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This report is written by MaltSci based on the latest literature and research findings

What causes Alzheimer's disease? ​

Abstract ​

Alzheimer's disease (AD) is a leading cause of dementia, marked by progressive cognitive decline and memory loss. Despite extensive research, the precise etiology of AD remains unclear, reflecting its multifactorial nature involving genetic, environmental, and lifestyle influences. Genetic factors, particularly the apolipoprotein E (ApoE) gene, have been identified as significant risk factors, with the ε4 allele associated with increased disease susceptibility. Familial AD, linked to mutations in the amyloid precursor protein and presenilin genes, highlights the genetic underpinnings of early-onset forms of the disease. Environmental factors, such as air pollution and heavy metal exposure, have emerged as critical contributors to AD pathogenesis, promoting oxidative stress and neuroinflammation. Lifestyle choices, particularly diet and physical activity, also play a crucial role in modulating AD risk, with healthy dietary patterns and regular exercise shown to have protective effects on cognitive function. Pathologically, AD is characterized by the accumulation of amyloid-beta plaques and neurofibrillary tangles formed by hyperphosphorylated tau protein, leading to neuronal dysfunction and death. Neuroinflammation and vascular dysfunction further exacerbate the disease process. Current research trends focus on identifying biomarkers for early diagnosis and developing multitarget therapeutic strategies aimed at modifying disease progression. Understanding the intricate web of factors contributing to AD is essential for advancing treatment options and improving patient outcomes.

Outline ​

This report will discuss the following questions.

  • 1 Introduction
  • 2 Genetic Factors
    • 2.1 Role of Apolipoprotein E (ApoE) Gene
    • 2.2 Familial Alzheimer's Disease and Genetic Mutations
  • 3 Environmental Influences
    • 3.1 Impact of Air Pollution
    • 3.2 Influence of Heavy Metals and Toxins
  • 4 Lifestyle Factors
    • 4.1 Diet and Nutrition
    • 4.2 Physical Activity and Cognitive Engagement
  • 5 Pathological Mechanisms
    • 5.1 Amyloid-beta and Tau Pathology
    • 5.2 Neuroinflammation and Vascular Contributions
  • 6 Current Research and Future Directions
    • 6.1 Emerging Biomarkers
    • 6.2 Novel Therapeutic Approaches
  • 7 Conclusion

1 Introduction ​

Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder characterized by progressive cognitive decline, memory loss, and ultimately, a decline in the ability to perform daily activities. It is the most prevalent cause of dementia, affecting millions of individuals globally and imposing a significant burden on healthcare systems and families [1]. Despite extensive research efforts spanning over a century, the precise etiology of AD remains elusive, underscoring the complexity of this disease. Current understanding suggests that AD is not attributable to a single factor; rather, it results from an intricate interplay of genetic, environmental, and lifestyle influences that contribute to its onset and progression [2].

The significance of elucidating the causes of Alzheimer's disease cannot be overstated. As the global population ages, the incidence of AD is projected to rise sharply, highlighting an urgent need for effective therapeutic interventions and preventive strategies [1]. A comprehensive understanding of the multifactorial nature of AD is essential for the development of novel treatment modalities that not only address symptoms but also target the underlying pathophysiological processes [3]. Recent advancements in research have begun to unravel the contributions of various factors, including genetic predispositions, environmental toxins, lifestyle choices, and the roles of neuroinflammation and vascular dysfunction [1][2].

Current literature emphasizes the role of genetic factors, particularly the apolipoprotein E (ApoE) gene, which has been implicated as a major risk factor for sporadic AD [1]. Furthermore, familial AD has been linked to specific genetic mutations, including those in the amyloid precursor protein (APP) and presenilin genes [4]. In addition to genetic influences, environmental factors such as air pollution, heavy metal exposure, and lifestyle choices including diet and physical activity have been shown to impact the risk of developing AD [5][6]. The intricate relationship between these factors highlights the necessity for a holistic approach in AD research, as the interactions among genetic, environmental, and lifestyle factors can significantly influence disease onset and progression [1].

The pathological mechanisms underlying AD are complex and multifactorial. Central to the pathology are the accumulation of amyloid-beta plaques and neurofibrillary tangles composed of hyperphosphorylated tau protein [1][2]. These hallmark features disrupt neuronal function and are associated with neuroinflammation, oxidative stress, and vascular abnormalities [7]. Recent studies have begun to elucidate the connections between these pathological processes and the cognitive decline observed in AD patients [1].

This report is organized as follows: First, we will delve into the genetic factors associated with AD, examining the role of the ApoE gene and familial genetic mutations. Next, we will explore environmental influences, focusing on the impacts of air pollution and exposure to heavy metals and toxins. Following this, lifestyle factors such as diet and physical activity will be discussed in relation to their contribution to AD risk. We will then investigate the pathological mechanisms of AD, specifically the roles of amyloid-beta and tau pathology, along with neuroinflammation and vascular contributions. Finally, we will review current research trends and future directions in the field, including emerging biomarkers and novel therapeutic approaches that aim to address the multifactorial nature of AD [1][4].

By synthesizing recent findings, this report aims to provide a comprehensive overview of the various elements that may lead to Alzheimer's disease, reinforcing the importance of a multifaceted approach in both research and treatment strategies. Understanding the intricate web of factors contributing to AD will ultimately inform future therapeutic interventions, with the goal of improving patient outcomes and quality of life.

2 Genetic Factors ​

2.1 Role of Apolipoprotein E (ApoE) Gene ​

Apolipoprotein E (ApoE) is recognized as the most significant genetic risk factor for late-onset Alzheimer's disease (AD). The APOE gene, located on chromosome 19, encodes three major isoforms: ApoE2, ApoE3, and ApoE4. The presence of the APOE ε4 allele has been associated with an increased risk of developing AD, while the ε2 allele appears to confer a protective effect against the disease. The APOE ε4 allele is linked to a higher likelihood of developing AD at an earlier age, whereas the ε2 allele is associated with a delayed onset [8][9][10].

The pathological mechanisms through which ApoE influences AD risk are multifaceted. One critical role of ApoE is its involvement in lipid metabolism, which is essential for neuronal health and function. Specifically, ApoE is involved in the clearance of amyloid-beta (Aβ), a peptide that aggregates to form plaques characteristic of AD. The isoforms of ApoE exhibit differential effects on Aβ metabolism; for instance, ApoE4 has been shown to enhance Aβ deposition in the brain, whereas ApoE2 may facilitate its clearance [11][12].

In addition to its effects on amyloid metabolism, ApoE is implicated in various other biological pathways that are relevant to AD pathogenesis. These include neuroinflammation, synaptic plasticity, and the maintenance of neuronal health. The isoform-specific interactions of ApoE with other molecules may also influence the progression of AD through pathways unique to the disease [13][14].

Recent research has highlighted the importance of the cellular context in which ApoE operates. For instance, astrocytes are the primary source of ApoE in the brain, and their metabolic functions are crucial for supporting neuronal activity. Studies indicate that astrocytes expressing the ApoE4 isoform demonstrate impaired glucose metabolism, which may contribute to neuronal dysfunction and AD pathology [15].

Furthermore, emerging evidence suggests that the effects of ApoE extend beyond amyloid pathology to include tau-related neurodegeneration, which is another hallmark of AD. Neuronal expression of ApoE4 has been associated with increased neurotoxicity and greater risk of tau pathology, implicating ApoE in multiple facets of the disease [12].

In summary, the genetic factor of ApoE plays a pivotal role in the etiology of Alzheimer's disease through its influence on lipid metabolism, amyloid and tau pathologies, and neuroinflammatory processes. The differential effects of its isoforms underscore the complexity of its role in AD and highlight the potential for targeted therapeutic strategies aimed at modulating ApoE function to mitigate disease risk and progression [10][12].

2.2 Familial Alzheimer's Disease and Genetic Mutations ​

Alzheimer's disease (AD) is recognized as the most common cause of dementia, with its etiology being complex and multifactorial. A significant aspect of this complexity lies in the genetic factors contributing to both familial and sporadic forms of the disease.

Familial Alzheimer's disease (FAD), which typically manifests with an early onset (before the age of 65), is associated with rare mutations in specific genes. These mutations primarily occur in the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes. The inheritance pattern for these mutations is autosomal dominant, which means that a single copy of the mutated gene can lead to the development of the disease, resulting in nearly 100% penetrance in affected families (Castillo-Ordoñez et al. 2024) [4].

In contrast, late-onset Alzheimer's disease, which typically occurs after the age of 65, is generally regarded as polygenic or multifactorial. The most clearly identified genetic risk factor for late-onset AD is the apolipoprotein E (ApoE) gene, specifically the epsilon4 allele (ApoE ε4). This allele has been shown to influence the age of onset of the disease but is neither necessary nor sufficient on its own to cause AD (Bird 2008) [16].

Genetic studies have shown that while familial cases often involve clear genetic mutations, the majority of Alzheimer's cases are sporadic and arise from a complex interplay of genetic susceptibility factors and environmental influences. Research indicates that the heritability of Alzheimer's disease is substantial, with estimates suggesting a heritability of around 74% for late-onset cases (Gatz et al. 1997) [17]. Furthermore, genome-wide association studies (GWAS) have identified over 20 risk loci associated with Alzheimer's disease, which explain a significant portion of the heritability (Cuyvers et al. 2016) [18].

In addition to these genetic factors, environmental interactions also play a crucial role in the pathogenesis of Alzheimer's disease. Factors such as lifestyle, diet, and other health conditions may influence the expression of genetic predispositions, suggesting that both genetics and environment contribute to the overall risk of developing the disease (Chandra & Pandav 1998) [19].

Overall, the genetic underpinnings of Alzheimer's disease illustrate a duality: familial cases often reveal clear genetic mutations, while sporadic cases highlight the intricate interplay between genetic risk factors and environmental influences. This complexity underscores the necessity for continued research into the genetic and epigenetic mechanisms involved in Alzheimer's disease to enhance understanding and treatment strategies.

3 Environmental Influences ​

3.1 Impact of Air Pollution ​

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by cognitive decline and memory loss. While genetic factors play a significant role in its etiology, recent research highlights the substantial impact of environmental factors, particularly air pollution, on the development and progression of AD.

Air pollution is recognized as a significant public health threat, and its association with neurodegenerative diseases, including AD, has garnered increasing attention. Various studies have demonstrated that exposure to airborne particulate matter (PM) is linked to cognitive impairment and an elevated risk of developing AD. For instance, a study by Israel et al. (2023) found that exposure to different sizes of PM resulted in differential transcriptional changes in mouse brains, which correlated with Alzheimer's-related pathology, including increased levels of intracellular amyloid-beta and phospho-Tau, despite no detection of extracellular amyloid plaques [20].

Furthermore, Hussain et al. (2023) propose that air pollution may impair glymphatic clearance, a critical process for removing waste products from the brain, thus contributing to AD pathogenesis. The authors suggest that systemic inflammation, neuroinflammation, and other health dysfunctions induced by air pollution could hinder glymphatic function, leading to an accumulation of neurotoxic substances in the brain [21].

Epidemiological studies have also corroborated these findings. Kilian and Kitazawa (2018) reviewed evidence linking air pollution exposure with cognitive decline and an increased risk of AD, particularly emphasizing pollutants from traffic, such as nitrogen dioxide and particulate matter [22]. Moreover, the Ginkgo Evaluation of Memory Study indicated that long-term exposure to PM2.5 was associated with a 20% higher risk of dementia [23].

Specific pollutants have been shown to influence neurodegenerative processes. For example, exposure to sulfur dioxide (SO2) was associated with a faster decline in memory scores among patients with AD, while PM2.5 exposure was linked to a decline in visuospatial scores in genetically predisposed individuals [24]. This suggests that not only does air pollution correlate with cognitive decline, but it may also accelerate the clinical progression of AD.

The biological mechanisms through which air pollution affects brain health are multifaceted. Airborne pollutants can induce oxidative stress and neuroinflammation, leading to neuronal damage and exacerbating neurodegenerative processes [25]. Furthermore, exposure to specific constituents of particulate matter has been shown to trigger the formation of amyloid plaques in vitro, highlighting a potential pathway through which air pollution could contribute to AD [26].

In summary, the interplay between air pollution and Alzheimer's disease is supported by a growing body of evidence indicating that environmental pollutants contribute to the risk and progression of this neurodegenerative disorder. Continued research is necessary to elucidate the precise mechanisms involved and to develop strategies for mitigating the impact of air pollution on brain health. Addressing air quality could be a critical component of public health initiatives aimed at reducing the burden of Alzheimer's disease.

3.2 Influence of Heavy Metals and Toxins ​

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressive cognitive decline and is influenced by various environmental factors, particularly exposure to heavy metals and toxins. The etiology of AD is multifactorial, with both genetic and environmental components playing significant roles. Heavy metals such as lead, mercury, arsenic, cadmium, and copper have been implicated in the pathogenesis of AD through various mechanisms.

Elevated levels of heavy metals in the environment have been associated with increased risks of developing neurodegenerative diseases, including AD. Studies indicate that exposure to these metals can lead to oxidative stress, mitochondrial dysfunction, neuroinflammation, and protein aggregation, which are critical processes involved in the progression of AD. For instance, copper has been shown to interact with amyloid-beta (Aβ) proteins, accelerating plaque formation and contributing to neurodegeneration [27]. This relationship underscores the significance of metal ion concentrations in the brain, where an imbalance can exacerbate the pathological features of AD.

Lead and mercury are particularly noteworthy due to their neurotoxic effects. They have been shown to disrupt cellular homeostasis and interfere with intracellular processes, contributing to mitochondrial dysfunction and oxidative stress. These metals can induce glial cell reactivity, a hallmark of brain inflammation, and increase the expression of amyloid precursor protein, which is crucial in the development of Aβ aggregates [28]. Chronic exposure to lead, for example, can lead to alterations in gene expression related to AD, further complicating the disease's pathology [29].

Arsenic exposure has also been linked to AD, with evidence suggesting it may induce epigenetic changes that affect gene regulation and contribute to oxidative stress [30]. The World Health Organization has set strict limits on arsenic levels in drinking water due to its toxic effects on human health, emphasizing the potential risks associated with environmental exposure [30].

The accumulation of heavy metals in the central nervous system is particularly detrimental, as it can lead to decreased enzymatic activity and increased protein aggregation, which are hallmarks of neurodegeneration [31]. For example, the aggregation of amyloid beta and the formation of neurofibrillary tangles are exacerbated by metal toxicity, leading to neuronal loss [31].

Furthermore, heavy metals can compromise the autophagy-lysosomal pathway, a critical cellular process for maintaining neuronal health by degrading damaged proteins and organelles [32]. Disruption of this pathway due to metal exposure can result in the accumulation of harmful substances and increased neuronal injury, contributing to the development of AD [32].

In summary, the influence of heavy metals and toxins on the etiology of Alzheimer's disease is substantial. These environmental factors can lead to oxidative stress, inflammation, and disruption of critical cellular processes, ultimately contributing to the neurodegenerative processes characteristic of AD. Addressing heavy metal exposure and understanding its implications for AD may provide insights into preventive and therapeutic strategies for this debilitating disease.

4 Lifestyle Factors ​

4.1 Diet and Nutrition ​

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressive cognitive decline, memory loss, and behavioral changes. While genetic factors play a significant role, various lifestyle and environmental factors, particularly diet and nutrition, are increasingly recognized as influential in the onset and progression of AD.

Dietary habits are crucial in modulating the risk of developing AD. Studies have shown that diets high in saturated and trans fats, refined carbohydrates, and low in fiber are associated with cognitive dysfunction. Conversely, diets rich in mono- and polyunsaturated fats, antioxidants, and fiber, such as the Mediterranean diet, have been linked to better cognitive function and a reduced risk of major chronic degenerative diseases, including AD. For instance, a meta-analysis indicated a significant association between greater adherence to the Mediterranean diet and a reduced risk of AD [33].

Furthermore, the consumption of specific fatty acids plays a pivotal role in the pathology of AD. Research indicates that long-chain polyunsaturated fatty acids from fish oil may contribute positively to brain health and may help mitigate the progression of AD [34]. Additionally, the interaction between dietary components and genetic predispositions, such as the presence of the ApoE4 allele, further complicates the relationship between diet and AD risk [19].

Antioxidant-rich diets are also essential in promoting brain health. These diets contribute to glucose control, weight management, and cardiovascular well-being, which are critical for reducing the risk of AD. Regular physical exercise complements a healthy diet by enhancing insulin sensitivity and promoting overall health, which can delay or prevent the progression of AD [35].

The impact of nutrition extends beyond direct dietary components; it also influences the gut-brain axis. Diet affects the gut microbiota, which plays a significant role in cognitive function and AD progression. Certain microbiota metabolites derived from a healthy diet can positively influence brain function [36].

In summary, Alzheimer's disease is influenced by a myriad of factors, with diet and nutrition emerging as critical components in its etiology. Adopting a balanced, antioxidant-rich diet, along with healthy lifestyle practices, can potentially reduce the risk of developing AD and improve cognitive health [37][38][39].

4.2 Physical Activity and Cognitive Engagement ​

Alzheimer's disease (AD) is a complex neurodegenerative disorder influenced by various factors, including lifestyle choices such as physical activity and cognitive engagement. Evidence suggests that modifiable lifestyle activities play a significant role in the cognitive health of individuals, particularly those at risk for late-life Alzheimer's disease.

Physical activity has been consistently linked to better cognitive outcomes. For instance, a study involving cognitively healthy middle-aged individuals at risk for late-life AD found that more frequent engagement in physically, socially, and intellectually stimulating activities was associated with improved cognitive performance, particularly in verbal and visuospatial memory functions (Heneghan et al., 2023). This suggests that an active lifestyle may mitigate cognitive decline even before the onset of clinical symptoms of Alzheimer's disease.

Moreover, cognitive engagement through various activities has shown protective effects against cognitive decline. Bocancea et al. (2025) assessed cognitive and physical activity levels in a large cohort and discovered that higher levels of current cognitive and physical activities were associated with better cognitive performance, particularly in the context of brain atrophy associated with Alzheimer's disease. Although the study indicated that these activities did not significantly affect the rate of cognitive decline or clinical progression, they were associated with reduced mortality risk, highlighting the potential long-term benefits of sustained cognitive and physical engagement.

The impact of lifestyle factors is further elucidated by research indicating that cognitive activities, including both lifetime and current engagement, can positively influence cognitive performance independent of Alzheimer's disease biomarkers (Vemuri et al., 2012; Gidicsin et al., 2015). In this regard, intellectual lifestyle factors were found to correlate with better cognitive performance, suggesting that an active mind may help delay the onset of dementia symptoms.

Sex differences also play a role in how lifestyle factors affect Alzheimer's pathology. For example, Bachmann et al. (2022) reported that while higher cognitive activity was linked to better cognitive performance, the association between physical activity and amyloid burden was more pronounced in men. This indicates that the benefits of physical and cognitive activities may vary by sex, further complicating the understanding of lifestyle influences on Alzheimer's disease.

The cumulative evidence suggests that an active lifestyle characterized by regular physical exercise and cognitive engagement can serve as a protective factor against cognitive decline and Alzheimer's disease. These findings advocate for the promotion of physical and cognitive activities as integral components of strategies aimed at reducing the risk of Alzheimer's disease and enhancing cognitive resilience throughout the lifespan. Therefore, individuals, particularly those in mid-life and beyond, may benefit from integrating both physical and cognitive activities into their daily routines to potentially mitigate the risks associated with Alzheimer's disease.

In conclusion, while Alzheimer's disease is influenced by genetic and environmental factors, modifiable lifestyle choices, particularly physical activity and cognitive engagement, are crucial in shaping cognitive health and may offer pathways for prevention and delay of disease onset.

5 Pathological Mechanisms ​

5.1 Amyloid-beta and Tau Pathology ​

Alzheimer's disease (AD) is characterized by complex pathological mechanisms primarily involving the accumulation of amyloid-beta (Aβ) peptides and tau protein aggregates, which play critical roles in the disease's progression. The amyloid cascade hypothesis remains a widely accepted framework to explain the pathogenesis of AD, positing that the accumulation of Aβ triggers a cascade of neurotoxic events leading to neurodegeneration.

Aβ is known to form plaques in the extracellular space, while tau, a microtubule-associated protein, becomes hyperphosphorylated and aggregates to form neurofibrillary tangles (NFTs) within neurons. This hyperphosphorylation disrupts tau's normal function of stabilizing microtubules, resulting in impaired neuronal function and ultimately cell death [40]. The interplay between Aβ and tau is crucial, as recent evidence suggests that Aβ accumulation may lead to tau hyperphosphorylation, thereby contributing to synaptic impairment and neuronal loss [41].

The mechanisms underlying tau pathology are primarily driven by various post-translational modifications, particularly phosphorylation and truncation, which alter tau's conformation and promote its aggregation into toxic forms [42]. These tau aggregates are implicated in the neuroinflammatory response and oxidative stress, which further exacerbate neuronal damage [43]. Furthermore, the NLRP3 inflammasome, a component of the innate immune system, has been shown to play a role in tau pathology, with its activation leading to increased tau hyperphosphorylation and aggregation [7].

The relationship between Aβ and tau is complex, with evidence indicating that both proteins may independently contribute to neurodegeneration. While Aβ accumulation is often seen as an initiating event, the presence of tau pathology correlates more closely with cognitive decline and neuronal loss [41]. This has led to the dual pathway hypothesis, which suggests that common upstream triggers may cause abnormalities in both Aβ and tau [41].

In addition to their roles in AD, Aβ and tau have been implicated in various other neurological disorders, indicating that their dysregulation may have broader implications beyond Alzheimer's disease [44]. The ongoing research aims to elucidate these complex interactions and explore therapeutic strategies targeting both Aβ and tau to halt or reverse the progression of Alzheimer's disease [41][44].

In summary, Alzheimer's disease is driven by the pathological accumulation of Aβ and tau, with their interactions contributing to synaptic dysfunction, neuroinflammation, and ultimately neuronal death. Understanding these mechanisms is crucial for developing effective therapeutic interventions.

5.2 Neuroinflammation and Vascular Contributions ​

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressive cognitive decline and memory impairment, with a multifactorial etiology that includes neuroinflammation and vascular contributions. The pathogenesis of AD involves various interconnected mechanisms, prominently featuring neuroinflammation and vascular dysfunction.

Neuroinflammation plays a significant role in the development and progression of Alzheimer's disease. It is characterized by the activation of glial cells, including microglia and astrocytes, which release pro-inflammatory cytokines and chemokines. This inflammatory microenvironment exacerbates neuronal dysfunction and contributes to the cognitive decline associated with AD. Research has shown that neuroinflammation is not only a consequence of amyloid-beta and tau pathology but also a driving factor in the disease process. Various studies indicate that inflammatory mediators, such as cytokines (e.g., TNF-α, IL-1β), are involved in the progression of AD, promoting neurodegeneration and synaptic dysfunction [45][46][47].

In addition to neuroinflammation, vascular contributions are crucial in the pathophysiology of Alzheimer's disease. The brain's high energy demand and its reliance on a continuous blood supply make it particularly vulnerable to vascular dysfunction. Evidence suggests that cerebrovascular factors, including chronic cerebral hypoperfusion, may initiate or exacerbate the pathological processes of AD. This dysfunction can lead to reduced cerebral blood flow, oxidative stress, and further neuroinflammation, creating a vicious cycle that accelerates cognitive decline [48][49][50].

The interplay between neuroinflammation and vascular factors is complex. For instance, endothelial dysfunction and the production of reactive oxygen species can impair vascular health, leading to reduced blood flow and nutrient delivery to neurons, which may further trigger neuroinflammatory responses [51][52]. Moreover, age-related vascular changes may precede the development of AD pathology, suggesting that vascular health is a critical factor in the disease's onset and progression [49].

In summary, the pathogenesis of Alzheimer's disease involves a multifaceted interaction between neuroinflammation and vascular contributions. The activation of inflammatory pathways and the impairment of cerebral blood flow collectively drive the neurodegenerative processes characteristic of AD. As research progresses, understanding these mechanisms may reveal new therapeutic targets aimed at mitigating the impact of neuroinflammation and vascular dysfunction in Alzheimer's disease [43][53][54].

6 Current Research and Future Directions ​

6.1 Emerging Biomarkers ​

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressive cognitive decline and functional impairment. The etiology of AD is multifactorial, involving a combination of genetic and environmental factors. The disease is primarily marked by the presence of senile plaques, which are rich in amyloid-β peptide, and neurofibrillary tangles, primarily composed of hyperphosphorylated tau protein. These hallmarks contribute to neuronal dysfunction and death, leading to the clinical manifestations of dementia [55].

Research has identified several critical mechanisms underlying the pathogenesis of AD, including the amyloid cascade hypothesis, neuroinflammation, oxidative stress, and vascular pathology. The amyloid cascade hypothesis posits that the accumulation of amyloid-β is a central event that triggers a cascade of pathological processes, ultimately resulting in neurodegeneration [1]. Neuroinflammation, driven by the activation of microglia, plays a significant role in the progression of the disease, as it can exacerbate neuronal injury [56]. Oxidative stress has also been highlighted as a key contributor to neuronal damage in AD, with studies showing increased oxidative stress markers in patients with mild cognitive impairment, a precursor to AD [57].

Emerging biomarkers are critical for understanding the disease's mechanisms and for early diagnosis. Current research is focusing on identifying biomarkers that can be detected in various biological fluids, such as cerebrospinal fluid (CSF), blood, and even ocular tissues. For instance, the levels of amyloid-β and tau proteins in CSF have been validated as biomarkers that complement clinical diagnosis and improve diagnostic accuracy [58]. Furthermore, novel approaches, including metabolomics and neuroimaging, are being explored to identify additional biomarkers that could facilitate early diagnosis and monitor disease progression [59].

The identification of biomarkers is not only crucial for diagnosis but also for developing new therapeutic strategies. As the understanding of AD mechanisms deepens, there is an increasing focus on translating these insights into effective treatments. Disease-modifying therapies are anticipated to be most beneficial when administered early in the disease course, emphasizing the need for reliable biomarkers that can signal the onset of AD before clinical symptoms appear [60].

In summary, Alzheimer's disease arises from a complex interplay of genetic and environmental factors, with key pathological features including amyloid-β accumulation, tau pathology, neuroinflammation, and oxidative stress. Ongoing research into emerging biomarkers holds promise for improving early diagnosis and developing targeted therapies, which are essential for enhancing patient outcomes in this devastating disease [1][61][62].

6.2 Novel Therapeutic Approaches ​

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by a multifactorial etiology. The pathogenesis of AD is not fully understood; however, it is associated with a combination of genetic, environmental, and lifestyle factors that contribute to its development and progression.

Key pathological features of AD include the accumulation of amyloid-beta plaques and neurofibrillary tangles composed of hyperphosphorylated tau protein. These features are central to the amyloid cascade hypothesis, which posits that the accumulation of amyloid-beta initiates a series of neurodegenerative processes leading to synaptic dysfunction and neuronal death [43]. In addition to amyloid and tau pathologies, synaptic dysfunction, characterized by synapse loss and deficits in synaptic plasticity, has been identified as a significant contributor to cognitive decline in AD [43].

Research has also highlighted the role of neuroinflammation and oxidative stress in AD. Age-related factors, such as inflammation and metabolic dysregulation, have been shown to exacerbate the disease's progression [43]. Furthermore, epigenetic modifications, including DNA methylation and histone modifications, have been implicated in the regulation of gene expression associated with AD pathology, indicating that epigenetic treatments could serve as potential therapeutic targets [63].

Despite the significant advancements in understanding the pathophysiological mechanisms of AD, current therapeutic approaches remain largely symptomatic. Traditional medications, such as acetylcholinesterase inhibitors and NMDA receptor antagonists, provide only modest benefits and do not modify disease progression [64]. This highlights the urgent need for innovative treatment strategies that address the underlying mechanisms of AD rather than merely alleviating symptoms.

Recent research has shifted towards multitarget therapeutic approaches that aim to tackle multiple pathways involved in AD. These strategies involve the development of small molecules that can simultaneously modulate various pathological processes, including amyloid and tau pathologies, neuroinflammation, and synaptic dysfunction [65]. Moreover, the exploration of novel biological agents, such as neural stem cells, presents a promising avenue for delivering disease-modifying therapies directly to affected brain regions [66].

In conclusion, the etiology of Alzheimer's disease is multifaceted, involving a complex interplay of amyloid and tau pathologies, neuroinflammation, oxidative stress, and synaptic dysfunction. Future therapeutic approaches must focus on a comprehensive understanding of these mechanisms to develop effective treatments that not only alleviate symptoms but also modify the disease course. Continued research into the molecular underpinnings of AD will be essential for identifying novel therapeutic targets and improving patient outcomes [67][68][69].

7 Conclusion ​

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by a complex interplay of genetic, environmental, and lifestyle factors. Key findings indicate that genetic factors, particularly the apolipoprotein E (ApoE) gene and familial mutations, significantly contribute to AD risk and onset. Environmental influences, such as air pollution and exposure to heavy metals, exacerbate the disease's progression through mechanisms like oxidative stress and neuroinflammation. Additionally, lifestyle factors, including diet and physical activity, play a critical role in modulating cognitive health and may serve as preventive measures against AD. Pathological mechanisms, primarily involving amyloid-beta and tau aggregation, alongside neuroinflammation and vascular dysfunction, underscore the need for a holistic approach to understanding and treating AD. Current research is focused on identifying emerging biomarkers for early diagnosis and developing novel therapeutic strategies that address the underlying disease mechanisms. Future research should prioritize a multifaceted understanding of AD, integrating genetic, environmental, and lifestyle factors to inform innovative treatment modalities and improve patient outcomes.

