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

Document Type

Journal Article


Nature Publishing Group


Faculty of Health, Engineering and Science


School of Medical Sciences




This article was originally published as: Lim, Y., Villemagne, V., Laws, S. , Pietrzak, R., Snyder, P., Ames, D., Ellis, K., Harrington, K., Rembach, A., Martins, R. N., Rowe, C., Masters, C., & Maruff, P. (2014). APOE and BDNF polymorphisms moderate amyloid β-related cognitive decline in preclinical Alzheimer’s disease. Molecular Psychiatry, online first(online first), 1-7. Original article available here


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 (BDNFVal/Val, BDNFMet) 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−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+/BDNFMet participants showed a significantly faster rate of decline on verbal and visual EM, and language over 54 months compared with ε4−/BDNFVal/Val participants (d=0.90–1.02). At least two genetic loci affect the rate of Aβ-related cognitive decline. Aβ+ε4+/BDNFMet individuals can expect to show clinically significant memory impairment after 3 years, whereas Aβ+ε4+/BDNFVal/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.



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Open Access