APOE loss-of-function variants: Compatible with longevity and associated with resistance to Alzheimer's disease pathology

Augustine Chemparathy; Yann Le Guen; Sunny Chen; Eun Gyung Lee; Lesley Leong; John E. Gorzynski; Tanner D. Jensen; Alexis Ferrasse; Guangxue Xu; Hong Xiang; Michael E. Belloy; Nandita Kasireddy; Andrés Peña-Tauber; Kennedy Williams; Ilaria Stewart; Lia Talozzi; Thomas S. Wingo; James J. Lah; Suman Jayadev; Chadwick M. Hales; Elaine Peskind; Daniel D. Child; Sigrun Roeber; C. Dirk Keene; Le Cong; Euan A. Ashley; Chang En Yu; Michael D. Greicius

doi:10.1016/j.neuron.2024.01.008

APOE loss-of-function variants: Compatible with longevity and associated with resistance to Alzheimer's disease pathology

Augustine Chemparathy, Yann Le Guen, Sunny Chen, Eun Gyung Lee, Lesley Leong, John E. Gorzynski, Tanner D. Jensen, Alexis Ferrasse, Guangxue Xu, Hong Xiang, Michael E. Belloy, Nandita Kasireddy, Andrés Peña-Tauber, Kennedy Williams, Ilaria Stewart, Lia Talozzi, Thomas S. Wingo, James J. Lah, Suman Jayadev, Chadwick M. HalesElaine Peskind, Daniel D. Child, Sigrun Roeber, C. Dirk Keene, Le Cong, Euan A. Ashley, Chang En Yu, Michael D. Greicius

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

12 Scopus citations

Abstract

The ε4 allele of apolipoprotein E (APOE) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). Knockdown of ε4 may provide a therapeutic strategy for AD, but the effect of APOE loss of function (LoF) on AD pathogenesis is unknown. We searched for APOE LoF variants in a large cohort of controls and patients with AD and identified seven heterozygote carriers of APOE LoF variants. Five carriers were controls (aged 71–90 years), one carrier was affected by progressive supranuclear palsy, and one carrier was affected by AD with an unremarkable age at onset of 75 years. Two APOE ε3/ε4 controls carried a stop-gain affecting ε4: one was cognitively normal at 90 years and had no neuritic plaques at autopsy; the other was cognitively healthy at 79 years, and lumbar puncture at 76 years showed normal levels of amyloid. These results suggest that ε4 drives AD risk through the gain of abnormal function and support ε4 knockdown as a viable therapeutic option.

Original language	English
Pages (from-to)	1110-1116.e5
Journal	Neuron
Volume	112
Issue number	7
DOIs	https://doi.org/10.1016/j.neuron.2024.01.008
State	Published - Apr 3 2024

Keywords

Alzheimer's disease
apolipoprotein E
dementia
human genetics
long-read sequencing
loss of function
neurodegenerative disorders
structural variant

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10.1016/j.neuron.2024.01.008

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Chemparathy, A., Le Guen, Y., Chen, S., Lee, E. G., Leong, L., Gorzynski, J. E., Jensen, T. D., Ferrasse, A., Xu, G., Xiang, H., Belloy, M. E., Kasireddy, N., Peña-Tauber, A., Williams, K., Stewart, I., Talozzi, L., Wingo, T. S., Lah, J. J., Jayadev, S., ... Greicius, M. D. (2024). APOE loss-of-function variants: Compatible with longevity and associated with resistance to Alzheimer's disease pathology. Neuron, 112(7), 1110-1116.e5. https://doi.org/10.1016/j.neuron.2024.01.008

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title = "APOE loss-of-function variants: Compatible with longevity and associated with resistance to Alzheimer's disease pathology",

abstract = "The ε4 allele of apolipoprotein E (APOE) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). Knockdown of ε4 may provide a therapeutic strategy for AD, but the effect of APOE loss of function (LoF) on AD pathogenesis is unknown. We searched for APOE LoF variants in a large cohort of controls and patients with AD and identified seven heterozygote carriers of APOE LoF variants. Five carriers were controls (aged 71–90 years), one carrier was affected by progressive supranuclear palsy, and one carrier was affected by AD with an unremarkable age at onset of 75 years. Two APOE ε3/ε4 controls carried a stop-gain affecting ε4: one was cognitively normal at 90 years and had no neuritic plaques at autopsy; the other was cognitively healthy at 79 years, and lumbar puncture at 76 years showed normal levels of amyloid. These results suggest that ε4 drives AD risk through the gain of abnormal function and support ε4 knockdown as a viable therapeutic option.",

keywords = "Alzheimer's disease, apolipoprotein E, dementia, human genetics, long-read sequencing, loss of function, neurodegenerative disorders, structural variant",