References ​

  • [1] Jiejia Li;Liyun Wang;Xiaodan Zhang;Jianhua Shi;Yizhun Zhu;Han Wang;Xiangyang Zhu;Qing Zhu;Jia-Lie Luo. Translating Alzheimer's Disease Mechanisms into Therapeutic Opportunities.. Biomolecules(IF=4.8). 2025. PMID:41008597. DOI: 10.3390/biom15091290.
  • [2] Bhavarth P Dave;Yesha B Shah;Kunal G Maheshwari;Kaif A Mansuri;Bhadrawati S Prajapati;Humzah I Postwala;Mehul R Chorawala. Pathophysiological Aspects and Therapeutic Armamentarium of Alzheimer's Disease: Recent Trends and Future Development.. Cellular and molecular neurobiology(IF=4.8). 2023. PMID:37725199. DOI: 10.1007/s10571-023-01408-7.
  • [3] William Thomas Phillips;Joyce Gensberg Schwartz. Nasal lymphatic obstruction of CSF drainage as a possible cause of Alzheimer's disease and dementia.. Frontiers in aging neuroscience(IF=4.5). 2024. PMID:39497786. DOI: 10.3389/fnagi.2024.1482255.
  • [4] Willian Orlando Castillo-Ordoñez;Nohelia Cajas-Salazar;Mayra Alejandra Velasco-Reyes. Genetic and epigenetic targets of natural dietary compounds as anti-Alzheimer's agents.. Neural regeneration research(IF=6.7). 2024. PMID:37843220. DOI: 10.4103/1673-5374.382232.
  • [5] Hareram Birla;Tarun Minocha;Gaurav Kumar;Anamika Misra;Sandeep Kumar Singh. Role of Oxidative Stress and Metal Toxicity in the Progression of Alzheimer's Disease.. Current neuropharmacology(IF=5.3). 2020. PMID:31969104. DOI: 10.2174/1570159X18666200122122512.
  • [6] Luis E Santos;Sergio T Ferreira. Crosstalk between endoplasmic reticulum stress and brain inflammation in Alzheimer's disease.. Neuropharmacology(IF=4.6). 2018. PMID:29129774. DOI: 10.1016/j.neuropharm.2017.11.016.
  • [7] Soghra Bagheri;Ali Akbar Saboury;Luciano Saso. Sequence of Molecular Events in the Development of Alzheimer's Disease: Cascade Interactions from Beta-Amyloid to Other Involved Proteins.. Cells(IF=5.2). 2024. PMID:39120323. DOI: 10.3390/cells13151293.
  • [8] A D Roses;A M Saunders. ApoE, Alzheimer's disease, and recovery from brain stress.. Annals of the New York Academy of Sciences(IF=4.8). 1997. PMID:9329691. DOI: 10.1111/j.1749-6632.1997.tb48471.x.
  • [9] Philip B Verghese;Joseph M Castellano;David M Holtzman. Apolipoprotein E in Alzheimer's disease and other neurological disorders.. The Lancet. Neurology(IF=45.5). 2011. PMID:21349439. DOI: 10.1016/S1474-4422(10)70325-2.
  • [10] Courtney M Kloske;Michael E Belloy;Elizabeth E Blue;Gregory R Bowman;Maria C Carrillo;Xiaoying Chen;Ornit Chiba-Falek;Albert A Davis;Gilbert Di Paolo;Francesca Garretti;David Gate;Lesley R Golden;Jay W Heinecke;Joachim Herz;Yadong Huang;Costantino Iadecola;Lance A Johnson;Takahisa Kanekiyo;Celeste M Karch;Anastasia Khvorova;Sascha J Koppes-den Hertog;Bruce T Lamb;Paige E Lawler;Yann Le Guen;Alexandra Litvinchuk;Chia-Chen Liu;Simin Mahinrad;Edoardo Marcora;Claudia Marino;Danny M Michaelson;Justin J Miller;Josh M Morganti;Priyanka S Narayan;Michel S Naslavsky;Marlies Oosthoek;Kapil V Ramachandran;Abhirami Ramakrishnan;Ana-Caroline Raulin;Aiko Robert;Rasha N M Saleh;Claire Sexton;Nilomi Shah;Francis Shue;Isabel J Sible;Andrea Soranno;Michael R Strickland;Julia Tcw;Manon Thierry;Li-Huei Tsai;Ryan A Tuckey;Jason D Ulrich;Rik van der Kant;Na Wang;Cheryl L Wellington;Stacie C Weninger;Hussein N Yassine;Na Zhao;Guojun Bu;Alison M Goate;David M Holtzman. Advancements in APOE and dementia research: Highlights from the 2023 AAIC Advancements: APOE conference.. Alzheimer's & dementia : the journal of the Alzheimer's Association(IF=11.1). 2024. PMID:39031528. DOI: 10.1002/alz.13877.
  • [11] Fan Liao;Hyejin Yoon;Jungsu Kim. Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease.. Current opinion in lipidology(IF=4.6). 2017. PMID:27922847. DOI: 10.1097/MOL.0000000000000383.
  • [12] Lan Zhang;Yiyuan Xia;Yuran Gui. Neuronal ApoE4 in Alzheimer's disease and potential therapeutic targets.. Frontiers in aging neuroscience(IF=4.5). 2023. PMID:37333457. DOI: 10.3389/fnagi.2023.1199434.
  • [13] W J Strittmatter;A D Roses. Apolipoprotein E and Alzheimer's disease.. Annual review of neuroscience(IF=13.2). 1996. PMID:8833436. DOI: 10.1146/annurev.ne.19.030196.000413.
  • [14] Melissa Lamar;Lei Yu;Leah H Rubin;Bryan D James;Lisa L Barnes;Jose Marcelo Farfel;Chris Gaiteri;Aron S Buchman;David A Bennett;Julie A Schneider. APOE genotypes as a risk factor for age-dependent accumulation of cerebrovascular disease in older adults.. Alzheimer's & dementia : the journal of the Alzheimer's Association(IF=11.1). 2019. PMID:30321502. DOI: 10.1016/j.jalz.2018.08.007.
  • [15] Holden C Williams;Brandon C Farmer;Margaret A Piron;Adeline E Walsh;Ronald C Bruntz;Matthew S Gentry;Ramon C Sun;Lance A Johnson. APOE alters glucose flux through central carbon pathways in astrocytes.. Neurobiology of disease(IF=5.6). 2020. PMID:31931141. DOI: 10.1016/j.nbd.2020.104742.
  • [16] Thomas D Bird. Genetic aspects of Alzheimer disease.. Genetics in medicine : official journal of the American College of Medical Genetics(IF=6.2). 2008. PMID:18414205. DOI: 10.1097/GIM.0b013e31816b64dc.
  • [17] M Gatz;N L Pedersen;S Berg;B Johansson;K Johansson;J A Mortimer;S F Posner;M Viitanen;B Winblad;A Ahlbom. Heritability for Alzheimer's disease: the study of dementia in Swedish twins.. The journals of gerontology. Series A, Biological sciences and medical sciences(IF=3.8). 1997. PMID:9060980. DOI: 10.1093/gerona/52a.2.m117.
  • [18] Elise Cuyvers;Kristel Sleegers. Genetic variations underlying Alzheimer's disease: evidence from genome-wide association studies and beyond.. The Lancet. Neurology(IF=45.5). 2016. PMID:27302364. DOI: 10.1016/S1474-4422(16)00127-7.
  • [19] V Chandra;R Pandav. Gene-environment interaction in Alzheimer's disease: a potential role for cholesterol.. Neuroepidemiology(IF=4.0). 1998. PMID:9705582. DOI: 10.1159/000026175.
  • [20] Liron L Israel;Oliver Braubach;Ekaterina S Shatalova;Oksana Chepurna;Sachin Sharma;Dmytro Klymyshyn;Anna Galstyan;Antonella Chiechi;Alysia Cox;David Herman;Bishop Bliss;Irene Hasen;Amanda Ting;Rebecca Arechavala;Michael T Kleinman;Rameshwar Patil;Eggehard Holler;Julia Y Ljubimova;Maya Koronyo-Hamaoui;Tao Sun;Keith L Black. Exposure to environmental airborne particulate matter caused wide-ranged transcriptional changes and accelerated Alzheimer's-related pathology: A mouse study.. Neurobiology of disease(IF=5.6). 2023. PMID:37739136. DOI: 10.1016/j.nbd.2023.106307.
  • [21] Rashad Hussain;Uschi Graham;Alison Elder;Maiken Nedergaard. Air pollution, glymphatic impairment, and Alzheimer's disease.. Trends in neurosciences(IF=15.1). 2023. PMID:37777345. DOI: 10.1016/j.tins.2023.08.010.
  • [22] Jason Kilian;Masashi Kitazawa. The emerging risk of exposure to air pollution on cognitive decline and Alzheimer's disease - Evidence from epidemiological and animal studies.. Biomedical journal(IF=4.4). 2018. PMID:30080655. DOI: 10.1016/j.bj.2018.06.001.
