Editing Folate (section)

===Neurological disorders===
Conversion of homocysteine to methionine requires folate and vitamin B<sub>12</sub>. Elevated plasma homocysteine and low folate are associated with cognitive impairment, dementia and [[Alzheimer's disease]].<ref>{{cite journal |vauthors=Shen L, Ji HF |title=Associations between Homocysteine, Folic Acid, Vitamin B12 and Alzheimer's Disease: Insights from Meta-Analyses |journal=J. Alzheimers Dis. |volume=46 |issue=3 |pages=777–90 |date=2015 |pmid=25854931 |doi=10.3233/JAD-150140}}</ref><ref name=Ford2012/> Supplementing the diet with folic acid and vitamin B<sub>12</sub> lowers plasma homocysteine.<ref name=Ford2012/> However, several reviews reported that supplementation with folic acid alone or in combination with other B vitamins did not prevent development of cognitive impairment nor slow cognitive decline.<ref name=Li2014>{{cite journal |vauthors=Li MM, Yu JT, Wang HF, Jiang T, Wang J, Meng XF, Tan CC, Wang C, Tan L |title=Efficacy of vitamins B supplementation on mild cognitive impairment and Alzheimer's disease: a systematic review and meta-analysis |journal=Curr Alzheimer Res |volume=11 |issue=9 |pages=844–52 |date=2014 |pmid=25274113 }}</ref><ref name=Ford2012>{{cite journal |vauthors=Ford AH, Almeida OP |title=Effect of homocysteine lowering treatment on cognitive function: a systematic review and meta-analysis of randomized controlled trials |journal=J. Alzheimers Dis. |volume=29 |issue=1 |pages=133–49 |date=2012 |pmid=22232016 |doi=10.3233/JAD-2012-111739}}</ref><ref>{{cite journal |vauthors=Wald DS, Kasturiratne A, Simmonds M |title=Effect of folic acid, with or without other B vitamins, on cognitive decline: meta-analysis of randomized trials |journal=Am. J. Med. |volume=123 |issue=6 |pages=522–527.e2 |date=June 2010 |pmid=20569758 |doi=10.1016/j.amjmed.2010.01.017}}</ref>

Relative risk of [[autism spectrum disorder]]s (ASDs) was reported reduced by 23% when the maternal diet was supplemented with folic acid during pregnancy. Subset analysis confirmed this among Asian, European and American populations.<ref>{{cite journal |vauthors=Wang M, Li K, Zhao D, Li L |title=The association between maternal use of folic acid supplements during pregnancy and risk of autism spectrum disorders in children: a meta-analysis |journal=Mol Autism |volume=8 |page=51 |date=2017 |pmid=29026508 |pmc=5625821 |doi=10.1186/s13229-017-0170-8 |doi-access=free }}</ref> Cerebral folate deficiency (CFD) has been associated with ASDs. The cerebral folate receptor alpha (FRα) transports 5-methyltetrahydrofolate into the brain. One cause of CFD is autoantibodies that interfere with FRa, and FRa autoantibodies have been reported in ASDs. For individuals with ASD and CFD, meta-analysis reported improvements with treatment with [[folinic acid]], a 5-formyl derivative of [[tetrahydrofolic acid]], for core and associated ASD symptoms.<ref name="Rossignol2021">{{cite journal |vauthors=Rossignol DA, Frye RE |title=Cerebral folate deficiency, folate receptor alpha autoantibodies and leucovorin (folinic acid) treatment in autism spectrum disorders: A systematic review and meta-analysis |journal=J Pers Med |volume=11 |issue=11 |date=November 2021 |page=1141 |pmid=34834493 |pmc=8622150 |doi=10.3390/jpm11111141 |doi-access=free |url=}}</ref>

Some evidence links a shortage of folate with [[clinical depression]].<ref name="dep_coppen">{{cite journal|vauthors=Coppen A, Bolander-Gouaille C|s2cid=4828454|title=Treatment of depression: time to consider folic acid and vitamin B12|journal=Journal of Psychopharmacology|volume=19|issue=1|pages=59–65|date=January 2005|pmid=15671130|doi=10.1177/0269881105048899}}</ref>  An 2024 umbrella meta-analysis concluded that folate supplementation alleviates depression symptoms, while folate deficiency is associated with an increased risk of depression, suggesting folate as a beneficial [[Combination therapy|adjunctive]] treatment in managing depression.<ref>{{cite journal | vauthors = Gao S, Khalid A, Amini-Salehi E, Radkhah N, Jamilian P, Badpeyma M, Zarezadeh M | title = Folate supplementation as a beneficial add-on treatment in relieving depressive symptoms: A meta-analysis of meta-analyses | journal = Food Science & Nutrition | volume = 12 | issue = 6 | pages = 3806–3818 | date = June 2024 | pmid = 38873435 | pmc = 11167194 | doi = 10.1002/fsn3.4073 }}</ref> Other research also found a link between depression and low levels of folate.<ref>{{cite journal|vauthors=Gilbody S, Lewis S, Lightfoot T|title=Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: a HuGE review|journal=American Journal of Epidemiology|volume=165|issue=1|pages=1–13|date=January 2007|pmid=17074966|doi=10.1093/aje/kwj347|doi-access=free}}</ref><ref>{{cite journal|vauthors=Gilbody S, Lightfoot T, Sheldon T|title=Is low folate a risk factor for depression? A meta-analysis and exploration of heterogeneity|journal=Journal of Epidemiology and Community Health|volume=61|issue=7|pages=631–7|date=July 2007|pmid=17568057|pmc=2465760|doi=10.1136/jech.2006.050385}}</ref> The exact mechanisms involved in the development of schizophrenia and depression are not entirely clear, but the bioactive folate, [[Levomefolic acid|methyltetrahydrofolate]] (5-MTHF), a direct target of methyl donors such as [[S-adenosyl methionine]] (SAMe), recycles the inactive [[dihydrobiopterin]] (BH<sub>2</sub>) into [[tetrahydrobiopterin]] (BH<sub>4</sub>), the necessary [[Cofactor (biochemistry)|cofactor]] in various steps of monoamine synthesis, including that of [[dopamine]] and [[serotonin]]. BH<sub>4</sub> serves a regulatory role in monoamine neurotransmission and is required to mediate the actions of most antidepressants.<ref>{{cite journal|vauthors=Krebs MO, Bellon A, Mainguy G, Jay TM, Frieling H|title=One-carbon metabolism and schizophrenia: current challenges and future directions|journal=Trends in Molecular Medicine|volume=15|issue=12|pages=562–70|date=December 2009|pmid=19896901|doi=10.1016/j.molmed.2009.10.001}}</ref>