Value of Diet and Nutraceuticals in the Prevention and Treatment of Mixed Alzheimer’s Disease and Vascular Dementia

Abstract

Mixed dementia, most often caused by the coexistence of Alzheimer’s disease and vascular dementia pathologies, presents unique preventive and therapeutic challenges that may be addressed through dietary and nutraceutical interventions. Current evidence demonstrates that diets emphasizing polyphenol-rich foods like olive oil, berries, and leafy greens exert neuroprotective effects by reducing oxidative stress, inflammation, and amyloid pathology while improving cerebrovascular function. Specific bioactive compounds, including resveratrol, curcumin, quercetin, epigallocatechin gallate, N-acetylcysteine, and Huperzine A, among some others, have demonstrated therapeutic potential through their multimodal mechanisms targeting the pathogenic pathways of Alzheimer’s disease and vascular dementia, including Aβ and tau pathology, neuroinflammation, oxidative stress, and neurovascular dysfunction. However, our limited appreciation of the pharmacokinetics and pharmacodynamics of natural compounds and the inadequate extent of clinical studies underscore the need for further research. This review synthesizes current knowledge on diet and nutraceutical compounds that may be of value in the prevention and treatment of mixed Alzheimer’s disease and vascular dementia. We focus on their molecular mechanisms of action relevant to the dual pathophysiological basis of mixed Alzheimer’s disease and vascular dementia.

1. Introduction

Mixed dementia (MD) is a multifactorial neurodegenerative disorder and most often characterized by the cohabitation of Alzheimer’s disease (AD) and Vascular Dementia (VaD), two of the most prevalent forms of dementia worldwide [1]. The overlapping pathological features of these conditions accelerate neurodegeneration and cognitive impairment, complicating diagnosis and treatment. An autopsy-based study reported that 38% of elderly dementia patients exhibited signs of both AD and cerebrovascular disease: 30% had pure AD and only 12% had pure VaD. This suggested that MD could be far more common than generally appreciated [2]. Given the growing burden of MD in the aging population, identifying modifiable risk factors such as dietary composition and nutritional status has gained attention as a potential strategy for prevention and disease management [3].

MD presents a unique therapeutic challenge, as both neurodegenerative and vascular pathologies must be addressed [4]. A comprehensive management strategy is required for treating both cognitive declines related to AD and the vascular components that contribute to dementia. This approach may include lifestyle and dietary modifications, as well as pharmacological and nutraceutical interventions.

Growing evidence indicates that overall dietary patterns, specific foods, and individual natural compounds can shape the development and progression of MD. In particular, the Mediterranean diet (MeDi) and the Mediterranean-DASH Diet Intervention for Neurodegenerative Delay (MIND) diet are increasingly recognized as protective, largely because they prioritize antioxidant- and anti-inflammatory-rich foods such as fruits, vegetables, whole grains, nuts, and healthy fats like olive oil [5,6]. In addition, foods rich in flavonoids—including berries, green tea, and dark chocolate—have been reported to enhance synaptic plasticity, attenuate Aβ-related neurotoxicity, and improve cerebral blood flow [7,8,9,10,11].

Pharmacological treatments for MD are primarily aimed at the symptomatic relief of cognitive decline seen in AD while also addressing vascular risk factors. While there is no single medication approved specifically for MD, several drugs used to treat AD or cardiovascular diseases have demonstrated efficacy. Pharmacological medications such as cholinesterase inhibitors, anti-hypertensive drugs, and statins have all been considered as useful treatments for MD [12,13,14]. Despite this, the prognosis of MD is poor, and additional preventive and therapeutic strategies are urgently needed to counteract the rapidly rising MD prevalence. Dietary and nutraceutical interventions hold significant promise as strategies to mitigate cognitive decline and neurodegeneration in MD.

Beyond whole foods, isolated natural compounds exhibit targeted mechanisms against MD pathology. For examples, resveratrol, found in red grapes and berries, modulates Aβ metabolism, reduces tau hyperphosphorylation, and improves cerebral blood flow through activating endothelial nitric oxide synthase (eNOS) [15]. Curcumin, an active compound in turmeric, demonstrates similar multimodal effects, including inhibition of amyloid plaque formation, reduction of tau pathology, and improvement of vascular function [16,17]. Other compounds like epigallocatechin gallate (EGCG) from green tea and Huperzine A from Chinese club moss show neuroprotective effects through antioxidant, anti-inflammatory, and cholinergic mechanisms [18,19].

Despite these promising findings, challenges remain in translating preclinical results to clinical applications. Issues of bioavailability, optimal dosing, and long-term safety and efficacy require further investigation [20]. This review synthesizes current evidence on the potential of dietary patterns, specific foods, and natural compounds in MD management, with particular focus on the mechanisms of action of some individual nutraceutical compounds, while a more comprehensive analysis of the pharmacokinetics, toxicology, and clinical studies is beyond the scope of this review.

2. Dietary Patterns and Specific Foods

The relationship between diet and cognitive health has been researched extensively, showing that certain diet patterns and foods could potentially reduce the risk of AD and VaD. The MeDi and MIND diets have been demonstrated to reduce the risk of dementia [21,22]. The MeDi emphasizes plant-based foods, healthy fats such as olive oil, and moderate intake of fish and poultry. The MIND diet puts emphasis on consuming foods high in nutrients, such as leafy greens, nuts, and berries while limiting the consumption of saturated fats and processed sugars. There are some foods within the MIND diet that are reported to improve brain health on their own as well, such as olive oil and flavonoid rich foods.

2.1. Mediterranean Diet

The MeDi consists of whole grains, fruits, vegetables, nuts, fish, and olive oil. It also allows for moderate consumption of dairy products and alcohol with low consumption of meat. Both epidemiological studies and randomized controlled human trials have shown that the MeDi improves cognitive health and reduces the risk of dementia [23].

Many studies have demonstrated that those who are more adherent to a MeDi have better cognitive health. One study followed healthy individuals and individuals with mild cognitive impairments (MCI) for four and a half years and showed that those who were more adherent to the MeDi had a reduced likelihood of developing MCI as well as a decreased risk of the MCI becoming AD [6]. These findings suggest that certain diets do offer some protection against cognitive decline. Other studies have verified that adherence to the MeDi in aging populations can slow down cognitive decline [23]. The risk of developing AD and VaD is significantly higher in those over the age of 65 and doubles every five years afterwards [24]. This shows that consumption of the MeDi may have potential to delay some of the effects of AD and VaD.

Some other long-term studies have further documented that adherence to the MeDi can improve global cognitive function, memory, and executive function [25]. A longitudinal study focused more on the MeDi effects on brain structure and function; magnetic resonance imaging (MRI) testing showed that there was lower brain atrophy, especially in the gray matter, in people of 73–76 years old who adhered to the MeDi [26]. These results demonstrated that individuals who consume the MeDi diet experience slower brain aging and less brain structural damage, suggesting that the MeDi may potentially reduce the risk of mixed AD and VaD.

2.2. MIND Diet

The MIND diet is a hybrid dietary pattern designed specifically to reduce the risk of AD and other neurodegenerative diseases. Unlike the MeDi, the MIND diet places more emphasis on foods like berries and green leafy vegetables, which are rich in antioxidants, neuroprotective compounds, high in folate, and other B-vitamins critical for brain function, while limiting the intake of saturated fats, red meat, and added sugars [5]. This diet is a combination of the MeDi, which has been shown to improve cognitive health as noted above, and the Dietary Approaches to Stop Hypertension (DASH) diet, which has been reported to improve cardiovascular health [27,28].

The MIND diet has shown positive outcomes in cognitive health, especially in aging populations. A prospective study documented that strict adherence to the MIND diet decreased the risk of AD by 53%. Even those who moderately followed the diet showed a 35% decrease in risk of developing AD, demonstrating that even partial adherence to the MIND diet can reduce the risk for dementia [5]. These results illustrate that the MIND diet has specific qualities that are protective against AD and potentially VaD as well.