  • [23] Erin O Semmens;Cindy S Leary;Annette L Fitzpatrick;Sindana D Ilango;Christina Park;Claire E Adam;Steven T DeKosky;Oscar Lopez;Anjum Hajat;Joel D Kaufman. Air pollution and dementia in older adults in the Ginkgo Evaluation of Memory Study.. Alzheimer's & dementia : the journal of the Alzheimer's Association(IF=11.1). 2023. PMID:35436383. DOI: 10.1002/alz.12654.
  • [24] Young-Gun Lee;Seon-Jin Yoon;So Hoon Yoon;Sung Woo Kang;Seun Jeon;Minseok Kim;Dong Ah Shin;Chung Mo Nam;Byoung Seok Ye. Air pollution is associated with faster cognitive decline in Alzheimer's disease.. Annals of clinical and translational neurology(IF=3.9). 2023. PMID:37106569. DOI: 10.1002/acn3.51779.
  • [25] Lucio G Costa;Toby B Cole;Khoi Dao;Yu-Chi Chang;Jacki Coburn;Jacqueline M Garrick. Effects of air pollution on the nervous system and its possible role in neurodevelopmental and neurodegenerative disorders.. Pharmacology & therapeutics(IF=12.5). 2020. PMID:32165138. DOI: 10.1016/j.pharmthera.2020.107523.
  • [26] Aleksandar Sebastijanović;Laura Maria Azzurra Camassa;Vilhelm Malmborg;Slavko Kralj;Joakim Pagels;Ulla Vogel;Shan Zienolddiny-Narui;Iztok Urbančič;Tilen Koklič;Janez Štrancar. Particulate matter constituents trigger the formation of extracellular amyloid β and Tau -containing plaques and neurite shortening in vitro.. Nanotoxicology(IF=3.4). 2024. PMID:38907733. DOI: 10.1080/17435390.2024.2362367.
  • [27] Roshni Patel;Michael Aschner. Commonalities between Copper Neurotoxicity and Alzheimer's Disease.. Toxics(IF=4.1). 2021. PMID:33430181. DOI: 10.3390/toxics9010004.
  • [28] Florianne Monnet-Tschudi;Marie-Gabrielle Zurich;Corina Boschat;Anne Corbaz;Paul Honegger. Involvement of environmental mercury and lead in the etiology of neurodegenerative diseases.. Reviews on environmental health(IF=4.5). 2006. PMID:16898674. DOI: 10.1515/reveh.2006.21.2.105.
  • [29] Giasuddin Ahmed;Md Shiblur Rahaman;Enrique Perez;Khalid M Khan. Associations of Environmental Exposure to Arsenic, Manganese, Lead, and Cadmium with Alzheimer's Disease: A Review of Recent Evidence from Mechanistic Studies.. Journal of xenobiotics(IF=4.4). 2025. PMID:40278152. DOI: 10.3390/jox15020047.
  • [30] Daniele Antinori;Marco Lucarelli;Andrea Fuso. Oxidative stress - Alzheimer's disease - DNA methylation: the role of arsenic.. Essays in biochemistry(IF=5.7). 2025. PMID:40591736. DOI: 10.1042/EBC20253019.
  • [31] Md Tanvir Kabir;Md Sahab Uddin;Sonia Zaman;Yesmin Begum;Ghulam Md Ashraf;May N Bin-Jumah;Simona G Bungau;Shaker A Mousa;Mohamed M Abdel-Daim. Molecular Mechanisms of Metal Toxicity in the Pathogenesis of Alzheimer's Disease.. Molecular neurobiology(IF=4.3). 2021. PMID:32889653. DOI: 10.1007/s12035-020-02096-w.
  • [32] Shrabani Das;Lokesh Murumulla;Pritha Ghosh;Suresh Challa. Heavy metal-induced disruption of the autophagy-lysosomal pathway: implications for aging and neurodegenerative disorders.. Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine(IF=3.6). 2025. PMID:39960543. DOI: 10.1007/s10534-025-00665-x.
  • [33] Francesco Sofi;Claudio Macchi;Rosanna Abbate;Gian Franco Gensini;Alessandro Casini. Effectiveness of the Mediterranean diet: can it help delay or prevent Alzheimer's disease?. Journal of Alzheimer's disease : JAD(IF=3.1). 2010. PMID:20182044. DOI: 10.3233/JAD-2010-1418.
  • [34] Carlijn R Hooijmans;Amanda J Kiliaan. Fatty acids, lipid metabolism and Alzheimer pathology.. European journal of pharmacology(IF=4.7). 2008. PMID:18378224. DOI: 10.1016/j.ejphar.2007.11.081.
  • [35] Sachi Khemka;Aananya Reddy;Ricardo Isaiah Garcia;Micheal Jacobs;Ruhananhad P Reddy;Aryan Kia Roghani;Vasanthkumar Pattoor;Tanisha Basu;Ujala Sehar;P Hemachandra Reddy. Role of diet and exercise in aging, Alzheimer's disease, and other chronic diseases.. Ageing research reviews(IF=12.4). 2023. PMID:37832608. DOI: 10.1016/j.arr.2023.102091.
  • [36] Dulce M Frausto;Christopher B Forsyth;Ali Keshavarzian;Robin M Voigt. Dietary Regulation of Gut-Brain Axis in Alzheimer's Disease: Importance of Microbiota Metabolites.. Frontiers in neuroscience(IF=3.2). 2021. PMID:34867153. DOI: 10.3389/fnins.2021.736814.
  • [37] Neal D Barnard;Ashley I Bush;Antonia Ceccarelli;James Cooper;Celeste A de Jager;Kirk I Erickson;Gary Fraser;Shelli Kesler;Susan M Levin;Brendan Lucey;Martha Clare Morris;Rosanna Squitti. Dietary and lifestyle guidelines for the prevention of Alzheimer's disease.. Neurobiology of aging(IF=3.5). 2014. PMID:24913896. DOI: .
  • [38] Tianying Zhang;Xiaojuan Han;Xiaohua Zhang;Zhi Chen;Yajing Mi;Xingchun Gou. Dietary Fatty Acid Factors in Alzheimer's Disease: A Review.. Journal of Alzheimer's disease : JAD(IF=3.1). 2020. PMID:33074226. DOI: 10.3233/JAD-200558.
  • [39] Julia Doroszkiewicz;Jan Mroczko;Piotr Rutkowski;Barbara Mroczko. Molecular Aspects of a Diet as a New Pathway in the Prevention and Treatment of Alzheimer's Disease.. International journal of molecular sciences(IF=4.9). 2023. PMID:37445928. DOI: 10.3390/ijms241310751.
  • [40] Michael S Wolfe. Therapeutic strategies for Alzheimer's disease.. Nature reviews. Drug discovery(IF=101.8). 2002. PMID:12415246. DOI: 10.1038/nrd938.
  • [41] Alejandro R Roda;Gabriel Serra-Mir;Laia Montoliu-Gaya;Lidia Tiessler;Sandra Villegas. Amyloid-beta peptide and tau protein crosstalk in Alzheimer's disease.. Neural regeneration research(IF=6.7). 2022. PMID:35017413. DOI: 10.4103/1673-5374.332127.
  • [42] Abdullah Al Mamun;Md Sahab Uddin;Bijo Mathew;Ghulam Md Ashraf. Toxic tau: structural origins of tau aggregation in Alzheimer's disease.. Neural regeneration research(IF=6.7). 2020. PMID:31997800. DOI: 10.4103/1673-5374.274329.
  • [43] Yaojun Ju;Kin Yip Tam. Pathological mechanisms and therapeutic strategies for Alzheimer's disease.. Neural regeneration research(IF=6.7). 2022. PMID:34380884. DOI: 10.4103/1673-5374.320970.
  • [44] Morteza Abyadeh;Vivek Gupta;Joao A Paulo;Arezoo Gohari Mahmoudabad;Sina Shadfar;Shahab Mirshahvaladi;Veer Gupta;Christine T O Nguyen;David I Finkelstein;Yuyi You;Paul A Haynes;Ghasem H Salekdeh;Stuart L Graham;Mehdi Mirzaei. Amyloid-beta and tau protein beyond Alzheimer's disease.. Neural regeneration research(IF=6.7). 2024. PMID:37905874. DOI: 10.4103/1673-5374.386406.
  • [45] G Joseph Broussard;Jennifer Mytar;Rung-chi Li;Gloria J Klapstein. The role of inflammatory processes in Alzheimer's disease.. Inflammopharmacology(IF=5.3). 2012. PMID:22535513. DOI: 10.1007/s10787-012-0130-z.
  • [46] Bartosz Twarowski;Mariola Herbet. Inflammatory Processes in Alzheimer's Disease-Pathomechanism, Diagnosis and Treatment: A Review.. International journal of molecular sciences(IF=4.9). 2023. PMID:37047492. DOI: 10.3390/ijms24076518.
  • [47] Rituraj Niranjan. Molecular basis of etiological implications in Alzheimer's disease: focus on neuroinflammation.. Molecular neurobiology(IF=4.3). 2013. PMID:23420079. DOI: 10.1007/s12035-013-8428-4.
