Curcumin and omega-3 polyunsaturated fatty acids as bioactive food components with synergistic effects on Alzheimer's disease.

Curcumin and omega-3 polyunsaturated fatty acids (ω-3 PUFA) are multifunctional compounds which play an important role in Alzheimer's disease (AD) and little has been addressed about the role of these two compounds together in the progression of the disease. There is evidence of the beneficial effect of combined administration of ω-3 PUFA and other dietary supplements such as vitamins and polyphenols in the prevention of AD, although much remains to be understood about their possible complementary or synergistic activity. Therefore, the objective of this work is to review the research focused on studying the effect and mechanisms of action of curcumin, ω-3 PUFA, and the combination of these nutraceutical compounds, particularly on AD, and to integrate the possible ways in which these compounds can potentiate their effect. The most important pathophysiologies that manifest in AD will be addressed, in order to have a better understanding of the mechanisms of action through which these bioactive compounds exert a neuroprotective effect.

Vaccines and Dementia: Part II. Efficacy of BCG and Other Vaccines Against Dementia.

 There is growing awareness that infections may contribute to the development of senile dementia including Alzheimer's disease (AD), and that immunopotentiation is therefore a legitimate target in the management of diseases of the elderly including AD. In Part I of this work, we provided a historical and molecular background to how vaccines, adjuvants, and their component molecules can elicit broad-spectrum protective effects against diverse agents, culminating in the development of the tuberculosis vaccine strain Bacille Calmette-Guérin (BCG) as a treatment for some types of cancer as well as a prophylactic against infections of the elderly such as pneumonia. In Part II, we critically review studies that BCG and other vaccines may offer a measure of protection against dementia development. Five studies to date have determined that intravesicular BCG administration, the standard of care for bladder cancer, is followed by a mean ∼45% reduction in subsequent AD development in these patients. Although this could potentially be ascribed to confounding factors, the finding that other routine vaccines such as against shingles (herpes zoster virus) and influenza (influenza A virus), among others, also offer a degree of protection against AD (mean 29% over multiple studies) underlines the plausibility that the protective effects are real. We highlight clinical trials that are planned or underway and discuss whether BCG could be replaced by key components of the mycobacterial cell wall such as muramyl dipeptide. We conclude that BCG and similar agents merit far wider consideration as prophylactic agents against dementia.

Multisensory gamma stimulation promotes glymphatic clearance of amyloid.

The glymphatic movement of fluid through the brain removes metabolic waste1-4. Noninvasive 40 Hz stimulation promotes 40 Hz neural activity in multiple brain regions and attenuates pathology in mouse models of Alzheimer's disease5-8. Here we show that multisensory gamma stimulation promotes the influx of cerebrospinal fluid and the efflux of interstitial fluid in the cortex of the 5XFAD mouse model of Alzheimer's disease. Influx of cerebrospinal fluid was associated with increased aquaporin-4 polarization along astrocytic endfeet and dilated meningeal lymphatic vessels. Inhibiting glymphatic clearance abolished the removal of amyloid by multisensory 40 Hz stimulation. Using chemogenetic manipulation and a genetically encoded sensor for neuropeptide signalling, we found that vasoactive intestinal peptide interneurons facilitate glymphatic clearance by regulating arterial pulsatility. Our findings establish novel mechanisms that recruit the glymphatic system to remove brain amyloid.

