3.1 Estrogen and Progesterone Effect on AD

To begin, estrogen exhibits modest antioxidant effects by directly scavenging free radicals, contributing to neuroprotection [19]. It modulates the processing of APP, favoring the nonamyloidogenic pathway, which reduces the production of Aβ peptides [20]. This modulation is mediated through estrogen receptors that influence the activity of enzymes involved in APP cleavage [20]. Besides, estrogen improves cognitive functions by showing enhanced hippocampal and prefrontal cortex activity, which are crucial for memory and executive functions [21]. It enhances synaptic plasticity by increasing dendritic spine density and modulating neurotransmitter systems, including glutamatergic and cholinergic pathways [22]. This leads to improved cognitive functions and may counteract synaptic deficits observed in AD [22]. Estrogen's anti-inflammatory properties mitigate neuroinflammation, a factor implicated in AD progression [21].

Moreover, estrogen is shown to be able to alter human emotions, cognition, and other neuronal factors [23]. For instance, it is found to enhance tasks like inhibitory avoidance and object recognition, both of which decrease with age due to low levels of circulating estrogen affecting cognitive function, a finding that is beneficial in dementia and AD research [23]. Not only elucidated in females, the decrease in estrogen levels with ageing may be associated with the risk of cognitive decline and AD [24]. Besides, cognition is preserved and protected by estrogen, given that the latter promotes cholinergic activity, protects from toxic insults, increases neuronal synthesis, reduces the deposition of Aβ, and enhances its clearance [21].

Similarly, progesterone has been reported to be protective against various insults relevant to brain aging and neurodegenerative diseases, including AD [25]. It is proven that it possesses a neuroprotective role in AD since its neuroactive steroid properties reduce the process of neuroinflammation and autophagy dysfunction involved in the pathophysiology of AD [26]. Estrogen and progesterone can increase the expression of brain-derived neurotrophic factor (BDNF) mRNA, supporting neuronal survival and function [19]. Thus, targeting estrogen receptors may help prevent or control neurodegenerative processes characteristic of AD, suggesting a pathway for developing estrogen-based treatments [27].

As a result of the hormonal implications in AD, trials in hormonal therapy (HT) are on the rise [28]. These studies proved that HT preserves neuronal health by the corrective properties of estrogens, resulting in neuroprotective effects concerning dementia and cognition [28]. Recent literature indicates that early age at menopause is shown to be a risk factor for AD dementia, but women prescribed HT around menopause onset did not show increased risk [29]. The effects of HT, however, varied according to when it was initiated. Research indicates that starting any form of HT 5 years preceding the onset of menopause was associated with a lower risk of AD, whereas beginning HT 5 years or later did not result in a lower risk of AD [30]. However, the success of HT by itself is affected by predisposed risk factors—genetically predetermined—for other systemic diseases including cardiovascular risk factors [31]. Therefore, to recommend HT for an individual, the physician should consider the different aspects of the baseline characteristic including the genetic factors, cardiovascular risk, age, and the dose as well as the duration of this treatment till another effective modalities are available and switched to [28] (see Figure 1).

3.2 Testosterone Effect on AD

It has been demonstrated that the depletion of both estrogen and testosterone may be of great significance in AD development [35]. This is conceivable since these hormones are well-known regulators of several disease processes, including tau protein phosphorylation, reduced spine density, neuronal death, and Aβ accumulation [35].

It is noted that the neuroprotective effects of testosterone are thought to emerge from a decline in Aβ production, synaptic signaling refinement, and neuronal mortality prevention [36]. Testosterone has been shown to reduce Aβ levels and mitigate plaque formation, potentially preventing synaptic dysfunction [37]. Additionally, it exhibits anti-inflammatory properties by inhibiting pro-inflammatory cytokine production, contributing to neuroprotection in AD models [37]. Besides, it exerts its neuroprotective effects through androgen receptors, which can activate signaling pathways that promote neuronal survival and synaptic maintenance [22]. These pathways include the modulation of neurotrophic factors and inhibition of apoptotic processes [22].

