This comprehensive review synthesizes existing literature on Alzheimer's disease (AD), covering its epidemiology, risk factors, symptoms, diagnosis, management, caregiving, and treatments.

A systematic search was performed across multiple electronic databases, including PubMed, MEDLINE, Cochrane Library, and Scopus, from their inception to May 2024. The search strategy combined keywords and Medical Subject Headings (MeSH) terms related to Alzheimer's disease, such as “Alzheimer's disease,” “epidemiology,” “risk factors,” ‘symptoms,” “diagnosis,” “management,” “caregiving,” “treatment,” and “novel therapies.” Boolean operators (AND, OR) were used to refine the search and ensure comprehensive coverage of relevant articles.

Studies were included if they were peer-reviewed articles, reviews, or meta-analyses focusing on Alzheimer's disease, published in English, and addressed any of the following aspects of AD: epidemiology, risk factors, symptoms, diagnosis, management, caregiving, current treatments, and novel treatments. Exclusion criteria were non-peer-reviewed articles, editorials, commentaries, and conference abstracts, studies not related to Alzheimer's disease, and articles not available in English.

Full texts of potentially relevant studies were obtained and assessed for eligibility based on the inclusion and exclusion criteria. Data extracted from each study included epidemiological data (prevalence and incidence rates, demographic factors), risk factors (genetic, environmental, and lifestyle factors), symptoms and diagnosis (clinical features, diagnostic criteria, biomarkers, imaging techniques), management and caregiving (treatment approaches, caregiving challenges) and treatment data (efficacy and safety of current treatments, novel therapeutic approaches, clinical trial outcomes). A narrative synthesis was conducted to summarize findings across studies.

As this study involves a review of existing literature, ethical approval was not required. However, ethical standards were maintained by ensuring proper citation and acknowledgment of all sources.

β-Amyloid Precursor Protein (βAPP), a transmembrane protein, might have three different fates due to three distinct protease activities. α-secretase and β-secretase are cell surface proteases, whereas γ-secretase is an abnormal protease that cleaves membrane proteins inside their transmembrane regions. Ninety percentage of APP is cleaved primarily by the α -secretase, preventing the synthesis of the Aβ peptide. The remaining 10% of APP is cleaved by β and γ secretases to create either the harmless Aβ 40 peptide or the Aβ 42 peptide. Because the Aβ 42 peptide is more likely to aggregate than its A40 form, it is believed to be neurotoxic (26). Regarding previous statements, mutations in the gene encoding APP could cause substantial excess production of either total Aβ or increased Aβ-40/Aβ-42 ratio. This rise causes the accumulation of neurotoxic Aβ 42, which, based on the “amyloid hypothesis”, is the key and initial pathogenic event in all types of AD, monogenic or sporadic (8, 27). This hypothesis is supported by the fact that Down syndrome individuals with three copies of the APP gene (on chromosome 21) generally acquire the neuropathological abnormalities of AD by age 40 (28). Less than one percent of early-onset individuals have pathogenic mutations in APP (21, 29). In addition to harmful mutations, a protective variant called p. A673T was found in APP among Icelandic individuals. This variant is linked to a decrease in the production of the Aβ1-40 and Aβ1-42 peptides by ~40% (30).

PSEN1 and PSEN2 are both required proteins of the γ -secretase complex's catalytic core, which initiates the cleavage of APP (29). Mutant γ -secretase significantly shifts in Aβ1- 42/Aβ1- 40 ratio; due to that, mutations in PSEN1 and PSEN2 genes are related to AD pathogenesis (31). The significant difference between PSEN1 and 2 is the age at the onset, which PSEN1 is distinguished by, on average, 8.4 and 14.2 years younger onset than APP and PSEN2 mutations (32, 33). Mutations in PSEN1 causes the majority of familial EOAD cases. About 6% of EOAD patients have PSEN1 mutations, which cause the most severe type of AD (21). In contrast, PSEN2 mutations are uncommon, accounting for <1% of EOAD patients, and they may exhibit incomplete penetrance (21). Besides the three recognized causative AD genes, other well-replicated genes, including uncommon heterozygous mutations with low penetrance, affect the development of familial AD (34).

APOE gene on chromosome 19q13, which encodes the protein that makes up numerous plasma lipoproteins, was shown to be the primary susceptible gene in individuals with familial LOAD (21, 35–37). The three frequently encountered isoforms of APOE are ε2, –ε3, and –ε4. The most frequent form is ε3/ε3, which does not affect the development of AD (38). Nearly 40% of AD patients have the APOE 4 allele, demonstrating a significant risk-increasing impact of this isoform, which is also linked to the earlier onset of the disease (38, 39). However, this association is dose-dependent, meaning that if a person has two copies of ε4, they are more prone to experience symptoms at a younger age compared to someone with only one copy (36). So individuals who are homozygote for the ε4/ε4 gene tend to develop AD 10–15 years earlier than the average population (26). The ε2 allele, which is less common, seems to exert protective and beneficial effects when inherited alongside the ε3 allele, as opposed to individuals who carry two copies of the ε3 allele (40, 41). It is intriguing to note that while there is extensive molecular evidence linking APOE protein to AD-specific pathways, associations have been found between mutations in the APOE gene and the risk of various other neuropsychiatric disorders such as multiple sclerosis (42) and Parkinson's disease (43). Additionally, the APOE gene has supposed to be linked to age-related macular degeneration (44), several cardiovascular and cerebrovascular diseases (45, 46), and even longevity (41, 47).