Extra-Virgin Olive Oil in Alzheimer's Disease: A Comprehensive Review of Cellular, Animal, and Clinical Studies.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by several pathological hallmarks, including the deposition of amyloid-ß (Aß) plaques, neurofibrillary tangles, blood-brain barrier (BBB) dysfunction, increased oxidative stress, and neuroinflammation. Current treatment options include monoclonal antibody drugs, acetylcholinesterase, and n-methyl-d-aspartate (NMDA) antagonists. Although those treatments provide some improvements in patients' quality of life, they fail to prevent or cure AD. Current research aims to identify novel targets and tools for AD prevention and modification. In this context, several studies showed the beneficial effect of the Mediterranean diet in the prevention and treatment of AD. One integral component of the Mediterranean diet is olive oil and extra-virgin olive oil (EVOO), which is high in phenolic compounds. EVOO and other olive-related phenolic compounds have been shown to reduce the risk of developing mild cognitive impairment (MCI) and AD. In this review, we discuss the mechanisms by which EVOO and phenolic compounds exert neuroprotective effects, including modulation of AD pathologies and promotion of cognitive health. Findings indicate that EVOO and its phenolic constituents influence key pathological processes of AD, such as Aß aggregation, tau phosphorylation, and neuroinflammation, while also enhancing BBB integrity and reducing oxidative stress. The human studies cited reveal a consistent trend where the consumption of olive oil is associated with cognitive benefits and a decreased risk of AD and related dementias. In conclusion, EVOO and its phenolic compounds hold promising potential for the prevention and treatment of AD, representing a significant shift towards more effective strategies against this complex neurodegenerative disorder.

New precision medicine avenues to the prevention of Alzheimer's disease from insights into the structure and function of γ-secretases.

Two phase-III clinical trials with anti-amyloid peptide antibodies have met their primary goal, i.e. slowing of Alzheimer's disease (AD) progression. However, antibody therapy may not be the optimal therapeutic modality for AD prevention, as we will discuss in the context of the earlier small molecules described as "γ-secretase modulators" (GSM). We review here the structure, function, and pathobiology of γ-secretases, with a focus on how mutations in presenilin genes result in early-onset AD. Significant progress has been made in generating compounds that act in a manner opposite to pathogenic presenilin mutations: they stabilize the proteinase-substrate complex, thereby increasing the processivity of substrate cleavage and altering the size spectrum of Aß peptides produced. We propose the term "γ-secretase allosteric stabilizers" (GSAS) to distinguish these compounds from the rather heterogenous class of GSM. The GSAS represent, in theory, a precision medicine approach to the prevention of amyloid deposition, as they specifically target a discrete aspect in a complex cell biological signalling mechanism that initiates the pathological processes leading to Alzheimer's disease.

Perinatal choline supplementation prevents learning and memory deficits and reduces brain amyloid Aß42 deposition in AppNL-G-F Alzheimer's disease model mice.

Alzheimer's disease (AD) is characterized by cognitive and memory impairments and neuropathological abnormalities. AD has no cure, inadequate treatment options, and a limited understanding of possible prevention measures. Previous studies have demonstrated that AD model mice that received a diet high in the essential nutrient choline had reduced amyloidosis, cholinergic deficits, and gliosis, and increased neurogenesis. In this study, we investigated the lifelong effects of perinatal choline supplementation on behavior, cognitive function, and amyloidosis in AppNL-G-F AD model mice. Pregnant and lactating mice were given a diet containing either 1.1 g/kg (control) or 5 g/kg (supplemented) of choline chloride until weaning and subsequently, all offspring received the control diet throughout their life. At 3, 6, 9, and 12 months of age, animals were behaviorally tested in the Open Field Test, Elevated Plus Maze, Barnes Maze, and in a contextual fear conditioning paradigm. Immunohistochemical analysis of Aß42 was also conducted on the brains of these mice. AppNL-G-F mice displayed hippocampal-dependent spatial learning deficits starting at 3-months-old that persisted until 12-months-old. These spatial learning deficits were fully prevented by perinatal choline supplementation at young ages (3 and 6 months) but not in older mice (12 months). AppNL-G-F mice also had impaired fearful learning and memory at 9- and 12-months-old that were diminished by choline supplementation. Perinatal choline supplementation reduced Aß42 deposition in the amygdala, cortex, and hippocampus of AppNL-G-F mice. Together, these results demonstrate that perinatal choline supplementation is capable of preventing cognitive deficits and dampening amyloidosis in AppNL-G-F mice and suggest that ensuring adequate choline consumption during early life may be a valuable method to prevent or reduce AD dementia and neuropathology.