However, studies conducted on testosterone and its effects on cognitive decline display conflicting results, some of which demonstrate cognition and testosterone to have a positive linear relationship while others showing an inversely proportional relationship [23]. Lower testosterone levels in men have been associated with an increased risk of developing AD [37]. Testosterone replacement therapy in hypogonadal men has shown improvements in cognitive functions, though results are mixed, indicating the need for further randomized controlled trials [37].

Although all sex hormones, estrogen, progesterone, and testosterone, have been shown to influence Aβ levels, a hallmark of AD pathology, research indicates that women may exhibit greater Aβ deposition than men, even at similar clinical stages of AD [38]. This suggests that sex hormones may differentially influence amyloid pathology [38]. Sex-based differences have also been observed in tau pathology, with some studies reporting more pronounced tau deposition in women [38]. The relation between sex hormones and tau pathology remains an area of active investigation [38]. The presence of the APOE ε4 allele is a known risk factor for AD [39]. faster cognitive decline compared to male carriers, indicating a potential interaction between sex, genetics, and hormone levels [39] (see Figure 1).

3.3 Glucocorticoids and Thyroid Hormones Effect on AD

Glucocorticoids are recognized as cofactors that cause memory impairment and increase the brain's susceptibility to various insults [23, 40]. Chronic activation of glucocorticoid receptors by cortisol can impair synaptic plasticity and potentiate Aβ toxicity, exacerbating AD pathology [41]. Higher levels of cortisol have been reported in individuals with AD and mild cognitive impairment, correlating with cognitive decline and disease progression [42]. Elevated cortisol levels, often resulting from chronic stress, can lead to hippocampal atrophy by promoting neuronal apoptosis and reducing neurogenesis [41]. This negatively affects memory formation and retrieval in AD patients [41]. Therefore, the chronic elevation of cortisol may exacerbate neurodegenerative processes, suggesting that managing stress and cortisol levels could be a potential therapeutic avenue [42].

Studies also illustrated that there appears to be an association between cognitive decline and disorders of thyroid hormone [43]. These hormones regulate the expression of genes involved in neuronal differentiation, myelination, and synaptic function, and thus alterations in their levels can disrupt these processes, leading to impaired neuroplasticity in AD [41]. Besides, thyroid hormones influence mitochondrial function and oxidative stress responses, so any dysregulation in their levels can lead to increased oxidative damage, a hallmark of AD pathology [41]. Literature has also demonstrated that in the context of AD, low free T4 and high TSH levels were associated with a higher cerebral Aβ burden [44]. For that, thyroid hormone supplementation has been shown to restore cognitive deficits and reduce neuroinflammation in the hippocampus of sporadic Alzheimer's-like disease models [45].

3.4 Insulin Effect on AD

Insulin has an essential role in the brain's neuroplasticity highlighted by its heightened effects on learning and memory that is associated with upregulation of insulin receptors in the hippocampus and entorhinal cortex [46, 47]. For instance, insulin—by itself—acts as a trophic factor that directs and regulates neurogenesis by influencing neural stem cell proliferation and survival (by AKT signaling pathway) as well as facilitating neuroblast exit from quiescence (by insulin/IGF-1 signaling pathway) [32-34]. Thereby, insulin is critical for the memory and cognitive brain function [48]. On the other hand, insulin resistance (IR) leads to alteration in neurotransmitter release and metabolism regulation eventually causing neurodegenerative changes and synaptic plasticity deterioration [49].

At the molecular level, insulin is responsible for the regulation of tau gene expression, tau protein phosphorylation, APP, and shapes the balance between amyloidogenic and nonamyloidogenic pathways of the APP processing [50, 51]. In AD, hyperphosphorylation of tau is a hallmark causing impairment in the binding to microtubule contributing to the formation of NFTs [52]. Furthermore, low levels of insulin, decreased insulin sensitivity or disruption of insulin/IGF-1 signaling pathway (resulting in inhibition of PI3K/AKT and increased GSK3-β activation) facilitate an additional increase in NFT production by enhancing tau hyperphosphorylation, resulting in oxidative damage at the cellular level and exacerbating AD [51, 53].