A person with autosomal dominant inheritance has a 50% probability of transferring the disease-causing mutation to each offspring (48). If a person receives two mutant copies of a gene, one from each parent, the condition is said to be autosomal recessive. This would imply that while neither parent exhibits signs of the disorder, both parents contain a copy of a defective gene (22). Due to the identification of highly penetrant dominant AD-causing mutations, it has become widely believed that all instances of EOAD are caused by dominant alleles (49). It has been found through epidemiologic data that this belief is not consistent. Only about 10% of all cases follow this pattern, and the remaining 90% stay unexplained (50). A study carried out in 2012 demonstrated the genetic aspects of EOAD and the probable mechanism of inheritance by analyzing concordance between parents and offspring. Wingo et al. concluded that EOAD is completely linked to genetic mutations, but they declined an entirely dominant inheritance. They reported that EOAD is caused by autosomal recessive in most cases, and just 10% of individuals may be attributed to dominant variants (22). Autosomal inheritance is associated with EOAD, while LOAD inherits through a complex inheritance pattern, which refers to the complex nature of AD, that has been influenced by multiple factors, including genetic, environmental factors, and lifestyle (51).

Although smoking is primarily considered a risk factor for a variety of cardiovascular and pulmonary diseases, it is now undeniable that the negative health consequences of smoking extend beyond the aforementioned conditions to include some unexpected ones, such as neurocognitive and neurobiological conditions (52, 53). Despite the lack of research specifically investigating the negative effects of smoking on neurocognition and neurobiology, current evidence suggests that chronic smoking is associated with learning and memory deficits, global brain atrophy, and deficiencies in executive and intellectual abilities, all of which can precipitate the development of various neurodegenerative disorders, including AD (52). Accounting for 14% of AD cases worldwide, lifetime smoking is associated with earlier symptom onset and a 70% greater risk of AD development, and the risk increases significantly with higher cumulative smoking exposure (54, 55). Although these estimates are significant enough to consider smoking as an important risk factor for AD, it should be noted that there is even a possibility of an underestimation in the magnitude of the risk due to an unavoidable survival bias, which means that smokers who pass the selection process to enter the studies are probably healthier than those who are overlooked, and competing bias, which implies that the development of AD in studied smokers is precluded by smoking-related mortality (56).

Numerous potential mechanisms may contribute to smoking-related AD neuropathology, either directly or indirectly (52). To begin with, cigarette smoke contains several potentially cytotoxic and oxidizing constituents (e.g., phenolic compounds, nitrosamines, carbon monoxide, and free radicals) (57). Second, it raises the concentrations of proinflammatory cytokines in various parts of the brain, producing more free radicals (58). Third, it lowers the concentrations of glutathione and other antioxidants in the brain due to the increased demand to scavenge the amplified concentrations of free radicals (59). All these mechanisms, along with a few others that play minor roles, subject the brain to high levels of oxidative stress, which increases Aβ production and tau phosphorylation, potentially initiating the AD pathological process (60, 61).

Clinical studies suggest a bidirectional link between sleep and circadian sleep-wake rhythm disruptions and the developing of AD (62, 63). Poor sleep quality can exacerbate cognitive impairment in AD patients, and the risk of sleep disturbances rises dramatically as the disease progresses (64).

There is growing evidence linking sleep disturbances to the pathogenesis of AD (65). Several studies have demonstrated that sleep disturbances can increase Aβ levels in animal disease models and humans (66). A cross-sectional study indicated sleeping for 6 h or less was associated with more Aβ accumulation and decreased cognitive performance, particularly in memory (67).

Although sleep disturbances in AD are assumed to stem from pathological processes arising from Aβ accumulation, there may also be a bidirectional link between sleep-wake disruption and tau pathology (68). Lucey et al. found that the non-rapid eye movement (NREM) slow wave activity was inversely linked with tauopathy, suggesting that changes in NREM slow wave activity could help us detect tau pathology and cognitive impairment before or during the very early stages of symptomatic AD (69).

The pathogenesis of sleep disturbances and AD is not limited to pathological aspects alone; neuroinflammation is also a possible mechanism that connects these two issues (70). Abnormal sleep-wake cycles boost the synthesis of microglia Iba-1 and astrocyte glial fibrillary acidic protein and increase microglia-mediated proinflammatory release, further promoting the aggregation of Aβ and tau (71).

Besides these processes, the glymphatic system contributes significantly to the association between sleep and AD. The glymphatic system is a fast exchange and flow mechanism between Cerebrospinal fluid (CSF) and brain interstitial fluid (ISF) that relies on aquaporin 4 (AQP4) on the end foot of astrocytes to remove metabolites and abnormal proteins in the brain (72). Notably, fluid transport in the glymphatic system modulates lymphatic clearance periodically since it occurs during sleep, prolonged wave sleep, and it is inhibited during waking (73). Sleep disruptions can impair the glymphatic system function, resulting in Aβ and tau accumulation (66).

Evidence from both animal and human studies has demonstrated that chronic stress exposure detrimentally affects cognitive processes in many ways (74). Animal studies have shown that chronic stress and higher levels of glucocorticoids lead to structural remodeling in brain regions such as the prefrontal cortex and the hippocampus (74). This remodeling includes neuronal atrophy (75), dendritic shortening and spine loss (76, 77), and the suppression of neurogenesis (78). These changes ultimately result in cognitive impairments (79, 80). In humans, chronic stress experienced during early life or adulthood has a significant impact on cognitive skills and the development of distinct psychopathologies. However, individual differences indicate that different factors like sex and genetic composition may also play an essential role in the development of stress-related mental health issues, including MCI and AD (81).

