APOE and BDNF polymorphisms moderate amyloid β-related cognitive decline in preclinical Alzheimer's disease

Y. Y. Lim, V. L. Villemagne, S. M. Laws, R. H. Pietrzak, P. J. Snyder, D. Ames, K. A. Ellis, K. Harrington, A. Rembach, R. N. Martins, C. C. Rowe, C. L. Masters, P. Maruff

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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 (ε4 carrier ε4 + , ε4 non-carrier ε4) 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, M age =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 - ε4 -, Aβ + ε4 + individuals showed significantly faster rates of cognitive decline over 54 months across all domains (d=0.40-1.22), while Aβ + ε4 - individuals showed significantly faster decline only on verbal episodic memory (EM). There were no differences in rates of cognitive change between Aβ - ε4 - and Aβ - ε4 + groups. Among Aβ + individuals, ε4 + /BDNF Met participants showed a significantly faster rate of decline on verbal and visual EM, and language over 54 months compared with ε4 - /BDNF Val/Val participants (d=0.90-1.02). At least two genetic loci affect the rate of Aβ-related cognitive decline. Aβ + ε4 + /BDNF Met individuals can expect to show clinically significant memory impairment after 3 years, whereas Aβ + ε4 + /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 + ε4 - 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.

Original languageEnglish
Pages (from-to)1322-1328
Number of pages7
JournalMolecular Psychiatry
Issue number11
Publication statusPublished - Nov 2015
Externally publishedYes


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