Update on modifiable risk factors for Alzheimer's disease and related dementias.

PURPOSE OF REVIEW: All human beings undergo a lifelong cumulative exposure to potentially preventable adverse factors such as toxins, infections, traumatisms, and cardiovascular risk factors, collectively termed exposome. The interplay between the individual's genetics and exposome is thought to have a large impact in health outcomes such as cancer and cardiovascular disease. Likewise, a growing body of evidence is supporting the idea that preventable factors explain a sizable proportion of Alzheimer's disease and related dementia (ADRD) cases. RECENT FINDINGS: Here, we will review the most recent epidemiological, experimental preclinical, and interventional clinical studies examining some of these potentially modifiable risk factors for ADRD. We will focus on new evidence regarding cardiovascular risk factors, air pollution, viral and other infectious agents, traumatic brain injury, and hearing loss. SUMMARY: While greater and higher quality epidemiological and experimental evidence is needed to unequivocally confirm their causal link with ADRD and/or unravel the underlying mechanisms, these modifiable risk factors may represent a window of opportunity to reduce ADRD incidence and prevalence at the population level via health screenings, and education and health policies.

Long-Term Krill Oil Administration Alleviated Early Mild Cognitive Impairment in APP/PS1 Mice.

SCOPE: Alzheimer's disease is an age-dependent neurodegenerative disorder. Mounting studies focus on the improvement of advanced cognitive impairment by dietary nutrients. Krill oil (KO), a rich source of DHA/EPA and astaxanthin, is effective in improving cognitive function. The study mainly investigates the protective effects of long-term KO administration on early cognitive impairment. METHODS AND RESULTS: Results show that 2 months KO administration (50 and 100 mg kg-1 BW) can dramatically promote learning and memory abilities. Mechanism studies demonstrate that KO reduces amyloid ß concentration by regulating the amyloidogenic pathway, inhibits neuro-inflammation via regulating TLR4-NLRP3 signaling pathway, and prevents neuron injure. KO supplementation also enhances gut barrier integrity, reduces serum lipopolysaccharide leakage, and alters the gut microbiota by reducing Helicobacteraceae, Lactobacillaceae proportion, increasing Dubosiella and Akkermansia relative abundance. Particularly, a significant increase of isovaleric acid, propionic acid, and acetic acid levels is observed after KO supplementation. Correlation analysis shows that short-chain fatty acids (SCFAs), gut microbiota, and cognitive function are strongly correlated. CONCLUSIONS: The results reveal that KO relieves early mild cognitive impairment possibly for its role in mediating the gut microbiome-SCFAs-brain axis. Thus, KO may provide potential intervention strategies to prevent cognitive impairment in the early stages through the microbiota-gut-brain axis.

Glutathione-Mediated Neuroprotective Effect of Purine Derivatives.

Numerous basic studies have reported on the neuroprotective properties of several purine derivatives such as caffeine and uric acid (UA). Epidemiological studies have also shown the inverse association of appropriate caffeine intake or serum urate levels with neurodegenerative diseases such as Alzheimer disease (AD) and Parkinson's disease (PD). The well-established neuroprotective mechanisms of caffeine and UA involve adenosine A2A receptor antagonism and antioxidant activity, respectively. Our recent study found that another purine derivative, paraxanthine, has neuroprotective effects similar to those of caffeine and UA. These purine derivatives can promote neuronal cysteine uptake through excitatory amino acid carrier protein 1 (EAAC1) to increase neuronal glutathione (GSH) levels in the brain. This review summarizes the GSH-mediated neuroprotective effects of purine derivatives. Considering the fact that GSH depletion is a manifestation in the brains of AD and PD patients, administration of purine derivatives may be a new therapeutic approach to prevent or delay the onset of these neurodegenerative diseases.