Experimental evidence suggests that chronic stress and glucocorticoids play a dual role in the development of AD (74). Their key function in developing the disease is indicated by their ability to directly induce Tau hyperphosphorylation in rats' prefrontal cortex and hippocampus (82, 83). In addition, external glucocorticoids enhance the capacity of centrally administered Aβ to trigger excessive phosphorylation of Tau epitopes linked to AD, as well as the accumulation of Tau in the cytoplasm, and previous exposure to stress exacerbates the biochemical and behavioral consequences of glucocorticoids in animals infused with Aβ (82, 83). Therefore, long-term exposure to stress and glucocorticoids may have a gradual effect on the development and advancement of AD pathology (82).

Physically active individuals have a decreased prevalence and incidence of cognitive deficits and dementia, including AD (84–87). A meta-analysis of 16 prospective studies involving 163,000 non-psychotic participants indicated a 28 and 45% reduction in overall dementia and AD among those who were physically active compared to those who were less active, respectively (88).

Physical activity elicits several anatomic, cellular, and molecular modifications in the brain through the activation of a cascade of cellular and molecular processes that advance various physiologic phenomena, such as neurogenesis, synaptogenesis, angiogenesis, and stimulation of neurotrophic factors, which play a significant role in improving memory, learning, and brain plasticity (89–94). Normally, a dementia-free elderly will experience an annual hippocampal shrinkage of 1–2% (95). It has been demonstrated that moderate intensity exercise training can significantly reverse the shrinkage process of the hippocampal volume (95). A 1-year aerobic exercise intervention resulted in a 2% increase in hippocampal volume and neutralized the normal decline that occurs with aging (95), and older adults with life-long routine exercise have larger brain volume and enhanced executive function than those who are physically inactive (96). Several studies have also discovered an inverse association between the levels of physical activity and the plasma and brain Aβ load in the elderly without cognitive disorders (97, 98). Moreover, a 6-month aerobic exercise intervention in individuals with MCI resulted in a 24% reduction in the plasma Aβ levels when compared to the levels found in the control group (99). These findings, along with those of several preclinical studies on AD models (100–103), suggest that exercise may significantly regulate Aβ turnover and decrease tau phosphorylation (104).

Physical activity has been shown to have a positive effect on improving cognitive symptoms (105). AD patients who participated in a year-long moderate exercise program had a slower decline in their ability to perform activities of daily living and ameliorated their physical impairment (106, 107). Additionally, Aerobic exercise has been shown in some other studies to improve memory performance and cognitive function in aging, MCI, and AD patients (99, 108, 109).

Therefore, recent evidence suggests that physical activity strongly protects AD development, alleviates some AD-related clinical signs and symptoms, and slows disease progression (105). However, it has yet to determine the optimal duration of the activity, the type and intensity of the exercise, and when in a person's life it should transpire in order to optimize the potential protective effects (110).

The epidemiological data concerning the association between alcohol and cognitive decline and AD-type neurodegeneration have generated significant controversy, primarily due to the inconsistent and variable measurement parameters of both alcohol consumption and AD (111). However, a discernible trend has emerged, as indicated by epidemiological investigations, which propose that moderate alcohol intake diminishes the incidence of AD (112–114). In contrast, heavy alcohol consumption increases dementia and impairs cognitive and executive functioning (113, 115). Acetylcholine release in the hippocampus region, which improves learning and memory, is the most likely mechanism implicated in the protective effect of low alcohol consumption on cognitive impairment (116). Another proposed mechanism could be considered as reducing cardiovascular risk factors such as platelet aggregation or serum lipid profile (116). Also, alcoholic beverages, particularly red wine, contain polyphenols such as quercetin, morin, tannins, and resveratrol, which can inhibit amyloid aggregation and reduce oxidative stress, inflammation, and balance of protein homeostasis, all of which play essential roles in AD pathology (117). However, whether low alcohol consumption protects against AD is still debated (111) due to additional confounding factors such as the impact of social contact on alcohol drinking and disparities in alcohol metabolism (118).

In contrast, there is a greater degree of consensus in the literature regarding the impact of heavy alcohol consumption on the risk of developing AD and other types of dementia (118). Several studies have found a positive association between heavy alcohol consumption and risk of AD and dementia (114, 115, 119, 120); however, this has not been universally observed (119). Heavy alcohol consumption promotes a decline in cognitive performance comparable to that observed in AD (121). Loss of cholinergic neurons detected in AD patients, as well as hippocampal atrophy (122), have also been discovered in individuals consuming ethanol (123, 124), establishing a link between heavy alcohol consumption and cognitive decline, which may ultimately lead to the development of AD. A potential mechanism suggested for alcohol to induce AD is through the reduction of glymphatic function (125). The glymphatic system is crucial for the removal of brain waste, including Aβ (105). Since alcohol impairs glymphatic function, heavy drinking may lead to Aβ accumulation by decreasing its clearance, precipitating the cognitive dysfunctions observed in AD (105). In addition to the potential link to trigger dementia, alcohol abstinence after AD diagnosis appears to ameliorate the initial cognitive impairment noted (126). Also, it suggests that heavy alcohol consumption not only raises the risk of developing AD but also exacerbates its progression (115).