Neuroimaging studies have shown promise in the effect of the MIND Diet on both AD and VaD. Indeed, adherence to MIND diet reduces biomarkers for cerebral arteriosclerosis and results in slower rates of brain atrophy. The reduction in brain atrophy is especially noticeable in brain regions crucial for memory and executive function, such as the hippocampus and cortex [29]. These studies demonstrated that the MIND diet can mitigate both neurodegenerative effects and vascular dysfunction, making it potentially useful in MD prevention and treatment.

3. Olive Oil

Many studies have been conducted to examine the effects of certain foods on AD and VaD, rather than overall dietary patterns. Olive oil is one of the main components of both the MeDi and MIND diet. Olive oil contains high amounts of unsaturated fats and polyphenols, which both have anti-inflammatory and antioxidant properties [25,30].

Increased consumption of olive oil is associated with a reduced risk of cognitive decline [31]. Randomized controlled trials have examined the effects of olive oil on MCI. Individuals with MCI who consumed extra virgin olive oil (EVOO) showed improvement of blood–brain barrier (BBB) functionality and improved cognitive performance [32]. BBB dysfunction is a significant feature of both AD and VaD pathology, highlighting that the neuroprotective potential and anti-inflammatory properties of EVOO may make it useful in the prevention of neurodegenerative diseases including MD [1,33].

4. Flavonoid-Rich Foods

Foods such as fruits, vegetables, nuts, and whole grains are great sources of flavonoids. Like olive oil, these foods are also major components of the MeDi and MIND Diet. Flavonoid-rich foods, such as berries, tea, and dark chocolate, substantially promote cognitive health. For example, greater intakes of blueberries and strawberries appeared to delay cognitive aging by up to 2.5 years [9]. Research from the Framingham Offspring Cohort revealed that individuals with higher consumption of flavonoid-rich foods showed a decreased risk for developing dementia [11]. The Danish Diet, Cancer, and Health cohort also yielded similar findings. The Cohort did not find a significant association of flavonoid intake with AD but did show that moderate intake of flavonoids could decrease risk of dementia in general and reduce the risk of VaD [7]. This emphasizes the protective effects of flavonoids in vascular and cognitive health.

Randomized controlled trials have also investigated the effects of flavanol-rich foods on cognitive impairment. One study conducted a trial with high-flavanol cocoa and examined its effect on patients with MCI. The results showed that the group that consumed high-flavanol cocoa had significant improvements in executive function and processing speed [8]. Another study that employed blueberry supplementation in aging populations showed that the group who consumed more blueberries had improvements in cognitive health compared to the control group. This was seen more specifically in tasks involved in memory and learning [10]. These findings suggest that flavanol-rich foods may enhance neural pathways to improve cognitive function, underscoring the importance of these foods in the prevention of AD, VaD, and MD.

5. Individual Natural Compounds

While dietary patterns and specific foods can have an impact on one’s health and decrease the risk of developing MD, in recent studies, the emphasis has been shifted more toward examining the effects of individual natural compounds on neurodegenerative diseases. These compounds are often derived from foods or herbs that have a range of neuroprotective properties. Polyphenols such as curcumin and resveratrol have yielded promising effects in reducing Aβ accumulation and tau pathology [34,35]. Similarly, natural antioxidants like N-acetylcysteine (NAC) have been reported to improve cellular repair and reduce oxidative damage, suggesting potential benefits for MD [36]. Many comprehensive reviews highlight numerous natural compounds with promising anti-dementia effects, such as polyphenols and alkaloids [30,37,38]. This review will focus on a selected few that may target the dual AD-VaD pathology of MD.

Table 1. Summary of Nutraceutical Compounds with Potential MD–Modifying Effects.

Compound	Antioxidant Effects	Anti-Inflammatory Effects	Other Potential MD-Relieving Effects	References
Resveratrol	Nrf2 ↑ (SOD, catalase, GPx, HO-1)	IKK/NF-κB ↓; SIRT1-p65 deacetylation	↑ non-amyloidogenic APP; ↓ tau-P; ↑ eNOS/NO	[39,40,41,42]
Curcumin	Keap1–Nrf2 disruption → HO-1, GSH up	IκB stabilization → NF-κB ↓; microglia ↓	↓ Aβ (BACE1/γ-sec); ↓ tau-P (GSK-3β/PP2A); ↑ eNOS activity	[16,20,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58]
EGCG	SOD ↑; MDA ↓	NF-κB, microglia ↓; PKC modulation	↓ Aβ aggregation (BACE1/γ-sec); ↑ sAPPα; ↑ PI3K/Akt/eNOS → vasodilation	[18,59,60,61,62,63,64,65,66,67,68,69,70,71,72]
Quercetin	Nrf2/ARE activation; ROS ↓; lipid peroxides ↓	IκBα stabilization → NF-κB ↓; COX-2 ↓	Aβ & tau aggregation ↓; AChE inhibition; improves cell survival & behavior	[73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89]
Xanthohumol (XN)	Direct ROS scavenging; Nrf2 ↑; MDA ↓	NF-κB, NF-AT, AP-1 ↓	↓ Aβ plaques (BACE1, cholinesterase); ↓ tau-P; limits VSMC proliferation	[90,91,92,93,94,95,96,97,98,99,100,101,102,103,104]
Luteolin	ROS ↓; SOD & catalase ↑; HO-1, NQO1 ↑	IκBα stabilization; JNK/AP-1 ↓	↓ Aβ & tau pathology; improves memory in TBI & AD models	[105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126]
Berbamine HCl	Nrf2 ↑ (PC12); ORAC/SOAC activity	Cytokines ↓ (LPS/CoV models); autophagy ↑	↓ Aβ aggregation & NFTs; improves spatial memory	[127,128,129,130]
Huperzine A	nAChR–NF-κB inhibition; ROS ↓	AChE ↓ → NF-κB ↓	↑ non-amyloidogenic APP; ↓ tau-P; ↑ CBF; ↓ infarct size	[19,131,132,133,134,135,136,137,138,139,140,141]
N-Acetylcysteine	GSH precursor; peroxynitrite scavenging	IKK/NF-κB ↓; iNOS/NO ↓	↓ Aβ toxicity; ↑ neuronal survival; ↓ oxidative stress & infarct size	[36,142,143,144,145,146,147,148]
Octyl Gallate (OG)	ROS scavenging (in vitro)	Cytokines ↓	Potential vascular protection (data still preliminary)	[149,150,151,152,153]
Britannin	ROS generation ↓ (cell models)	NF-κB p65 & NLRP3 ↓	Early Aβ/tau inflammation ↓; needs further validation	[154,155]
Sulforaphane (SFN)	Nrf2–ARE activation → ↑ HO-1, NQO1, SOD, GPx; ↓ ROS, MDA; preserves BBB integrity	Reduces oxidative-stress driven inflammation; lowers apoptosis markers	↓ Aβ (BACE1/PS-1 ↓); ↓ Tau protein expression; ↓ infarct volume in ischemia; improves cognition in AD and VCI models	[156,157,158,159,160,161,162,163,164]

summarizes selected compounds with antioxidant, anti-inflammatory, and other MD-relieving effects. Because clinical studies using individual nutraceutical compounds in dementia management are much less conclusive than those using dietary patterns or specific foods, we do not comprehensively analyze these clinical studies in the discussion of these compounds, but instead only include a few paragraphs to briefly summarize this aspect at the end of this section.

5.1. Polyphenols

Polyphenols are a broad group of naturally occurring compounds that may improve cognitive health. Foods such as olive oil and dark chocolate contain large amounts of polyphenols. Their ability to modulate oxidative stress, inflammation, and neurodegeneration renders them promising in mitigating cognitive decline [37,86,165].

