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Potential Neuroregenerative and Neuroprotective Effects of Uridine/Choline-Enriched Multinutrient Dietary Intervention for Mild Cognitive Impairment: A Narrative Review

Abstract

In mild cognitive impairment (MCI) due to Alzheimer disease (AD), also known as prodromal AD, there is evidence for a pathologic shortage of uridine, choline, and docosahexaenoic acid [DHA]), which are key nutrients needed by the brain. Preclinical and clinical evidence shows the importance of nutrient bioavailability to support the development and maintenance of brain structure and function in MCI and AD. Availability of key nutrients is limited in MCI, creating a distinct nutritional need for uridine, choline, and DHA. Evidence suggests that metabolic derangements associated with ageing and disease-related pathology can affect the body’s ability to generate and utilize nutrients. This is reflected in lower levels of nutrients measured in the plasma and brains of individuals with MCI and AD dementia, and progressive loss of cognitive performance. The uridine shortage cannot be corrected by normal diet, making uridine a conditionally essential nutrient in affected individuals. It is also challenging to correct the choline shortfall through diet alone, because brain uptake from the plasma significantly decreases with ageing. There is no strong evidence to support the use of single-agent supplements in the management of MCI due to AD. As uridine and choline work synergistically with DHA to increase phosphatidylcholine formation, there is a compelling rationale to combine these nutrients. A multinutrient enriched with uridine, choline, and DHA developed to support brain function has been evaluated in randomized controlled trials covering a spectrum of dementia from MCI to moderate AD. A randomized controlled trial in subjects with prodromal AD showed that multinutrient intervention slowed brain atrophy and improved some measures of cognition. Based on the available clinical evidence, nutritional intervention should be considered as a part of the approach to the management of individuals with MCI due to AD, including adherence to a healthy, balanced diet, and consideration of evidence-based multinutrient supplements.

Key Summary Points

In Alzheimer disease (AD) and mild cognitive impairment (MCI) due to AD, there is strong evidence for a pathologic shortage of uridine, choline, and docosahexaenoic acid (DHA).
While attention to improving nutrition is strongly recommended in the management of MCI, changes to normal diet alone cannot correct the shortage of uridine observed in the plasma and brains of individuals with dementia.
Uridine and choline work synergistically with DHA to increase phosphatidylcholine formation, and there is a compelling rationale to combine these nutrients to provide neuroprotection and promote neurogenesis.
Clinical evidence from randomized controlled trials suggests that the use of a uridine-, choline-, and DHA-enriched multinutrient product may have a role in the management of individuals with MCI due to AD.

Digital Features

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Introduction

According to the diagnostic criteria developed by the National Institute on Aging-Alzheimer’s Association (NIA-AA) [1], mild cognitive impairment (MCI) may be differentiated from dementia by maintenance of functional independence and the absence of significant impairment in social or occupational functions [2]. The NIA-AA criteria also define ‘MCI due to Alzheimer’s disease (AD)’ to describe individuals who are symptomatic and have evidence of AD pathology prior to a diagnosis of dementia [1]. Individuals with MCI due to AD (the prodromal stage of AD, as defined using the International Working Group [IWG]-1 criteria [3]) are on a clinical pathway towards overt dementia. These individuals typically have mild cognitive and functional impairments, and pathologic changes shown by biomarkers [2,3,4]. Disease progression from MCI to AD is characterized by increasingly debilitating memory loss and cognitive impairment [5]. Worsening clinical symptoms correlate with a net loss of synapses [6], resulting from increased breakdown of existing synapses and reduced formation of new synapses [7]. These ominous pathophysiological changes begin even before the disease manifests clinically [6], and signal a need for early intervention [8, 9]. In MCI due to AD, there is an unmet medical need to stimulate the process of synapse formation (neuroregeneration) and to reduce neuronal loss and/or mitigate the adverse effects of neuronal breakdown products (neuroprotection) [10].

Pharmacologic approaches targeting synaptic dysfunction have been reviewed by other authors [10,11,12,13,14]. We wished to consider the challenge from a different perspective, looking at the importance of nutrient substrates involved in the metabolic pathways leading to synaptogenesis [15]. Evidence suggests that substrates needed simultaneously for the Kennedy/phosphatidylcholine (PC) pathway [16], namely uridine, choline, and docosahexaenoic acid (DHA), have important neuroregenerative and neuroprotective functions in the central nervous system (CNS) [17, 18]. In this review, we examine the evidence for a disease-related shortage in the bioavailability of uridine, choline, and DHA, and evaluate the potential for increasing brain levels of these nutrients to improve long-term outcomes in MCI due to AD. Other authors have highlighted the potential of dietary and nutritional intervention for MCI due to AD, while noting the limited evidence supporting effectiveness, particularly for single-agent nutrients [19,20,21,22]. It is not our intention to recapitulate previous comprehensive reviews; instead, we focus on uridine and choline in MCI due to AD, and highlight the particular challenge of correcting the shortfall in uridine availability.

Methods

We searched the PubMed database in May 2020 using various combinations of the following search terms: ‘mild cognitive impairment’, ‘Alzheimer’s disease’, ‘prodromal Alzheimer’s disease’, ‘uridine’, ‘choline’, and ‘docosahexaenoic acid’. The primary focus of the search was to identify studies in human subjects with MCI. In addition, we included nonclinical studies investigating the effects of nutrient interventions on neuronal structure and function. We selected the most relevant articles based on our knowledge of the field. The specific objectives of the literature review were to assess evidence showing changes in the levels of uridine and choline in patients with MCI and AD; the neurologic consequences of nutrient shortages; the possible neuroregenerative and neuroprotective effects of increasing nutrient supply; and outcomes data from controlled clinical trials investigating single or multinutrient supplements in patients with MCI. We considered the available evidence supporting the hypothesis that a shortage of specific nutrients leads to an inability to increase neuronal membrane formation to counteract the net loss of synapses occurring in MCI.

Compliance with Ethics Guidelines

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors. All clinical trials cited in this review provided ethical declarations in the original publications and were conducted in compliance with the Declaration of Helsinki.

Uridine and Choline are Crucial Molecules for Brain Function

Uridine

Uridine is the major form of pyrimidine nucleoside taken up by the brain, where it is used in nucleic acids and for the synthesis of membrane constituents [18]. In addition, uridine is a biologically active molecule in the brain with apparent roles in several CNS functions including memory and neuronal plasticity (reviewed in [18]). The effects of uridine on brain structures and functions appear to be mediated by its effects in promoting neuronal membrane formation and through interactions with specific uridine-nucleotide receptors (brain P2Y2 receptors) that control neuronal differentiation [15, 18, 23]. It has been suggested that activation of P2Y2 receptors by uridine triphosphate (UTP), released as a neurotransmitter from presynaptic terminals [24], could have a neuroprotective effect in neurodegenerative diseases such as AD [25]. Furthermore, UTP may be converted to cytidine triphosphate (CTP), which is a key intermediate used in the Kennedy cycle to generate PC for the synthesis of neuronal membranes (Fig. 1) [15]. Considering the important role that uridine has in brain structure and functions, it is not surprising that shortages in uridine supply can lead to neurological symptoms [26].

Fig. 1
figure 1

Pathways of phosphatidylcholine synthesis. EPA eicosapentaenoic acid, DHA docosahexaenoic acid, DAG diacylglycerol, UMP uridine monophosphate, CTP cytidine triphosphate, CDP-choline cytidine diphosphate-choline, Hcy homocysteine, Met methionine, UMP uridine monophosphate, Vit vitamin

Choline and DHA

Choline is an essential micronutrient that is required for normal brain development and cognitive functions throughout life [27, 28]. Choline modulates the expression of key genes related to memory, learning, and cognitive functions via epigenetic mechanisms [27]. The central importance of the cholinergic system in the pathophysiology of dementia has been reviewed extensively [29]. Choline is a limiting precursor of the neurotransmitter acetylcholine (ACh) [27]. Cholinergic deficit is a hallmark of AD [29, 30], and changes may be evident from the early stages of disease [31]. However, in MCI and early AD, cognitive deficits are not directly associated with cholinergic system loss, and research suggests that compensatory upregulation of choline acetyltransferase (ChAT) activity could be important in mitigating the progression of MCI to AD [32].

Drug therapy to increase cholinergic neurotransmission is standard in the symptomatic management of AD [33] and may be used in some individuals with MCI, despite a lack of strong evidence [5]. An alternative approach to counter deficits in the cholinergic system could be to improve the supply of choline and other substrates. As a key substrate of metabolic pathways (Kennedy and phosphatidylethanolamine N-methyltransferase [PEMT]) involved in the generation of PC [34, 35], choline is needed, together with DHA and uridine, for the synthesis of neuronal membranes (Fig. 1) [17].

Phospholipid abnormalities, consistently affecting PC species with five or six double bonds, for example PC-DHA [28], are well documented in the brains [36,37,38,39,40,41,42,43,44,45,46,47,48,49,50] and cerebrospinal fluid (CSF) [51,52,53] of patients with AD, and these changes are reflected in the plasma [54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70]. Disturbed phospholipid metabolism is evident early in the disease process and is observed in individuals with MCI [49, 50, 68, 71,72,73]. Studies in patients with AD have shown lower levels of PC-DHA, which is associated with faster cognitive decline than in control subjects [74,75,76], whereas the highest level of plasma PC-DHA was associated with a significant reduction in the risk of developing all-cause dementia in the Framingham Heart Study [77].

Availability of Key Nutrients is Limited in MCI, Creating a Distinct Nutritional Need for Uridine and Choline

Previously, two systematic meta-analyses have shown that patients with AD have significantly lower plasma and brain levels of specific nutrients, including DHA and choline-containing lipids, compared with age-matched controls with normal cognitive function [78, 79]. Studies have shown that levels of uridine are lower in the plasma and/or brains of patients with AD compared with age-matched healthy controls [80,81,82,83,84,85,86,87,88]. These changes occur in very mild AD even in the absence of protein/energy malnutrition [82]. In addition, metabolomic analyses have shown that increased brain cysteine levels associated with decreased uridine can characterize mild AD [80]. The authors suggested that a reduction in uridine in the CSF of patients with AD could mediate reduced synaptic plasticity and neuronal deficits [80].

Metabolomic analyses have also shown significant changes in neurotransmitter metabolism in the ACh pathway in CSF from individuals with AD [88], and in choline and tryptophan pathways in early AD [89]. High levels of homocysteine are observed in patients with AD, which can impair choline synthesis by interfering with the activity of the PEMT pathway [74]. Therefore, metabolic disturbances affecting the PEMT pathway can reduce the syntheses of PC and ACh.

One cross-sectional study examined levels of uridine, choline, folate, homocysteine, and other substrates in the blood and CSF of 148 individuals with MCI (age 66 ± 8 years, 37% female, mini-mental state examination [MMSE] 26.7) compared with 148 healthy, matched controls (age 59 ± 8 years, 38% female, MMSE 28.3) [83]. The analysis showed that subjects with MCI had significantly lower levels of uridine than controls both in the blood (mean ± standard deviation 3.64 ± 1.25 vs 4.08 ± 1.50, respectively; P < 0.05) and in the CSF (2.90 ± 0.60 vs 3.07 ± 0.59, respectively; P < 0.05). Subjects with MCI also had lower blood and CSF folate, and higher CSF homocysteine concentrations than control subjects (all P < 0.05) [83]. Blood and CSF levels of choline were not significantly different between MCI and control groups [83]. The study also included a cohort of 150 patients with AD (age 66 ± 7 years, 37% female, MMSE 20.5). While patients with AD had lower levels of CSF uridine and blood choline (and higher CSF homocysteine) than control subjects, the study showed no differences in blood and CSF levels of these nutrients between subjects with MCI and those with AD [83]. This finding supports the notion that changes in nutrient status start early in the course of AD [82]. The study also showed that blood levels of uridine, choline, betaine, folate, and homocysteine positively correlated with CSF levels in all groups [83]. However, the authors noted weaker correlations between blood and CSF levels of uridine and folate in subjects with AD than in control subjects, which they suggested could indicate decreased uptake into the brain [83]. The brain cannot synthesize choline, and plasma choline does not freely cross the blood–brain barrier [27]. The availability of choline to the brain may therefore be restricted by age-related changes in transport of plasma choline across the blood–brain barrier [27, 90, 91].

From a clinical perspective, it is important to know whether shortages in these key nutrients correlate with the severity of memory loss and cognitive impairment. A cross-sectional study of elderly subjects, aged 70–74 years, selected independently of their cognitive status, showed that low levels of choline in the plasma are associated with poor cognitive performance [92]. A National Health and Nutrition Examination Survey (NHANES) study found that inadequate intake of micronutrients including choline was significantly associated with lower working memory performance in healthy elderly subjects (aged ≥ 60 years) [93]. A prospective study involving a total of 551 individuals with subjective cognitive decline (SCD; n = 219, age 61 ± 8 years, 47% female), MCI (n = 135, age 66 ± 8 years, 40% female), or AD-type dementia (n = 197, age 67 ± 8 years, 50% female) looked at potential nutritional markers associated with clinical progression (defined as progression of SCD to MCI or dementia, progression of MCI to dementia, an increase of ≥ 1 point on clinical dementia rating scale or admission to a nursing home or death in subjects with AD, or self-reported progression of cognitive symptoms in all groups) [94]. Clinical progression was observed in 25 (11%) subjects with SCD, in 45 (33%) with MCI, and in 100 (51%) with AD. Preliminary results showed that clinical progression was associated with higher levels of low-density lipoprotein cholesterol in subjects with SCD (hazard ratio [HR] 1.92; 95% confidence intervals [CI] 1.05–3.52), and with lower levels of uridine in subjects with AD (HR 0.78; 95% CI 0.62–0.99). Lower levels of uridine were also associated with clinical progression in subjects with a positive amyloid test. Based on these findings, the authors recommended targeting uridine and cholesterol levels in individuals with cognitive decline [94].

In summary, the evidence suggests that metabolic derangements associated with ageing and disease pathology can affect the ability of the body to utilize nutrients and generate brain synapses [80, 87, 88]. This is reflected in lower levels of the nutrients as measured in the blood and brains of individuals with MCI and very mild AD, and progressive loss of cognitive performance.

Increasing Uridine and Choline Availability Promotes Neuroregeneration and is Neuroprotective

The metabolic pathways involved in the conversion of uridine to UTP and subsequently to CTP for use in the PC pathway depend on low-affinity enzymes; consequently, providing the brain with uridine will increase the formation of PC [17]. Preclinical experiments have shown that administration of uridine with other key substrates (choline and DHA) stimulates neuroregeneration (reviewed in [95]), increasing the production of synaptic proteins [96,97,98], the formation of neurites and synapses [98,99,100,101,102], and the levels of neurotransmission [96, 103,104,105], which in turn may lead to improvements in memory performance [103, 106,107,108,109]. Preclinical experiments have also shown that uridine administration may provide neuroprotection [95], evidenced by reducing Abeta production and plaque formation [103, 110], and diminishing neurodegeneration [103, 106, 107, 110]. It is important to note that these neuroprotective effects were observed by administering uridine with other nutrients including choline and DHA. For example, administering a multinutrient containing uridine, choline, and DHA was shown to protect the cholinergic system against Abeta42-induced toxicity in rats [103] and to reduce AD-like pathology in AbetaPP/PS1 mice [110].

There is evidence from the clinical setting showing that uridine administration may have positive effects on cognitive functions. A controlled study in 17 healthy volunteers showed that administration of uridine increases brain membrane phospholipid precursors (measured using 31-phosphorus magnetic resonance spectroscopy [MRS]) [111]. Another MRS study in healthy volunteers (n = 16) showed that administration of cytidine diphosphate-choline (CDP-choline) also affects phospholipid membrane turnover and may increase the availability of phospholipid membrane components needed to synthesize and maintain cell membranes [112].

There is only limited evidence from clinical studies to show that administration of uridine or choline improves cognitive performance. A small clinical trial (n = 12) showed that administration of CDP-choline (which increases uridine levels in the brain [113]) improved performance in individuals with relatively inefficient memory [114]. A population-based study in 1391 subjects (aged 36–83 years) free from dementia showed that concurrent choline intake was positively correlated with cognitive function tests and inversely correlated with white-matter hyperintensity volume [115]. Another population study (n = 2497 dementia-free men aged 42–60 years) showed that higher intake of PC was associated with lower risk of incident dementia and better cognitive performance [116]. In the dementia setting, a randomized controlled trial showed that choline alfoscerate decreased cognitive impairment due to mild to moderate AD [117].

The Nutritional Need for Uridine and Choline in MCI Cannot be Met with a Normal Diet or Single Supplements

Long-term adherence to a healthy diet appears to support cognitive function in ageing individuals at risk for dementia [20, 118, 119]. Recent research suggests that preventive strategies including diet, exercise, cognitive training, and vascular risk monitoring may be more effective if started early, before pronounced structural brain changes develop [120].

McGrattan and colleagues performed a systematic review of randomized controlled trials of dietary interventions (dietary pattern or supplements) in subjects with any form of MCI diagnosed by a physician according to internationally accepted criteria [121]. The literature search done in June 2016 identified 16 trials, including one using a multinutrient intervention containing uridine, choline, and DHA [122]. The authors reported inconsistent findings among the heterogenous studies, which overall did not provide clear evidence to support any particular dietary intervention to improve cognitive function in MCI, or evidence of a significant effect on progression from MCI to dementia [123]. Our literature search did not identify any more recent clinical studies of uridine or choline supplementation in subjects diagnosed with MCI due to AD.

The apparent nutritional need in MCI due to AD cannot be addressed simply by modifying the normal diet or administering multivitamin/mineral supplements, as these may unnecessarily increase the intake of other nutrients associated with increased risk of dementia (e.g. cholesterol, trans fatty acids, saturated fat, and vitamin A) [124, 125]. Dietary modifications to address shortages of uridine and choline in individuals with MCI due to AD appear to be particularly challenging. Uridine obtained from dietary sources is unavailable to the adult brain (due to degradation by the liver) [126], while food substances purported to increase uridine levels, such as beer [127], are impractical and potentially harmful. As an essential nutrient, choline must be obtained from the diet. Although available from many dietary sources, it is estimated that up to 90% of Americans consume below the adequate intake for choline [128].

Dietary supplements have been suggested to increase levels of specific nutrients in individuals with MCI and AD [28, 46, 113, 129, 130]; however, to date, nutrient intervention studies have shown that while single-agent supplements are effective in elevating plasma levels, they generally fail to demonstrate clinical benefits [131,132,133,134]. We found only limited evidence from randomized controlled clinical trials to support single-agent supplementation with uridine, choline (or CDP-choline), or DHA in MCI due to AD or probable AD [121, 135,136,137,138]. As uridine and choline work synergistically with DHA to increase PC formation, there is a compelling rationale for combining these nutrients [139].

Clinical Evidence for Uridine- and Choline-Enriched Multinutritional Intervention in MCI Due to AD

A specific uridine-, choline-, and DHA-enriched multinutrient (Souvenaid; Nutricia) has been developed to support synapse formation in patients with AD and MCI due to AD (Table 1). The first randomized controlled clinical trials of this multinutrient were conducted in patients with mild–moderate AD because of the high medical and nutritional needs in this population [140,141,142,143]. An early trial of the product in 527 patients with mild–moderate AD dementia (MMSE 19.5, receiving drug therapy for AD) showed no significant cognitive improvements over a 24-week intervention period [143]. The authors speculated that patients with moderate AD may have progressed to such an extent that neuronal damage and synaptic dysfunction was irreversible and not responsive to either pharmacologic or non-pharmacologic interventions. They suggested that the potential to benefit from multinutritional interventions to increase synaptogenesis may be limited in moderate AD compared with mild AD because of the higher levels of neurodegeneration [143]. Two further clinical trials showed that the multinutrient was associated with a statistically significant improvement in memory in patients with mild and very mild AD dementia (MMSE 23.9 [141] and MMSE 25 [142]) over 12–48 weeks, respectively [140,141,142]. Since the data implied effects were most likely to be achieved at the early end of the AD spectrum, the LipiDiDiet study was designed to test multinutrient intervention in patients with MCI due to AD (prodromal AD) [122].

Table 1 Randomized controlled studies of uridine- and choline-enriched nutrient intervention in subjects with a diagnosis of dementia

The LipiDiDiet study was a randomized, controlled, double-blind, parallel-group multicentre trial in 311 subjects with MCI due to AD (MMSE 26.6) [122], as defined by episodic memory disorder and evidence for underlying AD pathology [3]. Subjects were randomly assigned (1:1) to receive Souvenaid or a matched control product, taken every day for 24 months [122], with the option to enter an extension study period [144]. The primary endpoint was a change in a neuropsychological test battery (NTB; composite z-score based on Consortium to Establish a Registry for Alzheimer’s disease [CERAD] 10-word list learning immediate recall, CERAD 10-word delayed recall, CERAD 10-word recognition, category fluency, and letter-digit substitution test). The authors noted that cognitive decline in the LipiDiDiet study population was much lower than expected in both groups, so the primary endpoint was inadequately powered; no significant effect on the primary endpoint was found after 24 months. Interestingly, significant effects were observed for secondary endpoints, including Clinical Dementia Rating scale–Sum of Boxes (CDR-SOB) and Alzheimer Disease Composite Score (ADCOMS). The ADCOMS scale provides a composite clinical outcome measure and was designed for use in trials in MCI due to AD and mild AD dementia [145]. A post hoc analysis of data from the LipiDiDiet study showed that during the 24-month intervention period, worsening on ADCOMS was 36% less in the multinutrient group than in the control group; estimated mean treatment difference –0.048 (95% CI –0.090 to –0.007; P = 0.023) [146]. Magnetic resonance imaging (MRI) analyses also showed a significant reduction of hippocampal atrophy and less expansion of ventricular volume in subjects receiving the multinutrient intervention [122]. In line with previous trials in AD, the LipiDiDiet showed that administration of Souvenaid was well tolerated and had a high rate of adherence [122, 144].

Changes from baseline in the levels of uridine, choline, and other nutrients were not reported in the LipiDiDiet study, so it is not possible to correlate effects on clinical and brain imaging endpoints with an improvement in nutritional status. Previous randomized controlled trials in subjects with mild AD showed that Souvenaid increases levels of uridine, choline, DHA, and other key nutrients involved in PC formation [147, 148] and increases markers of phospholipid synthesis in the brain in subjects with mild AD [147]. These findings support the putative mode of action of the product on synapse formation.

At 24 months, there was no difference between groups in progression to dementia; however, preliminary data with long-term (3-year) intervention suggests a possible effect favoring multinutrient intervention [144]. Longer-term follow-up of the LipiDiDiet study will provide additional insights into the sustainability of effects observed with multinutrient intervention and hopefully elucidate additional information on which patients are most likely to benefit. It will be interesting to see whether expression of the apolipoprotein E4 (APOE4) gene modifies the effects of multinutrient intervention in MCI due to AD. APOE4, a major genetic driver of AD, is associated with decreased transport of DHA to the CSF [149] and appears to influence the effects of DHA supplementation in subjects with AD and MCI [138]. In subjects with early-stage AD, the effect of Souvenaid was assessed in predefined subgroups, including expression of the APOE4 genotype; however, no significant effect was observed [141].

Overall, clinical evidence suggests that a specific uridine- and choline-enriched multinutritional intervention may produce meaningful clinical benefits in MCI due to AD, possibly by addressing a conditional shortage in levels of uridine and other key nutrients essential for neuronal membrane formation. Additional studies are needed to extend the findings of the LipiDiDiet study to the presymptomatic stage of AD, and to correlate improvements in nutrient levels with cognitive benefits.

Conclusions

There is strong evidence from systematic reviews and meta-analyses showing a pathologic shortage of uridine and choline in AD, including MCI due to AD, particularly in the levels of these nutrients in the brain or CSF. While the shortfall appears relatively modest, compared with healthy age-matched controls, the impact on the metabolic pathways leading to synapse formation could be significant considering the ongoing loss of synapses that characterizes progression of MCI and AD. The uridine shortage cannot be corrected simply by modifying a normal diet, making uridine a conditionally essential nutrient in affected individuals. As an essential nutrient, choline must be obtained from the diet; however, correcting the shortfall in individuals with MCI through diet alone is challenging, because brain uptake from the plasma significantly decreases with ageing. Dietary supplements have been used to improve outcomes in subjects with MCI, but there is limited evidence of effectiveness for single-agent supplements and a lack of studies specifically in subjects with MCI due to AD. Preclinical research provides a strong rationale for multinutrient intervention providing supplemental uridine and choline alongside other substrates used in the metabolic pathways for PC formation. Administration of these nutrients at the same time has been shown to increase synapse formation and provide neuroprotection in models of dementia. Clinical trials of a specific multinutrient product containing uridine, choline, and DHA have shown that the benefits are most likely to be achieved at the very early stages of the AD spectrum, when there is still a possibility to influence the processes affecting synapse formation and loss. To date, there is no evidence that multinutrient intervention can prevent progression of MCI to AD; however, preliminary brain imaging data does suggest an observable slowing of neurodegeneration.

Based on this review, we recommend that nutritional intervention be considered as a part of the personalized approach to the management of individuals with MCI due to AD, including adherence to a healthy, balanced diet and consideration of evidence-based multinutrient supplements, as indicated. The selection of a multinutritional intervention should be based on strong evidence in a clearly defined population of subjects with MCI.

References

  1. Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7:270–9.