Overall, although numerous studies have investigated the effects of alcohol intake on AD, controversies still remain, mainly due to the heterogeneity that exists between the studies regarding the age of participants, pattern, and duration of alcohol consumption, types of alcoholic drinks consumed, and underlying medical conditions and comorbidities (118).

Several studies have concluded that midlife obesity, as evaluated by anthropometric measures such as BMI or the waist-to-hip ratio (WHR), is associated with an elevated risk of late-life AD and dementia in general, regardless of other risk factors (127–133). However, most of these studies have also agreed that there is a reverse causality impact, with BMI decreasing in the years before dementia onset (134). These studies demonstrated that the association between BMI and dementia is likely to be due to two distinct processes: a harmful effect of higher BMI, which is visible in long follow-up, and a reverse-causation effect that makes a higher BMI appear protective when the follow-up duration is short (134). In a prospective cohort study, the HR for AD was 0.89 (95% CI 0.81–0.98) among those with high late-life BMI; however, there was 20% increased risk of AD (95% CI 1.09–1.33) among those with greater BMI decrease from midlife to late-life (131). Moreover, another study found that HRs per 5-Kg/m² rise in BMI for dementia were 0.71 (95% CI = 0.66–0.77), 0.94 (0.89–0.99), and 1.16 (1.05–1.27) when BMI was measured 10, 10–20, and >20 years before dementia diagnosis (133). It has been claimed that this “obesity paradox” or weight loss just before and during the clinical phase of dementia is linked to an increase in energy expenditure and hypothalamic dysfunction (134).

Low nutritional quality is strongly associated with cognitive impairment and the development of AD (135). Additionally, Protein-calorie malnutrition increases the risk of mortality in AD patients (136). Consumption of refined carbohydrates or a high glycemic index diet can lead to increased Aβ peptide accumulation in the brain (137). This impact is even significantly worse in APOE-ε4 carriers (137). However, the exact mechanisms of this association are still not being unraveled (138, 139). A western dietary pattern increases the risk of AD by promoting inflammation, making changes in metabolism, and decreasing cerebral perfusion, all of which impair cognition (140). On the contrary, adherence to the Mediterranean diet is associated with a lower risk of developing AD (137). The Mediterranean diet, rich in fruits, vegetables, fish, and whole-grain cereals, has been associated with better cognitive outcomes, increased gray matter volume (141–143), and a lower risk of developing MCI and AD, and of converting from MCI to AD (144, 145).

While it is clear that adherence to the Mediterranean diet improves cardiovascular health and protects against cerebrovascular diseases (146, 147), the protective association between Mediterranean diet and AD does not appear to be mediated by its effects on stroke or vascular risk factors (148). A 3-year serial amyloid and FDG-PET imaging study found that middle-aged cognitively healthy adults who followed a Mediterranean-style diet showed lower amyloid plaque deposition and cerebral hypometabolism, regardless of APOE genotype or vascular risk factors (149). This finding supports the protective effect of the Mediterranean diet against AD (134).

A ketogenic diet may also be effective in preventing AD, as it reduces oxidative stress, inflammation, and the harmful consequences of altered glucose metabolism in the brain. Moreover, it can improve attention, verbal memory, and overall cognitive performance (137).

Furthermore, appropriate omega-3 polyunsaturated fatty acids, particularly EPA and DHA, are related to slower cognitive decline and a lower risk of AD (137). As a result, it is critical to counsel people at risk of developing of AD to consume sources of omega-3 such as seeds, fish, nuts, fish, and vegetable oils (150, 151).

Social isolation, traditionally known for its detrimental effects on both mental and physical wellbeing, has been shown to deteriorate cognitive function, accelerate psychological aspects of aging, and increase the likelihood of developing AD and overall dementia (152–155). However, it should be highlighted that this relationship is bidirectional, as early symptoms of AD may also lead the person to feel socially isolated (152). Social isolation has two aspects: objective, which includes the lack of social networks and reduced engagement in social activities, and perceived, which encompasses feelings of loneliness and inadequate social support (156). Evidence suggests a strong correlation between these aspects and cognitive decline (152).

Social isolation may influence AD development via psychological and neurobiological pathways (152). According to the cognitive reserve hypothesis, the brain uses pre-existing cognitive processes or activates compensating pathways to deal with brain damage (157). Lower education and occupational attainment and decreased participation in leisure activities have been associated with a lower cognitive reserve (157) and an increased risk of developing AD (158, 159). Social isolation reduces cognitive stimulation, potentially leading to lower cognitive reserve, thereby increasing the risk of cognitive decline (160).

Memory loss and cognitive impairment are key indicators of AD. The severity of cognitive impairment correlates best with the burden of neocortical neurofibrillary tangles, which are a hallmark of AD (231). Memory loss is among the first symptoms reported by patients suffering from AD. Disease pathology interferes with the formation of memories from the molecular level to the framework of neural networks (232). Prospective studies indicate an early decline in executive functions and episodic and semantic memory processing in the predementia period (233). Low performance in learning and memory functions may be the earliest cognitive manifestations of preclinical AD (234). Also, asymmetry in cognitive abilities may occur in the preclinical phase of AD (235). Memory test scores reflecting the difference between immediate and delayed recall are important in identifying which individuals with recent cognitive changes will progress to where they meet the criteria for Alzheimer's over time (236). Episodic memory decline is the most salient cognitive function that correlates with high levels of amyloid deposition and hypoconnectivity across large-scale brain networks (233).

