Alzheimer's disease (AD) is a devastating and progressive neurodegenerative disorder that leads to cognitive impairment, behavioral disturbances, and ultimately dementia and death [1, 2]. With an estimated 5.3 million people currently affected by AD dementia globally, projections indicate this figure will rise to over 13 million by 2050 [3]. Despite substantial advancements in understanding the pathology and mechanisms underlying AD since its first diagnosis in 1907 [4], there remains no cure. This lack of viable treatments highlights the critical need for innovative approaches beyond conventional therapeutic targets, particularly as the global burden of AD continues to increase.

The predominant hypothesis for AD pathology has long centered on the amyloid cascade theory, which attributes disease progression primarily to the excessive accumulation of amyloid-β (Aβ) peptides, especially Aβ42. These peptides are derived from amyloid precursor protein (APP) and accumulate in the brain due to decreased clearance rates [5]. As Aβ aggregates, it triggers a series of pathological processes, including the hyperphosphorylation of tau, a microtubule-associated protein. This hyperphosphorylation leads to the detachment of tau from microtubules, allowing them to form neurofibrillary tangles (NFTs), a key hallmark of AD [6]. These amyloid and tau pathologies contribute to synaptic dysfunction, neuronal death, and cognitive decline. However, despite decades of research on these canonical targets, therapeutic approaches focused solely on Aβ and tau have yielded limited clinical success. Post-mortem neuropathological assessment remains the definitive method for diagnosing AD [7]. Although research continues to explore ways to measure Aβ and tau load in living patients, the disease often remains undetected in its early, asymptomatic stages. AD is characterized by a long preclinical phase, during which individuals may appear cognitively intact but are still harboring significant pathological changes, including Aβ plaque deposition and tau tangle formation [8]. As the disease progresses, patients experience a variety of symptoms, including cognitive decline, visual and sensory disturbances, motor impairments, and sphincter dysfunction. Over time, the illness leads to significant reductions in life expectancy and imposes a tremendous burden on patients, caregivers, and healthcare systems. Given the limitations of current treatment options, it is increasingly recognized that alternative therapeutic strategies are needed. AD is a multifactorial disease with a complex pathology that goes beyond Aβ and tau accumulation. Neural inflammation, oxidative stress, myelin sheath destruction, oligodendrocyte death, and progressive neuronal degeneration are all key contributors to the disease process [9,10,11]. Moreover, research has shown that AD is not confined to changes in the grey matter, which houses neurons, but also involves alterations in white matter and oligodendrocytes, which play a crucial role in maintaining myelin integrity [12,13,14]. The early detection of axonal damage in AD patients indicates future irreversible impairments and the loss of synaptic connections, particularly in the medial temporal lobe and cerebral cortex [15]. While some compensatory mechanisms, such as oligodendrocyte-driven remyelination, can temporarily delay the clinical onset of symptoms, these processes are insufficient to halt disease progression [16]. As AD progresses, the typical cortical processing surrounding Aβ plaques is disrupted, leading to synaptic deterioration, cytoskeletal abnormalities, and atypical regenerative responses in axons [17]. Notably, this early disruption occurs without significant neuronal degeneration, which presents an opportunity for early intervention. Despite the development of disease-modifying therapies (DMTs) aimed at slowing AD progression, there has been limited success in achieving substantial clinical improvements. Over the last three decades, only four drugs have been approved for AD treatment, and they primarily focus on managing symptoms rather than addressing the underlying pathology [18]. Aducanumab, the first DMT approved for AD, represents a shift toward targeting Aβ plaques, but its clinical efficacy remains a subject of debate [19, 20]. Additionally, other promising DMTs, including Eli Lilly’s donanemab and Eisai’s lecanemab, are currently undergoing clinical trials and regulatory review. While these monoclonal antibodies (mAbs) have shown potential in preclinical studies, their efficacy in clinical settings remains uncertain [21]. Given the limited success of current approaches targeting Aβ and tau, there is a growing recognition of the need to explore alternative, non-canonical therapeutic targets. Emerging research areas suggest that other mechanisms, such as neuroinflammation, blood–brain barrier (BBB) dysfunction, and metabolic dysregulation, may play critical roles in the progression of AD. Inflammation in the central nervous system (CNS), for instance, is now understood to be a major driver of AD pathology, contributing to synaptic dysfunction and neuronal loss [9]. Additionally, the BBB, which regulates the exchange of molecules between the blood and the brain, becomes increasingly compromised in AD, allowing harmful substances to accumulate and exacerbating neurodegeneration [22, 23]. Another promising area of investigation is neuroimmunometabolism, which examines the relationship between immune cells and metabolic processes in the brain. Dysregulation in these pathways may contribute to the chronic inflammation observed in AD and other neurodegenerative diseases. Finally, the coagulation system, which plays a key role in maintaining vascular health, has also been implicated in AD. Disruptions in coagulation pathways may lead to cerebrovascular damage, further accelerating the progression of AD [24].

