Curcumin and Cognitive Function: A Systematic Review of the Effects of Curcumin on Adults With and Without Neurocognitive Disorders

This systematic review investigates the effect of curcumin on neurocognitive exams and inflammatory serum biomarkers in adults 18 years and older. We search PubMed, Science Direct, Google Scholar, Cochrane Library, and Multidisciplinary Digital Publishing Institute. Modeling the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA), we screened 1,284 studies with the keywords "neurocognitive disorders," "dementia," "cognitive health," "serum biomarkers," and "curcumin." We use the revised Cochrane Risk-of-Bias tool (RoB2) and the Newcastle-Ottawa Scale to select 12 open-access full-text articles published within 20 years. We include clinical trials, randomized controlled trials (RCTs), cohort studies, and human studies, excluding nonhumans, other design types, and schizophrenia. Despite gastrointestinal side effects, studies found curcumin significantly improves working memory in the following adult groups: non-demented, metabolically impaired, cognitively impaired, mood impaired, and chemotherapy impaired. Study limitations include variable population characteristics and few trials employing intention-to-treat analysis, emphasizing the need for shared clinical decision-making before curcumin therapy.


Introduction And Background
In 2023, Alzheimer's disease climbed to the fifth most common cause of death among American adults aged sixty-five years and older; in 2024, it maintains fifth rank, with approximately 6.9 million older adults currently living with this disease [1].Neurocognitive disorders like Alzheimer's disease stem from various medical conditions, and their progression can be measured using cognitive performance evaluations such as the Mini-Mental State Exam (MMSE) and Montreal Cognitive Assessment (MoCA) [2,3].The molecular pathophysiology of neurocognitive decline involves inflammation and cellular breakdown of nervous tissue, leading to the accumulation of inflammatory markers like beta-amyloid in the blood, which are measured to assess for neurodegeneration.Functional decline can lie dormant for years and affect previously healthy adults at different progression rates, but the cellular damage cannot revert once it ensues [4].Because there is no standard cure for dementia after the onset of cognitive decline, it is essential to explore preventive treatment options for healthy adults as well as adults with a variety of cognitive disorders [5].
Current treatments for cognitive decline, such as cholinergic agonists like Aricept, temporarily stimulate the brain but do not cure long-term functional deterioration and can cause side effects like bradycardia [5].Thus, there is a need for less toxic, more affordable, and naturally derived treatments to promote cognitive health.Curcumin, a natural polyphenol found in turmeric, has antioxidant and anti-inflammatory properties, which makes it a promising candidate for preventing and treating cognitive disorders.However, the limited bioavailability of curcumin poses a challenge, easily mitigated with enhancers such as piperine, found in black pepper, and lipid formulations [6,7].
A 2021 systematic review by Tsai et al. found that curcumin has greater benefits with working memory and cognitive speed, but no significant benefits in other cognitive domains.The limited amount of data calls for more clinical trials with an intention-to-treat protocol.Despite these findings, curcumin is not yet widely accepted as a standard treatment for cognitive disorders due to limitations in current clinical trials and minor gastrointestinal side effects.More research is needed to explore the best bioavailable form and effective dose of curcumin across various neurocognitive disorders [8].
With the increase in Alzheimer's morbidity after the coronavirus disease (COVID) pandemic, it is crucial to re-explore the therapeutic benefits of curcumin [1].This systematic review aims to update and expand on the findings of Tsai et al. by incorporating more recent studies [8].We include adults aged 18 and older to evaluate the effects of curcumin on cognitive performance and serum biomarkers in diverse patient populations, including those with and without neurocognitive disorders.

Review Methodology
This systematic review follows the rigorous Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines [9].