Personality changes occur alongside or sometimes before cognitive symptoms (237, 238). A systematic review showed increased neuroticism and decreased extraversion, openness, agreeableness, and conscientiousness (239, 240). A significant change from positive to negative characteristics in personality is detected after the beginning of AD (241).

Balance and mobility impairments are linearly correlated with cognitive function and can be observed at the beginning of the subjective cognitive decline stage (242). For instance, an impaired one-leg balance test indicates a higher cognitive decline (243). Standing balance in people with AD is significantly impaired across a range of static and dynamic balance conditions. Activity level, mobility measures, turning, and dual tasks are also impaired (244).

Gait parameters can differentiate between healthy elderly, mild cognitive impairment, and AD patients (245). Gait analysis can potentially contribute to the diagnosis and prognosis of cognitive impairment (246). Dual-tasking frequently results in gait disturbances, which may affect gait stability and increase the risk of falling (247). Overall, gait analysis can be a useful tool for identifying AD and monitoring its progression.

Loss of sensation may be an indicator of AD. AD patients have a sensory gating deficit, which may result from cholinergic dysfunction and alpha-7 nicotinic receptor loss (248). They also have an impaired sensation of pain, which means their pain tolerance is increased, and their reaction to pain is markedly diminished (249, 250). Loss of reflexes may be a relevant sign in the diagnosis of AD. The palmomental reflex is more frequent in AD patients even 2 years before diagnosing AD (251). Also the prevalence of primitive reflexes is correlated with dementia severity (252).

Abnormal eye movement or vision can indicate AD. Eye movements, including saccades and smooth pursuit, seem to be slower and less accurate as a result of the disease. Even subtle functions, such as microsaccades and pupillary dilations, are changed by AD (253). A decrease in concentration is one of the symptoms that comes with cognitive decline, which causes frequent eye and facial movements. These differences can be used to screen AD symptoms quickly, even with camera recordings (254).

Among the earliest symptoms seen in AD patients are visual impairments, particularly loss of contrast and color sensitivity, limited visual field, compromised visual attention, reduced stereopsis, and impaired object and face recognition (255–259). Anatomical changes within the eye have been detected before signs of cognitive impairment and memory loss appear (257). All parts of the visual system, including the optic nerve and the retina, may be affected in AD (260). According to a systematic review, the peripapillary retinal nerve fiber layer (RNFL) and macular thickness are significantly decreased in AD patients (261).

Among motor signs during AD, tremor is the least frequent and appears independent of disease progression (262–266). As AD progresses, the frequency of motor signs like speech/facial expression, rigidity, posture/gait, and bradykinesia also increase (266, 267).

As reviewed above, the physical examination results can help us diagnose AD, and in some cases, even better and sooner. Other diagnostic assessments are used with physical examination and can either confirm our diagnosis or rule out other diseases (268–270).

AD is a slow and progressive disorder, and it's been difficult for clinicians to identify the transitions from the asymptomatic phase to the symptomatic predementia and dementia phase (270). In cases of mild cognitive impairment (MCI), physical examination alone can't indicate the progression to AD, and here, the biomarkers are a great help in identifying this matter (271, 272). Additionally, all cognitive tests are influenced by some unchangeable variables like age, education, and cultural variations between individuals (270).

Intracellular alterations in individuals with AD may be detected early by using inflammatory markers (278). Interleukin-6, 12, and 18, as well as tumor necrosis factor (TNF) and transforming growth factor (TGF), have been shown to be present in increased concentrations in the blood of AD patients (279).

Additionally, glial cells may become pro-inflammatory if stimulated for an extended period, as in AD (280). Microglia and astrocytes express the inflammatory marker chitinase-3-like protein 1 (also known as YKL-40). Astrocytes close to Aβ plaques express YKL-40 in AD, and tau pathology positively correlates with this expression (281, 282). Another biomarker connected to AD's progression is glial fibrillary acidic protein (GFAP). Prins et al.'s cross-sectional investigation showed that preclinical AD patients had higher plasma levels of GFAP than healthy controls (283).

To identify reliable biomarkers in AD, researchers have focused on measuring Aβ and tau in CSF and blood, as well as using neuroimaging techniques such as FDG-PET, Pittsburgh compound B-PET, and MRI to measure hippocampal volume (327, 328). It is now advised to use a multi-marker strategy since none of these instruments can aid in diagnosing independently. As a result, the availability of non-invasive, readily accessible biomarkers is very valuable. Researchers have suggested various new biomarkers, such as inflammatory markers, fluorescent nanoparticles, and microRNAs.

According to a recent systematic review, a total of 10 microRNAs (miRNAs) have a substantially altered expression in individuals with AD compared to normal subjects, as evidenced by at least two independent investigations. Furthermore, the research highlights that over thirty miRNAs can differentiate between two distinct neurodegenerative disorders (329). AD patients ' extracellular fluid (ECF) and CSF were reported to have higher levels of some miRNAs, including pro-inflammatory miRNA-9, miRNA-125b, miRNA-146a, and miRNA-155 (330).

