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Preclinical effects of APOE ε4 on cerebrospinal fluid Aβ42 concentrations.
Alzheimers Res Ther 2017; 9(1):87AR

Abstract

BACKGROUND

From earlier studies it is known that the APOE ε2/ε3/ε4 polymorphism modulates the concentrations of cerebrospinal fluid (CSF) beta-amyloid1-42 (Aβ42) in patients with cognitive decline due to Alzheimer's disease (AD), as well as in cognitively healthy controls. Here, in a large cohort consisting solely of cognitively healthy individuals, we aimed to evaluate how the effect of APOE on CSF Aβ42 varies by age, to understand the association between APOE and the onset of preclinical AD.

METHODS

APOE genotype and CSF Aβ42 concentration were determined in a cohort comprising 716 cognitively healthy individuals aged 17-99 from nine different clinical research centers.

RESULTS

CSF concentrations of Aβ42 were lower in APOE ε4 carriers than in noncarriers in a gene dose-dependent manner. The effect of APOE ε4 on CSF Aβ42 was age dependent. The age at which CSF Aβ42 concentrations started to decrease was estimated at 50 years in APOE ε4-negative individuals and 43 years in heterozygous APOE ε4 carriers. Homozygous APOE ε4 carriers showed a steady decline in CSF Aβ42 concentrations with increasing age throughout the examined age span.

CONCLUSIONS

People possessing the APOE ε4 allele start to show a decrease in CSF Aβ42 concentration almost a decade before APOE ε4 noncarriers already in early middle age. Homozygous APOE ε4 carriers might deposit Aβ42 throughout the examined age span. These results suggest that there is an APOE ε4-dependent period of early alterations in amyloid homeostasis, when amyloid slowly accumulates, that several years later, together with other downstream pathological events such as tau pathology, translates into cognitive decline.

Authors+Show Affiliations

Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden. ronald.lautner@neuro.gu.se. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden. ronald.lautner@neuro.gu.se.Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden. Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases, San Francisco, CA, USA. Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA.Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.Istituto di Ricovero e Cura a Carattere Scientifico Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.Department of Neurology, University of Eastern Finland, Kuopio University Hospital, Kuopio, Finland.AXA Research Fund and UPMC Chair, Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Paris 06, Inserm, CNRS, Institut du cerveau et de la moelle (ICM), Département de Neurologie, Institut de la Mémoire et de la Maladie d'Alzheimer (IM2A), Hôpital Pitié-Salpêtrière, Boulevard de l'hôpital, F-75013, Paris, France.Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden. Memory Clinic, Skåne University Hospital, Malmö, Sweden.Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden. Memory Clinic, Skåne University Hospital, Malmö, Sweden.Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden. Department of Neurology, Skåne University Hospital, Lund, Sweden.Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden. Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.

Pub Type(s)

Journal Article
Multicenter Study

Language

eng

PubMed ID

29061195

Citation

Lautner, Ronald, et al. "Preclinical Effects of APOE Ε4 On Cerebrospinal Fluid Aβ42 Concentrations." Alzheimer's Research & Therapy, vol. 9, no. 1, 2017, p. 87.
Lautner R, Insel PS, Skillbäck T, et al. Preclinical effects of APOE ε4 on cerebrospinal fluid Aβ42 concentrations. Alzheimers Res Ther. 2017;9(1):87.
Lautner, R., Insel, P. S., Skillbäck, T., Olsson, B., Landén, M., Frisoni, G. B., ... Zetterberg, H. (2017). Preclinical effects of APOE ε4 on cerebrospinal fluid Aβ42 concentrations. Alzheimer's Research & Therapy, 9(1), p. 87. doi:10.1186/s13195-017-0313-3.
Lautner R, et al. Preclinical Effects of APOE Ε4 On Cerebrospinal Fluid Aβ42 Concentrations. Alzheimers Res Ther. 2017 Oct 23;9(1):87. PubMed PMID: 29061195.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Preclinical effects of APOE ε4 on cerebrospinal fluid Aβ42 concentrations. AU - Lautner,Ronald, AU - Insel,Philip S, AU - Skillbäck,Tobias, AU - Olsson,Bob, AU - Landén,Mikael, AU - Frisoni,Giovanni B, AU - Herukka,Sanna-Kaisa, AU - Hampel,Harald, AU - Wallin,Anders, AU - Minthon,Lennart, AU - Hansson,Oskar, AU - Blennow,Kaj, AU - Mattsson,Niklas, AU - Zetterberg,Henrik, Y1 - 2017/10/23/ PY - 2017/06/12/received PY - 2017/10/03/accepted PY - 2017/10/25/entrez PY - 2017/10/25/pubmed PY - 2018/6/21/medline KW - APOE KW - Alzheimer’s disease KW - Beta amyloid KW - Cerebrospinal fluid SP - 87 EP - 87 JF - Alzheimer's research & therapy JO - Alzheimers Res Ther VL - 9 IS - 1 N2 - BACKGROUND: From earlier studies it is known that the APOE ε2/ε3/ε4 polymorphism modulates the concentrations of cerebrospinal fluid (CSF) beta-amyloid1-42 (Aβ42) in patients with cognitive decline due to Alzheimer's disease (AD), as well as in cognitively healthy controls. Here, in a large cohort consisting solely of cognitively healthy individuals, we aimed to evaluate how the effect of APOE on CSF Aβ42 varies by age, to understand the association between APOE and the onset of preclinical AD. METHODS: APOE genotype and CSF Aβ42 concentration were determined in a cohort comprising 716 cognitively healthy individuals aged 17-99 from nine different clinical research centers. RESULTS: CSF concentrations of Aβ42 were lower in APOE ε4 carriers than in noncarriers in a gene dose-dependent manner. The effect of APOE ε4 on CSF Aβ42 was age dependent. The age at which CSF Aβ42 concentrations started to decrease was estimated at 50 years in APOE ε4-negative individuals and 43 years in heterozygous APOE ε4 carriers. Homozygous APOE ε4 carriers showed a steady decline in CSF Aβ42 concentrations with increasing age throughout the examined age span. CONCLUSIONS: People possessing the APOE ε4 allele start to show a decrease in CSF Aβ42 concentration almost a decade before APOE ε4 noncarriers already in early middle age. Homozygous APOE ε4 carriers might deposit Aβ42 throughout the examined age span. These results suggest that there is an APOE ε4-dependent period of early alterations in amyloid homeostasis, when amyloid slowly accumulates, that several years later, together with other downstream pathological events such as tau pathology, translates into cognitive decline. SN - 1758-9193 UR - https://www.unboundmedicine.com/medline/citation/29061195/Preclinical_effects_of_APOE_ε4_on_cerebrospinal_fluid_Aβ42_concentrations_ L2 - https://alzres.biomedcentral.com/articles/10.1186/s13195-017-0313-3 DB - PRIME DP - Unbound Medicine ER -