Could the cognitive benefits of amyloid-beta clearance grow in time for Alzheimer’s disease?

Abstract

Alzheimer’s disease (AD) is characterized histologically by amyloid-β (Aβ) deposition in the brain. Immunotherapies targeting Aβ clearance have become a leading treatment strategy. Although these therapies effectively reduce cerebral Aβ burden, their cognitive benefits remain modest during the trial period. This review systematically assesses the extent of Aβ clearance by immunotherapies and its related cognitive outcomes, focusing on whether cognitive benefits increase over time. We refine a model of the “lag effect” between plaque clearance and cognitive benefit, which is potentially influenced by clearance rate, treatment duration, disease stage, genetic factors, and aging. We also discuss the underlying biological mechanisms and potential neuroprotective targets. Future research should prioritize long-term studies, early intervention, personalized therapies, and combination approaches addressing multiple pathological pathways. Given limited short-term cognitive gains, optimizing outcomes will require tailoring treatments to individual patient factors—including genetics, disease progression, and aging—to minimize side effects and enhance long-term cognitive function.

Introduction

Alzheimer’s disease (AD) is a leading neurodegenerative disorder affecting elderly population worldwide, with a 10.5% prevalence in those aged 65 and older [1]. A hallmark of the disease is cerebral amyloid-β (Aβ) deposition, which underpins the Aβ cascade hypothesis, a key framework for understanding AD pathogenesis [1]. Evidence from animal models and early clinical trials indicates that reducing brain Aβ levels can yield measurable cognitive benefits, making Aβ clearance the primary therapeutic goal [2]. Current Aβ targeting immunotherapies fall into two categories: active immunization using Aβ vaccines and passive immunization using anti Aβ monoclonal antibodies [3]. Further phase 3 trials and long-term data are needed to confirm the efficacy of Aβ vaccines. In contrast, multiple phase 3 clinical trials involving monoclonal antibodies targeting Aβ have demonstrated that although these antibodies can effectively clear 71% to 84% of Aβ plaques in the brain, they only modestly slowed cognitive decline, as reflected by a 22% to 29% reduction in the decline of CDR-SB score during the trial period [4–10]. In this review, we investigate whether cognitive benefits following Aβ clearance through immunotherapy emerge gradually over time, exploring the possibility of a “lag” effect in treatment outcomes.

Anti-Aβ immunotherapies and cognitive outcomes

Current immunotherapies for AD primarily focus on reducing cerebral Aβ burden. Clinical outcomes from monoclonal antibody trials demonstrate a consistent association between the extent and rate of Aβ clearance and the magnitude of cognitive benefit. However, not all anti-Aβ antibodies have demonstrated clinical efficacy (Table 1). Solanezumab and Crenezumab, which target soluble Aβ monomers [11, 12], failed to significantly reduce parenchymal Aβ plaque deposition or slow cognitive decline [13–16]. Similarly, Bapineuzumab and Gantenerumab, despite showing reduced amyloid burden through positron emission tomography (PET) imaging, phase 3 clinical trial results indicated that Bapineuzumab could only lower amyloid by approximately 5 centiloids (CL) [17], and Gantenerumab could only bring 28% of the subjects below the Aβ positive threshold [18]. Therefore, neither of them achieved the primary cognitive endpoints [17, 18].

Table 1.

Phase 3 trials of antibodies against Aβ in Alzheimer disease.

Year	Drug name (Trial name)	Target	Subject population	Test period	Aβ removal effecacy	Cognitive outcomes	Reference
2016	Solanezumab (EXPEDITION 1&2)	Soluble Aβ	Mild to moderate AD	72 weeks	Failed to remove the formed Aβ plaques	No improvement in cognition	[15]
2023	Solanezumab (EXPEDITION 3)	Soluble Aβ	Mild to moderate AD	80 weeks	Not shown	Delayed 14–21% cognitive decline (Meta-analysis)	[13]
2023	Solanezumab (A4)	Soluble Aβ	Asymptomatic AD	240 weeks	Failed to significantly remove the formed Aβ plaques	No improvement in cognition	[14]
2019	Crenezumab	Soluble Aβ	Prodromal to mild AD	77 weeks	Failed to significantly remove the formed Aβ plaques	No improvement in cognition	[16]
2012	Bapineuzumab	Soluble Aβ and plaque	Mild to moderate AD	78 weeks	Slightly lowering of brain amyloid (~5 CL)	No improvement in cognition and Serious side effects	[157]
2016	Gantenerumab	Aβ plaque	Mild AD	116 weeks	Moderate lowering of brain amyloid (~55–66 CL)	No improvement in cognition	[18]
2020	Aducanumab	Aβ plaque	MCI to early dementia	78 weeks	Moderate lowering of brain amyloid (~54–64 CL)	Delayed 14–22% cognitive decline in EMERGE	[10]
2023	Donanemab	Aβ plaque	MCI to early dementia	72 weeks	Largely lowering of brain amyloid (~80–90 CL)	Delayed 29% cognitive decline	[6]
2023	Lecanemab	Aβ fibrils and plaque	MCI to early dementia	78 weeks	Moderate lowering of brain amyloid (~59 CL)	Delayed 27% cognitive decline	[5]

In contrast, immunotherapies that substantially remove amyloid plaques have demonstrated measurable cognitive preservation. In the EMERGE trial, aducanumab reduced Aβ levels to near-negative status (~21 CL), resulting in a 0.39-unit difference in CDR-SB change versus placebo [19, 20]. This small reduction relative to the 0-18-unit CDR-SB scoring scale was initially questioned for it clinically meaningful benefits. However, given the 1.74-unit decline of placebo group over the disease course, this represents a 22% slowing of cognitive deterioration, supporting its clinical significance [21]. Donanemab, which selectively targets pyroglutamate-modified Aβ (N3pG-Aβ) [22], reduced plaque burden by 84% compared to placebo, with 72% of participants reaching amyloid clearance thresholds within 18 months, leading to a 29–36% reduction in the rate of cognitive deterioration [6]. Lecanemab, which binds soluble Aβ oligomers and fibrils, reduced Aβ load by 59 CL, with 68% of patients achieving amyloid-negative status, correlating with a 27% slowing of disease progression [5]. These results indicate that modest reduction in Aβ levels is insufficient for meaningful clinical impact; rather, a critical threshold of Aβ clearance may be required to confer therapeutic benefit. It is strongly supported by the cross-compound analysis demonstrating that a critical threshold of Aβ clearance (as achieved by Aducanumab, Lecanemab, and Donanemab) is required to confer therapeutic benefit [21].

Notably, the speed of Aβ clearance appears to be a key determinant of clinical outcome. The divergent results between the ENGAGE and EMERGE trials of aducanumab suggest that faster clearance rates, approximately 3.5 CL/month in EMERGE versus 3 CL/month in ENGAGE [10, 23, 24], may bring cognitive benefits by more rapidly interrupting Aβ driven downstream pathological processes. The differences in clearance rates observed in the two trials might be attributed to the significantly shorter median exposure time in the high-dose group in the ENGAGE trial and the higher proportion of APOE ε4 carriers in the ENGAGE trial [21, 24]. Donanemab’s rapid early clearance rate may similarly underlie its pronounced clinical effect [6]. Collectively, evidence from clinical trials supports a positive correlation between the degree and speed of Aβ clearance and cognitive outcomes in AD [21, 23]. Faster clearance speed is equivalent to larger magnitude of Aβ reduction within a fixed time window [25]. Clinically meaningful delays in cognitive decline are observed only when Aβ removal is both substantial, achieving amyloid negative or near negative levels and sufficiently rapid, underscoring the importance of attaining a critical threshold of clearance within a defined therapeutic window [25].

Consequently, based on the “lead and lag scenario” proposed by Bart De Strooper and Eric Karran [25], we modified this model and derive a curve depicting the relationship between the degree and speed of Aβ clearance and cognitive benefits (Fig. 1). As monoclonal antibody therapies facilitate the removal of Aβ from the brain, the rate of cognitive decline gradually slows down. Therefore, a question is raised as to whether the cognitive benefits of amyloid-beta removal could grow in time for AD?

Fig. 1. The time-dependent curve of amyloid protein clearance and clinical response.