This review aims to highlight recent advancements in these emerging research areas, which have the potential to uncover novel molecular targets for AD therapy. By focusing on non-canonical mechanisms such as oligodendrocyte health, BBB integrity, neuroimmunometabolism, and the coagulation system (Fig. 1), we hope to pave the way for more targeted and effective treatments in the future. These research areas, ranked in decreasing order based on their potential for therapeutic advancements, represent promising new avenues for addressing the complexities of AD beyond Aβ and tau pathology. In doing so, they offer hope for developing disease-modifying treatments that could significantly alter the course of AD and improve patient outcomes.

Non-canonical targets in AD

AD is distinguished by a primary deficit in episodic memory. The presence of this ailment frequently coincides with a variety of intellectual deficits in domains such as organizational skills, speech, visuospatial abilities, and decision-making. Therefore, AD manifests as a gradual decline in cognitive abilities, particularly impairing the individual's capacity for making decisions [25]. On average, individuals diagnosed with AD have a survival period ranging from 7 to 10 years. Furthermore, it is important to note that there is presently no definitive diagnosis for this particular illness prior to death. The existence of senile plaques (SP), neurofibrillary tangles, and synaptic loss can only be confirmed via histological examination after death. This poses significant challenges in terms of early detection and intervention [14, 26].

SP is a well-established neuropathological characteristic seen in brains afflicted by AD and continues to be a plausible source of synaptic and neuronal degeneration. SP arises from a gradual buildup of Aβ inside the parenchyma [27].

The intricate process of Aβ formation from the APP via β- and γ-secretase complexes holds crucial significance in AD. The amyloidogenic pathway’s heightened activity in AD, potentially influenced by genetic irregularities in APP or β-secretase, underscores their role in initiating this pathological cascade [28]. Despite linking most AD cases to mutations in APP and β-secretase, the root causes of dementia largely remain elusive. [29]. This mystery is compounded by the fact that 96% of dementia cases are sporadic, lacking identifiable genetic alterations. Individuals affected by these cases exhibit Aβ accumulation without clear underlying changes, highlighting the complexity of dementia’s etiology and necessitating deeper exploration beyond identified genetic factors [30].

Hence, it has been postulated that changes in the breakdown or clearance of Aβ may also have a pivotal influence on the etiology of AD. The detrimental impacts of Aβ, as shown in both human subjects and experimental animals, include a spectrum of effects ranging from freely dispersed oligomers to densely aggregated SP [31, 32]. Various forms of Aβ have been linked to synaptic deterioration and the emergence of neuritic dystrophies. Moreover, some studies have posited that the aggregation of Aβ, similar to SP, could possibly play a role in the decline of dendritic spines [32]. Furthermore, it has been shown that senile compact plaques are linked to the atypical curvature of adjacent neurites and have the potential to disrupt cortical synaptic integration. There has been a suggestion that the presence of Aβ alone may have the ability to induce neuronal cell death in the hippocampus and entorhinal cortex during the progression of AD. Furthermore, these regions have significant relevance in the processes of learning and memory, rendering them very susceptible to the impact of this ailment.

