Cryo-electron microscopy studies have unequivocally elucidated two principal structural polymorphs of Aβ42 fibrils: Type I and Type II. These two conformations exhibit marked atomic-level distinctions. Type I fibrils manifest a right-handed helical twist, whereas Type II forms a left handed helical symmetry mediated by salt bridges (Figure 3A; Gremer et al., 2017). Despite their divergent conformations, both share a fundamental cross-β fold structure, a defining characteristic of amyloid proteins. Notably, this cross-β fold structure strikingly resembles the β-helical architecture of the prion protein (PrP^Sc). Both are composed of multiple stacked β-sheets, stabilized by an intricate network of hydrogen bonds, and culminate in highly ordered fibril structures (Shi et al., 2021; Wang et al., 2021). This shared structural foundation elucidates why Aβ can exhibit self-templating propagation properties analogous to PrP^Sc. For instance, Aβ Type II fibrils are particularly prone to inducing oxidative stress and mitochondrial dysfunction (Buchete and Hummer, 2007), a susceptibility potentially linked to their specific exposed surface areas or charge distribution. These characteristics also contribute to the strain specificity observed in PrP^Sc (Crowell et al., 2015).

The pathogenesis of prion diseases fundamentally involves the misfolding of prion protein (PrP) into recalcitrant PrP^Sc isoforms. Cryo-EM investigations have revealed that the pathogenic conformation of PrP^Sc typically adopts a unique β-helical fold structure, characterized by repeating β-sheet units stacked helically (Wang et al., 2021). This β-helical structure parallels the cross-β fold structures of Aβ and tau in its capacity to form stable, pathogenic aggregates. It not only bestows exceptional stability upon PrP^Sc but also dictates its propagation efficiency across diverse species, a phenomenon termed the “species barrier” (Crowell et al., 2015). For example, distinct PrP^Sc strains (e.g., VV1/VV2 types) exhibit variations in β-fold stability, directly influencing their amplification kinetics and pathogenicity. This structural heterogeneity mirrors the polymorphism observed in Aβ and tau, underscoring how subtle conformational disparities can engender significant differences in biological function and disease phenotypic diversity. A more profound understanding of the β-helical structure of PrP^Sc and its variations will enhance our comprehension of the conformational diversity of Aβ and tau in AD and their respective roles in disease progression.

While Aβ and tau proteins exhibit self-templating propagation properties akin to PrP^Sc, their transmissibility presents notable similarities and distinctions. Classic prions are renowned for their capacity to transmit disease across individuals and even species under experimental conditions, a core pathogenic attribute (Jucker and Walker, 2018). In contrast, the propagation of Aβ and tau primarily manifests as “prion-like” behavior, wherein they disseminate within an individual through self-templating mechanisms between cells and brain regions, typically without involving inter-individual transmission (Buchete and Hummer, 2007).

Experimental evidence indicates that Aβ and tau aggregates can, under specific conditions, induce normal proteins to misfold and form pathological aggregates, leading to pathological dissemination. For example, injecting brain extracts from Alzheimer’s disease patients into mice can induce the propagation of Aβ or tau pathology and neurodegeneration (Tarutani et al., 2023b; Zhang et al., 2020). This “seeding” capability parallels prion propagation (Jucker and Walker, 2018). However, the propagation of Aβ and tau generally lacks the “infectivity” characteristic of classic prions, meaning inter-personal transmission does not occur through routine contact (Lauwers et al., 2020). Studies suggest that the transmission efficiency and host range of Aβ and tau are typically more restricted than PrP^Sc, a limitation potentially attributable to the existence of a “species barrier” and the specificity of distinct protein conformations (Condello et al., 2020; Woerman et al., 2016).

