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APOE loss-of-function variants: Compatible with longevity and associated with resistance to Alzheimer's disease pathology.
Chemparathy, Augustine; Le Guen, Yann; Chen, Sunny; Lee, Eun-Gyung; Leong, Lesley; Gorzynski, John E; Jensen, Tanner D; Ferrasse, Alexis; Xu, Guangxue; Xiang, Hong; Belloy, Michael E; Kasireddy, Nandita; Peña-Tauber, Andrés; Williams, Kennedy; Stewart, Ilaria; Talozzi, Lia; Wingo, Thomas S; Lah, James J; Jayadev, Suman; Hales, Chadwick M; Peskind, Elaine; Child, Daniel D; Roeber, Sigrun; Keene, C Dirk; Cong, Le; Ashley, Euan A; Yu, Chang-En; Greicius, Michael D.
Affiliation
  • Chemparathy A; Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
  • Le Guen Y; Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA; Quantitative Sciences Unit, Department of Medicine, Stanford University, Stanford, CA, USA.
  • Chen S; Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA.
  • Lee EG; Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA.
  • Leong L; Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA.
  • Gorzynski JE; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
  • Jensen TD; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
  • Ferrasse A; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
  • Xu G; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
  • Xiang H; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
  • Belloy ME; Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
  • Kasireddy N; Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
  • Peña-Tauber A; Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
  • Williams K; Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
  • Stewart I; Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
  • Talozzi L; Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
  • Wingo TS; Emory University School of Medicine, Atlanta, GA, USA; Goizueta Alzheimer's Disease Center, Emory University School of Medicine, Atlanta, GA, USA.
  • Lah JJ; Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.
  • Jayadev S; Department of Neurology, University of Washington, Seattle, WA, USA.
  • Hales CM; Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA; Department of Neurology, University of Washington, Seattle, WA, USA.
  • Peskind E; Veterans Affairs Northwest Network Mental Illness Research, Education, and Clinical Center, Veteran Affairs Puget Sound Health Care System, Seattle, WA, USA; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.
  • Child DD; Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA, USA.
  • Roeber S; Center for Neuropathology and Prion Research, Faculty of Medicine, LMU Munich, Munich, Germany.
  • Keene CD; Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA, USA.
  • Cong L; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
  • Ashley EA; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA; Center for Inherited Cardiovascular Disease, Stanford University, Stanford, CA, USA; Division of Cardiology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
  • Yu CE; Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA; Department of Medicine, University of Washington, Seattle, WA, USA.
  • Greicius MD; Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA. Electronic address: greicius@stanford.edu.
Neuron ; 112(7): 1110-1116.e5, 2024 Apr 03.
Article in En | MEDLINE | ID: mdl-38301647
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Alzheimer Disease Type of study: Prognostic_studies / Risk_factors_studies Limits: Humans Language: En Journal: Neuron Journal subject: NEUROLOGIA Year: 2024 Document type: Article Affiliation country:
Fulltext
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Alzheimer Disease Type of study: Prognostic_studies / Risk_factors_studies Limits: Humans Language: En Journal: Neuron Journal subject: NEUROLOGIA Year: 2024 Document type: Article Affiliation country: