Dementia, and its most common form, Alzheimer's disease (AD), is a complex and progressive neurological disorder characterized by many neuropsychiatric symptoms, e.g. aggression, anxiety, depression and sleep disorder, and the better known symptoms associated with progressive memory loss and cognitive impairment, all of which can significantly alter the quality of life of those afflicted with this disorder (1, 2). Age is a major risk factor for dementia, and 1.5% of the population will be affected directly by dementia by the age of 65 and >20% of the population by the age of 85 (3). Neurocognitive disorders such as AD are expected to steadily increase in prevalence and incidence as the population ages. It is estimated that the global number of individuals suffering from dementia will reach 65 million by 2030 and 113 million by 2050 (2, 4). The impact of the high prevalence of dementia in the elderly is noteworthy, as seen in the substantial direct healthcare costs as well as in the devastating social costs for individuals and their families and caregivers (2). Yet, despite the growing importance of understanding dementia, we are still in search of effective methods for its diagnosis and treatment.

In this review, we provide a summary of the potential role of the amino acid D-serine, a potent co-agonist at the N-methyl-D-aspartate glutamate receptor (NMDAR), in normal and pathological aging, with a focus on neurocognition. A brief discussion on the diagnostic and therapeutic potential of D-serine is also included. The evidence suggests that this is a promising avenue of research into the pathophysiology of neurocognition and its potential treatment in dementing illnesses. Literature searches were performed in PubMed and Web of Science for the period January 1970 to May 2021, and the key search terms used were “D-serine and dementia”, “D-serine and Alzheimer's disease”, “D-serine and mild cognitive impairment”, “D-serine and LTP”, as well as “D-serine and NMDA receptors”. Only papers in English were used in preparation of the review, and some of the review papers found were searched for additional relevant references. Each reference used was screened by at least two of the authors.

Aging is a normal dynamic process, characterized by the development of a mild inflammatory environment and a progressive deterioration of certain physiological functions, including in the central nervous system (CNS) (5, 6). Although cognitive decline is relatively common in old age, the relationship between aging and degenerative dementias such as AD remains unclear. Whereas aging is a risk factor for AD, it is not inevitable that AD be part of the aging process. While obvious and oftentimes widespread structural changes can be seen within the CNS with dementia pathophysiology, normal aging is not associated with a significant loss of neurons (7); rather, brain alterations in normal aging are much more subtle, involving changes in connectivity and altered functions at the cellular and molecular level (8). Several cognitive domains are affected in normal aging and dementia, including learning and memory (particularly for newly acquired information), processing speed, working memory, and executive function (9, 10). An intriguing feature of aging is the variation of degree of cognitive impairment between individuals, from a mild deficit to a severe dementia, as in the case of AD (11, 12).

The decline in learning and memory performance during non-pathological aging appears to be primarily the result of alterations in neuronal network plasticity within the hippocampus (12). Memory formation is viewed as being closely dependent on the capacity of the brain to regulate long-lasting changes in neuronal communication via synapses, and appears to be proportional to the strength of those communications (13, 14). The first convincing support for neuronal plasticity changes underlying changes in cognition came in the 1970s when long-term potentiation (LTP), a mechanism now known to underpin synaptic strengthening critical for learning and memory, was characterized in the hippocampus (15). It was later shown that LTP was regulated in large part by NMDAR signaling (16–18).

Dynamic synapses facilitate remodeling of neuronal circuits, and changes in the functional properties of these networks could play a critical role in the induction of age-related memory decline (19). However, the mechanisms governing dynamic synapses in the brain are still not well understood (20, 21). The hippocampus is the area most frequently implicated in memory decline and this structure seems to be particularly vulnerable to aging (22–24). Interestingly, the circuits that are vulnerable to aging are composed to a large extent of glutamatergic neurons (25).

Proper brain functioning requires healthy neurons and neuronal connections, which in turn require properly functioning neurotransmitters and enzymes that supply these dendritic and neuronal connections. It has been shown repeatedly that deficits in glutamatergic transmission mediated by the NMDAR are related to cognitive impairment in both laboratory animals and humans. Administration of an NMDAR antagonist in rhesus monkeys impairs recognition memory (26), which represents cognitive impairment (27). Similarly, specific ablation of GRINs (Glutamate Ionotropic Receptor NMDA Type 1-3), i.e., the genes that encode for subunits of the NMDAR heterotetrameric complex, in the hippocampus or pharmacological blockade of NMDAR function can lead to brain atrophy, impaired neuroplasticity, reduced LTP and deficits in learning and contextual memory (18, 28, 29). In contrast, increasing NMDAR function by over-expression or reduced degradation in the hippocampus can enhance LTP and learning (30, 31).

