Toward Prevention and Reduction of Alzheimer’s Disease

Abstract

Different investigations lead to the urgent need to generate validated clinical protocols as a tool for medical doctors to orientate patients under risk for a preventive approach to control Alzheimer’s disease. Moreover, there is consensus that the combined effects of risk factors for the disease can be modified according to lifestyle, thus controlling at least 40% of cases. The other fraction of cases are derived from candidate genes and epigenetic components as a relevant factor in AD pathogenesis. At this point, it appears to be of critical relevance the search for molecular biomarkers that may provide information on probable pathological events and alert about early detectable risks to prevent symptomatic events of the disease. These precocious detection markers will then allow early interventions of non-symptomatic subjects at risk. Here, we summarize the status and potential avenues of prevention and highlight the usefulness of biological and reliable markers for AD.

Keywords

Alzheimer’s disease global prevention effort incidence molecular biomarkers prevention protocols risk factors tau protein

INTRODUCTION

The elderly population in the world today has grown over the last 50 years as a consequence of significant technological and scientific advances that allow people to extend their life expectancy. According to World Health Organization data, it is estimated that by 2050 more than 400 million people will reach the age of 80. Life extension has contributed to the appearance of diseases that are related to old age and for which there are no cures, including Alzheimer’s disease (AD) [1, 2]. This disease has turned into a global burden, as 1 of that 1 out of 3 people will die from AD or other kind of dementia [1]. Also, the costs in the United States derived from AD in 2023 are estimated to be $345 billion USD [1].

AD is characterized in a molecular level by two manly pathological features: neurofibrillary tangles (NFTs), formed by aggregations of hyperphosphorylated tau protein and amyloid plaques that are composed of accumulations of an abnormally processed peptide denominated as Aβ peptide [3]. At a clinical level, this disease mainly affects the memory and cognition of patients, commonly presenting at its earliest stages as an impairment of episodic memory that becomes more complex and limiting for the patient as the disease progresses [3].

At present, the social construct of old age is one of fear, loneliness and other discouraging feelings. Making the idea of becoming older something negative rather than positive. However, as will be revised further, there is still hope in the AD prevention and the measures that can be taken with the information given by an early diagnosis [4]. But the currently used tests only allow its identification at advanced stages of the disease, which contributes to a perception of AD that involves a series of negative aspects for the person, such as the loss of independence, driving privileges and most importantly the lost of personal identity.

Today there are 6 drugs approved by the Food and Drug Administration (FDA) that control the loss of memory and cognition characteristic of AD. These include the IgG1 anti-Aβ monoclonal antibodies, aducanumab, and lecanemab [5, 6]; cholinesterase inhibitors aimed solely at improving cognitive symptoms through cholinergic potentiation, donepezil, galantamine, and rivastigmine [7]; and the NMDA receptor antagonist, memantine [8], which acts on the inhibition of excitotoxicity mediated by hyperactivation of this receptor. In cases of moderate to severe AD, the combination of donepezil and memantine has been used to improve cognitive and functional capacity [9].

It should be noted that pharmacological therapy to treat the disease, specifically the use of monoclonal antibodies, has been part of a great controversy due to the safety issues they present. For this reason, and due to the complex and multifactorial nature of AD, research and the pharmaceutical industry have focused on the search for new therapies against the disease that act not on a single molecular target, but on multiple biological targets characteristic of the disease that also focus on its early detection. Early detection of AD allows the patient to follow specific protocols against the development and progression of the disease in time.

RISK FACTORS

In the context of this complex multifactorial disease, there are multiple risk factors for the development of AD. Those factors can be classified in two types: 1) the modifiable risk factors, that are related to a person’s lifestyle and thus can be prevented by changing their habits, and 2) non-modifiable risk factors, that as the name suggests can not be changed. Within this first category, the most relevant AD risk factors are diabetes mellitus, smoking, depression, stress, mental inactivity, sedentary lifestyle habits, obesity and nutritional problems, hypertension, dyslipidemia, low educational attainment, and vascular risk factors presented during midlife [10 –12]. It has been estimated that 40% of the AD cases can be attributable to these factors [10]. In contrast, non-modifiable risk factors correspond to genetic components, candidate genes, that can influence the probability that a person will develop AD in its later life [11].

In the context of the modifiable AD risk factors, vascular risk factors can contribute by four main mechanisms: increase of Aβ deposition, tau protein hyperphosphorylation, decreased cerebral perfusion, and cerebrovascular abnormalities [10 , 14]. Evidence suggests that these four mechanisms are mutually related, since vascular abnormalities can negatively affect the blood-brain barrier, decreasing the brain blood flow and brain blood supply causing damage to this tissue [11]. This in turn can increase the processing of the amyloid precursor (AβPP), decreases amyloid peptide clearance, and increases the hyperphosphorylation of tau protein and the formation of NFTs in the brain [5]. Related to vascular risk, hypertension is believed to be responsible for at least 50% increase in the risk of developing AD, because it causes elevated blood pressure that can have a negative impact on the blood-brain barrier and increase NFTs and Aβ levels as well as cause vascular abnormalities [10 –13].

