April 2021
Xiaohong Zhang, Guangyi Bao, Debiao Liu, Yu Yang, Xuezhi Li, Gaomei Cai, Yan Liu and Yili Wu
Abstract
Alzheimer’s disease (AD) is the most common type of neurodegenerative disease leading to dementia in the elderly. Increasing evidence indicates that folate plays an important role in the pathogenesis of AD. To investigate the role of folate deficiency/possible deficiency in the risk of AD and the beneficial effect of sufficient folate intake on the prevention of AD, a systematic review and meta-analysis were performed.
The Web of Science, PubMed, CENTRAL, EBSCO, CNKI, CQVIP, and Wanfang databases were searched. The analysis of cross-sectional studies showed that the standardized mean difference (SMD) was −0.60 (95% confidence interval (CI): −0.65, −0.55), indicating that plasma/serum folate level is lower in AD patients than that in controls.
Moreover, the combined odds ratio (OR) of case-control studies was 0.96 (95% CI: 0.93, 0.99), while the combined ORs were 0.86 (95% CI: 0.46, 1.26) and 1.94 (95% CI: 1.02, 2.86) in populations with normal levels of folate (≥13.5 nmol/L) and folate deficiency/possible deficiency (<13.5 nmol/L), respectively. In addition, the risk ratio (RR) of the cohort studies was 1.88 (95% CI: 1.20, 2.57) in populations with folate deficiency/possible deficiency.
Furthermore, when the intake of folate was equal to or higher than the recommended daily allowance, the combined RR and hazard ratio (HR) were 0.44 (95% CI: 0.18, 0.71) and 0.76 (95% CI: 0.52, 0.99), respectively. These results indicate that folate deficiency/possible deficiency increases the risk for AD, while sufficient intake of folate is a protective factor against AD.
Keywords: Alzheimer’s disease, folate level, folate deficiency, sufficient folate intake, meta-analysis
Introduction
Alzheimer's disease (AD) is the most common type of neurodegenerative disease leading to dementia in the elderly. A progressive memory loss and deterioration of other cognitive functions are the main clinical manifestations, while extraneuronal neuritic plaques, intraneuronal neurofibrillary tangles, and neuronal loss are the neuropathological hallmarks of AD (Hebert et al., 2013; Bakota and Brandt, 2016; Mantzavinos and Alexiou, 2017; Li et al., 2018). According to the age of onset, AD is classified into early-onset AD (EOAD) and late-onset AD (LOAD). Compared with EOAD (onset before age 65), LOAD (onset after age 65) accounts for 95% or more of AD cases (Alzheimer's Association, 2012).
With the rapid increase of the aging population worldwide, over 50 million people were living with dementia globally in 2019 and the number is said to increase to 152 million by 2050 (Alzheimer's Disease International, 2019). The total cost for dementia was about 1 trillion US dollars in 2019 and it will be doubled by 2030 (Alzheimer's Disease International, 2019). AD accounts for 60–80% of dementia. Preventing or delaying the onset of AD is a priority as there is no effective treatment for AD.
Increasing evidence has indicated that dietary patterns and nutrition are implicated in the pathogenesis of AD (Otaegui-Arrazola et al., 2014). Thus, healthy diet and the balance of nutrients including vitamins are key factors in AD prevention. For example, marginal vitamin A deficiency promotes Aβ generation, the major component of neuritic plaques, and subsequent cognitive deficits (Zeng et al., 2017).
Increasing evidence suggests that folate, an essential vitamin, plays an important role in AD development (Jheng et al., 2016; Tian et al., 2016; Robinson et al., 2018; Guo et al., 2019). The normal range of plasma/serum folate ranges from 13.5 nmol/L to 45.3 nmol/L. Folate deficiency and possible deficiency are defined when the level of plasma/serum folate is <6.8 nmol/L and 13.5 nmol/L, respectively (WHO, 2015).
Previous studies showed that low folate level is not only associated with specific domains of cognitive functioning, e.g., episodic recall and recognition (Wahlin et al., 1996; Hassing et al., 1999; Nurk et al., 2005; De Lau et al., 2007), but also associated with all types of dementia, including vascular dementia and AD (Clarke et al., 1998; Ebly et al., 1998; Morris, 2003; Zhuo et al., 2011; Douaud et al., 2013; Cascalheira et al., 2015).
In addition, folate/folic acid supplementation is beneficial to the improvement of cognitive functions in aged subjects and cases of mild cognitive impairment (Fioravanti et al., 1997; Morris, 2003; Durga et al., 2007; De Jager et al., 2012; Ma et al., 2019). Moreover, deprivation of folate increases tau phosphorylation, the major component of neurofibrillary tangles (Chan and Shea, 2006). However, there has not been a meta-analysis study to investigate the association between folate deficiency/possible deficiency and the risk of AD, as well as the benefical effect of sufficient folate intake on the prevention of AD.
This study aims to investigate the role of folate deficiency/possible deficiency in the risk of AD and the beneficial effect of sufficient folate intake on the prevention of AD in addition to updating the association between plasma/serum folate levels and AD. We designed and performed this systematic review and meta-analysis to evaluate the difference of folate levels between AD patients and healthy controls, the association of folate deficiency/possible deficiency with AD risk, and the effect of sufficient folate intake on the prevention of AD.
CONCLUSIONS
AD patients had lower levels of folate than healthy controls. Folate deficiency/possible deficiency may increase the risk for AD. Sufficient daily intake of folate may reduce the risk of AD occurrence. Trials have already shown that folic acid supplementation can slow cognitive decline and brain atrophy in patients with mild cognitive impairment (De Jager et al., 2012; Douaud et al., 2013; Ma et al., 2019).
These findings indicated that sufficient folate intake is preventive against AD. Randomized controlled trials are needed to verify the causality of sufficient folate intake or folic acid supplementation and AD prevention.