This figure illustrates the hypothesized relationship between the speed and extent of amyloid plaque clearance and the subsequent improvement in cognitive decline. The association between Aβ deposition and cognitive impairment requires biological processes such as neuronal death, synaptic damage, and tau protein accumulation. Cognitive function could not improve immediately after Aβ clearance but rather takes time for the pathological damage to subside and for the neurons to establish new network connections (Time lag effect). The approximately 18-month trial and observation period of clinical phase 3 trials may not be sufficient to observe significant cognitive benefits. After the approximately 18-month clinical trial period (Post-clinical trial period), cognitive function may continue to improve, and the faster Aβ is cleared below the negative threshold in the brain, the more significant the cognitive benefits would be. Anti-Aβ mAb, anti-amyloid-β monoclonal antibody.

Lag effect between amyloid removal and cognitive improvement

Lessons from clinical trials

Although Gantenerumab failed to meet primary endpoints in its phase 3 trial, subsequent open-label extension (OLE) data from patients with dominantly inherited AD (DIAD) revealed significant Aβ plaque reduction after three years of treatment [26]. In the subgroup receiving the longest treatment duration (mean 8.44 years), CDR-SB progression was reduced by 57% (HR 0.57), though statistical significance was not achieved, likely due to limited sample size [26]. This effect was not detected in the cohort that underwent treatment for a shorter duration (2-3 years). This suggests that long-term use of Gantenerumab can reduce the level of Aβ plaques in the brain of DIAD patients, and cognitive benefits may accrue with prolonged treatment.

Aducanumab, studied in the phase 1b PRIME trial and its long-term extension (LTE), clearly demonstrated a lag effect between Aβ clearance and cognitive benefit over 48 months [27]. During the 12-month placebo-controlled period, the 10 mg/kg fixed-dose and titration-to-10 mg/kg cohorts achieved significant Aβ reduction (dose-dependent decline in composite SUVR). However, this early Aβ clearance did not translate to a significant slowing of CDR-SB score decline compared to the placebo group. In contrast, by month 48 (12-month controlled period + 36-month LTE), the cognitive benefit became prominent and expanded substantially: the 10 mg/kg fixed and titration groups had adjusted mean CDR-SB changes of 3.83 and 3.68, respectively, versus 6.15 in placebo switchers—representing a ~ 40% reduction in cognitive decline [27]. These data confirm that aducanumab’s cognitive benefit is delayed relative to early Aβ clearance, with a marked expansion of CDR-SB decline slowing by 48 months, supporting a lag effect between pathological modification and clinical improvement in AD.

Lecanemab, which demonstrated efficacy in the Clarity AD trial [5], showed sustained cognitive benefits in an OLE study over 36 months. Compared to the ADNI cohort, the reduction in CDR-SB score decline increased from 0.52 at 18 months to 1.01 by 36 months (0.324 units per 12 months) [8]. The follow-up data for the subsequent year was disclosed, showing that cognitive benefits continued to expand. The reduction in CDR-SB scores increased from 1.01 at 36 months to 1.75 by 48 months in the ADNI cohort (0.744 units per 12 months). Similar results were also observed in the BioFINDER cohort, with scores rising from 1.40 at 36 months to 2.17 by 48 months, and over half of the subjects exhibiting cognitive improvement in the low-tau group [28]. The above results suggest that although the reduction of Aβ has reached its maximum, the rate of cognitive benefit continues to increase over time. The difference in CDR-SB scores changed from 0.324 units/year from 18 to 36 months to 0.744 units/year from 36 to 48 months. The maximum reduction in CDR-SB occurred much later than the maximum reduction in Aβ burden. Consistent with these observations, in the TRAILBLAZER-ALZ 2 LTE study, cognitive benefits in the donanemab-treated cohort continued to widen relative to the weighted ADNI control cohort—even among participants who had discontinued treatment following achievement of amyloid clearance and completion of the limited-duration dosing regimen. Specifically, the treatment-associated slowing of CDR-SB progression increased from 0.6 points at 18 months to 1.2 points at 36 months [29]. However, it should be noted that the control groups in the above studies were not placebo groups but the ADNI and BioFINDER cohorts. Moreover, there was a lack of data on biomarker changes, implying the potential for certain biases. Nevertheless, these findings still suggest that monoclonal antibody-mediated Aβ clearance may result in sustained cognitive benefits.