It has been estimated that type 2 diabetes can increase by 1.3 up to 5.5 times the risk of developing AD due to its impairing effects on insulin, and with this in glucose metabolism [11 , 15]. Insulin receptors control synaptic density and are involved in the cholinergic system, being vital in synaptic plasticity and circuit function [13, 16]. Deficiency or resistance to insulin can cause an increased action of β- and γ-secretases, both important enzymes in the production of amyloid peptide, a reduction of the clearance of this peptide and an induction of the hyperphosphorylation of tau protein [17]. Impairment in Aβ clearance is mediated by competition generated in hyperinsulinemia with the insulin-degrading enzyme, while tau hyperphosphorylation increase is mediated by the inhibition of glycogen synthase kinase 3β (GSK3β) that occurs via activation of the insulin receptors that phosphorylate phosphoinositide 3-kinase (PI3K), which in turn phosphorylate GSK3β [10 , 13]. Thus, due to all the above, AD is considered by some researchers as another variant of diabetes, the type 3 diabetes [16].

Several studies show that midlife obesity can increase the risk of developing AD by 60% [10 , 18]. Mechanistically speaking, this is due to insulin resistance and pro-inflammatory effects derived from obesity that can increase pro-inflammatory cytokine secretion originating from the adipose tissue, these can promote insulin resistance and brain inflammation [18]. High blood cholesterol levels also increase AD risk, which is related to: increase of Aβ deposits and NFT formation in the brain, cognitive impairment, neuroinflammation, cholinergic neuron’s impairment and cerebral microhemorrhages [11 –13].

Smoking is a controversial risk factor for AD, but it has been estimated that it might be responsible for 14% of the AD cases due to oxidative to oxidative stress, inflammatory processes, and cerebrovascular impairments [10 , 13]. There is clinical evidence that suggests that smoking leads to cognitive decline that directly correlates with the amount of cigarette packs consumed per day and that nicotine can increase tau phosphorylation [13].

Stress and depression are other factors to consider in the risk of AD. Chronic stress causes hyperactivation of the hypothalamic-pituitary-adrenal axis, which increase cortisol levels, that in turn can increase Aβ deposition in the hippocampus and prefrontal cortex, and tau phosphorylation followed by neurodegeneration in the hippocampus [11 , 19]. Stress is also related to vascular risk, oxidative stress, activation of mineralocorticoid receptors that are involved in learning and memory and decreasing of neurotrophic factors like brain-derived neurotrophic factor (BDNF) [10]. Similar to the effect of stress, a decrease in BDNF production and increase in Aβ deposition have been correlated with depressive disorders [13, 19].

Additionally, other modifiable risk factors have been researched in the context of AD. Hearing loss is a highly prevalent risk factor that increases the risk of developing dementia, being estimated that 9% of dementia cases are attributable to hearing impairments in midlife [20, 21]. Many plausible mechanisms have been proposed to this correlation AD-hearing loss, but the two most relevant refer to a possible common pathology between them that structurally affects the cochlea and auditory pathway as an AD-related pathology, and a decrease in cognitive stimulation by the loss of hearing resulting in a diminished social interaction and an impoverished environment which affects cognitive reserve [20, 21].

Sleep disturbances have also been discussed in the context of AD, but there is controversy as some researchers consider this to be a symptom and even a possible clinical biomarker of the early stages of the disease and others consider sleep loss as a risk factor for developing AD [22]. The studies that propose sleep disturbances as a risk factor, present two main molecular mechanisms to support this hypothesis: 1) There is evidence in animal models that sleep deprivation affects Aβ clearance in the brain and there has been suggested that sleep disturbances can be related to inflammatory and oxidative processes in the brain that are linked to impaired Aβ clearance [22 –25]; 2) Other studies also performed in animal models suggest that sleep deprivation causes changes in tau metabolism and an increase in accumulations of phosphorylated tau in the brain [23, 24].

Education attainment has also been listed as a factor that can decrease the risk of AD [10, 11]. This factor has been associated with the concept of cognitive reserve, that consists of the resilience capacity of the brain against neurodegeneration [10, 11]. Low levels of education, among other factors, can diminish this cognitive reserve and increase the risk of developing dementia [10, 11].

Considering the variety of risk factors that can play a role in the development of AD, risk score systems have been created with the objective of mitigating lifestyle related risk factors [12]. These systems were developed mostly by analyzing data from observational studies and enable the prediction of AD development risk in late life [12]. The most relevant of these risk score systems are the Cardiovascular Risk Factors, Aging and Dementia score (CAIDE) which can predict the risk of AD within 20 years, the Lifestyle for Brain Health score (LIBRA) that evaluates midlife risk factors, and the Australian National University Alzheimer’s Disease Risk Index score (ANU-ADRI) that predicts the risk of dementia development within 6 years [12].

In the context of non-modifiable risk factors, age and gender are important aspects to take into consideration; 2/3 of AD patients are women, highlighting gender as an important factor to consider in this disease and the age of onset of the symptoms in patients helps classify variations of AD [11, 26].