ADscreen: A speech processing-based screening system for automatic identification of patients with Alzheimer's disease and related dementia.

Alzheimer's disease and related dementias (ADRD) present a looming public health crisis, affecting roughly 5 million people and 11 % of older adults in the United States. Despite nationwide efforts for timely diagnosis of patients with ADRD, >50 % of them are not diagnosed and unaware of their disease. To address this challenge, we developed ADscreen, an innovative speech-processing based ADRD screening algorithm for the protective identification of patients with ADRD. ADscreen consists of five major components: (i) noise reduction for reducing background noises from the audio-recorded patient speech, (ii) modeling the patient's ability in phonetic motor planning using acoustic parameters of the patient's voice, (iii) modeling the patient's ability in semantic and syntactic levels of language organization using linguistic parameters of the patient speech, (iv) extracting vocal and semantic psycholinguistic cues from the patient speech, and (v) building and evaluating the screening algorithm. To identify important speech parameters (features) associated with ADRD, we used the Joint Mutual Information Maximization (JMIM), an effective feature selection method for high dimensional, small sample size datasets. Modeling the relationship between speech parameters and the outcome variable (presence/absence of ADRD) was conducted using three different machine learning (ML) architectures with the capability of joining informative acoustic and linguistic with contextual word embedding vectors obtained from the DistilBERT (Bidirectional Encoder Representations from Transformers). We evaluated the performance of the ADscreen on an audio-recorded patients' speech (verbal description) for the Cookie-Theft picture description task, which is publicly available in the dementia databank. The joint fusion of acoustic and linguistic parameters with contextual word embedding vectors of DistilBERT achieved F1-score = 84.64 (standard deviation [std] = ±3.58) and AUC-ROC = 92.53 (std = ±3.34) for training dataset, and F1-score = 89.55 and AUC-ROC = 93.89 for the test dataset. In summary, ADscreen has a strong potential to be integrated with clinical workflow to address the need for an ADRD screening tool so that patients with cognitive impairment can receive appropriate and timely care.

[Dihydroquercetin as a systemic neuroprotector for the prevention and treatment of ß-amyloid-associated brain diseases]. / Digidrokvertsetin kak sistemnyi neiroprotektor dlya profilaktiki i lecheniya ß-amiloid-assotsiirovannykh zabolevanii golovnogo mozga.

Dihydroquercetin (DHQ) is a plant-derived polyphenol belonging to the group of flavonoids. In models associated with abnormal accumulation of ß-amyloid in the brain (Alzheimer's disease and cerebral amyloid angiopathy), DHQ demonstrates the ability to disaggregate toxic forms of ß-amyloid and prevent their formation. It is believed that this phenomenon underlies the protective effect of DHQ on brain neurons. However, pharmacokinetic data doubt the central mechanism of action of DHQ because this compound does not penetrate well into the brain. A hypothesis is put forward about the systemic nature of the neuroprotective action of DHQ, since this compound has multiple biological activities at the level of the whole organism. To characterize DHQ (and similar compounds), it is proposed to introduce the term «systemic neuroprotector¼.

Caffeine for Prevention of Alzheimer's Disease: Is the A2A Adenosine Receptor Its Target?

Alzheimer's disease (AD) is the most prevalent kind of dementia with roughly 135 million cases expected in the world by 2050. Unfortunately, current medications for the treatment of AD can only relieve symptoms but they do not act as disease-modifying agents that can stop the course of AD. Caffeine is one of the most widely used drugs in the world today, and a number of clinical studies suggest that drinking coffee may be good for health, especially in the fight against neurodegenerative conditions such as AD. Experimental works conducted "in vivo" and "in vitro" provide intriguing evidence that caffeine exerts its neuroprotective effects by antagonistically binding to A2A receptors (A2ARs), a subset of GPCRs that are triggered by the endogenous nucleoside adenosine. This review provides a summary of the scientific data supporting the critical role that A2ARs play in memory loss and cognitive decline, as well as the evidence supporting the protective benefits against neurodegeneration that may be attained by caffeine's antagonistic action on these receptors. They are a novel and fascinating target for regulating and enhancing synaptic activity, achieving symptomatic and potentially disease-modifying effects, and protecting against neurodegeneration.