    PubMed  PubMed Central  Google Scholar 

  2. Langa KM, Levine DA. The diagnosis and management of mild cognitive impairment: a clinical review. JAMA. 2014;312:2551–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, et al. Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol. 2007;6:734–46.

    PubMed  Google Scholar 

  4. Frisoni GB, Boccardi M, Barkhof F, Blennow K, Cappa S, Chiotis K, et al. Strategic roadmap for an early diagnosis of Alzheimer’s disease based on biomarkers. Lancet Neurol. 2017;16:661–76.

    Google Scholar 

  5. Petersen RC, Lopez O, Armstrong MJ, Getchius TSD, Ganguli M, Gloss D, et al. Practice guideline update summary: mild cognitive impairment: report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018;90:126–35.

    PubMed  PubMed Central  Google Scholar 

  6. Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7:280–92.

    PubMed  PubMed Central  Google Scholar 

  7. de Wilde MC, Overk CR, Sijben JW, Masliah E. Meta-analysis of synaptic pathology in Alzheimer’s disease reveals selective molecular vesicular machinery vulnerability. Alzheimers Dement. 2016;12:633–44.

    PubMed  PubMed Central  Google Scholar 

  8. Livingston G, Sommerlad A, Orgeta V, Costafreda SG, Huntley J, Ames D, et al. Dementia prevention, intervention, and care. Lancet. 2017;390:2673–734.

    PubMed  PubMed Central  Google Scholar 

  9. Livingston G, Huntley J, Sommerlad A, Ames D, Ballard C, Banerjee S, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet. 2020;396:413–46.

    PubMed  PubMed Central  Google Scholar 

  10. Sun MK, Alkon DL. Neuro-regeneration therapeutic for Alzheimer’s dementia: perspectives on neurotrophic activity. Trends Pharmacol Sci. 2019;40:655–68.

    CAS  PubMed  Google Scholar 

  11. Canter RG, Penney J, Tsai LH. The road to restoring neural circuits for the treatment of Alzheimer’s disease. Nature. 2016;539:187–96.

    PubMed  Google Scholar 

  12. Chen Y, Fu AKY, Ip NY. Synaptic dysfunction in Alzheimer’s disease: mechanisms and therapeutic strategies. Pharmacol Ther. 2019;195:186–98.

    CAS  PubMed  Google Scholar 

  13. Jackson J, Jambrina E, Li J, Marston H, Menzies F, Phillips K, Gilmour G. Targeting the synapse in Alzheimer’s disease. Front Neurosci. 2019;13:735.

    PubMed  PubMed Central  Google Scholar 

  14. Skaper SD, Facci L, Zusso M, Giusti P. Synaptic plasticity, dementia and Alzheimer disease. CNS Neurol Disord Drug Targets. 2017;16:220–33.

    CAS  PubMed  Google Scholar 

  15. Wurtman RJ. Synapse formation in the brain can be enhanced by co-administering three specific nutrients. Eur J Pharmacol. 2017;817:20–1.

    CAS  PubMed  Google Scholar 

  16. Gibellini F, Smith TK. The Kennedy pathway—de novo synthesis of phosphatidylethanolamine and phosphatidylcholine. IUBMB Life. 2010;62:414–28.

    CAS  PubMed  Google Scholar 

  17. Wurtman RJ, Cansev M, Sakamoto T, Ulus IH. Use of phosphatide precursors to promote synaptogenesis. Annu Rev Nutr. 2009;29:59–87.

    CAS  PubMed  Google Scholar 

  18. Dobolyi A, Juhasz G, Kovacs Z, Kardos J. Uridine function in the central nervous system. Curr Top Med Chem. 2011;11:1058–67.

    CAS  PubMed  Google Scholar 

  19. Vlachos GS, Scarmeas N. Dietary interventions in mild cognitive impairment and dementia. Dialogues Clin Neurosci. 2019;21:69–82.

    PubMed  PubMed Central  Google Scholar 

  20. Scarmeas N, Anastasiou CA, Yannakoulia M. Nutrition and prevention of cognitive impairment. Lancet Neurol. 2018;17:1006–15.

    PubMed  Google Scholar 

  21. Solfrizzi V, Custodero C, Lozupone M, Imbimbo BP, Valiani V, Agosti P, et al. Relationships of dietary patterns, foods, and micro- and macronutrients with Alzheimer’s disease and late-life cognitive disorders: a systematic review. J Alzheimers Dis. 2017;59:815–49.

    CAS  PubMed  Google Scholar 

  22. Kane RL, Butler M, Fink HA, Brasure M, Davila H, Desai P, et al. (2017) Interventions to prevent age-related cognitive decline, mild cognitive impairment, and clinical Alzheimer’s-type dementia. Comparative Effectiveness Review No. 188. AHRQ Publication No. 17-EHC008-EF. Rockville, MD: Agency for Healthcare Research and Quality

  23. Jacobson KA, Delicado EG, Gachet C, Kennedy C, von Kugelgen I, Li B, et al. Update of P2Y receptor pharmacology: IUPHAR review 27. Br J Pharmacol. 2020;177:2413–33.

    CAS  PubMed  Google Scholar 

  24. von Kugelgen I, Hoffmann K. Pharmacology and structure of P2Y receptors. Neuropharmacology. 2016;104:50–61.

    Google Scholar 

  25. Cieslak M, Wojtczak A. Role of purinergic receptors in the Alzheimer’s disease. Purinergic Signal. 2018;14:331–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Connolly GP. Abnormal pyrimidine metabolism is the basis of some neurological diseases. Trends Pharmacol Sci. 1998;19:252.

    CAS  PubMed  Google Scholar 

  27. Bekdash RA. Neuroprotective effects of choline and other methyl donors. Nutrients. 2019;11:2995.

    CAS  PubMed Central  Google Scholar 

  28. Blusztajn JK, Slack BE, Mellott TJ. Neuroprotective actions of dietary choline. Nutrients. 2017;9:815.

    PubMed Central  Google Scholar 

  29. Hampel H, Mesulam MM, Cuello AC, Khachaturian AS, Vergallo A, Farlow MR, et al. Revisiting the cholinergic hypothesis in Alzheimer’s disease: emerging evidence from translational and clinical research. J Prev Alzheimers Dis. 2019;6:2–15.

    CAS  PubMed  Google Scholar 

  30. Hampel H, Mesulam MM, Cuello AC, Farlow MR, Giacobini E, Grossberg GT, et al. The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease. Brain. 2018;141:1917–33.

    PubMed  PubMed Central  Google Scholar 

  31. Haense C, Kalbe E, Herholz K, Hohmann C, Neumaier B, Krais R, Heiss WD. Cholinergic system function and cognition in mild cognitive impairment. Neurobiol Aging. 2012;33:867–77.

    CAS  PubMed  Google Scholar 

  32. DeKosky ST, Ikonomovic MD, Styren SD, Beckett L, Wisniewski S, Bennett DA, et al. Upregulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjects with mild cognitive impairment. Ann Neurol. 2002;51:145–55.

    CAS  PubMed  Google Scholar 

  33. Arvanitakis Z, Shah RC, Bennett DA. Diagnosis and management of dementia: review. JAMA. 2019;322:1589–99.

    PubMed  PubMed Central  Google Scholar 

  34. Fagone P, Jackowski S. Phosphatidylcholine and the CDP-choline cycle. Biochim Biophys Acta. 2013;1831:523–32.

    CAS  PubMed  Google Scholar 

  35. Vance DE. Phospholipid methylation in mammals: from biochemistry to physiological function. Biochim Biophys Acta. 2014;1838:1477–87.

    CAS  PubMed  Google Scholar 

  36. Farooqui AA, Rapoport SI, Horrocks LA. Membrane phospholipid alterations in Alzheimer’s disease: deficiency of ethanolamine plasmalogens. Neurochem Res. 1997;22:523–7.

    CAS  PubMed  Google Scholar 

  37. Ginsberg L, Rafique S, Xuereb JH, Rapoport SI, Gershfeld NL. Disease and anatomic specificity of ethanolamine plasmalogen deficiency in Alzheimer’s disease brain. Brain Res. 1995;698:223–6.

    CAS  PubMed  Google Scholar 

  38. Gottfries CG, Karlsson I, Svennerholm L. Membrane components separate early-onset Alzheimer’s disease from senile dementia of the Alzheimer type. Int Psychogeriatr. 1996;8:365–72.

    CAS  PubMed  Google Scholar 

  39. Grimm MO, Grosgen S, Riemenschneider M, Tanila H, Grimm HS, Hartmann T. From brain to food: analysis of phosphatidylcholins, lyso-phosphatidylcholins and phosphatidylcholin-plasmalogens derivates in Alzheimer’s disease human post mortem brains and mice model via mass spectrometry. J Chromatogr A. 2011;1218:7713–22.