Particular attention has been paid to learning and memory, and to whether activation of NMDARs could be altered in the course of aging. Various studies in wild-type rodents have revealed that aging is associated with reductions in the magnitude of LTP in the hippocampus and have implicated alterations in NMDAR signaling and a decline in the activation of NMDARs associated with a decrease in levels of D-serine, a co-agonist at the NMDA receptor. Therefore, age-related decreases in D-serine could be contributing to the cognitive decline (10). Since activation of the NMDAR co-agonist-binding site by D-serine and glycine is mandatory for the induction of synaptic plasticity, the LTP rescue observed in aged animals after supplementation with the co-agonist D-serine also suggests that the mechanisms managed by endogenous D-serine are altered with age (11).

Memory formation relies on the capacity of neuronal networks to manage long-term changes in synaptic communication. This property is driven, at least in part, by NMDARs (32). The NMDAR is a tetrameric ion channel that may be composed of many configurations of three subunits, i.e., GluN1, GluN2, and less commonly, GluN3 (33–35). To be activated, the NMDAR requires simultaneous binding of the agonist glutamate to the GluN2 subunit and a co-agonist to GluN1 (34–37). This binding is crucial for NMDAR activation and originally it was thought that the major co-agonist was glycine (10, 36, 37); however, later studies found that D-serine is more potent than glycine at binding to the co-agonist site on the GluN1 subunit of the NMDAR and stimulating the receptor in forebrain regions, including hippocampus (38). D-Serine has a regional distribution in the brain more similar to that of NMDARs than does glycine (39–41) and it has been reported that D-serine acts primarily at synaptic NMDARs whereas glycine acts primarily at extrasynaptic NMDARs (38). Interestingly, glycine is similar structurally to D-serine (Figure 1) and it is formed by conversion of L-serine catalyzed by the enzyme serine hydroxymethyltransferase.

Balanced NMDAR activity is required for optimal brain function. Hypo- or hyper-function of NMDAR-mediated neurotransmission can result in cognitive dysfunction or neurotoxicity, respectively. Depletion of D-serine diminishes NMDAR activity, LTP, and synaptic plasticity (33). NMDAR-mediated neurotransmission and its modulation by D-serine play a critical role in memory formation, learning, and neuronal plasticity (34, 42–44). In CNS development, D-serine shapes synaptogenesis and neuronal circuitry through activation of NMDARs and it is also a key player in astrocyte-mediated LTP associated with hippocampal plasticity (20).

The reports by Hashimoto et al. were the first to demonstrate high concentrations of D-serine in the rodent brain and in the human brain (45, 46). It was only later discovered that D-serine is enriched in brain regions containing high concentrations of NMDARs, such as the cerebral cortex, hippocampus, and amygdala (41). The source of D-amino acids in mammals was historically attributed to diet or intestinal bacteria (47) until the racemization of L-serine by serine racemase was identified as the endogenous source of D-serine (48) (see Figure 1 for structures of L- and D-serine). Serine racemase was first described to be exclusively present in astrocytes (49–51), but subsequent work has shown that serine racemase is also present in neurons (52). Thus, D-serine may be a glial transmitter as well as a neurotransmitter, and this has been a matter of considerable controversy [for discussions of this matter see: (52–54)]. Wolosker et al. (52) proposed that L-serine is synthesized in astrocytes and then shuttled to neurons where it is converted to D-serine. For a detailed description of D-serine circuits and the “serine shuttle”, see Wolosker and Balu (55).