5.1.1. Resveratrol

Resveratrol is a polyphenol and classified as a stilbene. Stilbenes are compounds that are synthesized by plants during injury or stress [166]. Resveratrol is commonly found in foods such as red grapes, berries, and peanuts. It has been identified to have neuroprotective effects. It also has the ability to combat oxidative stress, reduce inflammation within the body, protect vascular integrity, as well as modulate Aβ and tau pathology [167,168,169]. These properties make resveratrol a promising therapeutic candidate for AD, VaD, and MD.

Antioxidant Mechanisms

Oxidative stress is a hallmark of both AD and VaD and leads to neuronal damage and cognitive decline. Resveratrol’s antioxidant properties revolve around its ability to neutralize reactive oxygen species (ROS) and upregulate the body’s endogenous antioxidant pathways. One of the main pathways involved is the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Under normal conditions, Nrf2 is bound to the Kelch-like ECH-associated protein 1 (Keap1) in the cytoplasm and remains inactive and goes through degradation via the ubiquitin-proteasome system. When oxidative stress occurs, Keap1 undergoes a conformation change that causes the release of Nrf2. The unbound Nrf2 is now stabilized and active. It then translocates to the nucleus and binds to the antioxidant response elements (AREs) in the promoter region of target genes, which leads to the transcription of antioxidant and detoxification enzymes such as superoxide dismutase (SOD), catalase, glutathione peroxidase, and heme oxygenase-1 (HO-1) [39]. This process helps neutralize ROS and reduce oxidative stress. Resveratrol affects this pathway by disrupting the interaction between Keap1 and Nrf2, preventing Nrf2 from being degraded, allowing the protein to remain active. As a result, Nrf2 activates the expression of antioxidant genes to transcribe more antioxidant enzymes to enhance the cellular defense system and thus mitigate oxidative damage [39,169].

Resveratrol also exerts antioxidant activity via improving mitochondrial function, which is critical given the central role of mitochondria in ATP production and the generation of ROS as byproducts. Resveratrol can activate the sirtuin-1 (SIRT1) pathway, by binding to SIRT1 causing it to undergo a conformation change that increases its deacetylation activity [40]. This direct binding allows SIRT1 to deacetylate mitochondrial proteins, such as peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Consistent with this mechanism, resveratrol has been shown in preclinical models of acute neuronal injury to upregulate SIRT1 and activate PGC-1α, resulting in increased mitochondrial biogenesis and improved mitochondrial efficiency that reduces neuronal damage [170,171]. The increase in mitochondrial biogenesis and improvement in mitochondrial functionality allows for an increased production of ATP while minimizing the production of ROS.

Anti-Inflammatory Mechanisms

Neuroinflammation is a key pathological feature of both AD and VaD. Chronic activation of microglia leads to the release of pro-inflammatory cytokines, which exacerbates neuronal injury [172]. Resveratrol’s anti-inflammatory properties are primarily mediated through the suppression of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. In the absence of stimuli, NF-κB is inactive as it is bound to Inhibitor of κB (IκB). When exposed to pro-inflammatory signals, the IκB kinase (IKK) complex phosphorylates IκB, which then goes through the ubiquitin-proteasome system. This freeing of NF-κB allows it to translocate to the nucleus where it binds to DNA to promote the transcription of pro-inflammatory cytokines, such as IL-6 and TNF-α [173]. Resveratrol modulates this pathway in several ways. First, resveratrol inhibits the IKK complex, which blocks the phosphorylation of IκB and thereby keeps NF-κB inactive [41]. This reduces the ability of NF-κB to bind to the DNA and diminishes the expression of pro-inflammatory cytokines. Second, resveratrol also modulates this pathway in an indirect manner by its binding to SIRT1 [42]. The deacetylation properties of SIRT1 then lead to the reduction of NF-κB activation by targeting its p65 subunit, further diminishing the production of pro-inflammatory cytokines.

Aβ-Reducing Mechanisms

Aβ plaque accumulation is a central pathological feature of AD and MD. Resveratrol has been observed to modulate Aβ metabolism, reducing its production and promoting its clearance. One of the primary mechanisms by which resveratrol influences Aβ pathology is through the regulation of amyloid precursor protein (APP). Under normal conditions, APP is cleaved by α-secretase in the non-amyloidogenic pathway, which produces the neuroprotective soluble APPα (sAPPα). However, in AD, APP is cleaved by β-secretase (BACE1) and γ-secretase, leading to the production of Aβ peptides, which aggregate into toxic plaques causing damage in the brain [174]. Resveratrol stimulates the non-amyloidogenic pathway to upregulate the production of sAPPα through α-secretase cleavage. In vitro studies have demonstrated that resveratrol increases the expression of A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), which is a key α-secretase enzyme [174]. This increase in ADAM10 augments the production of sAPPα and reduces the buildup of Aβ peptides. Additionally, resveratrol has also been found to inhibit the activity of BACE1, further limiting Aβ production. A study using the APP/PS1 transgenic mouse AD model found that resveratrol as a dietary supplement administered to APP/PS1 mice significantly reduces Aβ plaque formation in the brain [175]. Other studies have used familial AD (5xFAD) mice to demonstrate that resveratrol reduced Aβ plaque deposition in the cortex and the hippocampus.

Tau-Modulating Mechanisms

The hyperphosphorylation and aggregation of tau protein into neurofibrillary tangles (NFTs) is another hallmark of AD and MD. Resveratrol has been found to reduce tau hyperphosphorylation and aggregation through multiple mechanisms. One of the key pathways involved is the AMP-activated protein kinase (AMPK) pathway. AMPK is a cellular energy sensor that regulates metabolic processes. The AMPK pathway is activated when there is low energy availability in the body. AMPK activation inhibits glycogen synthase kinase-3β (GSK-3β), a kinase that phosphorylates tau and promotes its aggregation [176]. Under normal physiological conditions, tau protein stabilizes microtubules in neurons to maintain neuronal structure and function. However, in AD, constant phosphorylation of the tau protein disrupts its binding to microtubules, leading to destabilization of the microtubule and ultimately to the formation of NFTs [177]. Resveratrol can modulate tau pathology through the activation of AMPK. When AMPK is activated, it phosphorylates and inhibits GSK-3β, thereby reducing tau hyperphosphorylation and preventing NFT formation [178]. In addition to the AMPK pathway, resveratrol modulates tau pathology through the activation of SIRT1 and protein phosphatase 2A (PP2A), a major tau phosphatase. PP2A plays a critical role in maintaining tau homeostasis by dephosphorylating tau and preventing its aggregation. In AD, PP2A activity is often reduced, leading to tau hyperphosphorylation and NFT formation. Resveratrol enhances PP2A activity by upregulating the SIRT1 pathway, thereby reducing tau phosphorylation and NFT formation [179]. Researchers showed that tau acetylation at lysine residues inhibits its degradation and promotes its aggregation into NFTs. Using postmortem brain tissue from AD patients, it was reported that acetylated tau levels were significantly elevated in AD brains compared to controls and this was thought to be mediated through the SIRT1 pathway. Indeed, in cultured cells, resveratrol deacetylates tau and promotes its degradation, thereby reducing tau aggregation and NFT formation [180]. Animal studies have confirmed the effect of resveratrol on tau pathology. For example, in a study using a tauopathy mouse model expressing human tau P301L, treatment with resveratrol for 3 months inhibited hyperphosphorylation of tau at multiple sites and decreased NFT formation in the hippocampus and cortex in these mice [181].

Vascular Protective Mechanisms

Vascular dysfunction is a key pathological feature of VaD and MD, and it also contributes to the progression of AD. The cerebrovascular system maintains brain homeostasis by regulating cerebral blood flow (CBF) to ensure that proper amounts of oxygen and nutrition can reach the brain and its neurons while also removing unwanted metabolic waste. Endothelial cells lining the blood vessels play a key role in this process by producing nitric oxide (NO) through endothelial nitric oxide synthase (eNOS). NO is a potent vasodilator that helps maintain vascular tone and integrity, protecting against vascular injury [182]. Vascular pathology often coexists with Aβ plaques and tau tangles that exacerbate neurodegeneration and cognitive impairment [183]. Reduced CBF, BBB disruption, and endothelial dysfunction are common features of VaD that lead to neuronal injury and synaptic loss [184]. These vascular changes contribute to neuronal injury and cognitive decline, as observed in MD. Resveratrol has been demonstrated to modulate vascular pathways by increasing the expression and activation of eNOS, thereby enhancing NO production and promoting vasodilation both systemically and in the brain [15,75,185,186,187].

