Effect of brain-derived neurotrophic factor Val66Met polymorphism and serum levels on the progression of mild cognitive impairment.
OBJECTIVE
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 CI(95%) [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 CI(95%) [1.6-12.1], P=0.004).


CONCLUSIONS
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.
Forlenza
Orestes Vicente
OV
Laboratory of Neuroscience-LIM 27, Department and Institute of Psychiatry, Faculty of Medicine, University of Sao Paulo, SP, Brazil. forlenza@usp.br
Diniz
Breno Satler
BS
Teixeira
Antonio Lucio
AL
Ojopi
Elida Benquique
EB
Talib
Leda Leme
LL
Mendonça
Vanessa Amaral
VA
Izzo
Giselle
G
Gattaz
Wagner Farid
WF
D000368:Aged; D000704:Analysis of Variance; D001057:Apolipoproteins E / Q000097:blood / Q000235:genetics; D019208:Brain-Derived Neurotrophic Factor / Q000097:blood* / Q000235:genetics*; D003072:Cognition Disorders / Q000097:blood* / Q000235:genetics*; D015331:Cohort Studies; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D011110:Polymorphism, Genetic / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012720:Severity of Illness Index
D001057:Apolipoproteins E; D019208:Brain-Derived Neurotrophic Factor