Serine racemase is expressed by many CNS cells, including pyramidal neurons in the cerebral cortex and the CA1 region of the hippocampus (41, 56), regions that also have high levels of D-serine (57). Wong et al. (58) have shown an age-dependent dendritic and postsynaptic localization of serine racemase in CA1 pyramidal neurons of the mouse. These same researchers, in studies using serine racemase knockout (KO) mice, showed a cell-autonomous role for this enzyme in regulating synaptic NMDAR function at Schaffer collateral (CA3)-CA1 synapses and found that single-neuron genetic deletion of serine racemase eliminated LTP at the age of 1 month and that this loss of LTP could be rescued by administering D-serine (58). The enzyme responsible for the catabolism (breakdown) of D-serine is D-amino acid oxidase (DAAO); this enzyme is most abundant in cerebellum and brain stem, areas with low levels of D-serine (59).

D-Serine levels vary across different CNS areas. The level of D-serine is in the order of 200–300 pmoles per milligram of tissue in the hippocampus and frontal cortex in mice, 20-fold higher than in the pancreas, lung, or testis and almost 50-fold higher than in muscle (60). Within the brain, highest levels of D-serine are in the cortex and hippocampus, and there are much lower levels in the cerebellum and brain stem, likely reflecting the regional variation in expression of serine racemase and DAAO (review: 61).

D-Serine, through its regulatory effect on glutamatergic transmission, participates in multiple processes, including synaptic plasticity (61, 62), cell migration and synaptogenesis (41, 63), and in homeostatic functions, as a mediator of hypercapnia-induced respiratory response (64). The production of D-serine and its tightly regulated release, mainly through calcium-dependent exocytosis (65), keep its concentration within a narrow range. Any deviation from this range may lead to pathology, with abnormally increased levels of D-serine associated with NMDAR-mediated neurotoxicity (66–68) and abnormally decreased levels of D-serine associated with impairments in functional plasticity and with memory deficits (11). The complexity of its actions and its modulatory effects are not well understood; indeed, Coyle et al. (69) referred to D-serine as a “shape-shifting NMDAR co-agonist” and provided a possible explanation for these dueling effects of D-serine on driving neuronal plasticity or neurodegeneration based on the localization of the activated NMDARs involved. It is known that synaptic NMDARs prompt trophic effects while extra-synaptic NMDARs on the dendrites or soma drive excitotoxicity (38, 70, 71). Coyle et al. (69) propose that D-serine synthesized by serine racemase binds preferentially to synaptic NMDARs and facilitates glutamatergic neurotransmission, while proliferation of inflammatory A1 astrocytes results in a new source of D-serine that is released into the extracellular space to activate extra-synaptic NMDARs.

D-Serine levels in the CNS change during development and aging. In early developmental stages, a transient increase in D-serine production matches a transient increase of NMDAR activity (72). The early postnatal period with high D-serine levels in glia coincides with a period of intense plasticity, synaptogenesis and maturation in the CNS, suggesting the existence of distinct functional roles for D-serine throughout development (72). Healthy newborn children have elevated CSF D-serine levels that are rapidly reduced during the first year of life and reach 15% of the initial concentration at 3 years of age (73).

In the hippocampus of normal aged rats, both D-serine (but not glycine) and serine racemase levels are decreased relative to younger rats (74, 75). In contrast, these reductions in D-serine and serum racemase are not observed in the LOU/c/jall rat strain regardless of age (5, 76). The LOU/c/jall strain of rat (derived from the Wistar strain) is a model of healthy aging (with resistance to obesity and lower oxidative metabolic rates than the routinely used other inbred strains of rats) (76). Interestingly, the possibility that D-serine-related pathways could be targeted by the age-related accumulation of reactive oxygen species (ROS) has been suggested (5), and LOU/c/jall rats do not develop oxidative stress (5, 76).

Significant efforts are being made to identify diagnostic markers and modifiable risk factors for AD, specifically any factor that influences the earliest stages of the disease process, when intervention might still provide therapeutic benefit. In this context, CSF levels of Aβ, total tau protein and hyperphosphorylated tau (p-tau) have now been included in diagnostic guidelines (114). Such CSF biomarkers have been advocated for research purposes, but sensitivity and specificity issues have generally raised concerns about their widespread clinical use (15). Madeira et al. (16) proposed that combining CSF D-serine levels with the Aβ/tau index could markedly increase the sensitivity and specificity of diagnosis of probable AD. However, Biemans et al. (115) and Nuzzo et al. (116) did not find a difference in CSF D-serine levels between AD patients and elderly controls.