    CAS  PubMed  Google Scholar 

  40. Grimm MO, Kuchenbecker J, Rothhaar TL, Grosgen S, Hundsdorfer B, Burg VK, et al. Plasmalogen synthesis is regulated via alkyl-dihydroxyacetonephosphate-synthase by amyloid precursor protein processing and is affected in Alzheimer’s disease. J Neurochem. 2011;116:916–25.

    CAS  PubMed  Google Scholar 

  41. Guan ZZ, Wang YN, Xiao KQ, Hu PS, Liu JL. Activity of phosphatidylethanolamine-N-methyltransferase in brain affected by Alzheimer’s disease. Neurochem Int. 1999;34:41–7.

    CAS  PubMed  Google Scholar 

  42. Han X, Holtzman DM, McKeel DW Jr. Plasmalogen deficiency in early Alzheimer’s disease subjects and in animal models: molecular characterization using electrospray ionization mass spectrometry. J Neurochem. 2001;77:1168–80.

    CAS  PubMed  Google Scholar 

  43. Igarashi M, Ma K, Gao F, Kim HW, Rapoport SI, Rao JS. Disturbed choline plasmalogen and phospholipid fatty acid concentrations in Alzheimer’s disease prefrontal cortex. J Alzheimers Dis. 2011;24:507–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Kou J, Kovacs GG, Hoftberger R, Kulik W, Brodde A, Forss-Petter S, et al. Peroxisomal alterations in Alzheimer’s disease. Acta Neuropathol. 2011;122:271–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Miatto O, Gonzalez RG, Buonanno F, Growdon JH. In vitro 31P NMR spectroscopy detects altered phospholipid metabolism in Alzheimer’s disease. Can J Neurol Sci. 1986;13:535–9.

    CAS  PubMed  Google Scholar 

  46. Nitsch RM, Blusztajn JK, Pittas AG, Slack BE, Growdon JH, Wurtman RJ. Evidence for a membrane defect in Alzheimer disease brain. Proc Natl Acad Sci USA. 1992;89:1671–5.

    CAS  PubMed  Google Scholar 

  47. Pettegrew JW, Panchalingam K, Hamilton RL, McClure RJ. Brain membrane phospholipid alterations in Alzheimer’s disease. Neurochem Res. 2001;26:771–82.

    CAS  PubMed  Google Scholar 

  48. Prasad MR, Lovell MA, Yatin M, Dhillon H, Markesbery WR. Regional membrane phospholipid alterations in Alzheimer’s disease. Neurochem Res. 1998;23:81–8.

    CAS  PubMed  Google Scholar 

  49. Wood PL, Barnette BL, Kaye JA, Quinn JF, Woltjer RL. Non-targeted lipidomics of CSF and frontal cortex grey and white matter in control, mild cognitive impairment, and Alzheimer’s disease subjects. Acta Neuropsychiatr. 2015;27:270–8.

    PubMed  Google Scholar 

  50. Wood PL, Medicherla S, Sheikh N, Terry B, Phillipps A, Kaye JA, et al. Targeted l (lipidomics) of frontal cortex and plasma diacylglycerols (DAG) in mild cognitive impairment and Alzheimer’s disease: validation of DAG accumulation early in the pathophysiology of Alzheimer’s disease. J Alzheimers Dis. 2015;48:537–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Fonteh AN, Chiang J, Cipolla M, Hale J, Diallo F, Chirino A, et al. Alterations in cerebrospinal fluid glycerophospholipids and phospholipase A2 activity in Alzheimer’s disease. J Lipid Res. 2013;54:2884–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Mulder C, Wahlund LO, Teerlink T, Blomberg M, Veerhuis R, van Kamp GJ, et al. Decreased lysophosphatidylcholine/phosphatidylcholine ratio in cerebrospinal fluid in Alzheimer’s disease. J Neural Transm (Vienna). 2003;110:949–55.

    CAS  Google Scholar 

  53. Mulder M, Ravid R, Swaab DF, de Kloet ER, Haasdijk ED, Julk J, et al. Reduced levels of cholesterol, phospholipids, and fatty acids in cerebrospinal fluid of Alzheimer disease patients are not related to apolipoprotein E4. Alzheimer Dis Assoc Disord. 1998;12:198–203.

    CAS  PubMed  Google Scholar 

  54. Casanova R, Varma S, Simpson B, Kim M, An Y, Saldana S, et al. Blood metabolite markers of preclinical Alzheimer’s disease in two longitudinally followed cohorts of older individuals. Alzheimers Dement. 2016;12:815–22.

    PubMed  PubMed Central  Google Scholar 

  55. Fiandaca MS, Zhong X, Cheema AK, Orquiza MH, Chidambaram S, Tan MT, et al. Plasma 24-metabolite panel predicts preclinical transition to clinical stages of Alzheimer’s disease. Front Neurol. 2015;6:237.

    PubMed  PubMed Central  Google Scholar 

  56. Gonzalez-Dominguez R, Garcia-Barrera T, Gomez-Ariza JL. Combination of metabolomic and phospholipid-profiling approaches for the study of Alzheimer’s disease. J Proteomics. 2014;104:37–47.

    CAS  PubMed  Google Scholar 

  57. Gonzalez-Dominguez R, Garcia-Barrera T, Gomez-Ariza JL. Metabolomic study of lipids in serum for biomarker discovery in Alzheimer’s disease using direct infusion mass spectrometry. J Pharm Biomed Anal. 2014;98:321–6.

    CAS  PubMed  Google Scholar 

  58. Gonzalez-Dominguez R, Ruperez FJ, Garcia-Barrera T, Barbas C, Gomez-Ariza JL. Metabolomic-driven elucidation of serum disturbances associated with Alzheimer’s disease and mild cognitive impairment. Curr Alzheimer Res. 2016;13:641–53.

    CAS  PubMed  Google Scholar 

  59. Goodenowe DB, Cook LL, Liu J, Lu Y, Jayasinghe DA, Ahiahonu PW, et al. Peripheral ethanolamine plasmalogen deficiency: a logical causative factor in Alzheimer’s disease and dementia. J Lipid Res. 2007;48:2485–98.

    CAS  PubMed  Google Scholar 

  60. Klavins K, Koal T, Dallmann G, Marksteiner J, Kemmler G, Humpel C. The ratio of phosphatidylcholines to lysophosphatidylcholines in plasma differentiates healthy controls from patients with Alzheimer’s disease and mild cognitive impairment. Alzheimers Dement (Amst). 2015;1:295–302.

    Google Scholar 

  61. Li D, Misialek JR, Boerwinkle E, Gottesman RF, Sharrett AR, Mosley TH, et al. Plasma phospholipids and prevalence of mild cognitive impairment and/or dementia in the ARIC Neurocognitive Study (ARIC-NCS). Alzheimers Dement (Amst). 2016;3:73–82.

    Google Scholar 

  62. Li D, Misialek JR, Boerwinkle E, Gottesman RF, Sharrett AR, Mosley TH, et al. Prospective associations of plasma phospholipids and mild cognitive impairment/dementia among African Americans in the ARIC Neurocognitive Study. Alzheimers Dement (Amst). 2017;6:1–10.

    Google Scholar 

  63. Mapstone M, Cheema AK, Fiandaca MS, Zhong X, Mhyre TR, MacArthur LH, et al. Plasma phospholipids identify antecedent memory impairment in older adults. Nat Med. 2014;20:415–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Mapstone M, Lin F, Nalls MA, Cheema AK, Singleton AB, Fiandaca MS, Federoff HJ. What success can teach us about failure: the plasma metabolome of older adults with superior memory and lessons for Alzheimer’s disease. Neurobiol Aging. 2017;51:148–55.

    CAS  PubMed  Google Scholar 

  65. Olazaran J, Gil-de-Gomez L, Rodriguez-Martin A, Valenti-Soler M, Frades-Payo B, Marin-Munoz J, et al. A blood-based, 7-metabolite signature for the early diagnosis of Alzheimer’s disease. J Alzheimers Dis. 2015;45:1157–73.

    CAS  PubMed  Google Scholar 

  66. Oresic M, Hyotylainen T, Herukka SK, Sysi-Aho M, Mattila I, Seppanan-Laakso T, et al. Metabolome in progression to Alzheimer’s disease. Transl Psychiatry. 2011;1:e57.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Proitsi P, Kim M, Whiley L, Simmons A, Sattlecker M, Velayudhan L, et al. Association of blood lipids with Alzheimer’s disease: a comprehensive lipidomics analysis. Alzheimers Dement. 2017;13:140–51.

