Abstract
Alzheimer’s Disease (AD) is a neurodegenerative disorder and represents the most common form of dementia in the elderly (about 80% of cases). The disease is clinically characterized by a progressive reduction in volume of the frontal and temporal lobes, of hippocampus and of amygdale, resulting from the degeneration of synapses and neurons and leading to loss of memory associated with changes in behavior and personality. These regions are also characterized by the occurrence of extracellular amyloid deposits or senile plaques and by the presence of intracellular neurofibrillary tangles composed of intraneuronal aggregates of hyperphophorylated tau protein. Although the clinical and neuropathological features have been well described, the etiology of the disease is still unknown. AD is a complex neurodegenerative disorder and most of the cases are sporadic forms (>90%), likely resulting from complex interactions between genetic and environmental factors, superimposed on cognitive decline due to aging. A familial history of the disease is observed in less than 10% of the cases. Familial AD is often characterized by earlier age at onset (<65 years) with respect to sporadic cases, and mutations in three genes (APP, PSEN1 and PSEN2) have been described as causative of familial forms.
Recently several clinical and epidemiological studies have focused on the possible correlation between AD and one-carbon metabolism. AD patients often show a decreased folate levels and increased homocysteine (hcy) levels in both blood and CSF. Folates are essential nutrients entirely derived from dietary source, and play a fundamental role in various biosynthetic processes, such as the synthesis of DNA and RNA precursors, the methylation of proteins and nucleic acids, and the synthesis of amino acids. Folates enter our body in the form of a complex mixture of compounds of polyglutamate, and require several transport systems to enter the cells, the best
characterized being the reduced folate carrier (RFC). Inside the cell, folate derivatives became part of various biosynthetic pathways.
In the present study we screened 378 late onset Alzheimer’s disease (LOAD) patients and 308 matched controls for the presence of the common MTHFR 677C>T, MTRR 66A>G, MTR 2756 A>G, and TYMS 28bp repeat polymorphisms, searching for association with disease risk and age at onset. Moreover, we searched for correlation between each of the studied polymorphisms and available data on plasma homocysteine (Hcy), serum folate and vitamin B12 values.
The frequencies of the MTHFR 677T allele (0.48 vs. 0.42; p=0.019) and of MTHFR 677CT (OR=1,46; 95%CI=1,03-2,06) and TT genotypes (OR=1,62; 95%CI=1,05-2,49) were significantly increased in LOAD subjects with respect to controls. The frequencies of the MTRR 66G allele (0.49 vs. 0.43; p=0.044) and of the MTRR 66GG genotype (OR=1,57; 95%CI=1,01-2,46) were significantly higher in LOAD patients than in controls. Significantly increased mean plasma Hcy levels (22.7+1.5 vs 14.5+1.5 μmol/L; p=0.037) and decreased serum folate values (5.7+0.6 vs. 7.8+0.8 ng/mL; p=0.005) were observed in LOAD subjects with respect to controls. Several interactions between the studied polymorphisms and biochemical biomarkers were observed. None of the studied polymorphisms was associated with disease age at onset.
