Title: Folic acid supplementation for patients at risk of dementia


Key words: folic acid, nutritional factors, chronic degenerative diseases, dementia, polymorphisms, ApoE4, methylenehydrofolate reductase, strokes, cardiovascular disease, CVD, genetic factors, MTHFR, homocysteine, vitamins, vitamin, B6, B12, B2, cognitive decline, geriatric patients, plasma folate, folate intake, genomics, B vitamins, supplementation, dietary folate, colorectal cancer, affective disorders, folate supplementation, spinal cord degeneration,  


Date: Oct 2006


Category: Micronutrients, Specific conditions


Nutrimed Module:


Type: Article


Author: Morgan, G

Folic acid supplementation for patients at risk of dementia

Genetic polymorphisms and their interactions with nutritional factors are increasingly being recognised as significant causes of chronic degenerative disease. In the case of dementia, two relatively common polymorphisms, the ApoE4 and the methylenetetrahydrofolate reductase (MTHFR) polymorphisms, have been associated with both cardiovascular disease and dementia (Regland 1999, Nishiyama 2000, Bottiglieri 2001). With dementia affecting 6-8% of the population over the age of 65 (Nourhashemi 2000), and one quarter of dementia cases being secondary to strokes and related cardiovascular disease (Morris 2003), it is increasingly important to identify at risk groups in the hope that modulation of genetic factors by nutritional interventions will help to reduce the growing incidence of dementia.


The MTHFR polymorphism is present in around 30% 0f the population. The homozygous form, present in 10-12% of the population, is associated with raised homocysteine levels (Verhoef 1997), shown to be an independent risk factor for vascular dementia and Alzheimer’s disease (AD) (McCaddon 2001, Seshadri 2002, McIlroy 2002). Homocysteine levels are modulated by the vitamin co-enzymes B12, B6 and folic acid and, significantly, by vitamin B2 levels in MTHFR homozygotes (McNulty 2002). Folate intake and plasma levels are the major determinants of homocysteine levels (Homocysteine Lowering Trialist’s Collaboration 1998), with raised homocysteine and depressed folate levels appearing to act synergistically in determining the severity of dementia (Clarke 1998, Morris 2001,Shea 2002, Religa 2003).


Both raised homocysteine (Bottiglieri 2001, Seshadri 2002) and depressed folate levels (Ebly 1998, Wang 2001, Maxwell 2002) have been shown to be independently linked to cognitive decline, stroke, and MRI changes of brain atrophy, particularly of the temporal lobes (Snowdon 2000, Toshifumi 2001, Vermeer 2002, Morris 2003). Homocysteine is toxic to neurones (Kruman 2000) and vascular epithelia (Hankey 1999), levels of 14mmol/l being associated with a doubling of the incidence of AD (Seshadri 2002). Studies have shown that daily supplementation of up to 5mgs folic acid leads to an up to 25% reduction in plasma homocysteine levels (Homocysteine Lowering Trialist’s Collaboration 1998).


To date, there is no evidence from intervention trials that folic acid supplementation, in lowering homocysteine levels, is able to reverse or reduce the incidence of dementia. However, a recent Cochrane meta- analysis (Malouf 2003) looked at only 4 trials, all with durations of less than 12 weeks, 3 of the studies being in established AD cases. The negative results must be regarded as methodologically flawed, given the undetermined time frame for the evolution of dementia, and other factors. A study involving geriatric patients admitted to a French hospital (Essami-Tjani 2000), showed no cognitive decline over a 12 month period, in spite of significant decline in folate status. However, more extended longitudinal studies over 3 years (Clarke 1998) and 8 years (Seshadri 2002) have shown baseline homocysteine levels to be independently linked to the future development of dementia. Subclinical folate deficiency may also pre-exist for several years and play a role in MTHFR-dependent homocysteine metabolism (Bottiglieri 2001, McCaddon 2002).


Homocysteine is now thought to be a more sensitive marker of functional folic acid status than plasma folate levels (Ubbink 1998, Quadri 2004). The decreased dietary folate intake seen in dementia may well represent a late stage in the evolution of an MTHFR polymorphism-dependent condition. Routine folate supplementation for those with a family history of dementia has been considered inadvisable at the present time in the absence of positive longitudinal intervention trials (Ubbink 1998, Reutens 2002). However there are reasons to adopt a more interventionist approach. Recent advances in genomics now make it possible to determine an individuals MTHFR status at an early stage. It has been hypothesized that the interaction of the relatively common ApoE4 and MTHFR polymorphisms are synergistic in determining the risk of both cardiovascular disease and dementia (Regland 1999).


Monitoring of B-vitamin and folate status, and of inflammatory markers such as C-reactive protein, LDL-cholesterol and homocysteine, is now practical and will enable the changes associated with cardiovascular disease and dementia to be identified at an early stage and supplementation to be instituted prophylactically many years in advance. Supplementation in long-term vitamin and mineral users has already been shown to be associated with higher plasma folate and lower homocysteine levels (Kato 1999). Given the variable bioavailability of dietary folate and the borderline status of many at risk groups, folic acid supplementation is much the most viable option (Sanderson 2003).


Additional benefits of folate supplementation are a reduced incidence of colorectal cancer (Kim 2003) and affective disorders (Godfrey 1990). Fears of promoting early stage colorectal cancer (Ryan 2001) and B12-related spinal cord degeneration (Brantigan 1996) can be addressed by concurrent B12 supplementation and routine blood and faecal blood tests as indicated. Given the rising rate of cardiovascular disease and dementia in the community, the cost and medical benefits of such protocols far outweigh any disadvantages. Routine folate supplementation for such groups is therefore to be recommended.



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