Implication from preclinical studies

Lecanemab received FDA approval in 2023 based on its ability to clear Aβ and moderately slow cognitive decline. However, real-world evidence after its market launch indicates that the rate of cognitive decline remained at 1.11 points per year (measured by CDR-SB) after seven months of treatment, a rate comparable to the placebo group in the Clarity AD trial. This suggests that Lecanemab’s therapeutic effect may not be immediate but instead exhibits a time-lag before cognitive stabilization becomes evident [7]. This “lag” phenomenon appears to be corroborated by studies utilizing animal models as well [30]. For instance, research involving APP/PS1 mice treated with the A16 monoclonal antibody, Aβ clearance occurred within two days, yet cognitive improvement was not observed until approximately 20 days later [30]. Researchers proposed that Fc-mediated microglial activation and synaptic pruning may transiently offset the benefits of amyloid removal, delaying functional recovery. These observations align with clinical trial data showing that amyloid reduction often precedes measurable cognitive improvement. Across multiple monoclonal antibody trials, amyloid negativity is generally achieved after 18 months of treatment, yet maximal cognitive benefit appears to accumulate over a longer period [5, 6, 10, 18]. It is hypothesized that clearance related transient responses—such as microglial activation, complement pathway engagement, and synaptic stripping—may initially mask cognitive gains [30]. These “side effects” may affect the cognitive benefits of patients, and Aβ immunotherapy may require a longer period of time to achieve better cognitive function recovery.

Factors affecting cognitive recovery

Intervention duration

Intervention duration is a critical factor in Aβ immunotherapy efficacy, influencing outcomes in two key ways: (1) Under the condition of ensuring safety, it is essential to minimize the duration required to reduce Aβ load in the brain below the negative threshold as much as possible [25]. (2) The timing of cognitive benefits lags behind the pathological Aβ clearance. Current monoclonal antibodies—Aducanumab, Lecanemab, and Donanemab—show that most patients achieve negative Aβ status only after 18 months of treatment [5–7, 10]. However, the associated cognitive benefits do not correspond with this timeline for the pathological clearance of Aβ. Notably, significant cognitive improvements were not observed at 18 months post-treatment. It is likely that cognitive benefits represent long-term effects following Aβ clearance and may become more pronounced over extended periods. Therefore, the current 18-month treatment cycle may be insufficient for evaluating long-term outcomes related to efficacy indicators such as cognitive function levels.

Soluble Aβ oligomers

Soluble Aβ oligomers are more neurotoxic than insoluble plaques and are considered the primary drivers of sustained neurotoxicity and progressive cognitive decline [31–33]. Donanemab selectively targets and effectively clears mature, insoluble Aβ plaques. It has been proposed that plaques may act as pathological reservoirs, and that rapid removal could under certain conditions, be accompanied by a transient redistribution toward soluble fibrillar and oligomeric Aβ species, potentially compromising cognition—a phenomenon referred to as the “dust-raising effect” [34–36]. However, the extent to which such transient shifts occur in humans and their clinical relevance remain uncertain, as soluble Aβ species are not routinely or longitudinally quantified in most antibody trials. Lecanemab preferentially binds protofibrils, which are upstream aggregates in the amyloid cascade, directly neutralizing toxic species [37]. Differences in the magnitude and timing of clinical effects observed across phase 3 trials (e.g., over the 12- to 18-month timeframe) [5, 10, 38], may reflect, at least in part, differences in target engagement profiles and downstream biology; nevertheless, cross-trial comparisons are inherently limited by heterogeneity in study designs, populations, endpoints, exposure, and safety-related dose modifications. Notably, neither antibody directly targets soluble oligomers, whose persistence may limit cognitive recovery [4, 5, 19]. These observations imply that the clearance of plaques and fibrils by monoclonal antibodies may inadvertently elevate levels of more toxic soluble Aβ oligomers, which may be a potential factor affecting cognitive recovery [34]. However, the concept of “dust-raising” effect needs further validation in the future.

Disease stage at treatment

AD progresses gradually and is classified into seven stages based on clinical symptoms, ranging from asymptomatic to severe dementia. These stages can be categorized into three groups: preclinical (stages 0–2), mild cognitive impairment (stage 3), and dementia (stages 4–6) [1]. When patients progress to the dementia stage, a substantial number of neurons have already undergone degeneration [39]. Due to the irreversible nature of evident neuronal loss and the disruption of neural circuits [40], it is challenging to achieve cognitive benefits through the implementation of existing treatment options at this advanced stage [41]. Current strategies for AD treatment emphasize the importance of early intervention, particularly through monoclonal antibody immunotherapy targeting Aβ [41]. These approaches are primarily aimed at patients in the pre-dementia and clinical pre-stage phases. As previously noted, results from phase 3 clinical trials involving Donanemab demonstrate a 29% reduction in cognitive decline in the whole populations [4]. However, subgroup analyses focusing on participants with low and medium levels of tau protein revealed that Donanemab can delay declines in CDR-SB scores by as much as 36% [4]. It suggests the variability in treatment responses among patients at different stages of progression, indicating that individuals at earlier stages may gain greater cognitive benefits from therapeutic interventions.

