Importanţa factorilor de risc neuropsihiatrici ai bolii Alzheimer în stabilirea planurilor alimentare

Introduction

Alzheimer’s disease is becoming an increasingly significant public health issue worldwide, as it is the most common neurodegenerative disease. Numerous therapeutic strategies have been investigated in recent decades; however, curative treatment is not yet available. Currently, prevention is paramount, which can be achieved through neurosupportive nutrition, physical activity and a stress-free lifestyle⁽¹⁾. The pathogenesis of Alzheimer’s disease is driven by various pathophysiological features, including the formation of tau protein aggregates and Aβ plaques, neuroinflammation, oxidative stress, synaptic dysfunction and metabolic changes. These pathophysiological alterations manifest in cognitive decline⁽²⁾.

Among the psychosomatic and neuropsychiatric risk factors for Alzheimer’s disease, depression can also be mentioned. Depression is characterized by a depressed mood, a reluctance to engage in daily activities and a lack of motivation. According to statistics, it afflicts more than 280 million people worldwide, accounting for approximately 3.5% of the global population. Depression occurs in all age groups⁽³⁾. According to the literature, the precise causal relationship between Alzheimer’s disease and depression remains controversial, as it is unclear whether depression plays a role in the pathogenesis of the disease as a risk factor, an early neurodegenerative symptom, or a psychological reaction occurring due to cognitive decline⁽⁴⁾. Growing evidence suggests that depression acts as a risk factor in the development of cognitive decline. Hudon et al. (2020) investigated how four neuropsychiatric symptoms, including depression, influenced the onset of cognitive decline. Over an average follow-up period of 4.2 years, they found that neuropsychiatric symptoms demonstrated a significant progression toward cognitive decline⁽⁵⁾.

Depression manifesting up to 25 years earlier can also be linked to the subsequent onset of Alzheimer’s disease⁽⁶⁾. The neuropsychological symptoms associated with depression, such as anxiety, irritability, aggression and sleep disturbances, frequently manifest in patients with Alzheimer’s disease as well. Examining the relationship between depression and Alzheimer’s disease from a neurobiological perspective reveals that, underlying, both conditions are identical processes. Disruption of neurotransmitter systems – serotonin (5-HT), norepinephrine (NE), dopamine (DA) and acetylcholine (ACh) pathways – can be observed in both conditions. Elevated levels of proinflammatory cytokines associated with neuroinflammation (IL-1β, IL-6, TNF-α) play a crucial role in neuronal damage. Hypothalamic-pituitary-adrenal (HPA) axis dysfunction (elevated cortisol levels) is present in both cases – potentially exacerbating cognitive decline further –, and a reduction in brain-derived neurotrophic factor (BDNF) levels is also demonstrable⁽⁷⁾. Along with the decrease in BDNF levels, PSD-95 levels also decline in the prefrontal cortex and the hippocampus. PSD-95 is a protein associated with synaptic maturation⁽⁸⁾.

The lack of neuroplasticity, particularly in the hippocampus, further exacerbates the detrimental link between cognitive decline and depression⁽⁹⁾. The link between depression and cognitive decline is also reinforced by the presence of elevated reactive oxygen species (ROS)⁽¹⁰⁾. Elevated levels of neurofilament light chain (NfL) indicate a neurodegenerative disorder. NfL levels are associated with both depressive symptoms and cognitive performance. Elevated NfL levels can be linked to a decline in cognitive performance⁽⁶⁾.