Selection Criteria
The studies in this review meet the stringent Population, Intervention, Comparator, Outcome, and Study Design (PICOS) criteria, understood in systematic reviews, to ensure a clear and structured approach to study selection and analysis.The population criteria (P) include adults aged 18 years and older, both with and without neurocognitive disorders.The intervention criteria (I) include supplementation with curcumin.The comparator criteria (C) include placebo or alternate supplementation.The outcome criteria (O) include cognitive status measured by cognitive performance exams or inflammatory serum biomarkers.The study design criteria (S) include open-access full-text articles, clinical trials, randomized controlled trials (RCTs), cohort studies, human studies, and studies published in the last twenty years.Given the lack of a cure for long-term cognitive decline, it is crucial to include populations at risk of dementia prior to onset [5].Thus, we include adults aged 18 years and older, covering various patient populations, including healthy patients and those at risk of or already diagnosed with Alzheimer's disease, as modeled by Tsai et al. [8].We manually screen relevant articles for inclusion based on the PICOS criteria described.
We exclude interventions other than curcumin, nonhuman models, case reports, case series, meta-analyses, reviews, systematic reviews, studies lacking data on cognitive performance or serum biomarkers, non-open access articles, and non-full-text articles.These exclusions focus on curcumin intervention in neurocognitive disorders and ensure the reliability and relevance of the included studies.Findings show sufficient data from the eleven clinical trials and one cohort study, while other excluded study design types did not enhance or add new information to this review.We also exclude studies involving patients with schizophrenia due to the ongoing fluctuations in mental status that could skew the results of our study in unmeasurable ways, not addressing neurocognitive decline.

Search Strategy
To ensure a comprehensive review, investigators Aida Jeanette Francis (AJF) and Aneri Parikh (AP) independently conducted thorough searches across multiple databases to gather relevant articles for investigating the outcomes of curcumin intervention in neurocognitive disorders.These databases include PubMed, Science Direct, Google Scholar, Cochrane Library, and Multidisciplinary Digital Publishing Institute (MDPI).We searched databases from May 1, 2024, through June 30, 2024, using advanced search techniques and keywords combined with Boolean terms to identify relevant articles.We selected the following keywords for all databases searched: neurocognitive disorders, dementia, cognitive health, serum biomarkers, and curcumin.We used several Medical Subject Heading (MeSH) terms for the PubMed Database to perform an advanced search.Upon further investigation, no MeSH term was available for the keyword cognitive health in the PubMed database.Furthermore, the following medical subject headings in the PubMed database were applied only to the keyword curcumin: "administration and dosage," "adverse effects," "analogs and derivatives," "analysis," "isolation and purification," "metabolism," "pharmacokinetics," "pharmacology," "therapeutic use," and "toxicity."After performing an advanced search, we applied the following selection criteria in the search filters on PubMed: "abstract," "free full text," "clinical trial," "humans," and "from 2004/1/1 -2025/

Study Selection Process
Two authors, AJF and AP, comprehensively evaluated each study's internal validity using two quality assessment tools.This review covers two specific study designs: RCTs and cohort studies.The revised Cochrane risk-of-bias (RoB2) tool was applied for randomized control trials, as seen in Table 2 [10].The Newcastle-Ottawa tool was used for cohort studies, as seen in Table 3 [11].

Bias arising from the randomization process [10]
Bias resulting from diverging from the intended intervention [10] Bias due to missing outcome data [10] Bias in the approach to measure the outcome [10] Bias in the selection of the report [

TABLE 2: RoB2 tool for randomized trials
Each RCT was evaluated for bias, receiving a rating of "Low," "High," or "Some Concerns" [10].

Search Results
The search strategy identified 1284 studies across five databases, including PubMed, Science Direct, Google Scholar, Cochrane Library, and MDPI.After filtering out 104 duplicate articles, AJF and AP screened the remaining 1180 studies for PICOS criteria by scanning each study's title, abstract, and design type.Ultimately, 15 full-text articles were retrieved.Subsequently, we excluded one clinical trial because no open-access or full-text version was available [7].The remaining 14 studies were evaluated for internal validity using quality assessment tools.Two of the 14 full-text or open-access studies were excluded due to irrelevant outcomes and population measures and are not included in the tables [24,25].Ultimately, 12 studies met appropriate internal validity standards for inclusion in this systematic review, as seen in Table 2 and Table 3 [12][13][14][15][16][17][18][19][20][21][22][23].Figure 1 shows the findings of the study selection process [9].

Internal Validity of Each Study
Each RCT was thoroughly assessed for bias using the RoB2 assessment tool, receiving a rating of "Low," "High," or "Some Concerns".The included studies were of high quality and low bias.Table 2 presents the RoB2 quality assessment tool for screening each RCT, demonstrating the results of our evaluation process [10].
The single retrospective cohort study was thoroughly assessed for bias using the Newcastle-Ottawa tool.The included study was of high quality and low bias, as seen by the high number of stars awarded.Table 3 displays the Newcastle-Ottawa quality assessment results for the included cohort study [11].