author = "Augustine Chemparathy and {Le Guen}, Yann and Sunny Chen and Lee, {Eun Gyung} and Lesley Leong and Gorzynski, {John E.} and Jensen, {Tanner D.} and Alexis Ferrasse and Guangxue Xu and Hong Xiang and Belloy, {Michael E.} and Nandita Kasireddy and Andr{\'e}s Pe{\~n}a-Tauber and Kennedy Williams and Ilaria Stewart and Lia Talozzi and Wingo, {Thomas S.} and Lah, {James J.} and Suman Jayadev and Hales, {Chadwick M.} and Elaine Peskind and Child, {Daniel D.} and Sigrun Roeber and Keene, {C. Dirk} and Le Cong and Ashley, {Euan A.} and Yu, {Chang En} and Greicius, {Michael D.}",

note = "Publisher Copyright: {\textcopyright} 2024 Elsevier Inc.",

year = "2024",

month = apr,

day = "3",

doi = "10.1016/j.neuron.2024.01.008",

language = "English",

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Chemparathy, A, Le Guen, Y, Chen, S, Lee, EG, Leong, L, Gorzynski, JE, Jensen, TD, Ferrasse, A, Xu, G, Xiang, H, Belloy, ME, Kasireddy, N, Peña-Tauber, A, Williams, K, Stewart, I, Talozzi, L, Wingo, TS, Lah, JJ, Jayadev, S, Hales, CM, Peskind, E, Child, DD, Roeber, S, Keene, CD, Cong, L, Ashley, EA, Yu, CE & Greicius, MD 2024, 'APOE loss-of-function variants: Compatible with longevity and associated with resistance to Alzheimer's disease pathology', Neuron, vol. 112, no. 7, pp. 1110-1116.e5. https://doi.org/10.1016/j.neuron.2024.01.008

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T1 - APOE loss-of-function variants

T2 - Compatible with longevity and associated with resistance to Alzheimer's disease pathology

AU - Chemparathy, Augustine

AU - Le Guen, Yann

AU - Chen, Sunny

AU - Lee, Eun Gyung

AU - Leong, Lesley

AU - Gorzynski, John E.

AU - Jensen, Tanner D.

AU - Ferrasse, Alexis

AU - Xu, Guangxue

AU - Xiang, Hong

AU - Belloy, Michael E.

AU - Kasireddy, Nandita

AU - Peña-Tauber, Andrés

AU - Williams, Kennedy

AU - Stewart, Ilaria

AU - Talozzi, Lia

AU - Wingo, Thomas S.

AU - Lah, James J.

AU - Jayadev, Suman

AU - Hales, Chadwick M.

AU - Peskind, Elaine

AU - Child, Daniel D.

AU - Roeber, Sigrun

AU - Keene, C. Dirk

AU - Cong, Le

AU - Ashley, Euan A.

AU - Yu, Chang En

AU - Greicius, Michael D.

PY - 2024/4/3

Y1 - 2024/4/3

N2 - The ε4 allele of apolipoprotein E (APOE) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). Knockdown of ε4 may provide a therapeutic strategy for AD, but the effect of APOE loss of function (LoF) on AD pathogenesis is unknown. We searched for APOE LoF variants in a large cohort of controls and patients with AD and identified seven heterozygote carriers of APOE LoF variants. Five carriers were controls (aged 71–90 years), one carrier was affected by progressive supranuclear palsy, and one carrier was affected by AD with an unremarkable age at onset of 75 years. Two APOE ε3/ε4 controls carried a stop-gain affecting ε4: one was cognitively normal at 90 years and had no neuritic plaques at autopsy; the other was cognitively healthy at 79 years, and lumbar puncture at 76 years showed normal levels of amyloid. These results suggest that ε4 drives AD risk through the gain of abnormal function and support ε4 knockdown as a viable therapeutic option.

AB - The ε4 allele of apolipoprotein E (APOE) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). Knockdown of ε4 may provide a therapeutic strategy for AD, but the effect of APOE loss of function (LoF) on AD pathogenesis is unknown. We searched for APOE LoF variants in a large cohort of controls and patients with AD and identified seven heterozygote carriers of APOE LoF variants. Five carriers were controls (aged 71–90 years), one carrier was affected by progressive supranuclear palsy, and one carrier was affected by AD with an unremarkable age at onset of 75 years. Two APOE ε3/ε4 controls carried a stop-gain affecting ε4: one was cognitively normal at 90 years and had no neuritic plaques at autopsy; the other was cognitively healthy at 79 years, and lumbar puncture at 76 years showed normal levels of amyloid. These results suggest that ε4 drives AD risk through the gain of abnormal function and support ε4 knockdown as a viable therapeutic option.

KW - Alzheimer's disease

KW - apolipoprotein E

KW - dementia

KW - human genetics

KW - long-read sequencing

KW - loss of function

KW - neurodegenerative disorders

KW - structural variant

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U2 - 10.1016/j.neuron.2024.01.008

DO - 10.1016/j.neuron.2024.01.008

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C2 - 38301647

AN - SCOPUS:85186087826

SN - 0896-6273

VL - 112

SP - 1110-1116.e5

JO - Neuron

JF - Neuron

IS - 7

ER -

APOE loss-of-function variants: Compatible with longevity and associated with resistance to Alzheimer's disease pathology

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