Novel Vaccine against Pathological Pyroglutamate-Modified Amyloid Beta for Prevention of Alzheimer's Disease.

Post-translationally modified N-terminally truncated amyloid beta peptide with a cyclized form of glutamate at position 3 (pE3Aß) is a highly pathogenic molecule with increased neurotoxicity and propensity for aggregation. In the brains of Alzheimer's Disease (AD) cases, pE3Aß represents a major constituent of the amyloid plaque. The data show that pE3Aß formation is increased at early pre-symptomatic disease stages, while tau phosphorylation and aggregation mostly occur at later stages of the disease. This suggests that pE3Aß accumulation may be an early event in the disease pathogenesis and can be prophylactically targeted to prevent the onset of AD. The vaccine (AV-1986R/A) was generated by chemically conjugating the pE3Aß3-11 fragment to our universal immunogenic vaccine platform MultiTEP, then formulated in AdvaxCpG adjuvant. AV-1986R/A showed high immunogenicity and selectivity, with endpoint titers in the range of 105-106 against pE3Aß and 103-104 against the full-sized peptide in the 5XFAD AD mouse model. The vaccination showed efficient clearance of the pathology, including non-pyroglutamate-modified plaques, from the mice brains. AV-1986R/A is a novel promising candidate for the immunoprevention of AD. It is the first late preclinical candidate which selectively targets a pathology-specific form of amyloid with minimal immunoreactivity against the full-size peptide. Successful translation into clinic may offer a new avenue for the prevention of AD via vaccination of cognitively unimpaired individuals at risk of disease.

Effect of Inhibiting Butyrylcholinesterase Activity Using Fractionated Coffee Extracts Digested In Vitro in Gastrointestinal Tract: Docking Simulation and Calorimetric and Studies.

Butyrylcholinesterase (BChE) is a major enzyme from the alpha-glycoprotein family that catalyzes the hydrolysis of neurotransmitter acetylcholine (ACh), lowering the concentration of ACh in the nervous system, which could cause aggravation of Alzheimer's disease (AD). In select pathological conditions, it is beneficial to reduce the activity of this enzyme. The aim of this study was to evaluate the degree of BChE inhibition by coffee extracts fractionated into mono- and diesters of caffeic acid/caffeine, digested in vitro in the gastrointestinal tract. The bioactive compounds from coffee showed high affinity for BchE, -30.23--15.28 kJ/mol, and was the highest for the caffeine fraction from the green Arabica extract. The isolated fractions were highly effective in inhibiting BChE activity at all in vitro digestion phases. It has been shown that the fractionation of coffee extracts could be potentially used to obtain high prophylactic or even therapeutic effectiveness against AD.

ß-sitosterol Protects against Aluminium Chloride-mediated Neurotoxicity.