Study Characteristics of Each Study
Among the RCTs, four found significant efficacy in healthy middle-aged and older adults, three found significant efficacy in adults with obesity and pre-diabetes, two found efficacy in adults with pre-existing cognitive impairment and dementia, one found significant efficacy in adults with major depressive disorder (MDD), and one found efficacy in adults with chemotherapy-induced cognitive impairment (CICI) [12][13][14][15][16][17][18][19][20][21][22].
The single included retrospective cohort study also found significant dose-specific improvements in cognitive performance with bioavailable curcumin, suggesting that the therapeutic effects of curcumin are dose-dependent and increase with the frequency of curcumin consumption [23].We detailed the characteristics of each study in Table 4.

Comparative Analysis of Key Findings Between Studies
In total, 10 of the 11 RCTs demonstrated statistically significant improvements in outcome measures for treatment groups administered bioavailable curcumin compared to alternate supplementation, as outlined in Table 4 [12][13][14][15][16][17][18][19]21,22].Curcumin significantly improved, p <0.05, working memory and mood in healthy older adults with no prior cognitive or psychosocial impairments, with a 20% improvement in cognitive performance, suggesting potential benefits in preventing cognitive decline in healthy non-demented adults [12][13][14][15].Curcumin significantly improved, p <0.01, cognitive performance, verbal memory, and cerebrovascular reactivity, as reflected in changes in blood flow to the brain, which can be measured with various imaging techniques in adults with obesity and prediabetes, indicating benefits for metabolic and cognitive health [16][17][18].Curcumin showed significant improvements, p <0.05, in cognitive and locomotive function as well as a reduction in biomarkers as listed in Table 4, with improved MMSE scores by 15% for adults with pre-existing cognitive impairment and dementia, highlighting its potential for palliative neuroprotection [19,20].Curcumin significantly enhanced, p <0.05, cognitive performance scores by 18% and attenuated serum inflammatory biomarkers in adults with major depressive disorder, suggesting curcumin as an adjuvant treatment for depression [21].Curcumin significantly improved, p <0.05, cognitive function tests with a good safety profile in adults with CICI, supporting the use of curcumin in managing the cognitive side effects of chemotherapy [22].One single RCT by Ringman et al. showed no statistically significant outcome improvement.However, the study should have used an appropriately bioavailable form of curcumin, stressing the importance of utilizing bioavailable pharmacologic formulations combined with piperine or lipid compounds [20,6].This systematic review found that in 11 of the 12 included studies, cognitive performance and serum biomarkers were significantly improved in groups that consumed bioavailable forms of curcumin compared to placebo or alternate interventions [12][13][14][15][16][17][18][19][21][22][23].All-together, results found that there is a statistically significant improvement in cognitive performance and serum biomarkers for adults age 18 and older with the following characteristics: non-demented healthy adults, adults at risk of or already diagnosed with metabolic disorders, adults with pre-existing cognitive decline, adults with mood disorders, and adults with cognitive chemotherapy side effects.These significant findings were consistent across multiple patient populations and study types, suggesting that bioavailable forms of curcumin can effectively improve cognitive performance and serum biomarkers across various neurocognitive disorders [12][13][14][15][16][17][18][19][20][21][22][23].

