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Abstract
Objectives. Abnormalities in neurotrophic systems have been reported in Alzheimer's disease (AD), as shown by decreased serum brain-derived neurotrophic factor (BDNF) levels and association with BDNF genetic polymorphisms. In this study, we investigate whether these findings can be detected in patients with mild cognitive impairment (MCI), which is recognized as a high risk condition for AD. We also address the impact of these variables on the progression of cognitive deficits within the MCI-AD continuum. Methods. One hundred and sixty older adults with varying degrees of cognitive impairment (30 patients with AD, 71 with MCI, and 59 healthy controls) were longitudinally assessed for up to 60 months. Baseline serum BDNF levels were determined by sandwich ELISA, and the presence of polymorphisms of BDNF and apolipoprotein E (Val66Met and APOE*E4, respectively) was determined by allelic discrimination analysis on real time PCR. Modifications of cognitive state were ascertained for non-demented subjects. Results. Mean serum BDNF levels were reduced in patients with MCI and AD, as compared to controls (509.2±210.5; 581.9±379.4; and 777.5±467.8 pg/l respectively; P<0.001). Baseline serum BDNF levels were not associated with the progression of cognitive impairment upon follow-up in patients with MCI (progressive MCI, 750.8±463.0; stable MCI, 724.0±343.4; P=0.8), nor with the conversion to AD. Although Val66Met polymorphisms were not associated with the cross-sectional diagnoses of MCI or AD, the presence of Met-BDNF allele was associated with a higher risk of disease-progression in patients with MCI (OR=3.0 CI95% [1.2–7.8], P=0.02). We also found a significant interaction between the APOE*E4 and Met-BDNF allele increasing the risk of progression of cognitive impairment in MCI patients (OR=4.4 CI95% [1.6–12.1], P=0.004). Conclusion. Decreased neurotrophic support, as indicated by a reduced systemic availability of BDNF, may play role in the neurodegenerative processes that underlie the continuum from MCI to AD. The presence of Met-BDNF allele, particularly in association with APOE*E4, may predict a worse cognitive outcome in patients with MCI.
Acknowledgements
This work was funded by grants from Rede Instituto Brasileiro de Neurociência (IBN Net/Finep), Fundação de Amparo á Pesquisa do Estado de São Paulo (FAPESP, 02/12633-7), Associação Beneficente Alzira Denise Hertzog da Silva (ABADHS).
The sponsors and funders did not have any influence in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.
Statement of interest
The authors have neither financial disclosure nor conflict of interest concerning the information provided in this manuscript. Orestes V. Forlenza and Breno S. Diniz had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.