Comprehending these differences in transmissibility holds significant implications for the diagnosis, prevention, and therapeutic strategies of Alzheimer’s disease. Although AD is not contagious, concerns regarding the potential “seeding” risk of Aβ or tau in certain medical procedures necessitate vigilance in the disinfection and handling of medical instruments. In essence, the “prion-like” behavior of Aβ and tau is fundamental to their pathological progression, yet their transmissibility diverges significantly from classic prions. This distinction facilitates a more accurate understanding of AD’s pathological mechanisms and guides future research endeavors.

Abnormal aggregation of tau protein is a defining characteristic of various neurodegenerative diseases, collectively termed tauopathies. Among these, tau pathology in AD possesses distinctive structural features. Cryo-EM structures of AD-specific tau fibrils reveal that their core region forms a unique C-shaped fold (Figure 3B), a structure functionally analogous to the β-helical structure of PrP^Sc in its capacity to drive self templating replication (Aragão Gomes et al., 2021; Fowler et al., 2025). During the formation of this conformation, PTMs of tau protein, particularly acetylation at the K317 site, have been demonstrated to significantly influence the conformation and aggregation properties of tau fibrils (Shi et al., 2021), thereby modulating their toxicity and propagation ability. For a comprehensive exposition on the regulatory mechanisms of PTMs concerning conformational heterogeneity and pathogenicity, please refer to Section “3.4 Post-translational modifications (PTMs): their role in conformational regulation.”

Beyond AD, other tauopathies such as PSP and CBD also exhibit unique tau subtype structures, which are intimately linked to their respective clinical manifestations. For instance, tau subtypes in PSP present as twisted helical shapes, whereas those in CBD display a more disordered, prion-like conformation (Aragão Gomes et al., 2021; Tarutani et al., 2023a,b; Zhang et al., 2020). These cryo-EM-elucidated structural diversities further substantiate the principle that “conformation determines function,” implying that distinct misfolded conformations lead to disparate disease phenotypes and propagation characteristics. This conformational diversity strongly aligns with the “strain” concept of PrP^Sc, indicating that the pathological processes of Aβ and tau also manifest similar “strain” phenomena. Different strains may correspond to varying disease progression rates, affected brain regions, and clinical presentations. Identifying these structural features provides crucial insights into disease mechanisms and may guide the development of more precise diagnostic tools and therapeutic modalities targeting specific tauopathy strains.

Post-translational modifications, such as the truncation and pyroglutamylation of Aβ, significantly impact protein aggregation and cytotoxicity. N-terminal truncation of Aβ, in particular, augments its propensity for further aggregation, thereby accelerating the formation of amyloid plaques. Pyroglutamylation, conversely, enhances its seeding activity (Bayer, 2022), indicating a synergistic role for this modification in promoting the amyloid pathology. The influence of these PTMs on Aβ fibril formation and expansion offers valuable therapeutic targets. Inhibiting specific truncation or modification events may mitigate the seeding capacity of Aβ peptides, consequently decelerating the progression of AD.

Tau phosphorylation constitutes another critical PTM that modulates tau’s functional properties. Specific phosphorylation hotspots, including Ser202/Thr205 (AT8 epitope) (Ballatore et al., 2007; Capocchi et al., 2024), are demonstrably associated with tau dissociation from microtubules. This modification precipitates tau’s detachment from microtubules, subsequently leading to the formation of folded helical filaments and promoting neurodegeneration. Phosphorylation driven microtubule disintegration plays a central role in tau-mediated neurotoxicity. Targeting tau phosphorylation sites through small molecules or gene editing techniques (DeVos et al., 2017; Yang and Qiu, 2024) holds therapeutic promise in tau-related neurodegenerative diseases, such as AD and frontotemporal dementia.

Exosomes are nanoscale extracellular vesicles that play a crucial role in intercellular communication (Carretero-González et al., 2018; Mu et al., 2023). In the context of AD, exosomes can encapsulate oligomeric Aβ and hyperphosphorylated tau proteins, facilitating their transfer from compromised neurons to adjacent healthy cells (Soliman et al., 2021). This process promotes the spread of pathological signals, thereby exacerbating synaptic and axonal damage and consequently impairing cognitive function (Li N. et al., 2022). Structural investigations have revealed that Aβ oligomers with exposed hydrophobic regions (e.g., Type II fibril derivatives) exhibit specific binding to GM1 gangliosides on exosomal membranes. This interaction significantly enhances vesicular packaging efficiency, markedly surpassing that observed with hydrophilic conformational strains (Thijssen et al., 2021).

Tunneling nanotubes (TNTs) constitute a class of membranous nanochannels that physically connect adjacent cells, enabling direct cytoplasmic communication, including the transfer of pathogenic protein aggregates (Notario Manzano et al., 2024). Studies have demonstrated that both Aβ and tau can exploit TNTs for intercellular propagation, displaying dissemination characteristics analogous to classic prions. Furthermore, this process is augmented by heightened neuronal activity (Chun et al., 2020; Jucker and Walker, 2018).

Synapses, serving as vital hubs for information exchange within neural networks, exhibit dysfunctional states that significantly accelerate the propagation of pathological proteins. Upregulation of the inflammatory cytokine interleukin-1 beta (IL-1β) promotes the expansion of TNT networks and exosome release, thereby creating “propagation hotspots.” Concurrently, reduced expression of the synaptic vesicle protein SV2A is correlated with the aberrant accumulation of Aβ and tau, suggesting a substantial role for synaptic transmission and its regulatory molecules in the dissemination of pathological proteins (Kong et al., 2021).

The Default Mode Network (DMN), a critical brain network implicated in memory, selfawareness, and social cognition, demonstrates high susceptibility in AD. Tau pathology preferentially originates in the medial temporal lobe region and subsequently propagates along synaptically connected pathways within the DMN, achieving trans-synaptic “jumping.” This process is guided by the connectome structure of the DMN (Malek-Ahmadi et al., 2020; Roemer-Cassiano et al., 2025). Specifically, C-shaped tau protein originating from the entorhinal layer (Malek-Ahmadi et al., 2020) preferentially binds to heparan sulfate proteoglycans (HSPGs) abundantly present in the DMN (Roemer-Cassiano et al., 2025), facilitating trans-synaptic propagation along hierarchical circuits (entorhinal cortex → hippocampus → neocortex). This hierarchical dissemination defines the Braak staging (Malek-Ahmadi et al., 2020; Therriault et al., 2022). The spatiotemporal characteristics of this process underscore the profound interconnectedness among distinct brain regions.

Aβ protein deposition stems not only from excessive production but also from impaired brain clearance mechanisms, particularly within perivascular regions. Compromised cerebral vascular drainage and blood-brain barrier (BBB) dysfunction exacerbate Aβ deposition (Kim et al., 2020). Specifically, impaired LRP1-mediated Aβ transport across the BBB and diminished glymphatic system function both contribute to increased Aβ accumulation within the brain parenchyma (Harrison et al., 2020; Kim et al., 2020). Apolipoprotein E4 (APOE4) further promotes Aβ enrichment in brain hub regions (e.g., the precuneus) by reducing Aβ hydrodynamic radius (Shi et al., 2021) and compromising meningeal lymphatic vessel structure and function (Peng et al., 2020), thereby accelerating protein homeostasis imbalance. This intricate pathway establishes a positive feedback loop: early DMN hyperactivity augments the synaptic release of tau protein, while compromised Aβ clearance provides a conducive microenvironment for its propagation and accumulation.

GM1 ganglioside anchors the hydrophobic core of Aβ oligomers, thereby promoting their conversion into toxic oligomers (Cebecauer et al., 2017). This interaction extends their extracellular half-life by 2.5-fold and enhances exosomal loading efficiency, consequently increasing Aβ aggregation propensity. This “molecular chaperone” effect offers a promising therapeutic target for intervening in “prion-like” propagation. Specifically, targeting GM1-Aβ binding may provide a viable strategy to modulate the conformational stability of Aβ, thereby disrupting its “prion-like” propagation cascade. Furthermore, lipid raft microdomains also confer protection to phosphorylated tau against phosphatase-mediated degradation (Li N. et al., 2022).