Anxiety, as a psychosomatic and neuropsychiatric symptom, also acts as a significant risk factor in the development of Alzheimer’s disease. Anxiety is a state that facilitates the recognition of potential threats in the environment and involves changes in the individual’s state, behavior and physiology. The substantial expansion of the prefrontal cortex in the human brain enhances the chances of survival; however, in today’s modern environment, complex and abnormal processes can lead to the emergence of anxiety disorders. Anxiety disorders can manifest relatively early in an individual’s life and rank among the most common psychiatric conditions⁽¹¹⁾. Individuals experiencing chronic anxiety throughout their lives have a 48% higher risk of developing Alzheimer’s disease, and in their case, mild cognitive impairment (MCI) progresses to Alzheimer’s disease at a faster rate. Stressors – that is, stimuli perceived as stress – trigger the activation of the HPA axis. The primary glucocorticoids released from the adrenal cortex are termed cortisol in humans (and corticosterone in rodents).

Through negative feedback, glucocorticoids can regulate HPA axis activation in the pituitary gland as well as in various brain regions, including the hippocampus, the frontal cortex and the hypothalamus. In patients with Alzheimer’s disease, abnormalities can be observed in stress systems, with a decrease in the number of CRF-immunoreactive cells and an increased expression of CRF receptors. Elevated cortisol levels can be detected as early as the MCI stage, suggesting that an enhanced stress response accelerates the development of Alzheimer’s disease⁽¹²⁾.

The lack of adequate and restful sleep also serves as a risk factor in the development of Alzheimer’s disease. Growing evidence suggests that a bidirectional relationship exists between sleep disturbances and Alzheimer’s disease⁽¹³⁾. Interactions between brain regions associated with memory and cognitive functions regulate the sleep-wake cycle. Sleep patterns generally change over the course of life. This can also imply that, with advancing age, difficulty falling asleep, multiple sleep fragmentations and a reduction in the time spent in the REM phase may occur⁽¹⁴⁾.

Levels of amyloid-beta (Aβ) plaques found in the interstitial fluid (ISF) and cerebrospinal fluid (CSF) are regulated by the sleep-wake cycle in both an acute and chronic manner. The accumulation of Aβ peptides also contributes to the production of reactive oxygen species (ROS)⁽¹⁰⁾. The neuronal cell death associated with Alzheimer’s disease is caused not by Aβ plaques, but by the accumulation of tau protein⁽¹⁵⁾. Tau is a protein that stabilizes microtubules through its interaction with tubulin. When proteins undergo hyperphosphorylation, they lose their binding capacity and detach from microtubules, causing the microtubules to disintegrate, while the tau proteins begin to aggregate with one another and form pathological protein tangles. Lacking its transport system, the cell undergoes cell death⁽¹⁶⁾.

In their study, Holth et al. (2019)⁽¹⁵⁾ investigated individuals aged between 30 and 60 years old, using lumbar catheters. The study revealed that, after a single night of sleep deprivation, the amount of Aβ in the CSF increased by 30%, whereas tau levels rose to an even greater extent, by more than 50%. In the same study, ISF tau levels in mice were low during the day, when mice spent 60% of their time sleeping; however, at night, when mice were awake 70% of the time, tau levels doubled. When mice were awakened during their daytime sleep period, tau protein levels measured in the ISF likewise doubled. The propagation and toxicity of tau are mediated by microglia, a process driven by NF-κB signaling⁽¹⁷⁾. After sleep deprivation, levels of the protein known as synuclein were also increased⁽¹⁵⁾. Alzheimer’s disease is accompanied by cholinergic degeneration alongside a reduction in the REM phase regulated by acetylcholine (ACh) tone, which can be attributed to the accumulation of tau protein. Elevated concentrations of orexin can also be detected in the cerebrospinal fluid, even in the early stages of the disease⁽¹³⁾.

Together, the orexin and acetylcholine systems play a key role in maintaining the balance between sleep and wakefulness. The body attempts to keep the brain awake through hyperactivation of the orexin system when cholinergic degeneration is severely advanced. This process leads to the disruption of the circadian rhythm⁽¹⁸⁾.

Materials and method

The PubMed database was analyzed for the period 2020-2026. We used as keywords “neuropsychiatric risk factors of Alzheimer’s disease” and “establishing dietary plans”, and we analyzed review and systematic review type articles. Three other criteria used were age (over 18 years old), articles to be free full text and published in English. We found and evaluated 40 specific articles.