Epigenetic components are important risk factors for early (when symptoms appeared before the 65 years of age) and late onset AD (when symptoms appeared after the 65 years of age) [11]. On the other hand, apolipoprotein E (APOE) polymorphism (APOE4 isoform) is the most relevant genetic variation for late onset AD [11, 12]. This can increase the risk 3-fold to 12-fold due to the promotion of Aβ polymerization, fibrillization and deposition in the brain and its deficient neuroprotective activity [11]. Additionally, a variation in the microglial gene TREM2 (triggering receptor expressed on myeloid cells 2) can affect phagocytosis of apoptotic neurons and clearance of Aβ deposits by microglia, neuronal survival and increase tau pathology via stress kinases such as JNK and ERK1/2 [19, 27].

Moreover, and in different context, familial AD that account for almost 2% of AD cases derives from relevant mutations that occur in APP, presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes. These mutations can favor the deposition of amyloid peptide in the brain [11]. All the latter is represented in Fig. 1.

Fig. 1

Modifiable and Non-modifiable risk factors for AD. This figure summarizes the most important risk factors for AD development, classifying them among lifestyle related risk factors (modifiable) and genetic and epigenetic components (non-modifiable). The hourglasses represent late and early onset of AD from left to right respectively.

EARLY DETECTION AND DIAGNOSIS OF AD

Markers based on structural imaging

Computed tomography (CT) and magnetic resonance imaging (MRI) are the two main technologies that for years have provided data on the brain structure of AD patients. While both can detect diffuse brain atrophy and ventriculomegaly, they have limited value in providing a reliable diagnosis for AD. CT is less expensive and more clinically available, but it does not provide the spatial or anatomical resolution needed to detect early changes in the brain, and it is not considered a criterion for early diagnosis. On the other hand, MRI consists of the visualization of enlargement of the cortical sulci and enlargement of the ventricles associated with AD. MRI is preferred as an image-based diagnostic test over CT due to its high spatial resolution and lack of ionizing radiation or X-rays, making it a non-invasive diagnostic test with no significant adverse health effects. However, it is only somewhat more sensitive in detecting advanced AD and is not effective in detecting the initial phases of the disease [28, 29].

Markers based on functional imaging

This type of imaging has revolutionized the diagnosis of AD as it accounts for various metabolic and biochemical changes in the brain, providing important information for understanding the underlying pathology and facilitating, in some cases, an early detection and differential diagnosis. These tests would solve the problem of MRI and CT, based solely on structural imaging, which do not elucidate the functional alterations at the molecular level caused by degeneration, which are ultimately responsible, in most cases, for brain atrophy. That said, investigation of the functional changes occurring in AD is crucial, as these may occur before any cognitive symptoms appear [30].

Perfusion single photon emission computed tomography (SPECT). A technique capable of detecting chemical and cellular changes related to a disease through the use of highly targeted radiotracers. SPECT evaluates cerebral perfusion and shows a correlation with metabolic changes characteristic of AD [28], however, is not widely used in the clinical routine. Studies of the accuracy of SPECT for diagnosing AD report sensitivities of 65–80% and specificities (for other dementias) of 72–87% [28, 31].

Positron emission tomography (PET). A molecular imaging technique that allows 3D images to be obtained of what is happening in the patient’s brain at the molecular and cellular level. Several tracers with different specificity have been developed to study AD patterns at different stages of severity. In particular, ligands are used to study synaptic dysfunction (cortical hypometabolism), Aβ deposition or the deposition of tau fibrillary tangles [28].

One of the problems with PET approaches is at the level of radiotracers, most of them recognize senile plaques of the amyloid, and current information indicates that amyloid components do not correlate well with the clinical output on AD, while tau oligomers exhibit a good correlation [32]. For cortical hypometabolism, tracers such as ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) PET measure cerebral glucose metabolism rates in different brain regions, indicating loss of neuronal activity [33]. On the other hand, for Aβ deposition, tracers for Aβ using specific ligands for this protein have shown high sensitivity and specificity for labelling amyloid deposits, as well as a correlation between the density of amyloid plaques on histology and have also been shown to have high clinical validity. Finally, to measure the deposition of tau fibrillary tangles, tau protein specific tracers are used, with the advantage that tau pathology correlates well with the clinical observations as evidenced in many studies over the past decade. However, tau aggregates are found in much lower concentrations (between 4 and 20 times less), meaning that the radiotracers must cross cell membranes to bind to the different oligomeric tau isoforms, without binding to Aβ [30]. Some of the most used radiotracers for PET imaging in AD are listed on Table 1.

Table 1

PET radiotracers in AD. Main characteristics of the radiotracers most commonly used in the diagnosis of AD by PET, in the upper part are those that measure Aβ deposition; in the lower part are those that measure tau fibrillary tangle deposition.