One further potential biomarker for the diagnosis of AD is fluorescent nanoparticle kits. The outcomes of efforts to develop these kits include the AD Diagnostic Kit WO2002/088706, which uses glutamine synthetase as an indicator, and WO2010/144634, which detects DNA methylation as an epigenetic marker to diagnose AD (331). Furthermore, Park et al. confirmed that the fluorescent nanoparticles they created and the WO2002/088706 kit would potentially give an early diagnosis of AD using plasma from AD patients (332).

Inflammatory biomarkers, including IL-6, CRP, and TNF-α, may be additional cutting-edge biomarkers for identifying AD due to the inflammatory character of the disease. However, a recent meta-analysis by Ng et al. found no difference in IL-6, CRP, and TNF levels between elderly with AD and controls (333).

Magnetic resonance imaging (MRI) is a non-invasive imaging technique that uses strong magnetic fields to generate detailed brain images. In AD diagnosis, MRI primarily assesses brain structure, detects atrophy, and rules out other potential causes of cognitive impairment, such as tumors or vascular abnormalities (336, 337). MRI scans reveal brain atrophy, particularly in regions critical for memory formation (336, 337). Advanced MRI techniques can quantify microstructural changes and accurately measure brain volume loss, aiding early AD detection and monitoring disease progression (336, 337). However, it should not be relied upon alone in identifying evidence of AD due to its low accuracy (338). The sensitivity of MRI in detecting AD in patients with mild cognitive impairment is 73%, and the specificity is 71% (338).

Computed tomography (CT) is another imaging modality used in Alzheimer's diagnosis, but less frequently than MRI (339). CT scans provide detailed cross-sectional brain images and can help rule out other pathologies that may mimic AD symptoms. CT scans can reveal structural abnormalities in the brain, such as ventricular enlargement or cortical atrophy, associated with AD (339). CT is often more readily available and quicker to perform than MRI, making it useful in specific clinical situations when MRI is contraindicated (336). In AD, microscopic histological changes are associated with focal atrophy in the medial temporal lobe region, including the hippocampus, reflecting the typical progression of neuropathology, which can be assessed in vivo using MRI (339, 340). Many studies have evaluated the diagnostic value of hippocampal atrophy for AD using MRI, with overall sensitivity and specificity estimated to be 85 and 88%, respectively (341).

Positron emission tomography (PET) is a powerful imaging technique that provides functional information about the brain's metabolic and molecular processes. PET scans detect specific hallmarks of AD pathology, such as the accumulation of amyloid plaque and intracellular hyperphosphorylated tau neurofibrillary tangles, as well as changes in glucose metabolism (342, 343). Amyloid plaques are deposits of beta-amyloid protein that accumulate between nerve cells, while neurofibrillary tangles are twisted tau protein fibers that build up inside nerve cells (344). Although imaging techniques cannot directly visualize neurofibrillary tangles, they can infer their presence by detecting associated brain atrophy and functional abnormalities (345). As amyloid-targeting therapeutics emerge in the treatment of AD, amyloid PET scans are being used to determine patients' eligibility for clinical trials and to assess treatment outcomes. Three Amyloid-β radiotracers, namely ¹⁸F-florbetaben, ¹⁸F-florbetapir, and ¹⁸F-flutemetamol, are currently approved by the FDA for use in clinical practice (346). Moreover, the development of numerous second-generation tau PET tracers with enhanced binding properties has been achieved. These tracers include [18F]MK6240, [18F]PM-PBB3, [18F]RO948, [18F]PI-2620, [18F]JNJ311, and [18F]Genentech Tau Probe 1 (GTP1) (347, 348). Each of these radiotracers has its own set of procedural guidelines and acceptable interpretation techniques, but they all share the fundamental property of binding to white matter, not gray matter. Accordingly, abnormal scans will demonstrate evidence of diminished gray-white differentiation, outward radiotracer extension from the white matter to the cortical surface, or increased radiotracer uptake by gray matter compared to white matter (349). In addition, the FDA has authorized the use of the ¹⁸F-flortaucipir radiotracer to visualize the distribution and density of NFTs in patients with cognitive impairment who are being assessed for AD. Since changes in tau PET binding are correlated with cognitive symptoms, this radiotracer provides value not only for diagnosing AD but also for tracking the spatiotemporal progression of tau pathology in longitudinal investigations (350).

Additionally, PET measures glucose metabolism, allowing clinicians to assess brain function and detect regions with reduced metabolic activity, which is indicative of Alzheimer's-related neuronal dysfunction (342, 351). PET can be used to study brain metabolism and visualize glucose metabolism using the metabolic tracer ¹⁸F-fluorodeoxyglucose (FDG) (352, 353). PET scans with FDG or other radiotracers provide insights into regional changes in cerebral blood flow and glucose metabolism, highlighting areas of reduced neuronal activity (352, 353). In AD, hypometabolism in the temporal, parietal, and posterior cingular regions distinguishes AD patients from controls with good discriminatory power (354, 355). Recent studies show that amyloid PET brain imaging is highly sensitive and specific for neuropathologically confirmed AD, while FDG PET is highly sensitive and moderately specific (356).

In conclusion, MRI and CT scans reveal progressive brain atrophy, especially in regions associated with memory and cognition. PET imaging, using multiradiopharmaceutical agents, identifies the presence and distribution of amyloid plaques and intracellular hyperphosphorylated tau neurofibrillary tangles in the brain. As our understanding of Alzheimer's disease advances, imaging techniques are expected to become increasingly refined, providing more accurate and informative insights into this devastating condition.