Aβ deposition is seen in the cerebral amyloid angiopathy (CAA) context, which is prevalent among the majority of individuals with AD [33, 34]. This deposition leads to the degradation or disruption of the BBB, hence impacting its overall performance. However, CAA may also manifest independently of AD, hence potentially serving as an indicator of vascular dementia (VaD) [34].

The deposition of Aβ pathology occurs prior to the occurrence of another significant neuropathological characteristic of AD, which involves the hyperphosphorylation and aggregation of tau protein into neurofibrillary tangles. Tau is a protein that is closely connected with microtubules and is highly expressed in the brain. It interacts with tubulin, facilitating the formation of microtubules. It provides support to various cytoskeletal structures and has a regulatory role in several key activities inside neurons. The involvement of tau protein in the pathophysiology of AD is significant, since its aberrant phosphorylation leads to its accumulation as intraneuronal deposits. These deposits manifest as filamentous aggregates in the soma and proximal dendrites [35].

Myelin, a multilayered membrane formed by specialized glial cells called mature oligodendrocytes, wraps around the axons of most neurons in the central nervous system (CNS). This essential structure is pivotal for the proper functioning of neural circuits, enhancing the transmission of nerve impulses through a process known as saltatory conduction. The efficient transmission of signals along myelinated axons is crucial for cognitive processes, motor functions, and overall neural communication. Oligodendrocytes originate from precursor cells known as oligodendrocyte progenitor cells (OPCs) [36]. The transition from OPCs to mature oligodendrocytes involves several stages: proliferation, migration, and differentiation. This intricate process results in the insulation of neuronal axons, allowing for rapid and efficient signal transmission [37]. In the context of neurodegenerative diseases, particularly AD, the remodeling and integrity of myelin become increasingly critical. AD is characterized by the accumulation of amyloid plaques and neurofibrillary tangles, which disrupt normal neuronal function and communication. Changes in myelin and oligodendrocyte function have been shown to play a significant role in the pathophysiology of AD. Studies suggest that alterations in myelin may contribute to the clinical manifestations and cognitive decline associated with the disease [38]. The myelin sheath is primarily composed of lipids, accounting for about 40% of CNS lipids. The lipid composition includes approximately 50% phospholipids, 40% glycolipids, and 10% cholesterol and cholesterol esters, along with polyunsaturated long-chain fatty acids [39]. Cholesterol, which is synthesized mainly by oligodendrocytes from ketone bodies, is critical for maintaining the structural integrity of myelin. It modulates the fluidity and permeability of the axonal membrane, thus influencing the rate of myelination and the overall health of the CNS. Notably, the predominant lipids in myelin—such as galactosyl ceramides and sulfatides—are essential for its stabilization and organization [39]. Research on the structural characteristics of the myelin sheath in AD has utilized advanced imaging techniques, including electron microscopy and magnetic resonance imaging (MRI), in both animal models and human subjects. For instance, the 5XFAD mouse transgenic model, which harbors multiple mutations in the APP and presenilin 1 (PS1) genes, exhibits amyloid deposits and synaptic deficits as early as 1.5 months of age [40]. Furthermore, myelin abnormalities in this model can be detected even earlier, coinciding with the onset of spatial memory deficits around 1 month of age [41]. In humans, studies have revealed a significant correlation between myelin abnormalities and the clinical manifestations of AD. Neuroimaging has shown that myelination irregularities occur in critical brain regions, particularly the hippocampus and corpus callosum—areas integral to memory and cognitive function [42,43,44]. The presence of conformational anomalies and thinning of the myelin sheath often precede the appearance of axonal lesions, suggesting a possible link to demyelination. During the preclinical phase of AD, MRI studies reveal changes in both longitudinal and transverse relaxation times, alongside increased myelin hydration levels [45]. Irregularities in white matter structure are frequently observed across various forms of AD, potentially indicating a progressive disease process [46]. Differences in T1-weighted/T2-weighted ratios have been documented between patients at risk and healthy controls, suggesting that early changes in myelin may reflect underlying pathological processes [47]. Several studies have linked myelin structural abnormalities to autoimmune disorders and the concentrations of Aβ1-42 peptides in affected individuals [48, 49]. The evaluation of cortical layer arrangements provides insights into the extent of deterioration, complementing volumetric atrophy data [42, 50]. MRI scans have revealed increased density areas in white matter corresponding to abnormalities associated with amyloid peptides and tau proteins in cerebrospinal fluid (CSF). These changes at the histological level suggest alterations in myelin structure, potentially influenced by factors such as iron ion accumulation [51]. Furthermore, diminished vascularization and oxygen delivery in hyper-dense regions are associated with axonal lesions, inflammatory responses, and disrupted blood–brain barrier permeability, culminating in micro-hemorrhagic structures [52]. Given the crucial role of oligodendrocytes and myelin in maintaining healthy neural communication, therapeutic strategies aimed at enhancing the function of OPCs may hold promise for addressing myelin deficits in AD. Recent studies indicate that antimuscarinic drugs, such as clemastine fumarate and benzatropine, can promote the differentiation of OPCs into mature oligodendrocytes capable of myelination. This effect has been observed both in vitro and in vivo, mediated through interactions with cholinergic receptors on OPCs [53, 54]. Additionally, the Piezo 1 receptor, involved in mechanosensory signaling, may also play a role in OPC behavior. Pharmacological inhibition of this receptor could create a niche environment conducive to OPC rejuvenation, potentially enhancing myelination in vivo [55]. Beyond receptor modulation, the mTOR signaling pathway has been recognized as a critical regulator of OPC development. The small molecule LY294002 has shown promise as a transcriptional regulator within this pathway, rejuvenating aged OPCs by promoting a more receptive state [56].