PET RADIOTRACERS IN AD
Based on Aβ deposition	Name of tracer	Sensitivity and specificity	Advantages	Disadvantages	FDA approval	References
	[¹¹C]PiB	sensitivity: ∼ 93.5% Specificity: ∼ 56.2%	less non-specific binding compared to ¹⁸F-radioligands. Discriminates between patients with mild AD and healthy controls.	radioactive half-life is only 20 minutes.	no approval	[34, 35]
	[¹⁸F]Florbetapir	sensitivity: ∼ 92% Specificity: ∼ 100%	half-life of 110 minutes. Strong discriminative ability between AD and MCI.	high cost and use of resources. Non-specific binding higher than ¹¹C-radioligands.	approved	[34 , 37]
	[¹⁸F]Florbetaben	sensitivity: ∼ 97.9% specificity: ∼ 88.9%	half-life of 110 minutes. Aβ uptake is related to cognitive dysfunction in AD.	high cost. Non-specific binding higher than ¹¹C-radioligands.	approved	[34 , 38]
	[¹⁸F]Flutemetamol	sensitivity: ∼ 88% specificity: ∼ 88%	half-life of 110 minutes. Better diagnosis than others with structural MRI.	high cost. Low accuracy in the prediction of the target Aβ stages. Non-specific binding higher than ¹¹C-radioligands.	approved	[34 , 39]
	[18F]Flutafuranol	sensitivity: ∼ 88.9% specificity: ∼ 91.4%	half-life of 110 minutes. Less non-specific binding.	less available for preclinical PET groups. Low use.	no approval	[34 , 40]
Based on tau fibrillary tangles deposition	[¹⁸F]THK5351	sensitivity: ∼ 82.6% specificity: ∼ 79.1%	good ability to differentiate between AD and MCI patients and healthy controls.	lack of specificity for tau. Positive screening alone does not establish a diagnosis of AD.	no approval	[35, 41]
	[¹⁸F]Flortaucipir	sensitivity: ∼ 89.9% specificity: ∼ 90.6%	clearer pattern of cortical uptake in AD patients and a lower degree of off-target binding. Better diagnosis of AD.	positive screening alone does not establish a diagnosis of AD.	approved	[35 , 43]
	[¹⁸F]MK-6240	unpublished	characteristically low relative affinity for MAO-B in silico.	positive screening alone does not establish a diagnosis of AD. Limited clinical studies.	no approval	[35]

AD, Alzheimer’s disease; Aβ, amyloid-β; FDA, Food and Drug Administration; MAO-B, monoamine oxidase B; MCI, mild cognitive impairment; MRI, magnetic resonance imaging; PET, positron emission tomography.

Functional magnetic resonance imaging (fMRI). Brain imaging during specific brain activity and at baseline. These images can show that the connectivity of a particular neural network has decreased or increased [44]. There is also the resting-state functional MRI (rs-fMRI) variant that has been widely recognized as it can help diagnose early stages of diseases before brain atrophy occurs [45].

Molecular biomarkers

Up to date, the only early detection molecular biomarkers available for AD at the clinical level are Alz-tau [46] and Precivitid AD^TM [47]. While for AD diagnosis, the two FDA approved technologies are based on the use of lumbar puncture to determine the levels of Aβ and tau protein in the cerebrospinal fluid (CSF) [48], which is correlated with cognitive status of the patient. Moreover, the levels of Aβ_1-42 and tTau in CSF correlate also with metabolic status characteristic of AD by brain PET-FDG. These two technologies are complementary [49].

However, although the neuroimaging tests and CSF biomarkers (e.g., Aβ, tTau), are the only FDA approved test for AD diagnosis, they are not a routine based clinical tests. In first place, they require complementation with neuropsychology for neurologist to reach a proper diagnosis. Secondly, about the CSF biomarkers, the sampling is invasive and require trained personnel. Finally, PET scans are costly due to the specific probes required and neurologist only use this method in specific cases [50].

Thus, research now is focused on reliable, non-invasive, and cost-efficient biomarkers for diagnosing AD that allows early detection of AD [50], as significant clinical-pathological and in vivo imaging evidence shows that the neuropathological process of AD and dementia begins decades before the earliest manifestation of cognitive or behavioral symptoms [51].

Currently, several blood-based biomarkers are under study, such as:

Mass-spectrometry of biological fluids: One of the novel approaches in the scope to validate a diagnostic tool for AD is the use of mass spectrometry for determination of molecular biomarkers, such as Aβ and tau, in biological fluids such as CSF and plasma [52]. In a blood-based diagnostic test, Kirmess et al. incorporated the evaluation of Aβ_42/40 ratio, APOE proteotype, and age in high resolution mass spectrometry, and it accurately identified the brain amyloid status for a clinical diagnosis [47]. Nonetheless, many of the studies so far in mass spectrometry had been performed in CSF samples, detecting novel molecules such as β-synuclein [53].

Digital ELISA:The major drawback in this case for tau protein analysis is the low quantity present in serum or plasma. Thus, a novel digital ELISA allows the detection of attomolar concentrations of tau protein [54].

Single-Molecule Arrays (SIMOAs) of p-Tau: This novel technology allows detection of phosphorylated tau within specific threonines: p-181, p-217, and more recently, p-231 [55]. There are currently six SIMOA platforms developed within these antibodies, in which they demonstrate their ultrasensitive detection and early diagnosis [56]. Another potential biomarker, plasma neurofilament light levels, were also evaluated in the SIMOA platform, and it was demonstrated that AD and mild cognitive impairment (MCI) patients have higher levels of neurofilament light when compared to controls [44, 57]. Finally, SIMOA can also evaluate Aβ₄₂ and Aβ₄₀ levels. Interestingly, in cognitively unimpaired subjects, women present more total tau markers and lower Aβ₄₂/Aβ₄₀ ratio [58].

