Affecting up to 27% of people aged 65 years and older (Scafato et al., 2010; Anderson, 2019; Jia et al., 2020; Bai et al., 2022), mild cognitive impairment (MCI) is considered a transitional stage between healthy aging and dementia (Jia et al., 2020; Bai et al., 2022; Han and Chul Youn, 2022; Morozova et al., 2022). Some individuals may notice a decline in cognitive function before being diagnosed with MCI, but show no objective impairment by neuropsychological tests and are generally considered clinically healthy, with normal daily functioning and independence (Jessen et al., 2020). This preclinical condition is known as subjective cognitive decline (SCD), which has been linked to an increased risk of future objective cognitive decline (Jessen et al., 2020). In addition to cognitive symptoms, non-cognitive symptoms in MCI include depression, anxiety, irritability, aggression, and apathy (Mougias et al., 2023). Several forms of MCI have been proposed, with varying clinical outcomes: degenerative (onset low and gradual), vascular (in patients with higher vascular risk), and anxiety and depression (in patients with a history of psychiatric syndromes) (Petersen, 2016). Also, new-onset cognitive impairment, associated with abnormal brain metabolism, has often been reported after coronavirus disease 2019 (COVID-19) (Beretta et al., 2023; Ferrucci et al., 2023).

Dementia is commonly classified as either dementia of primary origin (i.e., dementia of degenerative origin such as that associated with Alzheimer’s disease or Parkinson’s disease), dementia of secondary origin (i.e., dementia that is a consequence of conditions that cause cognitive impairment as a secondary effect such as vascular dementia), or mixed dementia (e.g., Alzheimer’s disease with simultaneous vascular dementia; Kabasakalian and Finney, 2009; Bello and Schultz, 2011).

While MCI is a risk factor for dementia (Knopman et al., 2021), not all patients with MCI go on to develop dementia (Mitchell and Shiri-Feshki, 2009; Bai et al., 2022; Han and Chul Youn, 2022) or Alzheimer’s disease (Mitchell and Shiri-Feshki, 2009); however, it is currently impossible to predict which patients with MCI will advance to Alzheimer’s disease (Bateman et al., 2012; Morozova et al., 2022). Other known risk factors for the development of Alzheimer’s disease include age >65 years, presence of the epsilon 4 allele of the apolipoprotein E (apoE) gene, female sex, diabetes mellitus, arterial hypertension, smoking, obesity, low levels of high-density lipoprotein cholesterol, hearing loss, traumatic brain damage, depression and social isolation, low physical activity, alcohol abuse, and air pollution (Knopman et al., 2021).

Chronic stress often manifests as depression/apathy and insomnia, and has been associated with cognitive impairment and Alzheimer’s disease, among other disorders (McEwen, 2006; Groeneweg-Koolhoven et al., 2017; Hamdy et al., 2018; Biella et al., 2019; Baek et al., 2020). The hippocampus, an area in the brain that is responsible for cognitive function, is known to adapt in response to stress (McEwen, 2006). Chronic stress and alterations in sleep patterns often result in reduction of neuronal trophism in the medial prefrontal cortex, and is linked with cognitive impairment and depression (McEwen et al., 2016). Furthermore, the presence of apathy and other neuropsychiatric disorders in patients with MCI may be a risk factor for the development of dementia (Ellwardt et al., 2015; Tomioka et al., 2015;van Dalen et al., 2018a; van Dalen et al., 2018b; Roberto et al., 2021).

Given an increasingly aging population globally and projected increase in associated dementia (Livingston et al., 2017; GBD 2019 Dementia Forecasting Collaborators, 2022), there is an urgent need to develop pharmacological therapies to reduce the symptoms of MCI and to delay the possible progression to dementia (Sagaro et al., 2023).

