title: Folate and Alzheimer: when time matters.
abstract: Folate is necessary for DNA and mtDNA integrity and via folate/B12-dependent methionine cycle for methylation of multiple substrates (epigenetic DNA and enzymes) and methylation of homocysteine. During embryogenesis, folate deficiency is a risk factor for neural tube defects and late in life for cognitive decline and Alzheimer's dementia (AD). It induces several Alzheimer pathomechanisms like oxidative stress, Ca(++) influx, accumulation of hyperphosphorylated tau and β-amyloid. But impact of folic acid supplementation on prevention or delay of dementia is a matter of debate. Six out of seven randomized controlled trials (RCT) with B vitamin intervention periods between 2 and 5.4 years reported about cognitive benefits in the supplemented groups mainly for those subjects with high homocysteine or low folate levels at baseline. This review tries to demonstrate the connection between folate deficiency and AD, analyses selected epidemiologic studies and RCT on folate/B12/homocysteine with long-observation periods (≥ 2 years RCT; ≥ 4 years observational) and attempts to find explanations for the controversy in literature like short follow-up, heterogeneity of subjects concerning age, recruitment, baseline cognition, inclusion criteria and probably "misleading"(not representative for the past) folate/B12/homocysteine levels due to not reported short-term use of multivitamins or food-fortification. Population-based studies-epidemiologic and interventional-starting in the fourth decade would provide the best information about the impact of folate on later development of AD. Mandatory folate fortification areas will be important future field studies for-like neural tube defects-hopefully declining AD incidence and disproving safety concerns.
authors.affiliation: Ludwig Boltzmann Institute of Aging Research, Langobardenstraße 122, 1220, Vienna, Austria. margareta.hinterberger@utanet.at
authors.forename: Margareta
authors.initials: M
authors.lastname: Hinterberger
authors.forename: Peter
authors.initials: P
authors.lastname: Fischer
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000209:etiology* / Q000378:metabolism*; D003072:Cognition Disorders / Q000209:etiology; D018450:Disease Progression; D005492:Folic Acid / Q000378:metabolism*; D005494:Folic Acid Deficiency / Q000150:complications*; D006801:Humans; D012307:Risk Factors
chemical_list: D005492:Folic Acid