The synthesis, wrapping, and maintenance of myelin require substantial energy and nutrient supplies [57]. Thus, oligodendrocytes have distinct nutritional prerequisites to sustain their myelination capabilities. Nutrient-based interventions for myelination aim to provide direct substrates for myelin sheath construction and maintain energy supply, ensuring optimal metabolic conditions for oligodendrocytes. Adequate provision of macro and micronutrients is essential for the manufacture and maintenance of myelin, enabling oligodendrocytes to build complex and extensive membrane structures [58]. Specialized dietary formulations and individual nutrients have demonstrated positive effects on white matter health following damage or demyelination. One notable nutritional supplement, Fortasyn® Connect, contains key nutrients such as docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), uridine monophosphate, choline, phospholipids, and several vitamins (B6, B12, C, E), folic acid, and selenium [59]. Developed to support synapse development in AD patients, Fortasyn® Connect has been shown to exert protective effects on cognitive performance in individuals with mild AD [60, 61]. Moreover, it has demonstrated neuroprotective properties in AD models, likely related to enhanced phospholipid metabolism and the preservation of oligodendrocyte populations following white matter damage [62, 63]. Given the potential for certain nutrients to support white matter maintenance, research into other beneficial compounds is warranted. Nutrients such as sphingomyelin [64], vitamins K and D [65], and taurine [66] have shown promise in protecting white matter from injury or demyelination. While the benefits of nutritional support in healthy aging remain speculative, there is substantial evidence indicating that dietary interventions can positively influence white matter repair and cognitive function in contexts related to white matter pathology. The role of white matter in facilitating communication between different brain regions cannot be overstated. It coordinates a range of activities, including neuronal signaling, cognitive processes, proprioception, motion coordination, and sensory transmission. Despite the limited research on oligodendrocyte function concerning brain aging, significant advancements have been made in identifying both internal and external factors influencing oligodendrocyte activity in aging brains. White matter degeneration throughout the aging process is widely recognized as a significant contributor to cognitive decline and reduced independence in later life. Future research can enhance our understanding of white matter ageing, which may lead to strategies aimed at preserving its functions by leveraging the adaptable properties of the oligodendrocyte lineage. Investigating the various factors contributing to the diminished regenerative capacity of white matter in ageing is ongoing. However, the CNS retains substantial capabilities for myelin regeneration. This assertion is supported by studies of individuals with AD, which indicate that significant myelin regeneration can occur even in advanced disease stages.