    PubMed  Google Scholar 

  68. Toledo JB, Arnold M, Kastenmuller G, Chang R, Baillie RA, Han X, et al. Metabolic network failures in Alzheimer’s disease: a biochemical road map. Alzheimers Dement. 2017;13:965–84.

    PubMed  PubMed Central  Google Scholar 

  69. Whiley L, Sen A, Heaton J, Proitsi P, Garcia-Gomez D, Leung R, et al. Evidence of altered phosphatidylcholine metabolism in Alzheimer’s disease. Neurobiol Aging. 2014;35:271–8.

    CAS  PubMed  Google Scholar 

  70. Wood PL, Mankidy R, Ritchie S, Heath D, Wood JA, Flax J, Goodenowe DB. Circulating plasmalogen levels and Alzheimer Disease Assessment Scale-Cognitive scores in Alzheimer patients. J Psychiatry Neurosci. 2010;35:59–62.

    PubMed  PubMed Central  Google Scholar 

  71. Pena-Bautista C, Roca M, Hervas D, Cuevas A, Lopez-Cuevas R, Vento M, et al. Plasma metabolomics in early Alzheimer’s disease patients diagnosed with amyloid biomarker. J Proteomics. 2019;200:144–52.

    CAS  PubMed  Google Scholar 

  72. Costa AC, Joaquim HPG, Forlenza O, Talib LL, Gattaz WF. Plasma lipids metabolism in mild cognitive impairment and Alzheimer’s disease. World J Biol Psychiatry. 2019;20:190–6.

    PubMed  Google Scholar 

  73. Iuliano L, Pacelli A, Ciacciarelli M, Zerbinati C, Fagioli S, Piras F, et al. Plasma fatty acid lipidomics in amnestic mild cognitive impairment and Alzheimer’s disease. J Alzheimers Dis. 2013;36:545–53.

    CAS  PubMed  Google Scholar 

  74. Selley ML. A metabolic link between S-adenosylhomocysteine and polyunsaturated fatty acid metabolism in Alzheimer’s disease. Neurobiol Aging. 2007;28:1834–9.

    CAS  PubMed  Google Scholar 

  75. Heude B, Ducimetiere P, Berr C, Study EVA. Cognitive decline and fatty acid composition of erythrocyte membranes—The EVA Study. Am J Clin Nutr. 2003;77:803–8.

    CAS  PubMed  Google Scholar 

  76. Tan ZS, Harris WS, Beiser AS, Au R, Himali JJ, Debette S, et al. Red blood cell omega-3 fatty acid levels and markers of accelerated brain aging. Neurology. 2012;78:658–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Schaefer EJ, Bongard V, Beiser AS, Lamon-Fava S, Robins SJ, Au R, et al. Plasma phosphatidylcholine docosahexaenoic acid content and risk of dementia and Alzheimer disease: the Framingham Heart Study. Arch Neurol. 2006;63:1545–50.

    PubMed  Google Scholar 

  78. de Wilde MC, Vellas B, Girault E, Yavuz AC, Sijben JW. Lower brain and blood nutrient status in Alzheimer’s disease: results from meta-analyses. Alzheimers Dement. 2017;3:416–31.

    Google Scholar 

  79. Lopes da Silva S, Vellas B, Elemans S, Luchsinger J, Kamphuis P, Yaffe K, et al. Plasma nutrient status of patients with Alzheimer’s disease: systematic review and meta-analysis. Alzheimers Dement. 2014;10:485–502.

    PubMed  Google Scholar 

  80. Czech C, Berndt P, Busch K, Schmitz O, Wiemer J, Most V, et al. Metabolite profiling of Alzheimer’s disease cerebrospinal fluid. PLoS ONE. 2012;7:e31501.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Ibanez C, Simo C, Barupal DK, Fiehn O, Kivipelto M, Cedazo-Minguez A, Cifuentes A. A new metabolomic workflow for early detection of Alzheimer’s disease. J Chromatogr A. 2013;1302:65–71.

    CAS  PubMed  Google Scholar 

  82. Olde Rikkert MG, Verhey FR, Sijben JW, Bouwman FH, Dautzenberg PL, Lansink M, et al. Differences in nutritional status between very mild Alzheimer’s disease patients and healthy controls. J Alzheimers Dis. 2014;41:261–71.

    CAS  PubMed  Google Scholar 

  83. van Wijk N, Slot RER, Duits FH, Strik M, Biesheuvel E, Sijben JWC, et al. Nutrients required for phospholipid synthesis are lower in blood and cerebrospinal fluid in mild cognitive impairment and Alzheimer’s disease dementia. Alzheimers Dement (Amst). 2017;8:139–46.

    Google Scholar 

  84. Wang G, Zhou Y, Huang FJ, Tang HD, Xu XH, Liu JJ, et al. Plasma metabolite profiles of Alzheimer’s disease and mild cognitive impairment. J Proteome Res. 2014;13:2649–58.

    CAS  PubMed  Google Scholar 

  85. Xu J, Begley P, Church SJ, Patassini S, Hollywood KA, Jullig M, et al. Graded perturbations of metabolism in multiple regions of human brain in Alzheimer’s disease: snapshot of a pervasive metabolic disorder. Biochim Biophys Acta. 2016;1862:1084–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Tsuruoka M, Hara J, Hirayama A, Sugimoto M, Soga T, Shankle WR, Tomita M. Capillary electrophoresis-mass spectrometry-based metabolome analysis of serum and saliva from neurodegenerative dementia patients. Electrophoresis. 2013;34:2865–72.

    CAS  PubMed  Google Scholar 

  87. Graham SF, Chevallier OP, Elliott CT, Holscher C, Johnston J, McGuinness B, et al. Untargeted metabolomic analysis of human plasma indicates differentially affected polyamine and l-arginine metabolism in mild cognitive impairment subjects converting to Alzheimer’s disease. PLoS ONE. 2015;10:e0119452.

    PubMed  PubMed Central  Google Scholar 

  88. Trushina E, Dutta T, Persson XM, Mielke MM, Petersen RC. Identification of altered metabolic pathways in plasma and CSF in mild cognitive impairment and Alzheimer’s disease using metabolomics. PLoS ONE. 2013;8:e63644.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Pena-Bautista C, Flor L, Lopez-Nogueroles M, Garcia L, Ferrer I, Baquero M, et al. Plasma alterations in cholinergic and serotonergic systems in early Alzheimer Disease: diagnosis utility. Clin Chim Acta. 2020;500:233–40.

    CAS  PubMed  Google Scholar 

  90. Inazu M. Functional expression of choline transporters in the blood-brain barrier. Nutrients. 2019;11:2265.

    CAS  PubMed Central  Google Scholar 

  91. Cohen BM, Renshaw PF, Stoll AL, Wurtman RJ, Yurgelun-Todd D, Babb SM. Decreased brain choline uptake in older adults. An in vivo proton magnetic resonance spectroscopy study. JAMA. 1995;274:902–7.

    CAS  PubMed  Google Scholar 

  92. Nurk E, Refsum H, Bjelland I, Drevon CA, Tell GS, Ueland PM, et al. Plasma free choline, betaine and cognitive performance: the Hordaland Health Study. Br J Nutr. 2013;109:511–9.

    CAS  PubMed  Google Scholar 

  93. Goldberg E, Kindilien S, Roberts M, Cohen D. Working memory and inadequate micronutrient consumption in healthy seniors. J Nutr Gerontol Geriatr. 2019;38:247–61.

    PubMed  Google Scholar 

  94. de Leeuw FA, Tijms BM, Hendriksen HMA, van de Rest O, de van der Schueren MAE, Visser M, et al. (2020) LDL cholesterol and uridine levels in blood are potential nutritional markers of AD progression; the NUDAD project. Alzheimer’s Association International Conference 2020, July 27–31; available online at https://alz.confex.com/alz/20amsterdam/meetingapp.cgi/Paper/43108

  95. van Wijk N, Broersen LM, de Wilde MC, Hageman RJ, Groenendijk M, Sijben JW, Kamphuis PJ. Targeting synaptic dysfunction in Alzheimer’s disease by administering a specific nutrient combination. J Alzheimers Dis. 2014;38:459–79.

    PubMed  Google Scholar 

  96. Cansev M, van Wijk N, Turkyilmaz M, Orhan F, Sijben JW, Broersen LM. Specific multi-nutrient enriched diet enhances hippocampal cholinergic transmission in aged rats. Neurobiol Aging. 2015;36:344–51.

    CAS  PubMed  Google Scholar 

  97. Savelkoul P, Merkes M, Kuipers A, Hageman R, Broersen L, Kamphuis P. P4–258: Multi-nutrient supplementation induces changes in synaptic protein expression. Alzheimers Dement. 2011;7:S796-S.

