Our study findings suggest that the effectiveness of nootropics combination with ChEI may be different according to the type of dementia. The difference in change in the MMSE total scores from baseline to endpoint between the ChEI only group and the ChEI and nootropics combination group was not evident, but the results implied a positive impact of ChEI augmentation with nootropics on some domains of cognitive function in certain types of dementia, particularly Alzheimer’s dementia. The impact of nootropics augmentation on ChEI in Alzheimer’s dementia was consistently depicted on the language domain after consideration of medical adherence and nootropics type.
Previous studies on nootropics revealed nootropics to have minimal, if any, effects on the prevention of cognitive decline. Most studies were either examined over a relatively short follow-up time or conducted with a limited number of subjects, and many of them focused on nootropic monotherapy rather than concomitant use with ChEI [6, 9, 10, 17, 23–25]. This study aimed to compare the nootropics and ChEI combination with ChEI monotherapy in an attempt to validate the effectiveness of nootropics in association with ChEI. We examined the change in not only MMSE total scores but also in its six subscale scores over a long period of exposure (300–400 days after the first prescription), which was considered long enough to elucidate the effect of the ChEI and nootropics combination. We categorized the subjects by dementia types in order to clarify the impact of nootropics combination in each type of dementia separately, and mainly focused on Alzheimer’s dementia, which is the most common neurodegenerative form of dementia. We did not limit nootropics to only one type of drug, but included multiple types of nootropics that are most frequently prescribed by clinicians in Korea, to speculate the effectiveness of different types of nootropics, particularly focusing on the two drugs that were most commonly used: choline alfoscerate and ginkgo biloba extract.
Choline alfoscerate is a derivative of phosphatidylcholine that enhances cholinergic transmission by upregulating acetylcholine (ACh) synthesis or release in the hippocampus [26, 27]; and thus, it ultimately facilitates learning and memory and decreases age-dependent structural changes, as seen in the frontal cortices and hippocampi of rats [7, 28]. Previous studies reported that the combination of choline alfoscerate with ChEI significantly increased ACh concentrations and prevented volume loss in the frontal and temporal lobe, hippocampus, and striatum in both rats  and in Alzheimer’s dementia patients . One study also showed that choline alfoscerate increased hippocampal neurogenesis and provided protection against seizure-induced neuronal death and cognitive impairment . A study on the supplementary effect of choline alfoscerate on speech detection and recognition among hearing aid users revealed that in the aging brain, nicotinic acetylcholine receptor activation in the medial geniculate body decreases, which contributes to deterioration in speech recognition and comprehension; and in such cases, choline precursor supplements could improve language functioning . Ginkgo biloba extract, on the other hand, is hypothesized to enhance amyloid β-induced hippocampal neuron dysfunction and death, amyloid β aggregation, and neurogenesis [32–34], and induce a significant decrease in the density of β-adrenoreceptors in the frontal cortex and hippocampus . Studies have shown that the hippocampus is closely associated with language production and verbal communication, either by contributing semantic memory to spoken language, processing the mismatch between the expected sensory consequences of speaking and perceived speech feedback, or via coupling between the hippocampal/supplementary motor area and the auditory cortex, anterior cingulate cortex, and cerebellum [31, 36]. These findings all suggest that nootropics, such as choline alfoscerate and ginkgo biloba extract, may enhance the cholinergic pathway in brain areas including the hippocampus, frontal lobes, and auditory cortex, which are critical in language processing and utilization, and enhance language function in association with ChEI administration. Language function is not only highly sensitive in detecting cognitive impairment in older age groups , but is also a biological marker that differentiates Alzheimer’s dementia from normal aging . To our knowledge, this study is the first to elucidate the effect of nootropics co-administered with ChEIs on the attenuation of language domain deterioration in Alzheimer’s dementia using clinical data. The possible effect of nootropics on delaying the deterioration of language function may be of great value, considering the association between cognitive decline and language function in the aging population and dementia patients.
The strength of this study lies in the methodological aspects of real-world data utilization. Many studies in Korea are actively conducted using the national claims database in an attempt to perform large-scale research . However, imperative baseline characteristics of each patient, including medical histories, medications, and laboratory findings, are missing when using the national claims databases. On the other hand, the clinical data warehouse from our university healthcare system is a composition of each patient’s clinical and demographic data. In this study, we were able to extract and collect critical information regarding each patient’s clinical and demographic backgrounds such as, but not limited to, the education level and BMI, specific MMSE subscale scores, and detailed dementia diagnosis. As a result, we were able to make corrections for many variables that could have affected the MMSE results, including other relevant diagnoses and medical history, such as hypertension and diabetes mellitus, Parkinsonism, and visual/hearing loss. Furthermore, this study is meaningful in that until now, there have only been a few, if any, studies on the effect of nootropics on ChEI efficacy outside of the only actively researched country, Italy [19, 20, 40].
The study had some limitations. Due to its retrospective nature, we were not able to control the treatment settings in terms of medication dosage, treatment duration, the overlapping periods of concomitant nootropic and ChEI use, and adherence monitoring. In order to compensate for these factors, we calculated and considered PDC, the number of days covered by the prescriptions in the total prescription periods, to reflect and consider drug adherence. Moreover, we only included subjects with MMSE scores within 300–400 days after the baseline, which might have excluded certain patients who could not take the annual MMSE test either due to a deleterious progression of dementia or because they no longer sought help or changed hospitals. In the near future, it seems that these limitations can be solved by conducting research based on a large database that combines real-world data from numerous hospitals (i.e., common data model). Finally, analyzing the six subscale domains of the MMSE may raise the issue of multiple comparison. However, through subsequent analyses, we induced consistent results at least in the Alzheimer’s dementia group, of which nootropics combination could have a subtle positive impact on the language domain. Surely, further studies that more deliberately focus on the separate cognitive domains should be performed with other more qualified neuropsychological tests. Still, this study would be of best effort to observe the effectiveness of nootropics utilizing the accumulated real-world data.