Choline alphoscerate is a choline-containing phospholipid naturally found in the brain, that has been identified as an essential nutrient (Kansakar et al., 2023; Sagaro et al., 2023). Due to its cognition-enhancing capabilities by counteracting reduced cholinergic tone, which is the basis of cognitive dysfunction, choline alphoscerate (Delecit®) is a prescription drug that is a useful treatment for cognitive impairment in Alzheimer’s disease, and other types of MCI and adult-onset dementias (Sagaro et al., 2023). Results of systematic reviews and meta-analyses suggest that choline alphoscerate not only improves cognitive performance but may also reduce cognitive decline (Parnetti et al., 2001; Sagaro et al., 2023). Indeed, in vitro data suggest that choline alphoscerate has neuroprotective effects against β-amyloid injury (Catanesi et al., 2020).

The aim of this narrative review is to discuss the pharmacological and clinical evidence regarding choline alphoscerate in order to highlight its usefulness in patients with MCI, including a potential protective role in β-amyloid (Aβ)1–42-induced microglia activation. This review will also evaluate the potential role of choline alphoscerate in promoting healthy sleep architecture.

Identification of supporting evidence for this narrative review, using structured literature searching of the PubMed database and ad hoc online searches, was conducted on 18 July 2024. The PubMed search terms included “choline alphoscerate” or “choline alphoscerate,” in combination with “pharmacology” or disease-related terms such as “mild cognitive impairment,” “sleep,” “apathy.” No other limits (e.g., time period, language, reviews) were applied to the searches. Search results were filtered for relevant preclinical and clinical studies. In addition, content for the article was identified based on the authors’ knowledge of the therapeutic area.

Choline is an essential nutrient for the body, required especially for the functioning of the brain and nervous system (National Institutes of Health, 2022; Gallo and Gámiz, 2023). It is implicated in neurotransmission, cell-membrane signaling, lipid transport, and methyl-group metabolism (Goh et al., 2021; National Institutes of Health, 2022; Gallo and Gámiz, 2023). In the brain, choline is a precursor of various metabolites, including the neurotransmitter acetylcholine, membrane phospholipids (i.e., phosphatidylcholine and sphingomyelin) and the methyl donor betaine (Figure 1; Goh et al., 2021; National Institutes of Health, 2022). Among these, acetylcholine is a crucial neurotransmitter involved in cognitive function, with acetylcholine deficiency implicated in the cognitive dysfunction that characterizes patients with dementia (Hampel et al., 2018).

Choline can be naturally synthesized in the body, mostly as phosphatidylcholine (National Institutes of Health, 2022; Gallo and Gámiz, 2023). Estrogen activates the gene that catalyzes choline biosynthesis (Goh et al., 2021; National Institutes of Health, 2022), which may account for between-sex differences observed in the risk of development of cognitive impairment and Alzheimer’s disease (Li and Singh, 2014; Rettberg et al., 2014). However, the amount of choline produced by the body is generally insufficient to meet human needs; thus, the diet is an important alternate source of choline (Hollenbeck, 2012; National Institutes of Health, 2022). The United States National Academy of Medicine (NAM) and the European Food Safety and Authority (EFSA) have specified adequate intake values for choline (Goh et al., 2021). However, it is also important to understand individual differences in choline bioavailability and utilization caused by genetic, age, sex, and ethnic differences, as well as the effects of dietary preferences, gut enterotype, intestinal absorption, and lifestyle.

Choline alphoscerate (C8H20NO6P) is a cholinergic drug that is widely used for enhancement of cholinergic transmission (Kansakar et al., 2023). Although also used as a food supplement, choline alphoscerate is available as a prescription drug, and therefore subject to tight regulation and rigorous testing to provide evidence of effectiveness and safety (Hathcock, 2001; Dwyer et al., 2018). In contrast, food supplements are self-regulated by the manufacturer, and proof of effectiveness and safety are not required except where health benefits are being claimed.