Additionally, insulin levels that are on the lower end of the spectrum or IR result in raised Aβ peptides levels by downregulating the activity of insulin degrading enzyme—that is responsible for the degradation of insulin and Aβ peptides—consequently forming cerebral amyloid plaques [53-55]. These plaques are responsible for neuroinflammatory reaction activation and synaptic plasticity disruption [56]. For instance, Aβ increase is the center of the neuroinflammatory hypothesis of the pathophysiology of AD, where neuroinflammation refers to recruitment of microglia and astrocytes—that release increasing amounts of cytokines, chemokines, and complements triggered by Aβ accumulation—and results in cell injury [57]. Furthermore, the accumulation of these peptides interferes with the insulin signaling pathway promoting the hyperphosphorylation of tau contributing to addition NFT formation [58].

Moreover, one of the pathways by which IR interferes with AD's pathophysiology is through peripheral hyperinsulinemia found due to oversecretion of insulin due to resistance [59, 60]. Insulin can cross the blood–brain barrier and reach the brain, where it is destroyed by the insulin-degrading enzyme that also acts on Aβ protein. The presence of excessive insulin competes with Aβ on the enzyme and leads to Aβ accumulation in the brain [59, 60].

Enhancing insulin sensitivity through lifestyle interventions or pharmacotherapy may offer neuroprotective benefits and mitigate AD progression [61-63]. In the light of what has been discovered in the field of IR and AD, studies showed that multiple antidiabetic drugs have an impact on AD [61-64]. A clinical trial showed that metformin, a first-line treatment for type 2 diabetes mellitus, acts on enhancing insulin peripheral sensitivity and decreasing hyperinsulinemia as a counter effect of IR, thus suggested to be effective in AD treatment [61]. Not only does metformin play a role in AD management, but also SGLT2 inhibitors do [64, 65]. Studies showed various mechanisms by which SGLT2 inhibitors affect AD; literature showed that it interferes with AD through the AD-IR link by decreasing peripheral hyperinsulinemia on the one hand and increasing the production of ketones as an alternative to glucose in certain areas of the brain [64, 65]. In addition, SGLT inhibitors play a pivotal role in AD management by suppressing acetylcholine esterase and increasing by that the presence of acetylcholine at the level of synapses [63]. Finally, recent clinical trials are held to investigate the beneficial effect of liraglutide, a GLP-1 agonist, in managing AD [62] (see Figure 1).

3.5 The Role of Microbiota in Alzheimer's Disease

The gut–brain axis facilitates the bidirectional communication between microbiota and AD [66]. Certain gut bacteria produce amyloid-like particles, which may seed amyloid plaque formation in the brain, a hallmark of AD [67]. Also, microbiota-derived bile acids have been shown to promote gamma-secretase activity through interactions with nicastrin subunits, influencing amyloid-beta production [68]. This highlights the role of gut metabolites in modulating AD-related enzymatic processes [68]. Besides, dysbiosis, or imbalance in gut microbiota, can lead to systemic inflammation, influencing neuroinflammatory processes that exacerbate AD pathology [66].

Research showed that estrogen, progesterone, and testosterone levels may influence gut microbiota composition, which in turn affects the neuroinflammatory processes linked to AD [69, 70]. These hormones have been shown to exert neuroprotective effects, potentially modulated by gut microbiota interactions; changes in gut microbiota composition can influence androgen and progesterone metabolism, affecting its availability and efficacy in neuroprotection related to AD [71]. Besides, studies showed that sex-specific differences in microbiome profiles have been observed, potentially explaining the higher prevalence of AD in women [69].

Not only do sex hormones affect gut microbiota, but so do glucocorticoids and thyroid hormones [72, 73]. It has been shown that chronic stress activates the hypothalamic–pituitary–adrenal (HPA) axis, increasing cortisol production [74]. This heightened cortisol can alter gut microbiota composition, which may further influence AD pathology through the gut–brain axis [74]. This imbalance may exacerbate neuroinflammation and cognitive decline in AD patients [72].

Moreover, dysregulation of thyroid function may alter gut microbiota, potentially affecting AD pathology through metabolic and inflammatory pathways [73]. Thyroid hormones are essential for neurodevelopment, and their interaction with gut microbiota may influence cognitive functions [73].