Low-density lipoprotein receptor-related protein 1 (LRP1) and Apolipoprotein E4 (APOE4) are pivotal molecules governing Aβ metabolism (Liu et al., 2017; Serrano-Pozo et al., 2021). LRP1 facilitates Aβ transport across the blood-brain barrier and its subsequent degradation (P et al., 2022). Conversely, genetic risk factors such as APOE4 significantly impair LRP1 function, leading to reduced Aβ clearance efficiency and concurrently augmenting central nervous system inflammatory responses (Li Y. et al., 2022). Additionally, the TREM2 R47H mutation compromises microglial phagocytosis of phosphorylated tau, further exacerbating pathological protein accumulation (Buchete and Hummer, 2007). These factors collectively enhance the “prion-like” propagation capacity of pathological proteins, thereby driving the progression of neurodegeneration.

Protein misfolding cyclic amplification technology, first reported by Saborio et al. (2001), operates on the principle of repeatedly disrupting newly formed PrP^Sc aggregates using ultrasound. This process exposes additional “seed” surfaces, thereby accelerating the conversion of normal prion protein (PrPC) to PrP^Sc. Analogous to the cyclic amplification in polymerase chain reaction (PCR), PMCA can amplify minute quantities of PrP^Sc by millions of times within hours to days, reaching detectable levels. The primary advantage of PMCA lies in its exceptional sensitivity, theoretically capable of detecting single PrP^Sc molecules. It has been successfully employed for detecting PrP^Sc in diverse biological samples, including cerebrospinal fluid, blood, urine, lymphoid tissues, and even skin biopsies (Chen et al., 2024; Pritzkow et al., 2023; Soto et al., 2005). For instance, one study demonstrated PMCA’s efficacy in detecting PrP^Sc from skin biopsy samples.

Crucially, Tau-RT-QuIC not only confirms the presence of tau pathology but also differentiates tau strains associated with various tauopathies (e.g., AD, PSP, CBD). Cerebrospinal fluid samples from patients afflicted with distinct tauopathies exhibit unique amplification kinetic curves and product conformations in Tau-RT-QuIC reactions, reflecting the underlying structural disparities of tau protein aggregates across these diseases (Frey et al., 2024; Tarutani et al., 2023a; Wang et al., 2024). For example, the Tau-RT-QuIC amplification curve in AD patients typically displays a distinctive biphasic pattern. The initial lag phase may correlate with the rapid nucleation of AD-specific C shaped tau folds, while the subsequent lag phase might be associated with p-tau396/404- driven fibril elongation. This “conformational fingerprinting” capability enables Tau-RT-QuIC to facilitate precise differential diagnosis between AD and other tauopathies like PSP/CBD, thereby guiding clinicians toward more accurate diagnoses and informed treatment decisions (Lathuiliere and Hyman, 2021).

Real-Time Quaking-Induced Conversion (RT-QuIC) technology demonstrates exceptional advantages in the differential diagnosis of tau pathology. This technique, through the in vitro amplification of specific tau protein seeds, enables the differentiation of conformational strains of tau protein across various neurodegenerative diseases (Tennant et al., 2020). Furthermore, RT-QuIC holds considerable promise for detecting early or atypical tau pathology, although its standardization and validation in routine clinical practice remain areas requiring further development.