Alz-Tau^®: This novel and cutting-edge biomarker is based on tau in platelets [59]. In comparison to all the previous tests described, Alz-tau^® is a relatively simple technology that can be easily implemented in clinic [32, 60]. The test is based on the identification of high molecular weight (HMW) and low molecular weight (LMW) tau protein variants in platelets and obtention of an algorithm HMW/LMW after densitometric analysis of western blot bands [46]. The biomarker’s clinical trials conducted in AD patients and cognitively healthy subjects showed that the HMW/LMW tau ratio is significantly higher in AD than in control subjects [32 , 60]. This biomarker has been validated by five clinical trials [61], with high possibilities of clinical implementation. All these technologies are summarized in Fig. 2.

Fig. 2

Markers based on imaging and molecular biomarkers for AD. Diagnostic tests based on both structural and functional imaging are summarized on the left; some of the most clinically relevant molecular biomarkers are shown on the right.

PREVENTION OF AD

Physical exercise

Among the modifiable lifestyle aspects that can help in the prevention of AD, physical activity stands out for its benefits in decreasing the risk of developing AD. There are 5 main mechanisms for which it fulfills this function: changes in the brain that generate cognitive improvements in a structural level, prevention of diseases which are in turn risk factors for AD, improving neuropsychological symptoms, stimulating neurotrophic factor’s production and other benefits mediated by irisin [11–13 , 62–65].

Physical activity can cause adaptations in the brain which generate improvements in cerebral blood flow thus increasing oxygenation in brain areas that are critical for cognitive performance, and it can also have a direct effect on neurogenesis in the adult hippocampus [11, 66]. Moreover, physical activity can increase cognitive reserve, which corresponds to the ability that the brain has to overcome damages and keep its normal functioning, decrease neuroinflammation, oxidative stress, and tauopathy, and it can also increase brain volume (especially in the hippocampus) and maintain brain neuroplasticity [11 –13].

Another mechanism that confers this protection is due to preventing health problems such as increased blood pressure and vascular risks, metabolic risks, stress, obesity, and inflammatory processes; it can as well improve the lipid profile of the body and improve the endothelial function [11 –13]. Evidence also suggests that physical activity can cause memory improvements in the patients, decrease their physical impairment and slower the decline in impairments to achieve daily activities [12, 13].

Regarding the mechanisms of physical exercise, these activities can increase the levels of BDNF, fibronectin type III domain containing protein-5 (FNDC5), insulin growth factor (IGF-1), and vascular endothelial growth factor levels that have beneficial effects among neurogenesis and synaptic plasticity [11 , 66]. FNDC5 and its cleaved fragment, irisin, have been found diminished in AD brain and CSF of AD mouse models [63 –65].

From a molecular point of view, what would occur after exercise is that increased expression of the hippocampal FNDC5 gene is stimulated through a PGC-1α/Errα transcriptional complex where proteolytic cleavage of the FNDC5 protein would then take place, producing irisin [49]. Then, irisin would act on neurons, through receptors that have not yet been identified, to generate an increase in BDNF expression through a signaling cascade stimulating the accumulation of cyclic adenosine monophosphate (c-AMP), activation of cAMP-dependent protein kinase (PKA) and phosphorylation of cAMP response element binding protein (CREB) (Fig. 3) [64].

Fig. 3

Beneficial effects of physical activity in AD prevention. This figure summarizes the mechanisms of physical activity that are beneficial for AD prevention. With respect to the molecular mechanisms shown in this figure, irisin is formed by the cleavage of FNDC5 induced by physical exercise. Irisin then stimulates BDNF production via the c-AMP/PKA/phosphorylated CREB. BDNF production can also be induced by the inhibition of HDAC by DBHB that is in turn stimulated by physical activity. BDNF binds to TrkB and induces beneficial effects in the brain, such as: increasing dendritic and axonal branching and synaptogenesis, increasing long-term potentiation and hippocampal neurogenesis, and enhancing memory and learning.

On the other hand, physical activity stimulates irisin-independent BDNF production due to Histone deacetylases (HDAC) inhibition (Fig. 3). The action of BDNF after binding to tropomyosin receptor kinase B (TrkB) is to induce neuritogenesis and synaptogenesis, increased hippocampal long-term potentiation (LTP), hippocampal neurogenesis, memory enhancement and learning [65] thus being considered a key factor in cognitive stimulation through physical exercise.

Intervention studies have reported a positive association between cognition and physical activity or cognitive training. In this way, the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), a large-scale, randomized controlled trial to assess a multidomain approach to prevent cognitive decline in at-risk elderly people [67]. During 2-year multidomain lifestyle intervention that incorporated dietary counselling, physical exercise, cognitive training, and vascular and metabolic risk monitoring in 60–77-year-old subjects showed positive outcomes on the overall cognition, executive functioning, and processing speed, body mass index, dietary habits, and physical activity [67]. The beneficial effects on cognition observed in FINGER, have led to a global approach to risk reduction and prevention of dementia through World-Wide FINGERS network which currently includes several countries [68]. This network of multidomain intervention aims to reduce risk across the spectrum of cognitive decline from at-risk asymptomatic states to early symptomatic stages in different geographical, cultural, and economic settings.