Furthermore, IR is a known risk factor for AD [75]. Emerging evidence suggests that gut dysbiosis may promote IR, thereby contributing to AD pathogenesis [75]. Modulating gut microbiota could potentially improve insulin sensitivity and mitigate AD progression [75]. Insulin plays a critical role in glucose metabolism, and its interaction with gut microbiota can influence cognitive functions [73]. Alterations in gut microbiota affecting insulin signaling may have implications for AD progression [73].

4.1 Synaptic Dysfunction in AD

As previously stated, AD is a net result of the coaccumulation of extracellular amyloid plaques, the Aβ peptide, and intraneuronal NFT, the tau protein [76]. These were found to occur years preceding neuropathological impairment, whereas the first signs implicated in AD cognitive deterioration begin when profound synaptic loss ensues [77].

Regarding synaptic dysfunction in the pathophysiological features of AD, studies suggested that it intercedes neuronal degeneration and is directly associated with cognition diminution [78]. Specifically the loss of synaptic density leads to functional impairment of synaptic plasticity, thus participating in AD pathogenesis [79].

Besides, synaptic density impairment in AD exhibits a strong relationship with the level of cognitive diminution. This proposes that impaired synaptic transmission resulting from toxic oligomeric species could estimate the disease severity better than neuronal loss at the disease's end stage. This is upheld by studies conducted on preclinical models where Aβ peptide and tau protein influence said synaptic plasticity by affecting the hippocampal LTP, responsible for memory and learning [80-82].

For instance, excitatory synaptic transmission is adherently controlled via the number of activated N-methyl-d-aspartate receptors (NMDARs) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) at the synapse, where the NMDARs activation plays a pivot role in synaptic plasticity (LTP/LTD) depending on the extent of the amount of intracellular Ca²⁺ concentration rise in the dendritic spines and the resultant further intracellular downstream activations [83]. Furthermore, for LTP to occur it requires the activation of synaptic NMDARs and an increase in intracellular {Ca²⁺}, which results in AMPARs activation and dendritic spines growth potentiation. While LTD requires the internalization of NMDARs, the activation of the perisynaptic NMDARs and the lesser increase in intracellular {Ca²⁺} leading to spinal shrinkage and synaptic loss [83]. Aβ oligomers effect on synaptic plasticity comes not only from its own intracellular accumulation and internalization but also from its influence over the NMDA and AMPA receptors [84, 85]. Whereby the excess Aβ acts on the synaptic cleft to block the glutamate uptake, decreasing its clearance and resulting in overstimulation of the NMDARs until a certain point where receptor desensitization occurs followed by these receptors internalization and thus synaptic response reduction and depression ensues [86].

Moreover as the glutamate spills over the synapse, it can activate the extra and perisynaptic R2B-enriched NMDARs as well as the metabotropic glutamate receptors (mGluRs) which are all involved in the facilitation of LTD by Aβ [87]. The excessive and inappropriate activation of NMDARs by the Aβ oligomers can lead to LTP suppression [88].

4.2 Neurogenesis

Neurogenesis, defined as the formation of new neurons from neuronal stem cells, has gained much interest in the research field [89]. It is apparent that the hippocampus, entorhinal cortex, and olfactory bulb harbor NFT tangles and Aβ plaques precortical progression. Since these cerebral areas, especially the hippocampus, are indicated in neurogenesis, they are most likely altered in AD [90, 91]. Recent research suggests that adult hippocampal neurogenesis (AHN) declines early in AD due to unknown pathophysiological mechanisms, contributing to cognitive diminution.

To illustrate, neurogenesis is reduced by ageing since progenitor cells and immature neurones progressively wane, stemming from inflammatory and hormonal modulations [92-94].

Additionally, ageing causes a decline in several hormones that have an impact on brain plasticity: for instance, insulin growth factor-1, vascular endothelial growth factor, and especially ghrelin. These have been demonstrated to promote hippocampal neurogenesis and synaptic plasticity, exhibiting neuroprotective effects [95, 96].

Neurogenesis is also affected by several other factors like that of nutrition, oxidative stress, neuroinflammation, brain injury, and opioid addiction [97, 98].

4.3 Glial Plasticity

Nonneuronal cells, such as glial cells, are essential for neuronal activity which was proposed by the quadripartite synapse model [99]. Glial cells are situated closely to the synapse and have a characteristic rapid alteration in response to environmental triggers, suggesting their critical position in synaptic manipulation [100, 101].