Implications of Results in Clinical Practice
Our comprehensive systematic review delves into the potential of curcumin to significantly impact cognitive performance and serum biomarkers in adults at risk of or already experiencing various degrees of neurocognitive disorders.By synthesizing data from 12 studies, we aimed to gain deeper insights into curcumin's potential as a preventive and palliative treatment for the cognitive health of adults aged 18 and above.This review involved a meticulous analysis of the methods and outcomes of 11 clinical trials and one cohort study, explicitly determining whether curcumin significantly enhances cognitive performance or serum biomarkers in adults at risk of or already diagnosed with cognitive disorders.Our main objective was to gather compelling evidence that advocates for integrating curcumin into standard therapy to enhance neurocognitive health, and we aim to guide clinical decisions regarding the preventive and therapeutic use of curcumin for neurocognitive disorders.This research offers a promising outlook for neurocognitive health, expanding potential treatment options by exploring curcumin [12][13][14][15][16][17][18][19][20][21][22][23].
Neurocognitive disorders encompass a wide range of conditions, with Alzheimer's disease being the most well-understood and extensively studied.The disease, characterized by inflammation and neuronal damage, leads to the accumulation of beta-amyloid proteins and a tau cascade, ultimately resulting in the breakdown of the cortical white matter of the brain, visible on imaging.Functional impairments eventually arise, impacting activities of daily living differently, depending on the rate of progression of cognitive decline [26].The degree of neurocognitive decline is assessed by implementing cognitive performance tests, brain images, and serum biomarkers [4,26].Symptoms of Alzheimer's and other neurodegenerative diseases progress gradually with age and include a decline in cognitive performance exams like the MMSE and the MoCA [2,3].
Current therapeutic interventions for neurocognitive disorders include cholinesterase inhibitors and Nmethyl-D-aspartate receptor antagonists, such as donepezil and memantine.However, these treatments do not reverse or cure actively progressing neurocognitive disorders but focus on preventing further decline.Modifiable risk factors for Alzheimer's prevention include diabetes, obesity, social isolation, sedentary lifestyle, alcohol use, and hypertension.Recent treatment strategies emphasize the rapid detection of serum biomarkers to identify and delay early cognitive decline.New pharmacologic strategies aim to combat inflammatory biomarkers, including beta-amyloid, tau, and general inflammation [26].Curcumin, a polyphenol of turmeric, has been shown to have antioxidant and anti-inflammatory properties, making it a promising treatment approach against neurodegeneration [6].This systematic review explores the potential of curcumin to inhibit the development of inflammatory serum biomarkers and improve cognitive health.
Curcumin's main medicinal benefits stem from its antioxidant and anti-inflammatory properties, which make it a promising treatment approach against neurodegeneration.Moreover, curcumin offers several advantages, including a high safety profile, low toxicity, easy accessibility, and low cost.It also has minimal drug-to-drug interaction; however, curcumin's limitations include gastrointestinal issues and skin color changes at extreme doses.Another notable drawback of curcumin therapy is its limited bioavailability, primarily due to inadequate absorption and swift excretion.However, this limitation can be overcome with enhancers like piperine in black pepper and liposome bodies, as they increase absorption through the gastrointestinal tract and blood-brain barrier [6,7].This reassurance of safety and accessibility should instill confidence in curcumin's potential use and application.
The studies in this systematic review collectively suggest that bioavailable forms of curcumin are a promising treatment option for cognitive decline in adults 18 and older, as observed in cases both with and without neurocognitive disorders.Four of the included clinical trials, with 318 patients enrolled and 254 patients completing the trials, found that curcumin was associated with statistically significant improvements in cognitive performance and serum biomarkers in healthy, non-demented adults [12][13][14][15].Three of the included RCTs, with 229 patients enrolled and 211 patients completing the trials, found curcumin was associated with statistically significant improvements in cognitive performance and serum biomarkers in adults at risk of type 2 diabetes or other metabolic disorders who were either overweight, obese, metabolically unstable as apparent on labs, or actively pre-diabetic [16][17][18].One clinical trial, with 48 patients enrolled and completing trials, discovered that a highly absorbable type of curcumin was linked to a statistically significant enhancement in cognitive function and serum biomarkers among adults experiencing pre-existing cognitive impairment or dementia [19].One of the clinical trials, with 120 patients enrolled and completing the study, discovered that curcumin was linked to a statistically significant enhancement in cognitive function and serum biomarkers in adults with major depressive disorder [21].One RCT, with 78 patients enrolled and completing the study, found that curcumin was associated with a statistically significant improvement in cognitive performance for adults experiencing CICI [22].The single cohort study, with 2751 patients enrolled and completing the study, found that a higher frequency of curcumin consumption in the form of dietary curry among Singaporean community dwellers was associated with a statistically significant improvement in attention, short-term working memory, visual-spatial constructional ability, language, and executive function among older adults [23].Diverging from the majority of the trials, only one of the clinical trials found no statistically significant effects of curcumin in adults with likely dementia; however, this is due to the low bioavailability of the curcumin formulation for this single case [20].Ultimately, 11 of the 12 studies (nearly 92%) found that curcumin was associated with statistically significant improvement in cognitive performance or serum biomarkers for each patient population analyzed [12][13][14][15][16][17][18][19][21][22][23].Collectively, the studies suggest that curcumin has significant neuroprotective effects and can significantly prevent cognitive decline or neurodegeneration in nondemented healthy adults, adults at risk of or already diagnosed with metabolic disorders, adults with preexisting cognitive decline, adults with mood disorders, and adults with cognitive chemotherapy side effects [12][13][14][15][16][17][18][19][20][21][22][23].The beneficial results are not acute and are more effective after several weeks of treatment [13].Thus, similar to the findings of a prior study by Tsai et al., this review also indicates that the statistically significant benefits of curcumin are dose-specific and affect each cognitive domain differently depending on the administration regimen, characteristics of the patient population, pharmacologic form of curcumin, and length of treatment.While not all cognitive domains and their corresponding brain regions responded uniformly, curcumin consistently and significantly benefited the working memory domain of cognitive performance in all the studies [8,[12][13][14][15][16][17][18][19][20][21][22][23].This potential of curcumin to prevent cognitive decline expands the options for promoting cognitive health.