Results

To understand the importance of diet in the prevention of Alzheimer’s disease, we must understand how the disease develops and how this process relates to nutrients.

Role of antioxidants

Oxidative stress contributes to the endogenous oxidative damage of lipids, proteins and DNA structure. Oxidative stress is an underlying cause of aging processes and chronic diseases, including the development of Alzheimer’s disease. Oxidative stress and the formation of beta-amyloid plaques, the characteristics of the disease, are closely linked. To reduce oxidative stress, adequate antioxidant intake must be ensured. Adequate intake of vitamins C, D and E has been proven to reduce the risk of developing the disease. Daily supplementation with 2000 IU of α-tocopherol also slows disease progression⁽¹⁹⁾. Curcumin, derived from Curcuma longa, also possesses potent antioxidant properties, as shown in Table 1.

The antioxidant role of caffeine is significant; however, to achieve the daily intake required to exert an antioxidant effect, 400 milligrams of caffeine – equivalent to three to five cups of coffee – is needed. In some individuals, this amount may induce unpleasant side effects, such as tremors, palpitations and arrhythmias⁽²⁰⁾.

Among plant-derived antioxidants, pterostilbene found in blueberries shares a structural similarity to resveratrol; however, the bioavailability rate of pterostilbene is considerably higher (80%)⁽²¹⁾. Antioxidant plants also include ashwagandha (Withania somnifera), cat’s claw (Uncaria tomentosa), Ginkgo biloba and saffron (Crocus sativus)⁽²²⁾.

TNF-α – tumor necrosis factor-alpha; Il-6 – interleukin-6; IL-1β – interleukin 1 beta; ROS – reactive oxygen species; MDA – malondialdehyde, a widely recognized marker of lipid peroxidation; AChe – choline acetyltransferase activity; NO – nitric oxide level; SOD – superoxide dismutase activity; CAT – catalase activity;
PC – protein carbonyl; 4-HNE – 4-hydroxynonenal; NFTs – neurofibrillary tangles; BDNF – brain-derived neurotrophic factor; PSD-95 – postsynaptic density protein 95

Vitamins B9 and B12 directly affect blood levels of homocysteine (Hcy). Elevated Hcy levels constitute a risk factor for Alzheimer’s disease. Deficiencies in vitamins B9 and B12 cause the conversion of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH), which directly degrades into Hcy (hemocysteine). High Hcy levels result in central nervous system damage, thereby contributing to Alzheimer’s disease. Furthermore, elevated levels of Hcy promote the production of proinflammatory cytokines (TNF-α, IL-6). Coadministration of vitamins B9 and B12 demonstrated a positive therapeutic effect in patients living with Alzheimer’s disease. These vitamins reduced TNF-α levels as well as IL-6 levels in the cerebrospinal fluid (CSF)⁽²³⁾. Intake of NAD+ precursors, such as nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), also provided numerous benefits for the nervous system. Although data regarding the NMN and NR content of food items are currently limited, their levels are detectable in vegetables, meats and dairy products. Broccoli, avocados and edamame possess higher levels of NAD+ precursors.

The roles of NMN and NR in the prevention of Alzheimer’s disease are essential. In addition to enhancing aerobic capacity, NMN exerts cardiovascular protective effects, reduces oxidative stress and inhibits inflammation. Preclinical studies indicate that NR confers favorable effects on synaptic plasticity, learning, memory and motor functions, while also reducing neuroinflammation, hippocampal neuronal apoptosis, tau levels and DNA damage, as well as enhancing neurogenesis⁽²⁴⁾.