5.1.2. Curcumin

Curcumin is a polyphenol found in turmeric. It belongs to the class of curcuminoids, which are known for their potent anti-inflammatory, antioxidant, and neuroprotective properties [43]. Curcumin has been established to have potential therapeutic effects in neurodegenerative diseases. Its ability to modulate AD pathology, such as Aβ plaque formation and tau pathology, as well as its effects on vascular dysfunction makes it a promising candidate for addressing the comorbid effects of AD and VaD [49,58].

Curcumin’s antioxidant properties are primarily mediated through its ability to inhibit ROS production and enhance endogenous defenses. One of the primary pathways involved is the Nrf2 pathway. Similarly to resveratrol, curcumin enhances this pathway by disrupting the Keap1-Nrf2 interaction thereby stabilizing Nrf2 [52]. In vitro studies have demonstrated that curcumin treatment of neuronal cells increases activation of the Nrf2 pathway, as evidenced by increased expression of HO-1 and glutathione levels, leading to upregulation of antioxidant enzymes and protection against neuronal damage [45]. In vivo studies using APPsw transgenic mice showed that curcumin significantly reduced lipid peroxidation, an indicator of oxidative damage [47]. Another study using a rat model of chronic cerebral hypoperfusion found that mice treated with curcumin exhibited reduced oxidative stress markers in the hippocampus that were associated with improved cognitive function [188].

Similarly to resveratrol, curcumin’s anti-inflammatory effects are primarily mediated through the inhibition of the NF-κB pathway [53]. Curcumin has also been found to inhibit the activation of NF-κB in microglia, reducing the release of inflammatory mediators and protecting neurons from cytokine-induced damage [56]. Curcumin was found to significantly reduce lipopolysaccharide (LPS)-induced production of TNF-α and IL-6 [20]. Animal studies have confirmed these in vitro findings; curcumin effectively prevented neuroinflammation and cognitive impairment induced by LPS in mice. Specifically, curcumin reduced LPS-induced pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6, in the hippocampus and prefrontal cortex. Curcumin treatment preserved memory function of the mice as demonstrated in the Novel Object Recognition (NOR) test [54]. These findings suggest that curcumin exerts protective effects by attenuating neuroinflammation in the hippocampus and prefrontal cortex that ultimately preserves cognitive function, highlighting curcumin’s therapeutic potential against inflammation-induced cognitive decline. Another study looked at the effects of curcumin in a mouse model of traumatic brain injury (TBI). Curcumin treatment significantly reduced neuroinflammation by suppressing the activation of microglia and astrocytes. The anti-inflammatory effects coincided with improvement of spatial memory and cognitive function as assessed in the Morris Water Maze (MWM) [16].

Curcumin has also been known to modulate Aβ metabolism by reducing its production and promoting its clearance. One of the primary mechanisms by which curcumin influences Aβ pathology is through the inhibition of BACE1 and γ-secretase [57]. In addition, curcumin can cross the BBB, bind directly to Aβ plaques and facilitate Aβ clearance [189]. Furthermore, curcumin may prevent the aggregation of Aβ peptides into toxic oligomers, as Thioflavin T fluorescence assays have demonstrated that curcumin binds to Aβ peptides and destabilizes the Aβ fibrils, thereby reducing Aβ plaque formation [50]. Curcumin also promotes the clearance of Aβ by upregulating the expression of neprilysin, an enzyme that degrades Aβ peptides [55]. Animal models of AD have confirmed curcumin’s ability to reduce Aβ plaque burden and improve cognitive function. A study using APP/PS1 transgenic mice showed that curcumin reduces Aβ plaque deposition in the cortex and hippocampus accompanied with improvements in spatial memory [55]. Similarly, a study using APPsw mice demonstrated that curcumin reduced Aβ plaque burden and improved cognitive function by enhancing microglial clearance of Aβ from the brain [48].

Curcumin has been observed to reduce tau hyperphosphorylation and prevent NFT formation through multiple mechanisms, including the inhibition of GSK-3β and the activation of PP2A [44], similar to that of resveratrol. Curcumin also can disrupt β-sheet structures which are crucial for stabilizing and elongation of tau fibrils; this prevents the formation of tau tangles [51]. In vitro studies using SH-SY5Y neuronal cells have demonstrated that curcumin treatment significantly reduces tau phosphorylation by inhibiting GSK-3β activity, ultimately preventing its aggregation [46]. Animal models of tauopathy have provided further evidence for curcumin’s ability to reduce tau pathology, improve cognitive function [48], and restore working memory [190].

Curcumin has also been shown to improve vascular function by enhancing eNOS activity and increasing NO production to help maintain vascular integrity in both in vitro and in vivo models. It can suppress TNF-α-induced expression of lectin-like oxidized LDL receptor-1 (LOX-1) in human umbilical vein endothelial cells (HUVECs), reducing oxidative stress and inflammation through antioxidant mechanisms [17]. Animal models, particularly hypertensive animals, have revealed evidence of curcumin’s vascular benefits. A study showed that curcumin and tetrahydrocurcumin improved vascular relaxation by ameliorating eNOS inhibition in hypertensive rats [191]. Another study using a rat model of chronic cerebral hypoperfusion found that curcumin significantly improved CBF and reduced oxidative stress in the brain, in addition to its suppression of neuroinflammation through modulation of microglial activation [192].

5.1.3. Epigallocatechin Gallate (EGCG)

EGCG is found in green tea and has been widely studied for its neuroprotective effects, particularly in the context of neurodegenerative diseases. As a polyphenolic compound, EGCG exhibits strong antioxidative, anti-inflammatory, and anti-amyloidogenic properties [18]. Studies indicate that EGCG can cross the BBB, allowing it to exert direct effects on both neuronal and vascular components of the brain [68].

Similarly to resveratrol and curcumin, EGCG ameliorates oxidative stress by disrupting the Keap1-Nrf2 interaction [193]. In vitro studies using endothelial cells showed that EGCG induces the expression of HO-1 through the activation of Nrf2 signaling pathways [69]. Another animal study used D-galactose-induced aged mice to model oxidative stress and neurodegenerative changes associated with aging and showed that EGCG treatment improved the learning ability and memory retention in those mice. EGCG increased the antioxidant enzyme activity in total superoxide dismutase (T-SOD) and glutathione peroxidase (GSH-Px), while significantly reduced levels of malondialdehyde (MDA), a marker of oxidative stress [62].

EGCG’s anti-inflammatory effects are also like that of resveratrol and curcumin [18]. EGCG has been observed to inhibit the activation of microglia, reduce the release of inflammatory cytokines, and protect neurons from cytokine-induced damage [64]. Other studies have reported that EGCG can affect the protein kinase C (PKC) pathway, which plays a pivotal role in cellular inflammatory responses to oxidative stress. When exposed to ROS, PKC can be activated through various mechanisms, including direct oxidation of its regulatory domains or through upstream signaling pathways. When PKC becomes active it can modulate several downstream targets involved in cell survival, apoptosis, and inflammation. Its activation has been revealed to influence the NF-κB pathway [194]. In vitro studies have shown that EGCG can activate PKC, leading to the modulation of cell survival genes. EGCG-induced PKC activation was associated with increased expression of anti-apoptotic proteins and decreased expression of pro-apoptotic factors, thereby enhancing neuronal cell survival under oxidative conditions [65].