Study limitations
There are several limitations to this study.First, the wide range of neurocognitive disorders assessed in this review, each with a different baseline pathophysiology, may have contributed to heterogeneous responses to curcumin, thus affecting the uniformity of the data.Second, this study did not include a meta-analysis, preventing the determination of how differences in neurocognitive disorders might have influenced the results.In future studies, conducting a meta-analysis of the data would be beneficial.Third, the number of available trials was limited.However, the data remains significant enough to suggest that curcumin consistently benefits patients with various neurocognitive disorders, particularly in the working memory domain.Despite the limited sample size, the outcome was objectively consistent and statistically significant across the studies included.Finally, most studies employed per-protocol analysis, excluding data from noncompliant participants.Including participant data using an intention-to-treat analysis would reduce bias and provide a more accurate representation of the outcomes.Future clinical trials should follow, using the intention-to-treat analysis, as primarily recommended by Tsai et al. [8].

Conclusions
This systematic review found that curcumin supplementation causes a statistically significant improvement in cognitive performance as well as serum biomarkers for adults age 18 and older with the following characteristics: non-demented healthy adults, adults at risk of or experiencing metabolic disorders, adults with pre-existing cognitive decline, adults with mood disorders, and adults with cognitive chemotherapy side effects.The studies indicate that bioavailable curcumin offers therapeutic benefits across different stages and causes of cognitive decline, improving working memory and preventing neurodegeneration in a dose-specific manner that remains to be specified.This evidence supports the use of curcumin as a preventive, adjunctive, or alternative therapy for neurocognitive disorders.However, curcumin has some gastrointestinal side effects to consider during shared medical decision-making with a patient before treatment.Future meta-analyses and RCTs should follow and implement the intention-to-treat outcome analysis.
Terms])) AND ((ffrft[Filter]) AND (fha[Filter]) AND (clinicaltrial[Filter]) AND (humans[Filter]) AND (2004/1/1:2025/1/1[pdat] with statistically significant results in cognitive performance and serum levels as below: improved WM at 12 weeks (Serial Threes and Sevens, and virtual Morris Water Maze), lower fatigue at four and 12 weeks (Profile of Mood States), lower mood-related confusion at four weeks, and higher glucose Longvida® preparations of curcumin improve WM and mood in healthy older adults.was associated with statistically significant results in time to treatment for the MoCA (P<0.050).At six months, cognitive function declined in the placebo group, but not in the curcumin group.No other differences were detected The study suggests curcumin can potentially prevent cognitive decline, but more research is needed to investigate changes in cognitive measures in form of Theracurmin® was associated with statistically significant results in improved verbal memory (p=0.002),improved visual memory (p=0.006),improved attention (p<0.0001), and decreased FDDNP binding in the amygdala (p=0.04) and hypothalamus (p=0.02) as observed on PET The results suggest daily curcumin in the form of Theracurmin® can improve memory and attention in nondemented adults.The coinciding FDDNP-PET results correlate these functional benefits with decreases in the neurodegenerative proteins amyloid and tau in brain areas controlling emotions and recall Kuszewski et al. (2020) The following statistically significant findings were observed: isolated curcumin caused improvement in CVR in a WM test and improved performance in a verbal memory test for males only, isolated fish oil caused improved CVR for processing speed tests in males only, and combining fish oil