AD is a condition that causes a gradual loss of cognitive abilities. Research has explored the potential neuroprotective effects of N-methyl-D-aspartate (NMDA) receptor antagonists for AD. These antagonists are critical for synaptic plasticity and transmission (416). Excessive activation of glutamate receptors, particularly the NMDA type, can lead to excitotoxic effects on neurons and is thought to contribute to neurodegeneration. Synaptic dysfunction in AD may be attributed to atypical activation of the NMDA receptor. The NMDA receptor antagonist memantine is especially effective in blocking the receptor and reducing the influx of calcium (Ca2+) ions into neurons, thereby preventing toxic intracellular events from occurring (416). Memantine may slow cognitive decline by reducing excitotoxicity and promoting neuroplasticity through modulation of glutamate transmission (417). In AD, acetylcholine is a neurotransmitter that is significantly depleted. Some antidepressants, like trazodone, have anticholinergic properties, which can be useful for managing agitation and behavioral symptoms in AD patients by modulating the cholinergic system (418).

Active and passive immunization are the two immunotherapeutic approaches which promote amyloid beta and tau clearance.

Some anti-Aβ antibodies have shown promising effects in trails, including aducanumab (488), lecanemab (435), and donanemab (438). The first two were approved by the US FDA in 2021 and 2023, respectively. Solanezumab is a monoclonal antibody (mAb) that targets monomeric Aβ peptide. It has been investigated in phase 3 clinical trials, with three unsuccessful trials reported in 2014, 2021, and 2023 (489–491). Bapineuzumab (492), crenezumab (493), and gantenerumab (494) are also anti-Aβ antibodies which have failed to show beneficial effects in improving cognitive functions in phase 3 clinical trials in AD patients. To date, three anti-tau antibodies—semorinemab (495), gosuranemab (496), and tilavonemab (497)—have failed to slow the progression of AD in phase 2 trials.

New emerging therapies are being investigated to identify new therapeutic agents for AD. This includes BIIB080, an investigational therapy and an antisense oligonucleotide (ASO) targeting tau expression. In a phase 1 randomized clinical trial, BIIB080 was evaluated in AD patients and was found to reduce tau biomarkers. The effects of this agent are being further evaluated in phase 2 trials (498). Another new agent under study is trontinemab, a bispecific modular fusion protein composed of gantenerumab and a human transferrin receptor, which aids in crossing the blood-brain barrier. This agent is still being studied for potential use in clinical trials (499).

Intravenous immunoglobulin (IVIg) and plasma exchange are two other treatment options which have been studied but not shown as promising results as mAbs (500, 501).

Gene therapy uses different strategies and targets specific regions of the brain in order to treat AD, for example, acting directly on amyloid precursor protein, increase neuroprotection, boosting autophagy-mediated pathways, targeting inflammatory pathways, and modulating genes related to lipid metabolism (502). Most of these strategies exhibit positive results in improving cognition in animal models. However clinical studies have shown inconclusive results mostly related to delivery methods used in gene therapy (503). Gene therapy has shown a great potential for treating AD, but for now clinical results are not ready to be relied on and it needs more evaluations in order to be used in AD treatment.

The majority of stem cells used in AD therapy include neural stem cell (NSC), mesenchymal stem cell (MSC), embryonic stem cell (ESC), and induced pluripotent stem cell (iPSC) (504). NSC has been studied on cellular level and animal models (505–512). Generally, NSC therapy appears to be more effective in early stage of AD. MSC therapy is studied the most and has entered clinical levels (513). It uses different mechanisms in the brain and ultimately can improve cognition (514). ESC is studied in animal models and higher memory ability was achieved as the result (515). In the past few years iPSC is the most studied stem cell in clinical levels and has shown some promising results, but there is a risk for infection and tumorigenicity which indicates the need for more investigations (516, 517). Overall, stem cell therapy has shown to be a promising treatment for AD in the future, but for now it needs a lot more investigations specially in clinical levels to become available.

Digital therapeutics (DTx) is an emerging field that provides evidence-based therapeutic interventions via internet and software, employing tools such as mobile devices, computers, videogames, apps, sensors, and virtual reality. DTx is used as an adjunctive therapy in AD for improving memory, cognition, functional abilities, and managing motor symptoms (518).

As previously mentioned, caregivers play a crucial role in detecting early changes in a patient's cognitive abilities and can significantly contribute to the early diagnosis of individuals with AD. Therefore, it is propose that mHealth applications designed to support caregivers should incorporate a category of AD diagnosis tests. This functionality should encompass various cognitive dimensions and track the progression of cognitive impairment over time. This feature allows caregivers to administer cognitive tests to identify early signs of cognitive decline and share the results with physicians to facilitate personalized treatment options (534).

Spouses and adult children who care for family members with AD often experience five distinct phases of caregiving throughout the course of the disease. These phases involve monitoring initial symptoms, navigating the diagnosis process, assisting with instrumental and basic activities of daily living, and preparing for the future. Although it is evident that involving AD caregivers in the patient's care management is beneficial, they are frequently excluded from the care team or undervalued in their role. Many caregivers desire active involvement in decision-making processes related to AD care, ranging from diagnosis to treatment (535, 536). Considering that AD is characterized by progressive cognitive decline, the information that caregivers can provide is notable. They can advocate for the patients and offer insights that no other healthcare professional within the care team can provide. Additionally, caregivers often neglect their own needs while providing care, leading to a higher likelihood of having multiple chronic conditions. For instance, studies have shown that 35% of caregivers aged 45–64 and 53% of those over 65 have two or more chronic conditions. Individuals with chronic conditions may face limitations due to their own illness, making it increasingly challenging to provide care as the disease progresses and requiring more extensive self-care (537, 538).