The group of polyunsaturated omega-3 fatty acids includes DHA, EPA and ALA. High plasma levels of DHA and EPA, as well as a lower omega-6 to omega-3 ratio, are associated with a reduced risk of developing Alzheimer’s disease. MRI examinations have shown that patients with low levels of DHA and EPA exhibit smaller total brain volume and reduced abstract reasoning. A significant improvement in cognitive functions was observed in malnourished children following dietary supplementation with DHA. Similarly, in adults, an increase in gray matter volume in the corticolimbic region (the area responsible for regulating fear and stress) was observed after PUFA dietary supplementation. EPA and DHA are essential components of cell membranes in the brain, as they are incorporated into membrane phospholipids. The three-dimensional structure of these polyunsaturated fatty acids reduces the thickness of the cell membrane bilayer, thereby enhancing its permeability. DHA increases membrane fluidity, whereas EPA acts as a messenger within central nervous system cells⁽²⁵⁾.

Various preclinical studies have demonstrated that DHA reduces Aβ production, exerts beneficial effects on cerebral blood flow and decreases the presence of neuroinflammatory markers. Dietary supplementation with DHA and EPA during the late stages of the disease reduced Aβ production; however, no significant improvement occurred in the patients’ cognitive functions. Timely intervention is therefore crucial, highlighting the need to place strong emphasis on prevention⁽¹⁾.

Role of probiotics

Probiotics also play a prominent role in the prevention of psychiatric and neurodegenerative diseases. The bidirectional communication between the enteric nervous system (ENS) and the central nervous system (CNS) is referred to as the gut-brain axis (GBA). The GBA establishes a link between the emotional and cognitive functions of the brain and peripheral intestinal functions. Dysbiosis of the gut microbiome is associated with depression, anxiety and the development of Alzheimer’s disease⁽²⁶⁾.

Probiotics directly influence the brain’s biochemical components, such as serotonin, γ-aminobutyric acid (GABA) and dopamine. They may also delay mild cognitive impairment by attenuating inflammatory responses and oxidative stress. In studies investigating the association between Alzheimer’s disease and probiotics, the most frequently used probiotic microorganisms belong to the genera Lactobacillus and Bifidobacterium. The effects of species such as Lactococcus, Streptococcus, Enterococcus, Bacillus clausii and Enterococcus faecium SF68 have also been investigated within probiotics, as well as the strain Escherichia coli Nissle 1917.

The interaction between the gut microbiota and the expression of central immune cells plays an essential role in the development of Alzheimer’s disease and other neuropsychiatric symptoms. Adverse alterations in the gut microbiota, alongside increased intestinal permeability, can cause the activation of proinflammatory cytokines, leading to the translocation of Aβ oligomers from the gut to the brain.

Numerous studies report a relationship between the composition of the gut microbiota and the deposition of Aβ and tau proteins in the brain. A potential correlation exists between the pathogenic Helicobacter pylori and the hyperphosphorylation of tau proteins⁽²⁷⁾.

Table 1 presents the impact of dietary interventions upon Alzheimer’s disease-related neuropsychiatric biomarkers, based on articles evaluated.

Discussion

A nutrient-deficient diet represents a major risk factor in the development of neuropsychiatric symptoms, which can later lead to the development of Alzheimer’s disease. Therefore, a proper, nutrient-dense diet is one of the primary aspects of disease prevention. Neurotransmitters such as serotonin, dopamine and norepinephrine play key roles in regulating appetite, mood and cognitive functions. Various nutrients – including amino acids found in meats, fish, dairy products and seeds (tryptophan, phenylalanine, histidine), B vitamins, choline and glutamic acid – contribute to the synthesis of these neurotransmitters. Depression and anxiety can be reduced through the intake of marine-derived omega-3 fatty acids, as the fatty acids present in omega-3 regulate dopaminergic and serotonergic neurotransmission⁽³⁹⁾.