OBJECTIVE: The objective of this study is to investigate the neuroprotective effects of ß- sitosterol using the AlCl3 model of Alzheimer's Disease. METHODS: AlCl3 model was used to study cognition decline and behavioral impairments in C57BL/6 mice. Animals were randomly assigned into 4 groups with the following treatments: Group 1 received normal saline for 21 days, Group 2 received AlCl3 (10 mg/kg) for 14 days; Group 3 received AlCl3(10 mg/kg) for 14 days + ß-sitosterol (25mg/kg) for 21 days; while Group 4 was administered ß-sitosterol (25mg/kg) for 21 days. On day 22, we performed the behavioral studies using a Y maze, passive avoidance test, and novel object recognition test for all groups. Then the mice were sacrificed. The corticohippocampal region of the brain was isolated for acetylcholinesterase (AChE), acetylcholine (ACh), and GSH estimation. We conducted histopathological studies using Congo red staining to measure ß -amyloid deposition in the cortex and hippocampal region for all animal groups. RESULTS: AlCl3 successfully induced cognitive decline in mice following a 14-day induction period, as shown by significantly decreased (p < 0.001) in step-through latency, % alterations, and preference index values. These animals also exhibited a substantial decrease in ACh (p <0.001) and GSH (p < 0.001) and a rise in AChE (p < 0.001) compared to the control group. Mice administered with AlCl3 and ß-sitosterol showed significantly higher step-through latency time, % alteration time, and % preference index (p < 0.001) and higher levels of ACh, GSH, and lower levels of AChE in comparison to the AlCl3 model. AlCl3-administered animals also showed higher ß-amyloid deposition, which got significantly reduced in the ß-sitosterol treated group. CONCLUSION: AlCl3 was effectively employed to induce a cognitive deficit in mice, resulting in neurochemical changes and cognitive decline. ß -sitosterol treatment mitigated AlCl3-mediated cognitive impairment.

Prevention of Alzheimer's Disease and Cognitive Decline with Diet and Lifestyle: Proceedings of the A. G. Leventis Foundation Conference.

The A. G. Leventis Foundation International Conference, "Prevention of Alzheimer's Disease and Cognitive Decline with Diet and Lifestyle", was held on May 11-12th, 2022 in Nicosia, Cyprus. This conference examined the role of diet and lifestyle for the prevention and treatment of Alzheimer's Disease and other forms of cognitive decline. Speakers from leading academic institutions presented evidence on healthy dietary patterns, with a particular focus on the traditional Mediterranean diet (MedDiet), in association with cognitive outcomes, mainly cognitive decline, dementia, and Alzheimer's disease, from both observational and interventional studies. Moreover, future directions for the potential use of olive oil, rich in polyphenols, for its therapeutic use as a nutraceutical, as well as nutritional interventions with high-quality dietary patterns (i.e. MedDiet) that support existing primarily observational evidence for the prevention of cognitive decline, as well as challenges in designing rigorous clinical trials are summarized and discussed within the conference proceedings.

The effect of a digital health coaching and health education protocol on cognition in adults at-risk for Alzheimer's.

Several modifiable lifestyle factors have been linked to cognitive ability and the risk of developing Alzheimer's disease and related dementias (ADRD). Health coaching (HC) is an intervention that addresses lifestyle factors associated with cognition. The effectiveness of an HC protocol was evaluated and compared with a health education (HE) intervention, representing the current standard of care, in a sample of 216 adults between the ages of 45 and 75 years who were at-risk for developing ADRD. Outcomes examined were global cognition, neuropsychological cognition, and Alzheimer's risk. HC participants received personalized coaching from a health coach focusing on nutrition, physical activity, sleep, stress, social engagement, and cognitive activity. HE participants received biweekly education materials focusing on the same modifiable lifestyle factors addressed by HC. Participants were assessed at baseline and again 4 months later. Self-reported global cognition scores improved only in the HC group (16.18 to 15.52, p = .03) and neuropsychological cognitive ability improved in the HE group (104.48 to 108.76, p < .001). When non-adherence in the HC group was accounted for, however, the mean change in neuropsychological score was similar between groups (p > .05), self-reported global cognition demonstrated an even larger mean improvement in the HC group (16.20 to 15.41, p = .01), and the HC group saw an improvement in ADRD protective risk score (- 10.39 to - 11.45, p = .007). These results indicate that HC and HE can both improve cognition, but HC may be more effective and may yield increased protection against ADRD risk.

Multicultural Healthy Diet to Reduce Cognitive Decline & Alzheimer's Disease Risk: Study protocol for a pilot randomized controlled trial.