Due to its high choline content (41% by weight) and its ability to cross the blood–brain barrier, choline alphoscerate is a useful source of choline (Kansakar et al., 2023). Compared with citicoline (CDP-choline), an alternative source of choline, choline alphoscerate is rapidly and directly metabolized into the active form of choline that is able to enhance release of the neurotransmitter acetylcholine and brain-derived neurotropic factor after administration; in contrast, citicoline is an indirect substrate because it requires additional metabolic steps to produce choline and, therefore, acetylcholine (Figure 2; Traini et al., 2013; Kansakar et al., 2023). Mean increases in free plasma choline levels are greater after administration of choline alphoscerate than after citicoline (25.8 versus 13.1 μmol/L) (Gatti et al., 1992). The above mentioned cholinergic precursors (choline alphoscerate and citicoline) represent one the first approaches attempting to relief cognitive impairment and they are still used today due to their demonstrated efficacy. However, is important to consider that other form of choline-containing phospholipids (alone or in combination with colinesterase inhibitors) failed to show significant efficacy in terms of cognitive improvement in controlled clinical trials (Kansakar et al., 2023).

In this context, choline alphoscerate, as well as being a valuable source of choline for acetylcholine synthesis, also provides choline for phospholipid biosynthesis and betaine formation (Figure 3; Kansakar et al., 2023). Choline alphoscerate is also a direct substrate for choline synthesis, with metabolism of choline alphoscerate providing both free choline for acetylcholine synthesis and phospholipids as components of nerve cells (Traini et al., 2013; Roy et al., 2022). The roles of each of these substances in the brain are briefly described below.

Choline also plays a role in sleep, which may impact memory and cognitive function. Cholinergic neurons are activated during rapid eye movement (REM) sleep, or dreaming sleep; REM is triggered by the firing and release of acetylcholine from pedunculopontine cholinergic neurons (Perry et al., 1999; Cools and Arnsten, 2022). With increasing neuronal arousal, cognitive performance increases due to activation of orexin and excitatory neurotransmitters (e.g., acetylcholine, noradrenalin, dopamine; Figure 4). It is also known that age-related decrease in memory retention is associated with impaired mechanisms of sleep-dependent memory consolidation (Mander et al., 2013).

Thus, ensuring adequate levels of acetylcholine in the brain may be useful in restoring sleep patterns in the aging brain, as well as possible prevention of sleep disorders, depression, and/or stress. In this regard, and as mentioned previously, choline alphoscerate is an important cholinergic precursor useful for improving reduced cholinergic tone in patients with dementia (Carotenuto et al., 2022), and is a precursor of phospholipids (Traini et al., 2013), which help to maintain the plasticity of neuronal membranes (García-Morales et al., 2015).

Based on our clinical experience, we advise choline alphoscerate be used in the following clinical scenarios:

The preferred schedule for choline alphoscerate administration is continuous, to ensure adequate concentrations of choline for enhancement of cholinergic tone. However, 3-monthly therapy cycles have demonstrated maintenance of drug effectiveness between the cycles.

Oral administration is the preferred option since it is less invasive; however, in patients where oral administration is not possible (e.g., in patients who are bedridden or care-dependent) choline alphoscerate can be administered intramuscularly. Also, in cases where initiation with a loading dose of choline alphoscerate is required, it is possible to start with intramuscular administration followed by transition to maintenance dosing with the oral formulation. Additionally, it is recommended that the dose be taken in the morning/early afternoon, in order to not interfere with night-time rest. The total daily dose of 1,200 mg of choline alphoscerate can be administered as 2 doses of 600 mg or 3 doses of 400 mg. This dosage is necessary for the patient to ensure adequate drug levels throughout the 12 h of wakefulness, while administration of the last dose by early afternoon avoids excessive cholinergic stimulation, and therefore activation/agitation, which could interfere with sleep.

The efficacy of choline alphoscerate on cognitive function is well established in patients with MCI, Alzheimer’s disease or cognitive impairment of vascular origin. However, emerging evidence suggests that the administration of this cholinergic precursor may also be useful as a preventive therapy against development of Alzheimer’s disease in patients with MCI and for the treatment of non-cognitive symptoms in patients with MCI. Further research is warranted.