Healthy diet, nutrition, and nutraceuticals

Experts consensus opinions on dementia prevention suggested that progression from MCI to dementia could be reduced by paying attention to modifiable risk factors related to lifestyle among them diet [20 , 70]. Diet plays an important role in AD prevention, an example of this is the role of the Mediterranean diet in AD which contains unsaturated fats and antioxidants that can decrease the risk of developing AD [11, 13]. There are some diet components that are necessary for neuronal protection such as fatty acids like fish oil, antioxidants like vitamins A, E, and C, vitamin D, fruits, vegetables, vitamins B6 and B12, and folate (B9) [5 , 11]. Among these, antioxidants are required for cell membrane stabilization and for protection against reactive oxygen species [11, 12]. Evidence shows that a Mediterranean diet can protect against cognitive and memory declines in the elderly population [13]. Some of the main mechanisms proposed to be responsible for these protective effects against AD are antioxidant properties, vascular and general anti-inflammatory effects, maintenance of neuronal membrane integrity, and upregulation of neurotrophic factors [12]. Moreover, whole coffee fruit extract stands out as a dietary source enriched in polyphenols, which has been shown to be a potent stimulant of endogenous BDNF in several clinical trials [71 –73]. Consuming this extract could not only enhance cognitive performance but also modulate brain activity possibly by increasing BDNF levels, relevant aspects in patients diagnosed with AD.

Regarding the anti-inflammatory effect, it should also be considered that inflammation is also associated with gut microbiome dysbiosis. Restoration of the gut microbiome is beneficial for cognitive disorders, as studies demonstrated that administration of probiotics in APPS1 transgenic mice had beneficial effects in Aβ accumulation in the hippocampal area [74]. Consistent with the latter, administration of three strains of Lactobaccilli and Bifidobacterium bifidum improved cognitive performance in AD patients [74]. In a recent work, it was demonstrated that oral administration of probiotics in a 3xTg-AD mice, through a manipulation of the microbiome, decreased the phosphorylated tau aggregates [75]. Also, several studies indicate that the gut microbiota may influence the synthesis of various neurotransmitters and neuromodulators, which affect gut-brain communication and brain function [76 –78]. It is necessary to have balanced bacteria because when pathogenic bacteria are more than beneficial ones, toxic substances can be secreted that are poured into the blood and can pass the blood-brain barrier and elicit neural damage.

In the context of glucose metabolism in the brain, it has been described that AD patients present a cerebral glucose hypometabolism compared with cognitively healthy subjects, opening a stream of research that focuses on the rescue of brain energy as a kind of treatment for AD [79]. Considering that ketone metabolism remains mostly undisturbed in AD and MCI subjects, it is shown that the administration of ketogenic supplements in MCI subjects’ diets moderately improved the cognitive decline [79]. Also, the subjects treated with ketogenic supplements showed significant improvements in episodic memory, verbal fluency, language ability, function, and processing speed [79].

Due to the complex and multifactorial nature of AD, novel therapies (multitarget, i.e., nutraceuticals) that act on the molecular pathway links to misfolded proteins (Aβ and tau), synaptic integrity, cognitive impairments, autophagy, and mitochondrial dysfunctions, as well as pro- and anti-inflammatory responses related to AD should be included [4 , 81]. In this context, the nutraceuticals could be effective to treat and prevent AD. Nutraceuticals are defined as bioactive chemical components that come from the diet and have protective properties against some diseases. They generate a multi-target approach to increase the percentage of effectiveness through various molecules that act at different sites in the brain, e.g., bioactive molecules that have proven to be effective as antioxidants or in controlling protein aggregations in neurodegenerative disease include curcumin [82], rosmarinic acid [83 –85], S-allyl-L-cysteine [86] and Oleuropein, plus its derivatives [87]. Significant improvement in cognitive impairment was observed in AD rat models with Clementine citrus oil (seeds) due to the high antioxidant activity [88]; however, mechanisms are not evident. Homotaurine also has been a focus of study for its role in cognition by acting as an agonist of GABA receptors. Homotaurine is an aminosulfonated compound used clinically as tramiprosate [89]. Clinical trials have shown decreased Aβ₄₂ levels in the CSF of patients with mild to moderate AD [90], like improvements in cognitive impairment [91].

Docosahexaenoic acid is a component that can help in the clearance of amyloid peptide as well as an important factor that together with uridine and choline play an important role in the neuronal membrane synthesis [11]. The latter is an essential component of AD pathogenesis, because most of the neuronal and synapsis losses in these pathologies occurs due to degeneration or alterations of neuronal membranes [11].