Lin et al. (109) found increased levels of DAAO in the serum of patients with mild cognitive impairment (MCI) and AD and observed that the severity of cognitive deficits correlated positively with DAAO blood levels, suggesting that this enzyme catabolizing D-serine may also serve as a biomarker for MCI/AD. These researchers found that DAAO levels were significantly lower in healthy controls than in the patients, and moreover, lower in patients with amnestic MCI than in those with moderate to severe AD (109). In the same study, D-serine levels in serum were reported to be higher in AD patients than in the healthy controls. The clinical benefit of DAAO inhibition in AD may be mediated in part by an antioxidant effect since D-serine degradation by DAAO generates hydrogen peroxide, a precursor to many ROS (10, 109). In a later study of D-serine levels in 144 patients with varying degrees of cognitive impairment, Lin et al. (117) concluded that higher D-serine levels predict worse cognitive function, particularly with regard to word recall, orientation, comprehension, and word-finding.

In a recent metabolomics study in a cohort of women aged 65–80 years old, Kimura et al. (118) reported a higher D-proline/(D-proline+L-proline) ratio in women with MCI compared to matched controls, and found this biomarker's accuracy was improved by further adding the D-serine/(D-serine+L-serine) ratio. Piubelli et al. (119) measured serum levels of D- and L-serine in AD patients with either a score of 1 (mild dementia) or 2 (moderate dementia) in the Clinical Dementia Rating Scale, and found that D-serine levels and the D-serine/total serine ratio increased significantly with disease progression. These researchers suggested using the combination of the above ratio with other blood-based biomarkers presently under development and reviewed by Hampel et al. (120).

The role of D-serine in AD is complex and the literature is often ambiguous. It has been suggested that some of the differences between findings in laboratory animals and human AD patients could be due to the fact that current animal models do not mimic the slow progression and the changes in Aβ and tau protein that occur in AD in humans (11). It has also been proposed that studies on D-serine and AD should be done at various stages of AD since at early stages with low levels of Aβ oligomers there is also decreased synthesis of L-serine and, hence, decreased D-serine levels and weaker NMDAR activation. However, at later stages when there is increased soluble Aβ, glia start to express more serine racemase and release large amounts of D-serine, resulting in NMDAR over-activation and resultant excitotoxicity, neurodegeneration and marked memory deficits (117). There is also some speculation that D-serine increases observed in AD patients may be part of a protective mechanism to counter Aβ signaling and prevent AD pathology (10).

As mentioned above, there is a loss of production of D-serine and a decline in NMDAR activation and a corresponding reduction of LTP magnitude in the normal aging process, which can be reversed in animal models by administration of D-serine (11). These findings imply that increasing D-serine levels in cases of initial cognitive decline or in early stages of AD may be therapeutically useful (10).

Findings that the co-agonist modulatory site was not saturated in vivo prompted investigators to consider whether exogenous D-serine could act as a cognitive enhancer (10). Although the focus of the present review is on dementia, it should be mentioned that much of the research on the effects of D-serine in cognition in humans has been done on schizophrenia (57, 121–130), reporting either cognitive benefits (121, 122, 125, 126, 130) or no effects on cognition (123, 128, 129). It is difficult to compare the studies since they were performed at several doses, the patients were taking antipsychotics (which presents a possible confound), and a variety of tests were conducted to measure cognition. Most of the studies were carried out using a daily dose of 30 mg/kg, but Kantrowitz et al. (126, 130) also used higher doses (60 and 120 mg/kg) and reported improvements in cognition.

D-Serine administration can improve cognition in aged rodents and correct age-related decline in synaptic plasticity (10). In mouse models, the learning deficits caused by NMDAR hypofunction can be rescued by administration of D-serine (131). Although conflicting results have been reported, D-cycloserine (Figure 2; a cyclized form of D-serine that is hydrolyzed to give D-serine and hydroxylamine) has been reported to improve memory functions in animal studies and in dementia patients (132, 133). Lin and Lane (133) speculated that D-cycloserine may have different effects on mood and learning depending on the stage of dementia involved. D-Serine given intraperitoneally to rats can increase NMDAR activation in the hippocampus and improve social memory in rats and recognition and working memory in mice (10). The potency of exogenous D-serine to enhance NMDAR activation appears significantly higher in hippocampal slices from aged rats when compared to effects in younger adult rats (134). Nikseresht et al. (135), using a rat model of AD (intracerebroventricular injection of Aβ), reported a synergistic memory-enhancing effect of D-serine and the mitochondrial calcium uniporter blocker RU360. The findings in this report suggested that the coadministration of these drugs ameliorated memory impairment, probably in part through an increase in hippocampal levels of cyclic AMP response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF).