One of the primary mechanisms by which EGCG influences Aβ pathology is through the inhibition of BACE1 and γ-secretase [18]. In vitro studies reported that EGCG reduced Aβ deposition and plaque formation, while increasing the sAPP formation [66]. A study using Aβ-expressing C. elegans demonstrated that EGCG reduced Aβ oligomer formation and toxicity; in addition, EGCG influenced the DAF-2 insulin-like signaling pathway, which is known to regulate stress resistance and longevity in C. elegans [59]. Other animal studies showed that mice treated with EGCG had reduced Aβ levels and plaque formation, with improved working memory compared to controls [70,195].

EGCG can also reduce tau hyperphosphorylation through inhibition of GSK-3β [18]. Studies have identified that EGCG exposure can influence post-translational modifications (PTMs) of tau protein. For instance, Neuroblastoma cells treated with EGCG demonstrated reduced tau phosphorylation at specific sites along with improved improving microtubule stability and organization [71]. In an aluminum chloride-induced neurotoxicity mouse model designed to mimic AD-like pathology, EGCG treatment showed significantly improved performance on the MWM and NOR tests. Histological analyses showed reduced NFT formation in the cortex and hippocampus of EGCG-treated rats [196]. Taken together, these studies show the potential neuroprotective effects that EGCG provides towards cognitive function in the setting of tauopathies.

EGCG is also reported to exert vascular protective effects. It has been shown that EGCG improves vascular function by enhancing eNOS activity and increasing NO production [18]. EGCG stimulates the production of ROS in vascular endothelial cells, which then activates Fyn kinase, a member of the Src family kinases. The activation of Fyn kinase triggers a signaling cascade involving phosphatidylinositol 3-kinase (PI3K) and Akt, leading to phosphorylation of eNOS and subsequent NO production [67]. The increased NO spreads into smooth muscle cells and causes vasodilation [63]. Animal studies have demonstrated that EGCG could affect CBF and reduce vascular inflammation in VaD models. A rat model with middle cerebral artery occlusion (MCAO), a well-established model for ischemic stroke, showed that EGCG treatment post-surgery resulted in a 9.9% decrease in infarct volume [60]. Other studies using mice with bilateral common carotid artery occlusion (BCCAO) found that EGCG treatment significantly preserved spatial learning and memory by enhancing SOD activity and reducing MDA levels [61]. The findings suggest that EGCG can improve vascular health after injury and improve cognitive function, making it a promising therapeutic agent for VaD and MD.

5.2. Flavonoids

Flavonoids are a diverse group of naturally occurring polyphenolic compounds found in various fruits, vegetables, and plant-derived beverages, such as tea and wine [197]. These compounds have been shown to have potent antioxidant, anti-inflammatory, and anti-proliferative properties, which contribute to their protective effects against chronic diseases, including cardiovascular disorders and neurodegenerative disease [197,198].

5.2.1. Quercetin

Quercetin is a flavonoid that is present in apples, berries, onions, and tea. It is recognized for its potent antioxidant and anti-inflammatory activity. Quercetin can cross the BBB and can mitigate oxidative stress, neuroinflammation, amyloidogenesis, tau pathology, and neurovascular dysfunction in the brain [81,82].

Quercetin’s antioxidant potential is derived from its ability to direct free-radical scavenging and activation of endogenous defense systems such as the Nrf2/ARE pathway [199]. In vitro studies found that primary cortical neurons that were exposed to quercetin exhibited Nrf2 nuclear translocation within 1 h, increased GSH synthesis, and protection against H₂O₂ [74]. Other studies found that quercetin reduced lipid hydroperoxide-induced ROS by directly neutralizing peroxyl radicals before they could initiate chain reactions, showing its direct role in ROS scavenging [87]. It was also observed that human red blood cells accumulated quercetin at concentrations 15-fold higher than extracellular levels, protecting against H₂O₂-induced hemolysis by scavenging extracellular radicals, further showing its protective abilities [200]. Animal studies report that mice fed quercetin for 10 weeks had higher brain expression of Nrf2 and lower protein carbonylation in aged brains [79]. Quercetin treated rats that underwent oxidative stress were observed to have lower lipid peroxidation and reduced protein carbonylation in the hippocampus compared to controls [80].

Quercetin also directly inhibits the NF-κB pathway by blocking IκBα degradation in LPS-stimulated BV2 cells [76]. In human astrocytes, quercetin was also observed to decrease IL-1β-induced COX-2 expression and inhibit IKKβ kinase activity [201]. Studies using atherosclerotic apoE-deficient mice showed that quercetin treatment led to reduction in aortic plaques [78,202]. In human CRP-transgenic mice, dietary quercetin was shown to suppress IL-1β-induced hepatic CRP expression [83]. The systemic anti-inflammatory effects support quercetin’s potential in attenuating vascular inflammation relevant to MD.

Quercetin was found to reduce Aβ production and the formation of toxic aggregates [73]. It could also reverse tau phosphorylation by modulating kinases such as MAPK and GSK-3β [82]. These findings suggest that quercetin exerts multifaceted neuroprotective effects by directly modulating AD pathology.

Recent VaD studies highlight quercetin’s anti-inflammatory actions using human brain microvascular endothelial cells (HBMECs), which mimics BBB injury seen in VaD. Quercetin treatment significantly improved cell viability and markers of endothelial repair, while reduced apoptosis and preserved mitochondrial membrane potential [85]. In hypoxic conditions, primary microglia treated with quercetin exhibited a reduction in pro-inflammatory cytokines [84]. In a mouse model with bilateral carotid artery stenosis (BCAS), quercetin treatment reduced demyelination in the hippocampus, increased anti-inflammatory markers, and reduced pro-inflammatory cytokines [88]. In a global cerebral ischemia-reperfusion injury mouse model, quercetin pretreatment improved neurological scores, decreased neuronal death and brain edema, and suppressed activation of microglia [89].

It is worth noting that quercetin has been identified as a natural senolytic compound that selectively clears senescent cells. Cellular senescence is a hallmark of both AD and VaD, where senescent glia and neurons contribute to chronic inflammation and impaired protein clearance, while in the vasculature, senescent endothelial and smooth muscle cells exacerbate atherosclerosis, BBB dysfunction, and cerebral hypoperfusion [203,204,205,206]. In vitro screenings of quercetin showed its ability to selectively induce apoptosis in senescent endothelial cells and fibroblasts by inhibiting PI3K/AKT and BCL-2 signaling, without affecting non-senescent cells. Quercetin showed more robust senolytic activity when administered in combination with dasatinib, a tyrosine kinase inhibitor and an apoptosis inducer [207]. In AD models, dasatinib along with quercetin (D + Q) reduced senescent oligodendrocyte progenitor cells (OPC) and tau hyperphosphorylation and restore synaptic density and improve CBF [206,208]. D + Q has also been shown to eliminate senescent cells in vascular smooth muscle cells by inducing apoptosis. Chromatin architecture in surviving cells reversed back to a more youthful-like state following D + Q treatment [77]. D + Q was also tested on atherosclerotic mice and was demonstrated to reduce aortic plaque calcification and improve vascular function by making the arteries less rupture prone [205]. This shows the promise of quercetin, especially in combination with dasatinib, as a multitarget therapeutic that can simultaneously address neuronal degeneration and vascular dysfunction, making the combination a compelling candidate for MD treatment.

5.2.2. Xanthohumol (XN)

XN is a prenylated flavonoid found in hops and beer, known for its potent antioxidant, anti-inflammatory, and neuroprotective properties. XN’s ability to modulate Aβ plaques, tau pathology, and vascular dysfunction makes it a promising candidate for addressing the comorbid effects of AD and VaD [97,209].

