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Nat Commun. 2016 Mar 7;7:10918. doi: 10.1038/ncomms10918.

Increased amyloidogenic APP processing in APOE ɛ4-negative individuals with cerebral β-amyloidosis.

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Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Simrisbanvägen 14, Malmö 212 24, Sweden.
Memory Clinic, Skåne University Hospital, Simrisbanvägen 14, Malmö 212 24, Sweden.
Department of Neurology, Skåne University Hospital, Getingevägen 4, Lund 222 41, Sweden.
Center for Imaging of Neurodegenerative Diseases, Department of Radiology and Biomedical Imaging, San Francisco Veterans Affairs Medical Center (SFVAMC) campus, 4150 Clement Street, University of California, San Francisco, California 94121, USA.
Department of Clinical Sciences, Diagnostic Radiology, Lund University, Box 117, Lund 221 00, Sweden.
Center for Medical Imaging and Physiology, Skåne University Hospital, Getingevägen 4, Lund 222 41, Sweden.
Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal 431 80, Sweden.


Increased APP (amyloid precursor protein) processing causes β-amyloid (Aβ) accumulation in autosomal dominant Alzheimer's disease (AD), but it is unclear if it also affects sporadic Aβ accumulation. We tested healthy controls and patients with mild cognitive symptoms (N=331) in the BioFINDER study, using cerebrospinal fluid (CSF) Aβ40 as a surrogate for amyloidogenic APP processing. We find that levels of brain Aβ fibrils (measured by 18F-flutemetamol PET) are independently associated with high CSF Aβ40 (P<0.001) and APOE ɛ4 (P<0.001). The association between CSF Aβ40 and brain Aβ is stronger in APOE ɛ4-negative than in positive people (P=0.0080). The results are similar for CSF Aβ38 and for a combination of CSF Aβ38 and CSF Aβ40. In conclusion, sporadic Aβ accumulation may be partly associated with increased amyloidogenic APP production, especially in APOE ɛ4-negative subjects. The risk for sporadic AD may consequently depend on increased Aβ production, in addition to decreased Aβ clearance.

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