with curcumin did not add benefits Improvements in processing speed following fish-oil consumption and memory following curcumin consumption in 50-80 years old males may correlate with improved circulatory function or CVR.form of dietary turmeric was associated with statistically significant results compared to cinnamon as follows: WM increased from 2.6 to 2.9 out of 3.0 (p=0.05);WM was inversely related to insulin resistance (R of 34.5% and p<0.01), not with serum biomarkers.WM responses to turmeric had significant beta-coefficients for turmeric, BMI, and insulin/glucose area under the curve Consumption of turmeric with white bread improves WM regardless of body fat, glycemia, insulin, or biomarkers.Findings suggest turmeric may benefit the cognitive performance of adults with pre-diabetes Curcumin is associated with statistically Published via California Institute of Behavioral Neurosciences & Psychology 2024 Francis et al.Cureus 16(8): e67706.DOI 10.7759/cureus.thefollowing serum biomarker levels: GSK-3β (−2.4±0.4 ng/mL, p=0.00001) as compared to placebo (p=0.0068 ), IAPP (−2.0±0.7 ng/mL, p=0.01) as compared to placebo (p=0.0163), and HOMA2-IR (p=0.0142)compared to placebo (p=0.9747)form of CGM compared to placebo and USC was associated with statistically significant results as follows: improved MMSE scores, improved Geriatric Locomotive Function Scale Scores, and improved serum biomarkers (brain-derived neurotrophic factor, beta-amyloid 42, tau protein, Interleukin 6, and tumor necrosis factorwas associated with no difference in clinical measures or serum biomarker measures compared to placebo [20].Serum levels of curcumin were low (7.32 ng/mL), and there were insignificantly lower serum hematocrit and increased serum glucose associated with curcumin [20].One subject (8%) in the placebo group withdrew due to worse memory, and five of twenty-four subjects (21%) withdrew in the curcumin group due to gastrointestinal (GI) side effects Curcumin was well-tolerated despite the GI side effects [20].No clinical or biochemical efficacy of Curcumin C3 Complex® was found in Alzheimer's disease [20].The lack of efficacy may be attributed to the limited bioavailability of 001) results as follows: cognitive improvement in forwarding and backward digit span (η²=0.286and η²=0.390),Trial Making Test-A and B (η²=0.161 and η²=0.026),verbal fluency task: letter and category (η²=0.105and η²=0.128),Tower of London (η²=0.211),and inflammatory markers: interleukin 6 and 1β (η²=0.

FIGURE 1 :
FIGURE 1: PRISMA flow diagram summary of search results ** Excluded article types are those that do not include open-access full-text articles, clinical trials, RCTs, cohort studies, human studies, or studies published in the last twenty years.MDPI: Multidisciplinary Digital Publishing Institute; PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses; PICOS: Population, Intervention, Comparator, Outcome, Study Design; RCT: randomized controlled trial

TABLE 3 : Newcastle-Ottawa quality assessment table for screening cohort studies
*Star point rating, a star is awarded for fulfilling each question within each subsection of the Newcastle-Ottawa assessment.

TABLE 4 :
[15]y characteristicsSerial Threes and Sevens and the virtual Morris Water Maze are used for cognitive performance exams; the Profile of Mood States is used for mood assessment.Biocurcuma, Theracurmin, CurQfen® , and Curcumin C3 Complex are all synthetic copyrighted brands of curcumin.A positron emission tomography radiotracer is used for tracking neurofibrillary tangles and amyloid aggregates in the brain[15].Cohen's d effect size measures the difference between group means.
Backward with higher scores in the "very often" and "often" groups, Verbal Fluency (Animals) with higher scores in the "very often" group, and Block Design with higher scores in the "occasional," "often," and "very often" groups.Cohen's d-effect size ranged from 0.130 to 0.186 for the significant differences observed.benefits, through metabolic, antiplatelet, and cardioprotective mechanisms