XN exerts its potent antioxidant effects through both direct scavenging of ROS and modulation of endogenous defense mechanisms including the Nrf2 pathway. In vitro studies demonstrate that XN has strong total oxygen radical absorbance capacity (ORAC), indicating its strong ability to scavenge free radicals and protect cells against oxidative damage [210]. In addition, XN also exhibits high singlet oxygen absorbance capacity (SOAC), which reflects its effectiveness in quenching singlet oxygen, a highly reactive form of oxygen that plays a role in oxidative damage, particularly in lipid peroxidation and protein oxidation. In a study, PC12 cells, a cell line commonly used to study neuronal function, were treated with XN and its analogs, and the results indicated that these compounds robustly activated Nrf2. XN’s antioxidant abilities have also been tested using two primary assays, the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging test and the ferric-reducing antioxidant power (FRAP) assay. The FRAP assay is used to measure the reduction of ferric ions (Fe³⁺) to ferrous ions (Fe²⁺). XN successfully neutralized these radicals. Mice treated with XN showed reduced levels of MDA and increased activity of key antioxidant enzymes, including SOD and catalase [211].

XN performs its anti-inflammatory function by modulating key signaling pathways involved in cytokine production and immune cell activation, including NF-κB, nuclear factor of activated T cells (NF-AT), and activator protein-1 (AP-1) pathways. XN is a potent inhibitor of NF-κB in T cells, leading to the inhibition of T-cell proliferation and the reduction of Th1 cytokine production [93]. In macrophages and monocytes, XN downregulates MCP-1 and TNF-α in LPS-stimulated cells, limiting monocyte recruitment and overall inflammatory signaling [99]. XN also acts AP-1 and NF-AT, two transcription factors involved in immune regulation. Unlike its suppressive effect on NF-κB, XN enhances IL-2 production in T cells by upregulating AP-1 and NF-AT activity [92]. However, XN can also induce apoptosis in dendritic cells, leading to reduced antigen presentation and immune overactivation in inflammatory conditions [100]. A study examining how XN affected pro-survival pathways in the brains of mice with accelerated senescence found that XN triggered signaling pathways that control inflammation. In particular, XN decreased pro-inflammatory cytokines and other indicators of neuroinflammation [96].

XN has been reported to ameliorate Aβ pathology through a variety of pathways. XN may lower the burden of amyloid plaque and related neurodegeneration by encouraging neuronal differentiation and modification of BACE1 activity [212,213]. XN reduced Aβ formation and modulated degradation of APP and its amyloidogenic fragments, leading to a reduction in Aβ levels in APPswe cells [95]. In the APP/PS1 mouse model, XN treatment decreased Aβ deposition in the hippocampus and markedly enhanced memory performance [101].

A few studies have been conducted to examine XN’s effects on tau proteins. In vitro studies showed that XN reduced the aggregation of tau proteins. Specifically, thioflavin T fluorescence assays showed that XN significantly reduced tau fibrillization in a dose-dependent manner [104]. In HEK293 cells that overexpress tau protein, XN diminished GSK3β activity and increased PP2A activity, thereby decreasing tau hyperphosphorylation [95]. Further in vivo studies are needed to confirm these findings.

XN has shown promise in inhibiting vascular smooth muscle cell (VSMC) proliferation. In vitro studies revealed that XN inhibited platelet-derived growth factor-BB (PDGF-BB)-induced proliferation and migration of VSMCs [98]. XN was further tested in an animal model of arterial injury. XN treated mice had less neointima formation and tissue growth around the injury compared to control [98]. Other studies using ischemic rat models showed that treatment with XN prior to ischemic injury reduced infarct size. XN also reduces expression of pro-inflammatory proteins, such as TNF-α and iNOS in those mice [103]. These results suggest XN may have potential in reducing vascular dysfunction in VaD and MD.

5.2.3. Luteolin

Luteolin is another intriguing flavonoid that is found in various fruits, vegetables, and herbs, such as celery, parsley, and chamomile. It has gained attention for its potent antioxidant, anti-inflammatory, and neuroprotective effects, and is considered as a promising candidate for addressing the pathologies associated with AD and VaD [115,122].

In vitro studies have demonstrated that luteolin significantly reduces ROS levels in cells exposed to oxidative stress. It upregulates endogenous antioxidant enzymes such as SOD and catalase, and the antioxidant genes HO-1 and NAD(P)H quinone dehydrogenase 1 (NQO1) through activating Nfr2 [108,109]. Luteolin also protects cells from oxidative stress by reducing stress-induced apoptosis via suppressing the expression of caspase-3 and caspase-9 [108,109]. An in vivo study documented that luteolin treatment reduced MDA levels and increased SOD and catalase in mice [125].

Luteolin exerts anti-inflammatory effects by modulating key signaling pathways involved in cytokine production and immune cell activation. In LPS-stimulated RAW 264.7 macrophages, luteolin inhibited the degradation of IκBα and the phosphorylation of Akt [107]. In microglial BV-2 cells, luteolin reduced IL-6 expression via the inhibition of c-Jun N-terminal kinase (JNK) phosphorylation and AP-1 activation [114]. In animal studies, luteolin given prior to an LPS insult reduced plasma IL-6 levels and inhibited IL-6 expression in the hippocampus, but not the cortex of the mice [114]. Luteolin also reduced vascular permeability and lowered levels of TNF-α and IL-6 in LPS-treated mice [118]. These findings suggest that luteolin could reduce systemic and CNS inflammation.

Luteolin can also modulate Aβ pathology. Luteolin reduced Aβ-induced mitochondrial dysfunction and apoptosis by activating PPARγ in neurons in vitro [112]. Luteolin could modulate APP processing by targeting mucin-type O-glycosylation. O-glycosylation is a post-translational modification in which N-acetyl-α-galactosaminyltransferases (GalNAc-Ts) initiates the addition of O-linked N-acetyl galactosamine (GalNAc) residues to proteins like APP [105]. Luteolin has been found to inhibit GalNAc-T activity, leading to reduction of APP O-glycosylation and Aβ production [105]. In a mouse model that overexpresses human APP and undergoes TBI, luteolin treatment reduced Aβ plaque burden and the production of inflammatory cytokines [119]. Studies using the 3xtg mouse model found that luteolin treatment decreased dense Aβ plaque formation and improved spatial memory [117].

The effects of luteolin on tau pathology are understudied. One in vitro study showed that luteolin significantly decreased tau phosphorylation through reducing zinc-induced ROS production in SH-SY5Y neuroblastoma cells [126]. Studies using Tg2576 mice suggested that luteolin may reduce the accumulation of hyperphosphorylated tau [112].

Luteolin also has significant vascular protective effects and may act against VaD. Studies have shown that luteolin reduces PDGF-induced proliferation and migration of VSMCs by downregulating the extracellular signal-regulated kinase (ERK) and PI3K pathways [116]. Other studies found that luteolin induced NO production and caused arterial relaxation, which is essential for blood pressure regulation [120]. In a cell culture BBB model, endothelial cells were treated with Aβ_1–40 to induce an inflammatory response and then treated with luteolin. The results showed that luteolin reduced the expression of pro-inflammatory cytokines and helped maintain the BBB integrity [124]. Studies using in vivo models have further explored luteolin’s effects on vascular function in the brain. In a rat CCH model, administration of luteolin improved spatial memory, accompanied by suppression of inflammation in both the cerebral cortex and the hippocampus [110]. Other studies using similar animal models found that luteolin improved cognitive function in both MWM and object recognition testing, possibly by increasing PI3K/Akt phosphorylation, which prevents neuronal death in the hippocampus and cerebral cortex [111]. Luteolin also improved long term potentiation (LTP), an electrophysiological correlate of synaptic strengthening and memory formation, in CCH mice [123].

5.3. Alkaloids

Alkaloids are naturally occurring nitrogen-containing alkaline compounds [38]. These compounds have been studied for their pharmacological effects, including neuroprotective and anti-inflammatory properties [214]. Among them, berbamine hydrochloride and huperzine A are particularly noteworthy.

5.3.1. Berbamine Hydrochloride

Berbamine hydrochloride is a bisbenzylisoquinoline alkaloid derived from plants such as Berberis amurensis and Berberis aristata. Its anti-inflammatory and Aβ inhibition properties could make it a potential therapeutic candidate for AD, VaD and MD.