    Google Scholar 

  98. van Deijk AF, Broersen LM, Verkuyl JM, Smit AB, Verheijen MHG. High content analysis of hippocampal neuron-astrocyte co-cultures shows a positive effect of Fortasyn Connect on neuronal survival and postsynaptic maturation. Front Neurosci. 2017;11:440.

    PubMed  PubMed Central  Google Scholar 

  99. Pooler AM, Guez DH, Benedictus R, Wurtman RJ. Uridine enhances neurite outgrowth in nerve growth factor-differentiated PC12 [corrected]. Neuroscience. 2005;134:207–14.

    CAS  PubMed  Google Scholar 

  100. Sakamoto T, Cansev M, Wurtman RJ. Oral supplementation with docosahexaenoic acid and uridine-5’-monophosphate increases dendritic spine density in adult gerbil hippocampus. Brain Res. 2007;1182:50–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Savelkoul P, Lotstra S, Kuipers A, Kamphuis P, Broersen L. P2–043: Combined nutrient supplementation enhances neurite outgrowth and synaptic protein expression in vitro. Alzheimers Dement. 2013;9:P359–60.

    Google Scholar 

  102. Wang L, Pooler AM, Albrecht MA, Wurtman RJ. Dietary uridine-5’-monophosphate supplementation increases potassium-evoked dopamine release and promotes neurite outgrowth in aged rats. J Mol Neurosci. 2005;27:137–45.

    PubMed  Google Scholar 

  103. de Wilde MC, Penke B, van der Beek EM, Kuipers AA, Kamphuis PJ, Broersen LM. Neuroprotective effects of a specific multi-nutrient intervention against Abeta42-induced toxicity in rats. J Alzheimers Dis. 2011;27:327–39.

    PubMed  Google Scholar 

  104. Janickova H, Rudajev V, Dolejsi E, Koivisto H, Jakubik J, Tanila H, et al. Lipid-based diets improve muscarinic neurotransmission in the hippocampus of transgenic APPswe/PS1dE9 Mice. Curr Alzheimer Res. 2015;12:923–31.

    CAS  PubMed  Google Scholar 

  105. Savelkoul PJ, Janickova H, Kuipers AA, Hageman RJ, Kamphuis PJ, Dolezal V, Broersen LM. A specific multi-nutrient formulation enhances M1 muscarinic acetylcholine receptor responses in vitro. J Neurochem. 2012;120:631–40.

    CAS  PubMed  Google Scholar 

  106. Jansen D, Zerbi V, Arnoldussen IA, Wiesmann M, Rijpma A, Fang XT, et al. Effects of specific multi-nutrient enriched diets on cerebral metabolism, cognition and neuropathology in AbetaPPswe-PS1dE9 mice. PLoS ONE. 2013;8:e75393.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Jansen D, Zerbi V, Janssen CI, van Rooij D, Zinnhardt B, Dederen PJ, et al. Impact of a multi-nutrient diet on cognition, brain metabolism, hemodynamics, and plasticity in apoE4 carrier and apoE knockout mice. Brain Struct Funct. 2014;219:1841–68.

    CAS  PubMed  Google Scholar 

  108. Koivisto H, Grimm MO, Rothhaar TL, Berkecz R, Lutjohann DD, Giniatullina R, et al. Special lipid-based diets alleviate cognitive deficits in the APPswe/PS1dE9 transgenic mouse model of Alzheimer’s disease independent of brain amyloid deposition. J Nutr Biochem. 2014;25:157–69.

    CAS  PubMed  Google Scholar 

  109. Wiesmann M, Jansen D, Zerbi V, Broersen LM, Garthe A, Kiliaan AJ. Improved spatial learning strategy and memory in aged Alzheimer AbetaPPswe/PS1dE9 mice on a multi-nutrient diet. J Alzheimers Dis. 2013;37:233–45.

    CAS  PubMed  Google Scholar 

  110. Broersen LM, Kuipers AA, Balvers M, van Wijk N, Savelkoul PJ, de Wilde MC, et al. A specific multi-nutrient diet reduces Alzheimer-like pathology in young adult AbetaPPswe/PS1dE9 mice. J Alzheimers Dis. 2013;33:177–90.

    CAS  PubMed  Google Scholar 

  111. Agarwal N, Sung YH, Jensen JE, daCunha G, Harper D, Olson D, Renshaw PF. Short-term administration of uridine increases brain membrane phospholipid precursors in healthy adults: a 31-phosphorus magnetic resonance spectroscopy study at 4T. Bipolar Disord. 2010;12:825–33.

    PubMed  PubMed Central  Google Scholar 

  112. Silveri MM, Dikan J, Ross AJ, Jensen JE, Kamiya T, Kawada Y, et al. Citicoline enhances frontal lobe bioenergetics as measured by phosphorus magnetic resonance spectroscopy. NMR Biomed. 2008;21:1066–75.

    CAS  PubMed  Google Scholar 

  113. Wurtman RJ, Regan M, Ulus I, Yu L. Effect of oral CDP-choline on plasma choline and uridine levels in humans. Biochem Pharmacol. 2000;60:989–92.

    CAS  PubMed  Google Scholar 

  114. Spiers PA, Myers D, Hochanadel GS, Lieberman HR, Wurtman RJ. Citicoline improves verbal memory in aging. Arch Neurol. 1996;53:441–8.

    CAS  PubMed  Google Scholar 

  115. Poly C, Massaro JM, Seshadri S, Wolf PA, Cho E, Krall E, et al. The relation of dietary choline to cognitive performance and white-matter hyperintensity in the Framingham Offspring Cohort. Am J Clin Nutr. 2011;94:1584–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Ylilauri MPT, Voutilainen S, Lonnroos E, Virtanen HEK, Tuomainen TP, Salonen JT, Virtanen JK. Associations of dietary choline intake with risk of incident dementia and with cognitive performance: the Kuopio Ischaemic Heart Disease Risk Factor Study. Am J Clin Nutr. 2019;110:1416–23.

    PubMed  Google Scholar 

  117. Moreno MDJM. Cognitive improvement in mild to moderate Alzheimer’s dementia after treatment with the acetylcholine precursor choline alfoscerate: a multicenter, double-blind, randomized, placebo-controlled trial. Clin Ther. 2003;25:178–93.

    Google Scholar 

  118. Lehtisalo J, Ngandu T, Valve P, Antikainen R, Laatikainen T, Strandberg T, et al. Nutrient intake and dietary changes during a 2-year multi-domain lifestyle intervention among older adults: secondary analysis of the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) randomised controlled trial. Br J Nutr. 2017;118:291–302.

    CAS  PubMed  Google Scholar 

  119. Scarmeas N, Stern Y, Mayeux R, Manly JJ, Schupf N, Luchsinger JA. Mediterranean diet and mild cognitive impairment. Arch Neurol. 2009;66:216–25.

    PubMed  PubMed Central  Google Scholar 

  120. Stephen R, Liu Y, Ngandu T, Antikainen R, Hulkkonen J, Koikkalainen J, et al. Brain volumes and cortical thickness on MRI in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER). Alzheimers Res Ther. 2019;11:53.

    PubMed  PubMed Central  Google Scholar 

  121. McGrattan AM, McEvoy CT, McGuinness B, McKinley MC, Woodside JV. Effect of dietary interventions in mild cognitive impairment: a systematic review. Br J Nutr. 2018;120:1388–405.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Soininen H, Solomon A, Visser PJ, Hendrix SB, Blennow K, Kivipelto M, et al. 24-month intervention with a specific multinutrient in people with prodromal Alzheimer’s disease (LipiDiDiet): a randomised, double-blind, controlled trial. Lancet Neurol. 2017;16:965–75.

    PubMed  PubMed Central  Google Scholar 

  123. McGrattan AM, McEvoy CT, McGuinness B, McKinley MC, Woodside JV. The effect of diet, lifestyle and/or cognitive interventions in mild cognitive impairment: a systematic review. Proc Nutr Soc. 2017;76:E114.

    Google Scholar 

  124. Morris MC, Evans DA, Bienias JL, Tangney CC, Bennett DA, Aggarwal N, et al. Dietary fats and the risk of incident Alzheimer disease. Arch Neurol. 2003;60:194–200.

    PubMed  Google Scholar 

  125. Corrada MM, Kawas CH, Hallfrisch J, Muller D, Brookmeyer R. Reduced risk of Alzheimer’s disease with high folate intake: the Baltimore Longitudinal Study of Aging. Alzheimers Dement. 2005;1:11–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Gasser T, Moyer JD, Handschumacher RE. Novel single-pass exchange of circulating uridine in rat liver. Science. 1981;213:777–8.