On the other hand, sodium selenate reduces hyperphosphorylated tau [92], activates PP2A phosphatase [93] and Wnt/β-catenin signaling [94] in AD models. A pilot study of 40 AD cases has shown that the supplementation of high-dose sodium selenate is well tolerated and can modulate CNS selenium concentration. However, individual variation in selenium metabolism must be considered to optimize potential benefits in AD [95]. Moreover, cognitive measures suggest slowing disease progression in AD patients [96].

The LipiDiDiet consortium, which studies the preclinical and clinical impact of nutrition in AD, affirm that dietary and nutritional interventions as part of broader lifestyle changes may contribute to improved cognitive performance among individuals at risk of progression to dementia [53, 75]. In this framework, they have carried out trials with Souvenaid (Fortasyn Connect^TM), a nutraceutical which contains docosahexaenoic acid; eicosapentaenoic acid; uridine monophosphate; choline; vitamins B12, B6, C, E, and folic acid; phospholipids; and selenium, and showed favorable effects on reduction in cognitive-functional decline (measured by the Clinical Dementia Rating-sum of boxes) and attenuation of hippocampal atrophy over 24–36 months of intervention in prodromal AD participants [53 , 75]. Moreover, 36 months of intervention with Souvenaid showed significant benefit as measured by the Neuropsychological Test Battery, as well as being safe and well tolerated by volunteers [53, 69]. These structures [97] and reductions in cognitive and functional decline in prodromal AD indicates that this nutraceutical plays a pivotal role in reducing the neurodegenerative process in AD, suggesting the importance of an accurate nutrition [69, 98].

Another nutraceutical linked to AD prevention is Cognitex^®, a brain health supplement that enhance memory and prevent cognitive decline. It contains L-α-glycerophosphocholine, phosphatidylserine (PS) with omega 3 fatty acids attached to its backbone (PS-omega 3), vinpocetine, uridine-5’-monophosphate, Pregnenolone, Sensoril^® extract, Sibelius^® extract, and wild-derived whole blueberry extract (Aurora blue^®). These nutrients have numerous benefits, supporting memory and developing cognitive function, as demonstrated by various studies. Moreover, an uncontrolled open label-trial to evaluate the efficacy of Cognitex^® (ClinicalTrials.gov Identifier: NCT00719953) demonstrated improved cognitive performance in the elderly with memory complaints [99]. The above has been supported by a multidomain Alzheimer’s preventive trial (MAPT study) that evaluated the efficacy of isolated omega-3 fatty acid supplementation and an isolated multidomain intervention combining healthy nutrition and physical exercise [97].

BrainUp-10^® is one of the nutraceuticals developed in Chile with neuroprotector and anti-aggregate effects. A formulation contains vitamin B6, vitamin B12, folic acid, and Andean Shilajit, ingredients that have been shown to help brain health [100 –102]. An interventional study with BrianUp-10^® in AD patients showed significant improvement in apathy and homocysteine decreased [103]. Further, the BrainUp-10^® consumption ameliorated neuropsychiatric distress of patients with AD [103]. Some of the beneficial effects of nutraceuticals in AD are summarized in Fig. 4.

Fig. 4

Effects of the diet and nutraceutical compounds in AD. This figure represents the different mechanisms by which the diet and nutraceutical compounds can impact in the development of AD and in neurodegenerative processes.

Cognitive stimulation tools

In this part of the review, we will focus on conveying the information of cognitive stimulation of a brain with cognitive impairment characteristic of AD through some brain training products and programs that currently exist. It should be noted that not all were included in this review, as these are scarce and there has been some controversy with their true efficacy in the prevention of AD.

The Lumo Lab team has been developing a brain training program called Lumosity^®, which consists of a series of games that develop cognitive skills such as memory, processing speed, problem solving, and many more. The effect that Lumosity has on the cognitive performance of users shows encouraging results, indicating that the group that was using the program for a period of time increased their cognitive performance twice as much compared to the control group that did not use the program [104]. Despite this, there are other studies that have found the same effects [105, 106] even considering that it should not be called a “brain training program” [107].

On the other hand, ActivaMente™ corresponds to a software under development by the International Center for Biomedicine (ICC) in Chile, which is aimed at both adults with an early diagnosis of AD and who have not yet developed symptoms, and simply cognitively healthy people looking to stimulate brain activity by specifically working different regions of the brain. Articles related to the effectiveness and functioning of this software are currently unpublished.

Meditation, mindfulness, and Qigong

Mindfulness is a practice that has the objective to purposefully pay attention to the present moment in a non-judgmental way, using the will to focus only on the stimuli, both internal and external, of what is happening in the present of the individual who is practicing this technique [4, 108]. Several mechanisms have been proposed to explain its benefits on preventing AD and improving memory and cognitive function in mild AD patients. It is important to consider that all the evidence referring to mindfulness has been obtained from observational studies. Among all the evidence available about this topic, six mechanisms stood out: First on a structural level, mindfulness can increase hippocampal volumes in healthy young adults and decrease the atrophy in this part of the brain in patients that suffer from MCI [85, 86]. This practice can also improve the connectivity between hippocampus and the cingulate cortex, as well as in an inter-hemispheric way, and increase gray matter in some brain areas [108, 109].