Phosphorylated tau protein (p-Tau) serves as a pivotal biomarker for AD, playing a critical role in both disease diagnosis and progression monitoring. For an extended period, pTau181 has been regarded as a classic indicator of AD-specific tau pathology in cerebrospinal fluid, with elevated levels frequently correlating with Aβ deposition and early neurodegeneration (Thijssen et al., 2021). However, in recent years, pTau217 has emerged as a superior next-generation biomarker, exhibiting markedly enhanced diagnostic performance. Research indicates that pTau217 levels can significantly increase even during the preclinical stage of AD, demonstrating a strong correlation with brain Aβ plaque and tau tangle burden. Its sensitivity and specificity surpass those of pTau181 (Gonzalez-Ortiz et al., 2023), particularly in distinguishing AD from other neurodegenerative disorders. Crucially, the detection of pTau217 in plasma also exhibits high accuracy, offering substantial potential for non-invasive early screening of AD (Palmqvist et al., 2020). Consequently, while pTau181 retains its diagnostic utility, pTau217 is progressively becoming the preferred biomarker for early AD diagnosis and monitoring. Their combined application can provide a more comprehensive perspective for precise AD diagnosis.

Phosphorylated tau at site 217 (p-Tau217), as a novel liquid biomarker, demonstrates exceptionally high sensitivity and specificity, outperforming earlier indicators such as p Tau181. Its concentration elevates even prior to observable cognitive decline, reflecting the progression of brain tau pathology. The integration of p-Tau217 with Positron Emission Tomography (PET) imaging technology, which targets Aβ fibrils (Pontecorvo and Mintun, 2011), can establish a multimodal diagnostic framework encompassing quantification and localization. This comprehensive approach provides a robust foundation for the early identification and disease progression tracking in AD. Specifically, the combination of RT-QuIC (for strain identification), p-Tau217 (as a liquid biomarker), and PET (for spatial imaging) constructs a holistic diagnostic strategy based on “conformation-quantification-localization.”

Passive immunotherapy involves the intravenous administration of exogenous monoclonal antibodies (mAbs) designed to specifically bind to and facilitate the clearance of pathogenic proteins. For instance, anti-Aβ monoclonal antibodies such as Aducanumab, Lecanemab, and Donanemab have achieved notable clinical progress. Lecanemab and Donanemab, by selectively targeting Aβ fibrils or plaques, have demonstrably slowed cognitive decline in AD patients, albeit with associated side effects such as amyloid-related imaging abnormalities-edema (ARIA-E) (Sims et al., 2023; van Dyck et al., 2023). While this class of therapies exhibits a rapid onset of action, the exogenous antibodies are subject to metabolic degradation, necessitating periodic re-administration to sustain therapeutic efficacy.

Active immunotherapy primarily stimulates the patient’s endogenous immune system to generate specific antibodies against pathogenic proteins. ACI-35, a tau vaccine developed for AD, aims to elicit a therapeutic effect by inducing the patient’s immune system to produce antibodies specifically targeting phosphorylated tau protein (particularly at the Ser396/404 sites) (Congdon et al., 2023). In contrast to passive immunization, which involves direct antibody injection, ACI-35 stimulates the body to mount an active immune response, thereby potentially offering more durable protection. Although phosphorylation modifications can influence the overall conformation of tau protein, ACI-35 primarily targets this specific post-translational modification rather than the broader three-dimensional aggregated structure of tau protein. Early clinical trials, including the Phase Ib study ISRCTN13033912 (completed in 2017) and the Phase Ib/IIa clinical trial NCT04445831 (conducted in 2022), have confirmed the favorable safety and tolerability profile of ACI-35 in patients with mild to moderate AD, along with its efficacy in inducing robust antibody responses (Congdon et al., 2023).

Immunotherapy represents a novel paradigm for precise intervention in AD. Future research endeavors will focus on optimizing antibody specificity and safety profiles, concurrently exploring combination therapy strategies to achieve more effective pathological clearance and cognitive improvement across various disease stages.

