title: APOE and BDNF polymorphisms moderate amyloid β-related cognitive decline in preclinical Alzheimer's disease.
abstract: Accumulation of β-amyloid (Aβ) in the brain is associated with memory decline in healthy individuals as a prelude to Alzheimer's disease (AD). Genetic factors may moderate this decline. We examined the role of apolipoprotein E (ɛ4 carrier[ɛ4(+)], ɛ4 non-carrier[ɛ4(-)]) and brain-derived neurotrophic factor (BDNF(Val/Val), BDNF(Met)) in the extent to which they moderate Aβ-related memory decline. Healthy adults (n=333, Mage=70 years) enrolled in the Australian Imaging, Biomarkers and Lifestyle study underwent Aβ neuroimaging. Neuropsychological assessments were conducted at baseline, 18-, 36- and 54-month follow-ups. Aβ positron emission tomography neuroimaging was used to classify participants as Aβ(-) or Aβ(+). Relative to Aβ(-)ɛ4(-), Aβ(+)ɛ4(+) individuals showed significantly faster rates of cognitive decline over 54 months across all domains (d=0.40-1.22), while Aβ(+)ɛ4(-) individuals showed significantly faster decline only on verbal episodic memory (EM). There were no differences in rates of cognitive change between Aβ(-)ɛ4(-) and Aβ(-)ɛ4(+) groups. Among Aβ(+) individuals, ɛ4(+)/BDNF(Met) participants showed a significantly faster rate of decline on verbal and visual EM, and language over 54 months compared with ɛ4(-)/BDNF(Val/Val) participants (d=0.90-1.02). At least two genetic loci affect the rate of Aβ-related cognitive decline. Aβ(+)ɛ4(+)/BDNF(Met) individuals can expect to show clinically significant memory impairment after 3 years, whereas Aβ(+)ɛ4(+)/BDNF(Val/Val) individuals can expect a similar degree of impairment after 10 years. Little decline over 54 months was observed in the Aβ(-) and Aβ(+) ɛ4(-) groups, irrespective of BDNF status. These data raise important prognostic issues in managing preclinical AD, and should be considered in designing secondary preventative clinical trials.
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.|Department of Neurology, Warren Alpert School of Medicine, Brown University, Providence, RI, USA.|Department of Neurology, Rhode Island Hospital, Providence, RI, USA.
authors.forename: Y Y
authors.initials: YY
authors.lastname: Lim
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.|Department of Nuclear Medicine and Centre for PET, Austin Health, Heidelberg, VIC, Australia.|Department of Medicine, Austin Health, University of Melbourne, Heidelberg, VIC, Australia.
authors.forename: V L
authors.initials: VL
authors.lastname: Villemagne
authors.affiliation: Centre of Excellence for Alzheimer's Disease Research and Care, Edith Cowan University, Joondalup, WA, Australia.|Sir James McCusker Alzheimer's Disease Research Unit, Hollywood Private Hospital, Perth, WA, Australia.|Co-operative Research Centre for Mental Health.
authors.forename: S M
authors.initials: SM
authors.lastname: Laws
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: R H
authors.initials: RH
authors.lastname: Pietrzak
authors.affiliation: Department of Neurology, Warren Alpert School of Medicine, Brown University, Providence, RI, USA.|Department of Neurology, Rhode Island Hospital, Providence, RI, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: Snyder
authors.affiliation: Academic Unit for Psychiatry of Old Age, Department of Psychiatry, St. Vincent's Health, University of Melbourne, Kew, VIC, Australia.|National Ageing Research Institute, Parkville, VIC, Australia.
authors.forename: D
authors.initials: D
authors.lastname: Ames
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.|National Ageing Research Institute, Parkville, VIC, Australia.
authors.forename: K A
authors.initials: KA
authors.lastname: Ellis
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.
authors.forename: K
authors.initials: K
authors.lastname: Harrington
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Rembach
authors.affiliation: Centre of Excellence for Alzheimer's Disease Research and Care, Edith Cowan University, Joondalup, WA, Australia.
authors.forename: R N
authors.initials: RN
authors.lastname: Martins
authors.affiliation: Department of Nuclear Medicine and Centre for PET, Austin Health, Heidelberg, VIC, Australia.|Department of Medicine, Austin Health, University of Melbourne, Heidelberg, VIC, Australia.
authors.forename: C C
authors.initials: CC
authors.lastname: Rowe
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.
authors.forename: C L
authors.initials: CL
authors.lastname: Masters
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.|CogState Ltd, Melbourne, VIC, Australia.
authors.forename: P
authors.initials: P
authors.lastname: Maruff
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000150:complications* / Q000000981:diagnostic imaging / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000814:Aniline Compounds / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D003072:Cognition Disorders / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D005818:Genetic Engineering; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D049268:Positron-Emission Tomography; D011569:Psychiatric Status Rating Scales; D013844:Thiazoles / Q000378:metabolism
chemical_list: C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D001057:Apolipoproteins E; D019208:Brain-Derived Neurotrophic Factor; D013844:Thiazoles