In a randomized controlled clinical trial (RCT) by Avellar et al. (9), 50 healthy elderly human adults received a single dose of D-serine or placebo, and the effects of D-serine administration on cognitive test performance and a mood scale were measured. In addition, blood samples were analyzed for levels of D-serine, L-serine, glutamate and glutamine. D-Serine levels measured while the participants were on placebo were inversely associated with aging. D-Serine administration improved performance in the Groton Maze Learning Test of spatial memory, learning and problem solving. Individuals who achieved higher increases in plasma D-serine levels after administration improved more in test performance. D-Serine administration was not associated with any significant changes in other cognitive domains, such as verbal working memory, visual attention or cognitive flexibility. There were also no changes observed in mood (9). In a similar study, but in young healthy adults, Levin et al. (136) demonstrated that D-serine administration improved attention, verbal learning and memory as well as subjective feelings of sadness and anxiety.

These above studies suggest an important role for D-serine in brain networks underlying memory impairment and provide useful information in the search for new therapeutic strategies for the treatment of memory deficits. However, an important question is whether the improvements seen so far with the addition of D-serine in animal models and healthy human controls will have real-life effects in AD (11).

In the aging brain, ROS accumulation may trigger age-related reduction of cognitive function through oxidative stress. Consequently, ROS accumulation could be viewed as a major process acting on the D-serine-related pathway in the aging hippocampus, especially considering that serine racemase activity is particularly sensitive to oxidative stress (105). Long-term dietary supplementation with L-N-acetylcysteine (L-NAC, a precursor to the antioxidant glutathione) prevented oxidative damage in the hippocampus and restored D-serine-dependent NMDAR activation and LTP induction in aged rats (20). These data provide evidence that maintaining elevated D-serine levels in the aging hippocampus through the control of the redox state is able to prevent the cellular injury underlying cognitive aging, specifically in the CA1 hippocampal area (11).

An increase in D-serine availability in the brain could be achieved by reducing its degradation by DAAO. Treatment of rats with a DAAO inhibitor has been reported to increase levels of D-serine in the cerebral cortex and midbrain (137). Although DAAO KO mice have been reported to have markedly increased levels of D-serine in cerebellum and brain stem but little or no change in D-serine levels in cortex or hippocampus (138, 139), support for a physiological role for DAAO in modulating cognition comes from the enhanced learning abilities reported for DAAO KO mice (57, 140). The DAAO inhibitor sodium benzoate, which also modulates the immune system and is an antioxidant, has been shown to improve cognition, global functioning and positive and negative symptoms of schizophrenia (141). Modi et al. (142), using an animal model of AD, reported that sodium benzoate reduced oxidative stress and protected memory and learning. In addition, in RCTs of 6 weeks daily treatment with sodium benzoate, Lin and colleagues reported that cognitive scores were improved in early stage dementia patients and in women, but not men, with later phase dementia (143).

The D-amino acid D-cysteine, which is derived from the gut, and is structurally related to D-serine (it is also referred to as thioserine; Figure 2) also exerts neuroprotection, but it does so via a DAAO-dependent conversion to H₂S (144). Interestingly DAAO has greater affinity for D-cysteine even though D-serine is found in far greater concentrations in the brain (145). It is all the more interesting that D-cysteine has been shown to be a potent inhibitor of serine racemase (146), thereby making it a potential treatment for pathologies where D-serine might exert deleterious effects, such as in AD.