The role of glial cells is to be activated when neuronal injury ensues. In neuronal degeneration, while the ageing brain already stimulates gliosis and elevates pro-inflammatory precursors, neurodegenerative diseases also promote chronic activation of glial and astrocyte cells, leading to their degeneration [76, 102, 103].

According to studies, glial cells have a direct effect on the short-term neuroplasticity of synaptic clefts and exhibit sole plasticity when reacting promptly to environmental challenges in an effort to maintain network homeostasis [99, 100, 102].

This highlights the point of intersection between neuronal and glial plasticity in supporting neuronal health and activity, suggesting the contribution of chronic gliosis to memory and loss in learning skills in AD [100, 102].

4.4 Therapeutic Strategies Targeting Neuroplasticity to Decrease Cognitive Decline in AD Patients

Several proposed pharmacological and nonpharmacological strategies and therapies are currently being performed; however, we still lack defined standards to follow (Table 1).

Of these pharmacological strategies, one targets neurotransmitters. For instance, cholinesterase enzyme inhibitors, such as Rivastigmine, Galantamine, and Donepezil, aim to enhance synaptic plasticity via increasing acetylcholine alongside NMDA antagonists like Memantine that affect glutamate [104]. In addition, neurotrophins like neuron growth factor (NGF), glial cell-derived neurotrophic growth factor (GDNF), and BDGF are recognized for their role in regulating the survival, growth, and development of the brain [104].

Some nonpharmacological strategies comprise physical exercise and aerobic training which is well-known for enhancing cognition as well as increasing neuroplasticity [105]. Another could be cognitive training and programs in brain fitness that focus on memory, attention, language, and problem-solving skills [106, 107].

Moreover, technology has marched its way in AD treatment strategies as virtual reality (VR) and augmented reality (AR), brain computer interfaces, wearable- and sensory-based technologies. For instance, a recent meta-analysis has found a significant improvement in cognitively impaired patients treated with VR compared to cognitive training programs [108].

VR, by providing a digital three-dimensional environment that allows the patient to interact, provide sensory inputs, and track changes, is helping in cognitive rehabilitation, for example, memory, visual attention, dual tasking, and treating psychological symptoms such as anxiety reduction and well-being elevation [108].

Nevertheless, such technologies should be used cautiously and relied on due to the fact of the presence of potential limitations regarding the device's availability as a therapy tool that is used under supervision in hospitals and other healthcare facilities due to safety concerns for patients [109]. Besides, the notable side effects discovered, which might hinder the patient from participation, such as negative emotions experienced by the patient when failing in specific activity demands by the technology, the simulator sickness, oculomotor dysfunction, and visual disturbances, in addition to neck pain and dizziness [109].

Furthermore, synaptic dysfunction is one of the first obvious pathophysiological traits of AD that is now widely prevalent, and it typically manifests before there is a notable neuronal loss [77, 110]. This further elucidates the hypothesis of synaptic plasticity deterioration as the pathological origin behind AD [78]. Therefore, stimulating enhancements in the synaptic plasticity provided by rTMS, at the neurobiological level, may implement a therapeutic strategy with long-lasting cognitive effects on the adjustment of neuroplasticity in AD [77, 111]. For instance, TMS is a noninvasive method that utilizes electromagnetic pulses to stimulate different cortical tissues in specific areas enhancing neuroplasticity by creating electrical current, stimulating action potential, and enhancing cortical reorganization [112]. Furthermore, rTMS—involving rhythmic electromagnetic pulse sequencing—alters neurotransmitter activity and produces effects resembling those of LTP or LTD promoting better neuroplasticity [113]. In fact, applied rTMS promises effective results declining the rate of cognitive deterioration and disease progression in patients with AD [114]. However, there are some safety concerns that go against the use of rTMS in some populations especially with the limited long-term data [115]. For example, using TMS in individuals with implantable devices (pacemakers, cochlear implants, etc.) or metals can produce unwanted effects ranging from heating up and causing tissue damage to malfunction, excessive stimulation, or demagnetization [115]. In addition, TMS can precipitate seizure which is considered the most severe acute side effect, and it can lead to hearing loss and psychiatric side effects [115].