Another mechanism is the decreasing property that mindfulness has on depression and stress, especially the latter in which context regulates glucocorticoid levels [86]. This also relates to the immunomodulatory property of mindfulness that can be achieved by this practice ability to diminish systemic inflammation and regulating glucocorticoids [109].

Mindfulness also has antioxidant properties and has effects over IGF-1 which is related to the metabolic syndrome [109]. Moreover, this practice can restore serotonin levels, an important factor in hippocampal neurogenesis, neuroprotection, and synaptic plasticity, which its levels are also impaired in MCI and AD [109].

Additionally, Qigong, a therapeutic approach of Traditional Chinese Medicine that involves postures, movements with mental focus, breathing exercises, and relaxation techniques, can improve recognition in vascular cognitive impairment patients as well as increasing gray matter volume in elderly patients [4]. Some of the beneficial effects of mindfulness on AD are represented on Fig. 5.

Fig. 5

Beneficial effects of mindfulness in the prevention of AD. This figure summarizes the main mechanisms by which the practice of mindfulness protects against AD.

CURRENT RESEARCH ON ALTERNATIVE THERAPIES FOR AD

Hyperbaric oxygenation therapy (HBOT)

HBOT is a treatment where a person breathes 100% subindex under increased atmospheric pressure. In AD, chronic hypoxia increases secretase activity and tau protein phosphorylation [110 –112]. HBOT has been shown to improve cognitive function in animal models and in patients with AD on a temporary basis [112 –114]. It alleviates disease symptoms by decreasing neuroinflammation [113], oxidative stress and neuronal apoptosis [115], and reducing tau protein phosphorylation [112, 113]. HBOT decreases the secretion of proinflammatory proinflammatory cytokines (IL-1, TNF-α) by reducing microglia around amyloid plaques [113] and increases the expression of anti-inflammatory cytokines (IL-4, IL-10) by reducing Caspase-3 activity and Bax expression levels [116]. It also increases glutathione activity, reduces malondialdehyde levels [112, 115], and reduces neuronal apoptosis via the NF-κB pathway [117]. Hyperbaric oxygen pre-treatment improves cognitive function and reduces hippocampal damage via p38 in a rat model of AD [111]. Side effects of HBOT are mild and reversible [112]. The effects of HBOT on cognitive function are still under investigation.

Plasmapheresis

Plasmapheresis or plasma exchange involves extracting blood plasma and replacing it with donated blood products to eliminate senescent or toxic factors [118]. Murine studies have shown that transferring plasma from a young mouse to an old mouse can promote neurogenesis, synaptic plasticity, and improve cognitive impairment in the old mouse, while human studies have shown small decreases in Aβ levels in plasma during treatment but no significant changes in amyloid peptide levels in CSF [119 –123]. Additionally, treated patients showed improvements in language and memory, as well as a stabilization of AD symptoms and structural changes in the brain [120 –123]. However, plasmapheresis has significant disadvantages, including lower scores in behavioral and functional tests [121], adverse effects such as infections and psychiatric disorders [121, 122], and a lack of convincing molecular and mechanistic evidence, suggesting that it should be carefully reviewed before being considered as a viable therapy for AD treatment.

Sensory stimulation devices

Various devices for cognitive enhancement have been developed, including gamma entrainment using sensory stimulus and ultrasound brain stimulation. Auditory tone stimulation has shown potential for inducing gamma frequency activity in the auditory cortex and hippocampal CA1 region but requires validation through human trials [124]. Meanwhile, ultrasound brain stimulation (transcranial pulse stimulation) has shown promise in improving functional networks and cognitive performance in AD patients, as well as potentially reducing cortical atrophy, but requires further clinical trials [125, 126]. Tactile stimulators like Brainpaths^®, registered with the FDA (N°3010937782), have also shown potential for improving memory, mood, and cognition in dementia patients, but more research is needed to fully understand their benefits and mechanism of action [127, 128].

CONCLUSIONS

Studies point to the need to find novel cost-efficient biomarkers for diagnosis for AD but also markers for early detection of the disease, at pre-symptomatic stages. An early detection will allow establishing personalized protocols for prevention or non-pharmacological treatment avenues for patents that evidenced a pathological process suggested by the biomarkers.

Considering that at least 40% of the risk factors corresponds to those named to as modifiable risk factors for prevention, these include: physical exercise that promote neurogenesis via activation of neurotrophic factors, cognitive stimulation, healthy nutritional protocols, mindfulness, and others. Most of them are linked to changes in lifestyles. Aging is inevitable but the biological age of the person depends on the type of life that the person has developed. In addition, there are other prevention tools such as HBOT, sensory stimulation, and eventually plasmapheresis that still require more studies to validate them. All the above highlights the importance of preventive approaches in regard to AD, out of which the most relevant is to maintain a healthy lifestyle.

Footnotes

ACKNOWLEDGMENTS

The authors have no acknowledgments to report.

FUNDING

This research has been funded by a grant from the “Ricardo Benjamin Maccioni Foundation” and by a FONDEF project from ANID, Chile.

CONFLICT OF INTEREST

Dr. Ricardo Maccioni is an Editorial Board Member of this journal but was not involved in the peer-review process nor had access to any information regarding its peer-review.

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