The fact that body fluid levels of D-serine have been reported to be altered in other psychiatric and neurological disorders, such as depression, anxiety, schizophrenia, bipolar disorder and hydrocephalus (16, 61, 147, 148) suggests that D-serine would not be a specific biomarker for AD. There are also potential challenges for the clinical use of D-serine, including the possibility of nephrotoxicity (149, 150). However, this nephrotoxicity may only be a problem with rats since it has not been reported in other species, including rodents such as mice and rabbits (151, 152). Even in rats, the nephrotoxicity is reversible and appears to occur only at high doses (152). In a comprehensive review of safety of D-serine across species, Meftah et al. (152) listed the studies on humans with D-serine that have been published and reported that only one subject in one study showed renal abnormalities. These researchers concluded that D-serine is safe and well tolerated in humans even at the highest dose (120 mg/kg) tested to date, but that people with pre-existing renal dysfunction should be excluded from clinical studies. Co-administration of a DAAO inhibitor with D-serine may be a strategy to prevent nephrotoxicity since lower doses of D-serine could be used and hence formation of peripheral metabolites of D-serine reduced (153). In mice, treatment with a DAAO inhibitor has been reported to render a low dose of D-serine effective in treating pre-pulse inhibition deficits caused by the NMDAR antagonist dizocilpine, compared to the same dose of D-serine alone (154).

Poor oral bioavailability can also limit the effects of D-serine on cognition. Accordingly, D-serine had better effects on cognition when administered as an adjunct to patients with schizophrenia when higher doses such as 60 mg/kg/day or higher were used (review: 61). In general, poor oral D-serine bioavailability may account for mixed results in clinical trials, and alternative treatment paradigms may need to be considered, including larger doses of D-serine or a combination of D-serine and sodium benzoate (thus using lower doses of both drugs while retaining high efficacy). Because D-serine and sodium benzoate have different pharmacokinetic and pharmacodynamic profiles, it is possible that D-serine may be especially useful for treating depression because of its acute and chronic antidepressant effects, whereas sodium benzoate may be a safer approach in older adults with impaired renal function (10).

Considerable evidence in the literature supports the involvement of D-serine in reduction of cognitive deficits, but there are some contradictory findings that indicate that further research is warranted. For example, Capitao et al. (155), in a study of a single dose (60 mg/kg) in human volunteers, found that D-alanine modulated emotional processing while D-serine did not. Some researchers have questioned the physiological role of DAAO in controlling D-serine availability because this enzyme is expressed at low levels in forebrain areas relevant to cognition such as the hippocampus and cortex, and D-serine levels have been reported to be elevated markedly in the cerebellum and brain stem but not in cortex or hippocampus of DAAO KO mice (138, 139). However, other researchers have found that systemic administration of a DAAO inhibitor to rats increases levels of D-serine in the cortex (137). Labrie et al. (140) reported that DAAO KO mice had a marked increase in levels of D-serine in the cerebellum, but also had a relatively small, but significant, increase in D-serine levels in the hippocampus and showed enhanced extinction and reversal learning.

Although it has been proposed that CSF and/or serum levels of D-serine could be novel biomarkers for AD (16, 119, 156), other researchers have reported that D-serine levels in these body fluids are unaltered in AD (115, 116). It has also been reported that perinatal epigenetic mechanisms play a role in the regulation of levels of D-serine in the brain (157), and future studies in AD should include epigenetic investigations on expression of serine racemase and DAAO genes. Dysregulation of aerobic glycolysis in the brain is often observed early in the course of AD, and Le Douce et al. (158) have shown that the astrocytic biosynthetic pathway for L-serine (the precursor for D-serine), which branches from glycolysis, is impaired in young AD mice and in AD patients. These researchers found that dietary supplementation with L-serine prevented the synaptic and behavioral deficits in AD mice, which suggests that oral L-serine could be a therapy for AD.