BACKGROUND: Emerging evidence indicates that healthy dietary patterns are associated with higher cognitive status; however, few clinical trials have explored this association in diverse middle-aged adults before the onset of cognitive decline. We use novel ambulatory methods to assess cognition in natural settings in tandem with diet recording. AIMS: We investigate whether the Multicultural Healthy Diet Study to Reduce Cognitive Decline & Alzheimer's Disease Risk, a pilot randomized controlled trial of an anti-inflammatory dietary pattern compared to usual diet, can mitigate cognitive decline and Alzheimer's Disease risk in a diverse population of 40-65 year old adults in Bronx, New York. METHODS: Primary cognitive outcomes assessed at nine months are collected in an ecological momentary assessment "measurement burst" design, over the course of participants' daily lives. These ultra-brief, ambulatory cognitive assessments examine processing speed, visuospatial working memory, short-term associative memory binding, long-term associative memory, and working memory capacity. Key secondary outcomes relate to comparing dietary intake between study arms with respect to cognitive outcomes. We assess diet with food records using the National Cancer Institute's Automated Self-Administered 24-h record and serum biomarkers. We further investigate the association of self-reported diet and dietary biomarkers with inflammatory-based biomarkers. CONCLUSION: This randomized controlled trial of diet and cognition for the first time combines novel measures of ambulatory cognitive assessment with web-based assessment of dietary intake recording. This new approach enabled the study to continue in the midst of the COVID-19 pandemic in remote format.

Olive oil and wine as source of multi-target agents in the prevention of Alzheimer disease.

Olive oil and wine are consumed daily worldwide, and they constitute the fundamental pillars of the healthy Mediterranean diet. Polyphenolic compounds, naturally present in both olive oil and wine, are responsible for their beneficial properties. Current studies have shown the neuroprotective effects of polyphenols independently of their well-known antioxidant action. In this work, we have focused on reviewing the protective effect of polyphenols from extra virgin olive oil and wine in Alzheimer´s disease (AD), to emphasise that both foods could be a possible therapeutic tool. Beneficial effects have been described in ß-aggregation, neurofibrillary tangles, autophagy and mitochondrial function, as well as in cerebral insulin resistance. Furthermore, to date, a harmful dose has not been described. Both pre-clinical and clinical works demonstrate that polyphenols act on neuropathological and cognitive disorders of AD, preventing or stopping the onset of this devastating disease. However, there are certain limitations in these studies, since it is very difficult to research diseases that lead to cognitive impairment. Although all the findings obtained are very encouraging, more studies should be carried out investigating the use of the polyphenols from olive oil and wine as therapeutic agents in the progression of AD. Therefore, more longitudinal studies in humans with a homogeneous cohort of patients are necessary to corroborate the efficacy of these nutraceuticals, as well as determine the most appropriate dose for this purpose.

Natural Products as Bioactive Agents in the Prevention of Dementia.

Dementia is a complex syndrome of neurological disorders which is associated with cognitive functions of the body. The present review focuses on the role and application of natural products in the treatment of dementia and related diseases. The studies highlight that there exist some potent synthetic/semisynthetic drugs that can effectively target dementia and related diseases. In contrast, despite the existence of a large library of natural products, only a few of them (galantamine, huperzine A, etc.) have been approved as drugs against dementia. This fact is not discouraging because a large number of natural products, including classes of polyphenols, alkaloids, isothiocyanates, phytocannabinoids, and terpenoids, are in the process of drug development stages against dementia and related diseases. It is because they display some promising and diverse biological activities, including antioxidant, acetylcholinesterase inhibitory activity, and anti-amyloidogenic properties, which are significantly associated with the prevention of dementia syndrome. The studies reported in the literature reveal that bioactive natural products particularly target Alzheimer's and Parkinson's diseases by suppressing the risks responsible for dementia. Huperzine A has been identified as a potent natural product against Alzheimer's disease. Despite the efficient role of natural products in preventing dementia, their direct application as drugs is still limited due to some controversial results obtained from their clinical trials; however, bioassay-guided drug development studies can prove them potential drugs against dementia and related diseases. This review provides useful information for researchers, pharmacologists, and medical doctors.