Incorporating caregivers as valuable assets within the healthcare team model can significantly enhance the quality of care provided. Previous reviews of dementia knowledge training for caregivers have demonstrated that such education generally leads to improved caregiver outcomes. However, most of these reviews have focused on training content, such as attitudes, beliefs, confidence, perceived competence, and self-efficacy. Additionally, these reviews have primarily assessed the effectiveness and outcomes of interventions rather than focusing on the evaluation instruments utilized in the programs. To address this, Burgio and colleagues recommended using standardized and recognized tools to prevent biased results and enhance the methodological rigor of studies. A previous systematic review of five validated instruments for evaluating dementia knowledge identified several limitations, including weak psychometric properties, outdatedness, and limited scope. Therefore, there is a clear need to understand further dementia knowledge instruments developed by the authors and previously published to improve their effectiveness and applicability. When individuals with dementia experience communication difficulties, it becomes increasingly challenging for them to participate socially and engage in interactions. This can lead to social isolation and hinder their ability to maintain relationships and contribute to society (539). Recognizing the importance of addressing both the cognitive and social consequences of dementia, the INTERDEM Social Health Taskforce and the European Working Group of People with Dementia (EWGPWD) emphasize the need to prioritize social health for this population (540).

One approach to improving communication between caregivers and individuals with dementia is through caregiver communication enhancement education and training techniques. One example of such a program is “FOCUSED” (541). FOCUSED is a structured program that aims to provide caregivers with information about AD and communication, correct any misconceptions about communicating with individuals diagnosed with the disease, and offer techniques to maximize communication potential (542). Various strategies are recommended, including using closed-ended or choice-based questions instead of open-ended ones, using direct and straightforward phrases, repeating key words and ideas, noting changes in conversation topics, employing direct contacts such as touch and eye contact, and utilizing comments and non-verbal cues to maintain the quality and flow of conversation (543, 544).

Other similar programs incorporate additional strategies, such as providing positive feedback when individuals with dementia follow through on requests, allowing sufficient time to respond to questions or requests, and engaging them in conversations about their lives and interests. Caregivers are also advised to provide specific instructions rather than general ones, use one-step instructions, and offer positive comments to the person with dementia (545). Furthermore, some programs teach caregivers personalized strategies to enhance communication with specific individuals with AD. These approaches rely on “conversation analysis”, which helps caregivers identify effective and ineffective conversation techniques and utilize the participants' strengths to improve their interactions. Additionally, activity-based interventions to increase communication can be conducted individually or in groups, incorporating specific activities (e.g., meal preparation) or various activities to stimulate communication. These groups typically focus on improving or maintaining functional skills, with communication being a central aspect (545, 546).

As discussed in the previous part, caregivers of Alzheimer's patients face many challenges. For maintaining physical and mental health, engaging in self-care strategies is crucial. It has been shown that self-care practices for professional caregivers have reduced occupational stress and increased resilience, a critical skill one acquires to bounce back from difficulties and stress at work (547). In addition to lowering burnout, distress, and diminished competence, self-care provides a positive and supportive work environment (548).

Also, there are many informal caregivers (ICGS) for Alzheimer's disease and related dementias (ADRD). In contrast to non-caregiving populations, ADRD ICGs practice less self-care (549), and stress and burden have been associated with less effective self-care (550, 551). Also, as a recent study showed, ICGs demand not only personal needs like maintaining their physical and mental health; providing enough information, awareness, and insight are also critical components that should be provided (552). In this article, we mention some important points of self-caring for both ICGs and formal caregivers in individualized institutions.

For caretakers, self-care must include both exercise and a balanced diet. Physical exercise could enhance mood, lessen stress, and increase general wellbeing (553). In addition, a balanced diet full of fresh produce, including vegetables and fruits, lean meats, and whole grains, may offer careers the nutrients they need to promote their wellbeing (554).

Caregivers may benefit from mindfulness and relaxation practices to reduce stress and improve their psychological wellbeing. According to studies, mindfulness techniques like deep breathing exercises and meditation aid in reducing symptoms of stress, depression, and anxiety. Regularly practicing mindfulness may assist caregivers in developing a feeling of peace and enhance their capacity to deal with the difficulties of caring (555, 556).

Caregivers should take time for themselves and partake in activities they like. Maintaining personal interests and hobbies is imperative. According to a study, satisfying activities may lower stress levels and enhance general wellbeing (557). Caregivers should recharge and keep a sense of identity apart from their caring position by taking breaks from their duties and making time for personal interests (558).

Social engagement and receiving social support are other examples of self-care demands. Studies of mostly female ADRD ICGs showed that support networks are crucial for stress management, sharing responsibilities and caring tasks, advocating for self-care, validating ICGs' needs for self-care, and offering self-care advocacy (559–563). Another study on ADRD ICGs showed that engaging in spiritual and religious activities like attending churches and praying provides them courage and emotional support (561, 564, 565).

In summary, self-care practices are essential to minimize adverse health consequences from caring for Alzheimer's patients and to achieve optimum health and quality of life outcomes. Caregivers must remember that not only prioritizing self-care and self-management is not selfish, but it is also a demand for patients' health.