The data presented in Table 1 outline information primarily based on preclinical research. To understand the significance of diet in the prevention of Alzheimer’s disease, attention must also be given to the bioavailability of food components. The bioavailability of curcumin, known as a constituent of Curcuma longa, is relatively low, which is mainly attributable to hepatic metabolism. To overcome this limitation, nanoemulsions, liposomal encapsulation and polymer-based nanoparticle systems have been developed. Cyclodextrin complexes and the alkaloid derived from Piper nigrum also contribute significantly to the bioavailability of curcumin. Clinical studies have shown that turmeric also contributes to the inhibition of NF-κB signaling⁽²⁸⁾, which plays a role in the formation of tau proteins⁽¹⁷⁾.

Extracts of Ganoderma lucidum exhibit sedative and memory-enhancing effects. This medicinal mushroom has recently attracted considerable attention in the prevention and treatment of neurodegenerative diseases. The bioavailability of G. lucidum likewise presents a challenge; however, RGLS (Removed G. Lucidum sporoderm) is a processed product that undergoes a complex manufacturing procedure, resulting in a high polysaccharide and triterpenoid content that enables more efficient utilization by the organism⁽³⁰⁾. The bioavailability of G. lucidum can also be increased through fermentation with Lactobacillus plantarum, as the polysaccharide molecules undergo size reduction during fermentation, thereby facilitating easier absorption⁽³¹⁾.

Inulin constitutes a group of naturally occurring complex carbohydrates present in various plant sources, such as wheat, onions and chicory. Due to the absence of the enzyme inulinase in the human body, it cannot be digested in the upper gastrointestinal tract, being partially fermented by the colonic microbiota. As inulin primarily affects the composition of the gut microbiome, it subsequently influences cognitive functions. Due to its sweet taste, it can be easily incorporated into the daily diet. The recommended daily intake of inulin for a 60-kg adult is 48.8 g/day according to the body surface area conversion formula applied by the FDA (mouse mg/kg divided by 12.3). While this figure is valid from a theoretical perspective, the recommended intake in clinical practice ranges between 5 and 15 g per day⁽³⁴⁾.

Although resveratrol is a popular antioxidant and polyphenolic compound, pterostilbene – found in blueberries (genus Vaccinium) – has a chemical structure similar to that of resveratrol; however, the bioavailability rate of pterostilbene is markedly higher at 80%, compared to only 20% for resveratrol⁽³⁸⁾. Pterostilbene is found not only in blueberries but also in relatively higher amounts in the berries of the Indian kino tree (Pterocarpus marsupium). Fresh blueberries contain 9.9 to 15.1 mg/kg of pterostilbene⁽⁴⁰⁾.

From the perspective of prevention, physical activity is essential, as it helps prevent cognitive decline. The beneficial effects of exercise are clearly demonstrated in studies conducted on animal models as well as in humans. In patients predisposed to Alzheimer’s disease or struggling with mild cognitive impairment (MCI), moderate yet regular exercise yielded clear improvements in both biochemical markers and cognitive functions. Regular physical activity – including gardening and artistic activities – not only improved cognitive functions but also reduced symptoms of depression. In patients with established disease, performing one-hour aerobic exercise sessions twice weekly improved problem-solving ability, elevated brain-derived neurotrophic factor (BDNF) levels and reduced the levels of neuroinflammatory markers and reactive oxygen species (ROS)⁽²⁾.

Conclusions

The impact of diet on neuropsychiatric symptoms is a relatively challenging topic to investigate, as researchers must predominantly rely on questionnaires and survey-based methodologies. Further research is needed regarding the bioavailability of active components found in food and the incorporation of these components into the diet for neuroprotective purposes. In the prevention of Alzheimer’s disease, not only does a diet rich in neuroprotective nutrients play a role, but physical activity and a low-stress lifestyle are also essential. By striving to avoid the nutrient-deficient diet typical of modern times, engaging in regular physical exercise and actively addressing stress management and prevention, not only depression, anxiety and sleep disorders are preventable symptoms, but also the onset of other chronic ilnesses, including Alzheimer’s disease.

Conflict of interests: none declared.

Financial support: none declared.

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