Conformation-specific antibodies constitute a class of antibodies capable of selectively recognizing the unique three-dimensional conformation of a protein, rather than merely its primary amino acid sequence (Desai et al., 2025). In the context of AD treatment, these antibodies primarily target the aberrantly misfolded conformations of Aβ and tau proteins, including their soluble oligomeric/fibrillar forms or tangles (Gaikwad et al., 2024; Zhang et al., 2024). Unlike conventional antibodies that target linear epitopes, conformational antibodies can differentiate between normally folded proteins and pathogenic misfolded proteins, thereby enabling a more precise therapeutic intervention (Desai et al., 2025). Monoclonal antibodies specifically targeting aggregated Aβ or tau conformations are currently undergoing clinical trials and are in the early stages of market introduction. Aducanumab, the first conformation-specific antibody approved for Alzheimer’s disease treatment, recognizes Aβ oligomers and fibrils (Beshir et al., 2022). It has demonstrated some capacity to improve patients’ cognitive function and slow disease progression. However, the discordant results observed in its EMERGE and ENGAGE trials have generated controversy (Budd Haeberlein et al., 2022), underscoring the critical importance of strain adaptability. Furthermore, associated side effects, such as cerebral edema, necessitate further evaluation and optimization. Donanemab, exhibiting superior fibril selectivity, has demonstrated more favorable cognitive maintenance effects and a reduced incidence of ARIA side effects (Reardon, 2023; Sims et al., 2023).

β-sheet breakers achieve non-immune-dependent conformational clearance by disrupting the core structure of pathogenic aggregates (Jani et al., 2021). The D3 peptide and its derivatives can bind complementarily to Aβ fibril structures, inducing their disaggregation. Animal studies have substantiated their efficacy in improving cognitive function (Bocharov et al., 2021; Widera et al., 2014). Polyphenolic compounds, such as Epigallocatechin gallate (EGCG) and curcumin, inhibit Aβ and tau aggregation by interfering with hydrogen bonds and aromatic stacking, concurrently exhibiting notable neuroprotective effects (Li et al., 2024; Xu et al., 2022). Their therapeutic potential in diseases like Alzheimer’s is progressively gaining recognition. While these β-sheet breakers have yielded encouraging results in preclinical investigations, they generally suffer from limitations such as low bioavailability and suboptimal targeting. Nanodelivery systems offer a promising avenue to regulate carriers for targeted drug delivery (Wang et al., 2025), thereby optimizing their pharmacokinetic properties through responsive release platforms.

Microenvironment reprogramming represents a burgeoning therapeutic strategy aimed at augmenting the clearance of pathological protein aggregates by modulating the brain’s immune system and cerebrospinal fluid clearance mechanisms. Low-density lipoprotein receptor-related protein 1 (LRP1), a multifunctional transmembrane receptor, is broadly expressed across various cell types and participates in the endocytosis/signal transduction of multiple ligands and the remodeling of the extracellular matrix (Herz and Bock, 2002). Within the central nervous system, LRP1 regulates Aβ transport across the blood-brain barrier (BBB) and its clearance via the glymphatic system (Ma et al., 2022). Impaired LRP1 function or its downregulated expression in the brains of AD patients is considered a significant contributor to reduced Aβ clearance efficiency, consequently promoting Aβ accumulation and plaque formation in the brain. LRP1 agonists have been shown to enhance CSF Aβ efflux and reduce brain deposition, leading to significant improvements in pathological manifestations in mouse models (Storck et al., 2016). This strategy systemically rectifies the “seeding-clearance” imbalance observed in prion models, offering novel insights for intervention at the seed level.

Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is a microglial surface receptor that modulates their phagocytic capacity for Aβ/tau and their inflammatory responses (Zhong et al., 2019). Activation of TREM2 can promote aggregate clearance while simultaneously suppressing excessive inflammatory responses, thereby mitigating neuroinflammation induced by overactive immune responses (Zhong et al., 2023). Early clinical drug candidates, such as AL002, have demonstrated potential in restoring microglial function and decelerating disease progression (Long et al., 2024). Real-time monitoring of microglial status through functional imaging or fluid biomarkers can guide TREM2-targeted therapy, facilitating individualized immune intervention.