Berbamine hydrochloride has been reported to exert anti-inflammatory effects in some cancers and infectious diseases [128,130], but its effects on neuroinflammation and vascular inflammation are less well documented. Few studies have tested the effects of berbamine hydrochloride on AD pathology and suggest that it could modulate Aβ aggregation and toxicity. For example, in neuroblastoma cells exposed to Aβ, berbamine hydrochloride reduced Aβ42 aggregation by disrupting the formation of Aβ fibrils [129].

Limited in vivo studies using AD mouse models have also suggested berbamine hydrochloride’s efficacy. Berbamine hydrochloride improved memory and learning in 3 different AD mouse models accompanied by reduced pyramidal cell lesion on hippocampal slices [127].

5.3.2. Huperzine A

Huperzine A is derived from the Chinese club moss Huperzia serrata. It is a licensed anti-AD drug in China and is best known for its potent AChE inhibitory activity [19]. However, Huperzine A’s therapeutic potential extends beyond AChE inhibition.

In vitro studies indicated that inhibition of AChE by Huperzine A leads to the accumulation of acetylcholine (Ach), which activates nicotinic acetylcholine receptors (nAChRs). The activation of nAChRs was found to inhibit the NF-kB pathway, reducing the expression of pro-inflammatory cytokines and preventing the uncontrolled activation of astrocytes and microglia [138].

Proteomic studies reveal that neuroblastoma cells that were pretreated with Huperzine A were protected from Aβ oligomer-induced cell death by downregulating p53 (Trp53) expression [131]. In addition, Huperzine A could shift APP processing towards the non-amyloidogenic pathway by upregulating the activity of α-secretase and downregulating BACE1 and Presenilin 1 (PS1). Huperzine A upregulates ADAM10, an α-secretase that promotes non-amyloidogenic APP processing, leading to a reduction in Aβ levels. Subsequent work identified direct interaction between Huperzine A and BACE1, suggesting that its inhibitory effects of amyloidogenesis is through direct inhibition of the enzyme [137]. Huperzine could also modulate tau phosphorylation through the modulation of GSK3 [137].

In in vivo studies, Huperzine A has been reported to affect the Wnt/β-catenin signaling pathway. Activation of the Wnt ligands trigger a cascade that stabilizes β-catenin, which allows it to translocate to the nucleus and activate the transcription of genes involved in cellular survival and differentiation. This signaling pathway is especially important in APP processing. Wnt/β-catenin signaling enhances α-secretase activity, promoting non-amyloidogenic APP cleavage, which reduces Aβ production [132]. Indeed, Huperzine A reduced Aβ plaque formation in both the hippocampus and cortex in APP/PS1 transgenic mice [132] and enhanced spatial learning and memory in rats [135].

Recent studies have tested the vascular effects of Huperzine A. In vitro studies have shown that Huperzine A improved the survival of and reduced ROS production in glial cells that underwent oxygen-glucose deprivation [136]. This implies that Huperzine A provides protective effects to neuronal cells to reduce damage and cell loss during ischemia. In vivo studies have tested Huperzine A’s effects on cerebral hypoperfusion. Huperzine A reduced pro-inflammatory cytokines and improved cognitive performance in rats with cerebral hypoperfusion [133]. In addition, Huperzine A restored cerebral blood flow to areas that had reduced blood flow, and reduced infarcts sizes in the cortex and the striatum in animals [141]. These results suggest that Huperzine A would be effective for MD.

5.4. Other Compounds

5.4.1. N-Acetylcysteine

N-acetylcysteine (NAC) is an acetylated cysteine compound and is a nutritional supplement. It is a glutathione precursor and shows antioxidant and anti-inflammatory activities. It also has well-documented neuroprotective potential [146].

NAC primarily functions as a precursor to cysteine, which is often the rate-limiting substrate for glutathione synthesis. NAC supplementation can replenish glutathione in the context of oxidative stress [142]. Glutathione peroxidases can reduce hydroperoxides, and glutathione-S-transferases can catalyze conjugation processes as part of cellular defense against oxidative stress [215]. NAC can reduce peroxynitrite-induced hemolysis by scavenging reactive species and preventing oxidative damage to erythrocyte membranes. NAC’s protective effects are attributed to its ability to scavenge and neutralize peroxynitrite and restore redox balance [216]. In an oxidative muscle damage animal models, NAC reduced MDA and protein carbonyls, and improved muscle function by decreasing the formation of structural protein cores [217]. In bile duct ligation (BDL) rats, NAC was able to reduce lipid peroxidation and ameliorate spatial memory and motor coordination deficits [218].

NAC has demonstrated anti-inflammatory effects in various disease models. In vitro studies using LPS treated macrophages showed that NAC suppresses inflammatory cytokines such as TNF-α, IL-1β, and IL-6 by suppressing NF-κB signaling [145]. Indeed, NAC was observed to directly inhibits IκB kinases [144]. NAC has also demonstrated to affect NO production. Studies using macrophages and glial cells demonstrated that NAC effectively inhibited NO production by suppressing the expression of iNOS [219]. These mechanisms are relevant in neuroinflammation, as excessive NO production contributes to oxidative stress and neuronal damage.

NAC has been investigated directly for its protective effects against AD pathology. NAC can mitigate Aβ toxicity, reduce oxidative stress, and modulate apoptotic pathways associated with neurodegeneration [146]. NAC prevented the Aβ toxicity by stimulating p35/cyclin-dependent kinase 5 (Cdk5) in cultured cortical neurons, and protected neurons from Aβ-induced cell death through inhibiting the Mixed-Lineage Kinase 3 (MLK3)-Mitogen-Activated Protein Kinase Kinase 7 (MKK7)-c-Jun N-terminal Kinase 3 (JNK3) signaling cascade, a pathway that plays a critical role in stress-induced neuronal apoptosis [220,221]. NAC could also promote neuron survival via activating the Ras pathway [148]. In in vivo studies, NAC administration in APP/PS1 mice reduced oxidative stress markers and enhanced the activity of key antioxidant enzymes such as SOD and glutathione peroxidase [222]. NAC pretreatment improved cognitive function in mice intracerebroventricularly injected with Aβ [223].

NAC has demonstrated vascular protective effects in animal models of ischemia–reperfusion injury, stroke, and cerebral ischemia, which is mainly attributable to its antioxidant properties [146]. In a rat model of focal cerebral ischemia, NAC administration reduced the infarct size and improved neurological outcomes [224]. Studies using ischemic stroke models reported that NAC treatment reduced ischemia–reperfusion injury in mice by decreasing inflammatory markers and preserving endothelial integrity [147]. Post-ischemic NAC treatment significantly reduced brain injury and neuroinflammation by decreasing pro-inflammatory cytokines [225]. NAC’s vascular benefits also extend to BBB protection. NAC administration reduced infarct size and BBB disruption while enhancing cerebral blood flow [143]. These findings underscore NAC’s role in vascular protection and its potential therapeutic application in VaD and MD.

5.4.2. Octyl Gallate

Octyl gallate (OG) is a synthetic ester of gallic acid widely used as a food preservative. It acts as an antioxidant due to its ability to scavenge free radicals and inhibit lipid peroxidation [151]. Recent studies have demonstrated that OG may also harbor neuroprotective properties.

OG improves cell viability via reducing intracellular ROS levels and GSH levels [226]. OG was also observed to significantly inhibit the production of hypochlorous acid (HOCl), a potent oxidant involved in the inflammatory response. The hydrophobicity of OG facilitates its cellular interaction and membrane penetration [227].

OG exerts anti-inflammatory activity by modulating the NLRP3 inflammasome and NF-κB pathways. OG binds to leucine-rich repeat (LRR) domain of NLRP3 and inhibits its activation and downstream inflammatory signaling [152]. NLRP3 activation is especially important in the context of AD, as NLRP3 activation in microglia is associated with enhanced Aβ aggregation, tau hyperphosphorylation, and cognitive decline [172]. In addition, OG inhibits the phosphorylation of p65, thereby keeping the NF-κB signaling pathway inactive [228]. In vivo studies using acute lung injury (ALI) mouse models have documented that OG treatment decreased lung inflammation [149].