The focus of this review has been on the involvement of D-serine in cognitive deficits, but dementia is complex and often there is a high degree of comorbidity with depression, anxiety, aggression, and/or sleep disorders. There is now an extensive body of literature indicating involvement of D-serine in each of these disorders. It may seem contradictory for D-serine to have antidepressant effects considering the known antidepressant effects of the NMDAR antagonist ketamine (159), but several preclinical and clinical studies report antidepressant actions of D-serine [reviews: (61, 160, 161)]. It has been proposed that the antidepressant actions of ketamine and D-serine may be due to common effects on α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) glutamate receptors and similar differential actions on synaptic vs. extra-synaptic NMDARs (160). Wolosker and Balu (55) have provided a comprehensive review of mainly preclinical studies suggesting a role of D-serine in fear conditioning and anxiety disorders. As an abnormal social behavior, aggression (often studied in mice as social interaction deficits with intruder strains of mice) has been observed in rodents to show an association with NMDAR function (162–165). Both D-cycloserine and D-serine have been reported to improve impaired social interaction skills, for example in inbred Balb/c mice used as models for autism (164–167). Nagai et al. (168) reported that mice treated neonatally with polyI:C (elicits viral-like immune responses) had emotional and cognitive deficits which could be ameliorated in adulthood by treatment with D-serine. With regard to sleep disorders, studies in mammals and Drosophila flies have shown that NMDARs and D-serine participate in sleep regulation (169–171). Drosophila has been used as a model for genetic studies of sleep for several years (172). In a detailed study of sleep in this model, Dai et al. (173) showed that sleep is regulated by D-serine through NMDAR1 and that intestinal expression of serine racemase is important for this sleep regulation.

Longitudinal studies, both preclinical and clinical, involving larger samples sizes will be needed in future research on D-serine, and such investigations should include both males and females, along with assessments of the comorbid disorders mentioned above.

In normal aging there is development of a mild inflammatory environment and progressive deterioration of several physiological functions, including cognition involving learning and memory performance. With aging, the degree of cognitive impairment can vary markedly among individuals. Memory formation depends on the capacity of the brain to regulate long-lasting changes in neuronal communication via synapses, and these changes in neuronal plasticity are dependent on LTP, which is regulated in large part by NMDARs. Functioning of NMDARs is in turn dependent on co-agonists, the most important of which appears to be D-serine. Numerous animal studies have shown that even with normal aging there is a reduction in the magnitude of LTP in the hippocampus accompanied by a decline in NMDAR action and a decrease in production and levels of D-serine. It has also been demonstrated in animal models that administration of D-serine can rescue the reduced NMDAR function and loss of LTP observed in aging.

Preclinical studies suggest that D-serine may be useful in treating cognitive impairment, but while abnormally decreased levels of D-serine are associated with impairments in functional plasticity, abnormally increased levels of D-serine can be associated with NMDAR-mediated excitotoxicity such as occurs in later-stage AD. Activation of microglia is part of a chronic inflammatory response in AD that increases release of glutamate and D-serine from glia and neurons, and Aβ also stimulates expression of serine racemase in microglia. It has been suggested that with cognitive deficits associated with normal aging and in early AD, there may be decreased expression of serine racemase, decreased levels of D-serine, NMDAR down-regulation and impaired synaptic plasticity, while in advanced AD serine racemase activation and D-serine levels are increased and NMDARs are overstimulated, resulting in excitotoxicity and dementia.

D-Serine and DAAO have been proposed as possible biomarkers in the diagnosis of AD, although there have been conflicting results reported and differences found in animal models and humans. Current animal models do not mimic the slow progression and the changes in Aβ and tau protein that occur in humans; it has also been proposed that future studies on D-serine in humans should be done at several stages of AD. Research to date suggests that earlier stages of AD would benefit from D-serine supplementation, whereas D-serine supplementation should be avoided in later stages of AD. DAAO inhibitors may also be useful for increasing brain D-serine levels and enhancing learning.

Although we understand a great deal about the roles of D-serine in brain function, about changes in its brain levels with normal and pathological aging, and about its potential role as a cognitive enhancer from experimental and preclinical studies, much still remains to be learned about its potentially targetable role in development, treatment and possibly even prevention of dementia in a clinical setting.

MO and GB conducted the initial literature search. Each reference was screened by at least two of the authors. MO prepared the initial draft of the manuscript and all authors then contributed to editing. All authors have agreed to submission of this version of the manuscript.

DM acknowledges financial support from the Office of Research, College of Medicine, University of Saskatchewan as well as from a philanthropic Saskatchewan family. DM also acknowledges the Saskatchewan Research Chair in Alzheimer disease and related dementias funded jointly by the Alzheimer Society of Saskatchewan and the Saskatchewan Health Research Foundation. GB has a TRIP Research Allowance (TRP-GB) from the Faculty of Medicine & Dentistry at the University of Alberta. EF acknowledges funding from CIHR (FRN 201803).

GB is an advisor to NeuraWell Therapeutics. The company had no involvement with this review. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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