaging.2021.01.008

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A4 Study Team, Insight 46 Study Team, Australian Imaging Biomarkers and Lifestyle (AIBL) Study, Alzheimer's Disease Neuroimaging Initiative, Belloy, M. E., Eger, S. J., Le Guen, Y., Napolioni, V., Deters, K. D., Yang, H. S., Scelsi, M. A., Porter, T., James, S. N., Wong, A., Schott, J. M., Sperling, R. A., Laws, S. M., Mormino, E. C., He, Z., ... Greicius, M. D. (2021). KL∗VS heterozygosity reduces brain amyloid in asymptomatic at-risk APOE∗4 carriers. Neurobiology of Aging, 101, 123-129. https://doi.org/10.1016/j.neurobiolaging.2021.01.008

@article{f6b2e22b7bb24f00a42101dbf3ccafda,

title = "KL∗VS heterozygosity reduces brain amyloid in asymptomatic at-risk APOE∗4 carriers",

abstract = "KLOTHO∗VS heterozygosity (KL∗VSHET+) was recently shown to be associated with reduced risk of Alzheimer's disease (AD) in APOE∗4 carriers. Additional studies suggest that KL∗VSHET+ 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∗VSHET+ reduces the risk of having an amyloid-positive positron emission tomography scan. Analyses were stratified by APOE∗4 status. KL∗VSHET+ 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 = "Alzheimer's disease, Amyloid, APOE4, Heterozygosity, KLOTHO, PET, Pre-clinical",

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

note = "Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",

year = "2021",

month = may,

doi = "10.1016/j.neurobiolaging.2021.01.008",

language = "English",

volume = "101",

pages = "123--129",

journal = "Neurobiology of Aging",

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A4 Study Team, Insight 46 Study Team, Australian Imaging Biomarkers and Lifestyle (AIBL) Study, Alzheimer's Disease Neuroimaging Initiative, Belloy, ME, Eger, SJ, Le Guen, Y, Napolioni, V, Deters, KD, Yang, HS, Scelsi, MA, Porter, T, James, SN, Wong, A, Schott, JM, Sperling, RA, Laws, SM, Mormino, EC, He, Z, Han, SS, Altmann, A & Greicius, MD 2021, 'KL∗VS heterozygosity reduces brain amyloid in asymptomatic at-risk APOE∗4 carriers', Neurobiology of Aging, vol. 101, pp. 123-129. https://doi.org/10.1016/j.neurobiolaging.2021.01.008

TY - JOUR

T1 - KL∗VS heterozygosity reduces brain amyloid in asymptomatic at-risk APOE∗4 carriers

AU - A4 Study Team

AU - Insight 46 Study Team

AU - Australian Imaging Biomarkers and Lifestyle (AIBL) Study

AU - Alzheimer's Disease Neuroimaging Initiative

AU - Belloy, Michael E.

AU - Eger, Sarah J.

AU - Le Guen, Yann

AU - Napolioni, Valerio

AU - Deters, Kacie D.

AU - Yang, Hyun Sik

AU - Scelsi, Marzia A.

AU - Porter, Tenielle

AU - James, Sarah Naomi

AU - Wong, Andrew

AU - Schott, Jonathan M.

AU - Sperling, Reisa A.

AU - Laws, Simon M.

AU - Mormino, Elisabeth C.

AU - He, Zihuai

AU - Han, Summer S.

AU - Altmann, Andre

AU - Greicius, Michael D.

PY - 2021/5

Y1 - 2021/5

N2 - KLOTHO∗VS heterozygosity (KL∗VSHET+) was recently shown to be associated with reduced risk of Alzheimer's disease (AD) in APOE∗4 carriers. Additional studies suggest that KL∗VSHET+ 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∗VSHET+ reduces the risk of having an amyloid-positive positron emission tomography scan. Analyses were stratified by APOE∗4 status. KL∗VSHET+ 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.

AB - KLOTHO∗VS heterozygosity (KL∗VSHET+) was recently shown to be associated with reduced risk of Alzheimer's disease (AD) in APOE∗4 carriers. Additional studies suggest that KL∗VSHET+ 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∗VSHET+ reduces the risk of having an amyloid-positive positron emission tomography scan. Analyses were stratified by APOE∗4 status. KL∗VSHET+ 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.

KW - Alzheimer's disease

KW - Amyloid

KW - APOE4

KW - Heterozygosity

KW - KLOTHO

KW - PET

KW - Pre-clinical

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U2 - 10.1016/j.neurobiolaging.2021.01.008

DO - 10.1016/j.neurobiolaging.2021.01.008

M3 - Article

C2 - 33610961

AN - SCOPUS:85100898549

SN - 0197-4580

VL - 101

SP - 123

EP - 129

JO - Neurobiology of Aging

JF - Neurobiology of Aging

ER -

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

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Keywords

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