  • [48] Ao Qian;Yuxi Lu;Yanting Zhang;Chenglong Yu;Peng Zhang;Wenjuan Liao;Yao Yao;Yunsong Zheng;Man Tong;Songhu Yuan. Mechanistic Insight into Electron Transfer from Fe(II)-Bearing Clay Minerals to Fe (Hydr)oxides.. Environmental science & technology(IF=11.3). 2023. PMID:37204932. DOI: 10.1021/acs.est.3c01250.
  • [49] Marta Cortes-Canteli;Costantino Iadecola. Alzheimer's Disease and Vascular Aging: JACC Focus Seminar.. Journal of the American College of Cardiology(IF=22.3). 2020. PMID:32130930. DOI: 10.1016/j.jacc.2019.10.062.
  • [50] Si-Qi Du;Xue-Rui Wang;Ling-Yong Xiao;Jian-Feng Tu;Wen Zhu;Tian He;Cun-Zhi Liu. Molecular Mechanisms of Vascular Dementia: What Can Be Learned from Animal Models of Chronic Cerebral Hypoperfusion?. Molecular neurobiology(IF=4.3). 2017. PMID:27206432. DOI: 10.1007/s12035-016-9915-1.
  • [51] Qian Zhang;Yaping Yan. The role of natural flavonoids on neuroinflammation as a therapeutic target for Alzheimer's disease: a narrative review.. Neural regeneration research(IF=6.7). 2023. PMID:37449593. DOI: 10.4103/1673-5374.373680.
  • [52] Michael T Heneka;Wiesje M van der Flier;Frank Jessen;Jeroen Hoozemanns;Dietmar Rudolf Thal;Delphine Boche;Frederic Brosseron;Charlotte Teunissen;Henrik Zetterberg;Andreas H Jacobs;Paul Edison;Alfredo Ramirez;Carlos Cruchaga;Jean-Charles Lambert;Agustin Ruiz Laza;Jose Vicente Sanchez-Mut;Andre Fischer;Sergio Castro-Gomez;Thor D Stein;Luca Kleineidam;Michael Wagner;Jonas J Neher;Colm Cunningham;Sim K Singhrao;Marco Prinz;Christopher K Glass;Johannes C M Schlachetzki;Oleg Butovsky;Kilian Kleemann;Philip L De Jaeger;Hannah Scheiblich;Guy C Brown;Gary Landreth;Miguel Moutinho;Jaime Grutzendler;Diego Gomez-Nicola;Róisín M McManus;Katrin Andreasson;Christina Ising;Deniz Karabag;Darren J Baker;Shane A Liddelow;Alexei Verkhratsky;Malu Tansey;Alon Monsonego;Ludwig Aigner;Guillaume Dorothée;Klaus-Armin Nave;Mikael Simons;Gabriela Constantin;Neta Rosenzweig;Alberto Pascual;Gabor C Petzold;Jonathan Kipnis;Carmen Venegas;Marco Colonna;Jochen Walter;Andrea J Tenner;M Kerry O'Banion;Joern R Steinert;Douglas L Feinstein;Magdalena Sastre;Kiran Bhaskar;Soyon Hong;Dorothy P Schafer;Todd Golde;Richard M Ransohoff;David Morgan;John Breitner;Renzo Mancuso;Sean-Patrick Riechers. Neuroinflammation in Alzheimer disease.. Nature reviews. Immunology(IF=60.9). 2025. PMID:39653749. DOI: 10.1038/s41577-024-01104-7.
  • [53] Zi-Zhen Si;Chen-Jun Zou;Xi Mei;Xiao-Fang Li;Hu Luo;Yao Shen;Jun Hu;Xing-Xing Li;Lun Wu;Yu Liu. Targeting neuroinflammation in Alzheimer's disease: from mechanisms to clinical applications.. Neural regeneration research(IF=6.7). 2023. PMID:36204826. DOI: 10.4103/1673-5374.353484.
  • [54] Xian Zhou;Paayal Kumar;Deep J Bhuyan;Slade O Jensen;Tara L Roberts;Gerald W Münch. Neuroinflammation in Alzheimer's Disease: A Potential Role of Nose-Picking in Pathogen Entry via the Olfactory System?. Biomolecules(IF=4.8). 2023. PMID:38002250. DOI: 10.3390/biom13111568.
  • [55] Sergio Davinelli;Mariano Intrieri;Claudio Russo;Alfonso Di Costanzo;Davide Zella;Paolo Bosco;Giovanni Scapagnini. The "Alzheimer's disease signature": potential perspectives for novel biomarkers.. Immunity & ageing : I & A(IF=5.6). 2011. PMID:21933389. DOI: 10.1186/1742-4933-8-7.
  • [56] Poornima Sharma;Anjali Sharma;Faizana Fayaz;Sharad Wakode;Faheem H Pottoo. Biological Signatures of Alzheimer's Disease.. Current topics in medicinal chemistry(IF=3.3). 2020. PMID:32108008. DOI: 10.2174/1568026620666200228095553.
  • [57] Rukhsana Sultana;Mauro Baglioni;Roberta Cecchetti;Jian Cai;Jon B Klein;Patrizia Bastiani;Carmelinda Ruggiero;Patrizia Mecocci;D Allan Butterfield. Lymphocyte mitochondria: toward identification of peripheral biomarkers in the progression of Alzheimer disease.. Free radical biology & medicine(IF=8.2). 2013. PMID:23933528. DOI: 10.1016/j.freeradbiomed.2013.08.001.
  • [58] Matthias Pawlowski;Sven G Meuth;Thomas Duning. Cerebrospinal Fluid Biomarkers in Alzheimer's Disease-From Brain Starch to Bench and Bedside.. Diagnostics (Basel, Switzerland)(IF=3.3). 2017. PMID:28703785. DOI: 10.3390/diagnostics7030042.
  • [59] Yang-Yang Wang;Yan-Ping Sun;Yu-Meng Luo;Dong-Hui Peng;Xiao Li;Bing-You Yang;Qiu-Hong Wang;Hai-Xue Kuang. Biomarkers for the Clinical Diagnosis of Alzheimer's Disease: Metabolomics Analysis of Brain Tissue and Blood.. Frontiers in pharmacology(IF=4.8). 2021. PMID:34366852. DOI: 10.3389/fphar.2021.700587.
  • [60] Alessandro Rabbito;Maciej Dulewicz;Agnieszka Kulczyńska-Przybik;Barbara Mroczko. Biochemical Markers in Alzheimer's Disease.. International journal of molecular sciences(IF=4.9). 2020. PMID:32183332. DOI: 10.3390/ijms21061989.
  • [61] Peter van Wijngaarden;Xavier Hadoux;Mostafa Alwan;Stuart Keel;Mohamed Dirani. Emerging ocular biomarkers of Alzheimer disease.. Clinical & experimental ophthalmology(IF=5.6). 2017. PMID:28147442. DOI: 10.1111/ceo.12872.
  • [62] Anand Kumar;Charles B Nemeroff;Joseph J Cooper;Alik Widge;Carolyn Rodriguez;Linda Carpenter;William M McDonald. Amyloid and Tau in Alzheimer's Disease: Biomarkers or Molecular Targets for Therapy? Are We Shooting the Messenger?. The American journal of psychiatry(IF=14.7). 2021. PMID:34734743. DOI: 10.1176/appi.ajp.2021.19080873.
  • [63] Rachel Coneys;Ian C Wood. Alzheimer's disease: the potential of epigenetic treatments and current clinical candidates.. Neurodegenerative disease management(IF=3.4). 2020. PMID:32552286. DOI: 10.2217/nmt-2019-0034.
  • [64] Anil Kumar;Arti Singh; Ekavali. A review on Alzheimer's disease pathophysiology and its management: an update.. Pharmacological reports : PR(IF=3.8). 2015. PMID:25712639. DOI: .
  • [65] Maria João Matos. Multitarget therapeutic approaches for Alzheimer's and Parkinson's diseases: an opportunity or an illusion?. Future medicinal chemistry(IF=3.4). 2021. PMID:34137271. DOI: 10.4155/fmc-2021-0119.
  • [66] James A Byrne. Developing neural stem cell-based treatments for neurodegenerative diseases.. Stem cell research & therapy(IF=7.3). 2014. PMID:25157920. DOI: 10.1186/scrt461.
  • [67] Tarana Umar;Rampratap Meena; Mustehasan;Pawan Kumar;Asim Ali Khan. Recent updates in the development of small molecules as potential clinical candidates for Alzheimer's disease: A review.. Chemical biology & drug design(IF=3.3). 2022. PMID:35996229. DOI: 10.1111/cbdd.14133.
  • [68] C A Lane;J Hardy;J M Schott. Alzheimer's disease.. European journal of neurology(IF=3.9). 2018. PMID:28872215. DOI: 10.1111/ene.13439.
  • [69] Francesca Mangialasche;Alina Solomon;Bengt Winblad;Patrizia Mecocci;Miia Kivipelto. Alzheimer's disease: clinical trials and drug development.. The Lancet. Neurology(IF=45.5). 2010. PMID:20610346. DOI: 10.1016/S1474-4422(10)70119-8.

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