    CAS  PubMed  Google Scholar 

  127. Yamamoto T, Moriwaki Y, Takahashi S, Tsutsumi Z, Ka T, Fukuchi M, Hada T. Effect of beer on the plasma concentrations of uridine and purine bases. Metabolism. 2002;51:1317–23.

    CAS  PubMed  Google Scholar 

  128. Wallace TC, Blusztajn JK, Caudill MA, Klatt KC, Natker E, Zeisel SH, Zelman KM. Choline: the underconsumed and underappreciated essential nutrient. Nutr Today. 2018;53:240–53.

    PubMed  PubMed Central  Google Scholar 

  129. Morris MC, Evans DA, Bienias JL, Tangney CC, Bennett DA, Wilson RS, et al. Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease. Arch Neurol. 2003;60:940–6.

    PubMed  Google Scholar 

  130. Zhang Y, Chen J, Qiu J, Li Y, Wang J, Jiao J. Intakes of fish and polyunsaturated fatty acids and mild-to-severe cognitive impairment risks: a dose-response meta-analysis of 21 cohort studies. Am J Clin Nutr. 2016;103:330–40.

    CAS  PubMed  Google Scholar 

  131. Freund-Levi Y, Eriksdotter-Jonhagen M, Cederholm T, Basun H, Faxen-Irving G, Garlind A, et al. Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial. Arch Neurol. 2006;63:1402–8.

    PubMed  Google Scholar 

  132. Quinn JF, Raman R, Thomas RG, Yurko-Mauro K, Nelson EB, Van Dyck C, et al. Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial. JAMA. 2010;304:1903–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Thal LJ, Rosen W, Sharpless NS, Crystal H. Choline chloride fails to improve cognition of Alzheimer’s disease. Neurobiol Aging. 1981;2:205–8.

    CAS  PubMed  Google Scholar 

  134. Fisman M, Merskey H, Helmes E, McCready J, Colhoun EH, Rylett BJ. Double blind study of lecithin in patients with Alzheimer’s disease. Can J Psychiatry. 1981;26:426–8.

    CAS  PubMed  Google Scholar 

  135. Engelborghs S, Gilles C, Ivanoiu A, Vandewoude M. Rationale and clinical data supporting nutritional intervention in Alzheimer’s disease. Acta Clin Belg. 2014;69:17–24.

    CAS  PubMed  Google Scholar 

  136. Andrieu S, Guyonnet S, Coley N, Cantet C, Bonnefoy M, Bordes S, et al. Effect of long-term omega 3 polyunsaturated fatty acid supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT): a randomised, placebo-controlled trial. Lancet Neurol. 2017;16:377–89.

    CAS  PubMed  Google Scholar 

  137. Phillips MA, Childs CE, Calder PC, Rogers PJ. No effect of omega-3 fatty acid supplementation on cognition and mood in individuals with cognitive impairment and probable Alzheimer’s disease: a randomised controlled trial. Int J Mol Sci. 2015;16:24600–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Yassine HN, Braskie MN, Mack WJ, Castor KJ, Fonteh AN, Schneider LS, et al. Association of docosahexaenoic acid supplementation with Alzheimer disease stage in apolipoprotein E epsilon4 carriers: a review. JAMA Neurol. 2017;74:339–47.

    PubMed  PubMed Central  Google Scholar 

  139. Grimm MOW, Michaelson DM, Hartmann T. Omega-3 fatty acids, lipids, and apoE lipidation in Alzheimer’s disease: a rationale for multi-nutrient dementia prevention. J Lipid Res. 2017;58:2083–101.

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Olde Rikkert MG, Verhey FR, Blesa R, von Arnim CA, Bongers A, Harrison J, et al. Tolerability and safety of Souvenaid in patients with mild Alzheimer’s disease: results of multi-center, 24-week, open-label extension study. J Alzheimers Dis. 2015;44:471–80.

    CAS  PubMed  Google Scholar 

  141. Scheltens P, Kamphuis PJ, Verhey FR, Olde Rikkert MG, Wurtman RJ, Wilkinson D, et al. Efficacy of a medical food in mild Alzheimer’s disease: a randomized, controlled trial. Alzheimers Dement. 2010;6(1–10):e1.

    Google Scholar 

  142. Scheltens P, Twisk JW, Blesa R, Scarpini E, von Arnim CA, Bongers A, et al. Efficacy of Souvenaid in mild Alzheimer’s disease: results from a randomized, controlled trial. J Alzheimers Dis. 2012;31:225–36.

    CAS  PubMed  Google Scholar 

  143. Shah RC, Kamphuis PJ, Leurgans S, Swinkels SH, Sadowsky CH, Bongers A, et al. The S-Connect study: results from a randomized, controlled trial of Souvenaid in mild-to-moderate Alzheimer’s disease. Alzheimers Res Ther. 2013;5:59.

    PubMed  PubMed Central  Google Scholar 

  144. Soininen H. 36-month LipiDiDiet multinutrient clinical trial in prodromal Alzheimer’s disease. Alzheimers Dement. 2020. https://doi.org/10.1002/alz.12172.

    Article  PubMed  PubMed Central  Google Scholar 

  145. Wang J, Logovinsky V, Hendrix SB, Stanworth SH, Perdomo C, Xu L, et al. ADCOMS: a composite clinical outcome for prodromal Alzheimer’s disease trials. J Neurol Neurosurg Psychiatry. 2016;87:993–9.

    PubMed  PubMed Central  Google Scholar 

  146. Hendrix SB, Soininen H, Visser PJ, Solomon A, Kivipelto M, Hartmann T. ADCOMS: a post-hoc analysis using data from the LipiDiDiet trial in prodromal Alzheimer’s disease 11th Clinical trials on Alzheimer’s Disease; October 24–27, 2018; Barcelona

  147. Rijpma A, Meulenbroek O, van der Graaf M, Lansbergen M, Sijben J, Heerschap A, Rikkert MO. The effect of Souvenaid on brain phospholipid metabolism in patients with mild Alzheimer’s disease: results of a randomised controlled 31P-magnetic resonance spectroscopy study. Neurobiol Aging. 2016;39:S7–8.

    Google Scholar 

  148. Rijpma A, Meulenbroek O, van Hees AM, Sijben JW, Vellas B, Shah RC, et al. Effects of Souvenaid on plasma micronutrient levels and fatty acid profiles in mild and mild-to-moderate Alzheimer’s disease. Alzheimers Res Ther. 2015;7:51.

    PubMed  PubMed Central  Google Scholar 

  149. Yassine HN, Rawat V, Mack WJ, Quinn JF, Yurko-Mauro K, Bailey-Hall E, et al. The effect of APOE genotype on the delivery of DHA to cerebrospinal fluid in Alzheimer’s disease. Alzheimers Res Ther. 2016;8:25.

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Funding

This manuscript is based on the proceedings of a round table funded by Nutricia and attended by the authors. Nutricia funded the rapid service fee for publication.

Medical Writing and/or Editorial Assistance

Editorial assistance in the preparation of this article was provided by Tim Kelly, Medi-Kelsey Limited. Support for this assistance was funded by Nutricia.

Authorship

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Disclosures

Barry Baumel, P. Murali Doraiswamy, Marwan Sabbagh, and Richard Wurtman have served as paid advisors to Danone Nutricia. P. Murali Doraiswamy has received research grants and/or advisory/speaking fees from several health and technology companies in this field. P. Murali Doraiswamy owns shares in several companies, whose products are not discussed here. P. Murali Doraiswamy is a co-inventor on several patents through Duke University. P. Murali Doraiswamy serves on the boards of several organizations. Marwan Sabbagh has received funding from Brain Health Inc, Harper Collins, NeuroReserve, NeuroTau, Neurotrope, Optimal Cognitive Health Company, uMethod Health, Versanum Inc., Alzheon, Athira, Biogen, Cortexyme, Neurotrope, Regeneron, Roche-Genentech, and Stage 2 Innovations. Richard Wurtman invented the nutrient mixture, which was patented by the Massachusetts Institute of Technology and licensed to Danone.

Compliance with Ethics Guidelines

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors. All clinical trials cited in this review were done in compliance with the Declaration of Helsinki.

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Baumel, B.S., Doraiswamy, P.M., Sabbagh, M. et al. Potential Neuroregenerative and Neuroprotective Effects of Uridine/Choline-Enriched Multinutrient Dietary Intervention for Mild Cognitive Impairment: A Narrative Review. Neurol Ther 10, 43–60 (2021). https://doi.org/10.1007/s40120-020-00227-y

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Keywords

  • Alzheimer disease
  • Choline
  • Docosahexaenoic acid
  • Mild cognitive impairment
  • Multinutrient
  • Uridine