OG has also been observed to exhibit neuroprotective properties, particularly in modulating Aβ pathology. A primary mechanism for this effect is through its ability to promote the anti-amyloidogenic processing of APP. OG upregulates ADAM10 expression, shifting APP processing to produce sAPPα [153]. It was reported that OG in combination with ferulic acid significantly improves cognitive function in mice by reducing both soluble and insoluble Aβ plaques in the cortex and hippocampus [150].

5.4.3. Britannin

Britannin is a natural sesquiterpene lactone extracted from Inula japonica Thunb, which is used in Traditional Chinese medicine to treat coughs and reduce phlegm. Recent studies suggest that Britannin has robust anti-inflammatory activity and possesses neuroprotective properties.

Britannin is thought to exert its anti-inflammatory effects via inhibition of NF-κB activation. Britannin suppresses NF-κB p65, thereby reduces the transcription of pro-inflammatory cytokines, and upregulates PPARγ, a nuclear receptor that regulates inflammation, cell proliferation, and apoptosis [154]. In addition, Britannin downregulates iNOS and COX-2 expression, leading to inhibition of NO and prostaglandin E2 (PGE2) production [229]. Moreover, Britannin was found to directly inhibit NLRP3 activation in vitro and in vivo [155]. In addition, Britannin was found to be able to inhibit AChE, showcasing its potential neuroprotective properties [230]. These results suggest that Britannin could be used for the prevention and treatment of AD, VaD, and MD by virtue of its strong anti-inflammatory and AChE inhibitory activities.

5.4.4. Sulforaphane

Sulforaphane (SFN) is an isothiocyanate derived from cruciferous vegetables, such as cabbage, broccoli, cauliflower, and brussels sprouts. This compound exhibits antioxidant, ant-inflammatory, and anti-apoptotic effects, making it a promising candidate for potential treatment for neurodegenerative diseases [162].

SFN is a potent activator of the Nrf2 antioxidant pathway. It induces the expression of HO-1 and glutathione-related enzymes, thereby reducing oxidative stress in neuronal and vascular cells [163]. In vitro, SFN has been found to attenuate neuronal cell death caused by Aβ-induced oxidation. In rodent models, SFN significantly reduced oxidative stress markers in the hippocampus, [159] and reduced neuronal apoptosis and enhanced spatial learning and memory [157]. These findings demonstrate that SFN directly counteracts oxidative damage triggered by Aβ. BBB damage occurs after oxidative stress, [231] and SFN could reduce oxidative damage and preserve BBB integrity after brain injury via enhancing Nrf2-driven gene expression [232]. Nrf2–ARE activation also attenuated oxidative stress and improved outcomes after experimental subarachnoid hemorrhage [233].

SFN also displays direct effects on Aβ and tau. In PS1 transgenic mice, SFN treatment decreased expression of BACE1 and PS-1, leading to inhibition of Aβ oligomer generation and improvement in spatial learning and memory [156]. Studies using 3xtg mice showed that oral SFN administration reduced both monomeric and polymeric forms of Aβ in the hippocampus [159]. In line with these studies, SFN was found not only inhibit the production of Aβ but also make it less prone to aggregation [160].

Fewer studies have focused on SFN effects on VaD. In rodents subjected to focal cerebral ischemia, SFN treatment resulted in significantly reduced infarct volume [164]. Similar results were observed in a hypoxic–ischemic injury model, wherein SFN provided neuroprotection through induction of Nrf2 [161].

5.5. Clinical Studies Relevant to MD Using Individual Natural Compounds

Clinical evidence for the effectiveness of natural compounds in the treatment of MD is still limited and mostly indirect. The best-studied agent is the standardized Ginkgo biloba extract EGb 761. Multiple randomized trials that enrolled patients with AD, VaD and MD together report modest but consistent benefits of EGb 761 (120–240 mg/day) on cognition, neuropsychiatric symptoms and activities of daily living over 22–52 weeks, with good tolerability, although some large prevention trials have been negative [234]. This data has led some researchers to consider EGb 761 an option when conventional antidementia drugs are poorly tolerated or insufficient, including for MD [235]. It must be noted that EGb761 is a mixture of multiple compounds, not a single purified compound. Huperzine A has been evaluated in several small trials in AD and VaD; meta-analyses indicate short-term improvements in global cognition and daily functioning, but overall study quality is low, follow-up is brief, and almost no trials stratify outcomes specifically for MD [139]. Other phytochemicals such as curcumin, resveratrol and ginsenosides have entered phase II trials in AD or prodromal states but results so far are inconclusive or show only subtle effects [236]. Recent narrative and clinical-trial reviews of curcumin and sulforaphane reinforce this translational gap, documenting biological activity, favorable safety, and modulation of inflammatory and redox pathways in human studies, but none of these trials specifically evaluate mixed AD–VaD cohorts [237,238,239].

Limited human pharmacokinetic (PK) and safety studies of natural compounds such as curcumin, resveratrol, and quercetin show acceptable short-term tolerability but significant limitations in exposure, variability, and interpretation. A major challenge for many phytochemicals is poor oral bioavailability. For example, curcumin exhibits very low systemic absorption and rapid metabolism, leading to low plasma concentrations of parent compound [240]. This has prompted development of multiple enhanced formulations. Similarly, quercetin also shows very low bioavailability (<1%) in humans [241]. Physiological variability due to diet, genetics, microbiome, age, and disease state further adds to inconsistent PK profiles among individuals, and few trials systematically explore these modifiers. Many clinical studies stop at plasma measurements without assessing target-site exposure (e.g., brain for neurodegenerative indications) or linking concentrations to pharmacodynamic biomarkers, which limits rational dose selection for efficacy. Safety data of natural compounds are often limited to short durations and small sample sizes, adequately characterizing common mild adverse events (e.g., gastrointestinal discomfort), but rare or long-term harms, effects in vulnerable populations (e.g., older adults), and compound–drug interactions are less defined. This is an important issue to address. For example, curcumin [242] and resveratrol [243] are known to interfere with coagulation system; therefore, caution must be taken when they are used by patients who also take antiplatelet/anticoagulant medicines. Finally, heterogeneous formulations and product quality issues make cross-study synthesis challenging and reduce confidence in translating PK/safety findings into clinical recommendations for nutraceutical compounds.

6. Concluding Remarks

The evidence presented in this review highlights the potential of certain diets, specific foods, and individual natural compounds in mitigating the comorbid effects of AD and VaD. Dietary patterns such as the MeDi and MIND diets have consistently been associated with cognitive benefits, reducing the risk of dementia. Individual dietary components such as olive oil and flavonoid-rich foods further support brain health, with studies demonstrating their ability to reduce cognitive decline, improve BBB integrity, and enhance neurovascular function.

Many natural compounds have shown neuroprotective effects through diverse mechanisms, including antioxidant, anti-inflammatory, Aβ/tau modifying, and vascular protective properties. These bioactive compounds not only reduce hallmark features of AD and VaD but also improve synaptic plasticity and neurovascular function. However, despite promising in vitro and in vivo evidence, clinical translation remains limited due to the general poor water solubility and low bioavailability, as well as the lack of detailed toxicology and efficacy studies of these nutraceutical compounds, especially in humans.

In conclusion, while dietary interventions and natural compounds represent a promising, convenient, and safe approach to combating dementia, future research should focus on long-term human trials, mechanistic studies in humans, and synergistic effects of combined interventions. Understanding how these compounds interact within the neurovascular unit and their impact on MD pathology will be critical for developing targeted strategies. Given the increasing burden of MD, integrating dietary and nutraceutical approaches into dementia prevention and treatment plans may offer a cost-effective and accessible means of preserving cognitive function and delaying disease progression.