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

作者：Lim Y Y; Villemagne V L; Laws S M; Pietrzak R H; Snyder P J; Ames D; Ellis K A; Harrington K; Rembach A; Martins R N; Rowe C C; Masters C L^*; Maruff P

来源：Molecular Psychiatry, 2015, 20(11): 1322-1328.

DOI：10.1038/mp.2014.123

Accumulation of beta-amyloid (A beta) 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 (epsilon 4 carrier[epsilon 4(+)], epsilon 4 non-carrier [epsilon 4(-)]) and brain-derived neurotrophic factor (BDNFVal/Val, BDNFMet) in the extent to which they moderate A beta-related memory decline. Healthy adults (n = 333, M-age = 70 years) enrolled in the Australian Imaging, Biomarkers and Lifestyle study underwent A beta neuroimaging. Neuropsychological assessments were conducted at baseline, 18-, 36- and 54-month follow-ups. A beta positron emission tomography neuroimaging was used to classify participants as A beta(-) or A beta(+). Relative to A beta(-)epsilon 4(-), A beta(+)epsilon 4(+) individuals showed significantly faster rates of cognitive decline over 54 months across all domains (d = 0.40-1.22), while A beta(+)epsilon 4(-) individuals showed significantly faster decline only on verbal episodic memory (EM). There were no differences in rates of cognitive change between A beta(-)epsilon 4(-) and A beta(-)epsilon 4(+) groups. Among A beta(+) individuals, epsilon 4(+)/BDNFMet participants showed a significantly faster rate of decline on verbal and visual EM, and language over 54 months compared with epsilon 4(-)/BDNFVal/Val participants (d = 0.90-1.02). At least two genetic loci affect the rate of A beta-related cognitive decline. A beta(+)epsilon 4(+)/BDNFMet individuals can expect to show clinically significant memory impairment after 3 years, whereas A beta(+)epsilon 4(+)/BDNFVal/Val individuals can expect a similar degree of impairment after 10 years. Little decline over 54 months was observed in the A beta(-) and A beta(+)epsilon 4(-) 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.

• 出版日期2015-11