Overall, targeted treatments to promote myelin preservation in the ageing population may be crucial for maintaining white matter functions vital for optimal cognitive performance. Given the interplay between oligodendrocyte health, myelin integrity, and cognitive function in AD, further exploration into therapeutic strategies that enhance oligodendrocyte activity and myelin repair could provide valuable insights into managing this complex disease (Fig. 2).

Multiple disease etiologies related to neuronal cells. (There are several causes and numerous cellular interactions involved in the development of AD. Harmful proteinopathies, particularly amyloid peptides, need to be incorporated into the intricate cellular milieu of the brain. The presence of several biological components contributes to the gradual and widespread deterioration of nerve cells, resulting in the irreversible symptoms of AD. This phenomenon occurs when the mechanisms responsible for eliminating hazardous peptides become overburdened, and it becomes noticeable only after a prolonged time of incubation. Modified neurons exhibit periods of reduced and increased excitability, along with impairments in the transportation of axons and synaptic activity, which impact the process of myelination/remyelination and the nourishment of oligodendrocytes. These cells are very susceptible to harm and their concentration declines significantly as one gets older. There seems to be a correlation between the level of neuronal participation and the degree of demyelination. This is particularly emphasized in AD, when there seems to be a lack of effective remyelination mechanisms. Astrocytes have a role in removing dysfunctional neurons and synapses. They play an active role in removing aberrant proteins and reducing inflammation. Similarly, the activation of microglia helps in the process of engulfing cellular waste. Similarly, these cells contribute to the initiation of the innate immune responses, the activation of the complement system, and the release of inflammatory cytokines.)

AD is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and alterations in behavior. One of the hallmark features of AD is the accumulation of Aβ plaques, which are linked to neuroinflammation and neurovascular dysfunction. Recent research has illuminated the critical role of the blood–brain barrier (BBB) in AD pathology, revealing that 80–85% of Aβ types are normally eliminated by the BBB [67]. However, emerging evidence suggests that disruptions in the BBB may serve as early indicators of neurodegenerative conditions, including AD as shown in Fig. 3 [68, 69]. Neuroimaging techniques, such as positron emission tomography (PET) and magnetic resonance imaging (MRI), have greatly advanced our understanding of the BBB's role in AD. These technologies allow for the observation of functional and molecular alterations in the brain associated with AD progression [70, 71]. Animal models of AD, alongside post-mortem human studies, have further highlighted significant changes that occur throughout various brain regions during the disease process [72,73,74]. The development of advanced brain imaging methods has significantly enhanced our capacity to detect alterations in blood vessels and the corresponding changes in cerebral blood flow. For instance, Kisler and colleagues (2017) demonstrated how sophisticated imaging can track these vascular changes, providing vital insights into the mechanisms by which cerebrovascular dysfunction contributes to neurodegeneration [23]. Additionally, molecular ligands, such as Aβ and tau, along with glucose and P-glycoprotein analogues like 18F-fluorodeoxyglucose and 11C-verapamil, facilitate in vivo monitoring of BBB transporters and receptor proteins [70]. These advancements have led to a deeper understanding of how dysfunction in cerebral blood vessels relates to neurodegenerative disorders. Recent studies employing dynamic contrast-enhanced MRI have confirmed the collapse of the BBB, revealing heightened gadolinium leakage in individuals with early AD, particularly in both white and grey matter [22]. This breach of the BBB has been substantiated by quantifying the accumulation of neurotoxic proteins derived from the bloodstream, including fibrinogen, thrombin, albumin, and immunoglobulin G (IgG). These proteins have been found to co-localize with Aβ deposits in the cerebral cortex and hippocampus of post-mortem brain tissues [75]. Furthermore, the presence of peripheral immune cells, such as macrophages [76] and neutrophils [