Genetics

Genetic background significantly influences AD susceptibility and progression [39, 42, 43]. The APOE ε4 allele remains the strongest genetic risk factor for sporadic AD, increasing disease likelihood by 4 to 16 folds [44, 45]. Large-scale longitudinal studies indicate that APOE ε4 accelerates cognitive decline in a dose-dependent manner, with homozygotes exhibiting both lower baseline cognition and faster deterioration [46]. Proposed mechanisms include BBB disruption, dysregulated cholesterol metabolism in oligodendrocytes, and impaired myelination [47, 48]. Furthermore, APOE ε4 status critically affects responses to anti-Aβ monoclonal antibodies. It markedly increases the incidence of ARIA [5, 10, 49], particularly ARIA-E, which was observed in approximately 70% of APOE ε4/ε4 patients receiving Lecanemab [5]. This adverse effect not limits treatment tolerability but also compromises potential cognitive benefits. In addition to APOE ε4, other genetic variants modulate AD progression. Carriers of the TREM2 H157Y variant experience accelerated cognitive decline [50], likely due to impaired microglial phagocytosis of Aβ [51]. The PKCα M489V variant contributes to synaptic dysfunction through disrupted plasticity and vesicle endocytosis [52]. Besides the role of individual genes, polygenic risk scores (PRS) enable a comprehensive assessment of an individual’s cumulative genetic risk burden, thereby facilitating the prediction of cognitive decline trajectories over time. Large-scale population-based studies have consistently demonstrated that a higher AD polygenic risk score is significantly associated with poorer cognitive performance and an accelerated rate of cognitive decline [53, 54]. These findings suggest that different genetic backgrounds affect the recovery of cognitive function [53, 54] and influence the therapeutic effect of Aβ monoclonal antibodies [10, 23], thereby limiting the cognitive benefits for patients receiving such treatments [23].

Age

Aging is one of the most clearly defined risk factors for AD [55]. In the general population, the risk of developing AD gradually increases with age [56]. Among AD patients, older age is associated with greater brain Aβ burden, severe tau tangles, cerebral amyloid angiopathy, and other downstream pathologies [57]. Meanwhile, Immunosenescence in older adults leads to chronic systemic inflammation, immune cell dysfunction, and reduced levels of cognitive protective factors [58–60]. These alterations impair neurogenesis and synaptic function, limiting cognitive recovery [61]. Furthermore, elderly individuals exhibit a higher incidence of adverse events associated with Aβ monoclonal antibody immunotherapy [62], restricting dosage and treatment duration and reducing efficacy. This increase may be related to heightened vascular fragility, exacerbated Aβ burden, and diminished BBB function [63, 64]. Together, these findings show that aging is linked to more severe AD pathology, immune dysregulation, and higher ARIA risk factors that collectively impair cognitive recovery. In contrast, younger age is associated with milder Aβ and tau pathology, a more stable immune environment, greater ARIA tolerance, better-preserved brain plasticity and cognitive reserve, and improved therapeutic outcomes with early intervention.

Comorbidities

Comorbidities are common in AD patients, especially the elderly, and exert a notable negative impact on the cognitive benefits of Aβ immunotherapy [48, 65–69]. Common concomitant conditions including vascular dementia, hypertension, diabetes, and chronic inflammatory diseases can synergistically exacerbate brain pathological damage: hypertension and diabetes impair cerebrovascular integrity, aggravate BBB dysfunction, and reduce the efficiency of Aβ clearance by monoclonal antibodies, ultimately affecting cognitive benefits [67, 68, 70, 71]. Additionally, comorbidities often increase the risk of adverse events such as ARIA, leading to treatment dose reduction or discontinuation [72]. Poor control of comorbidities thus hinders cognitive recovery [68], while active management of these conditions can optimize the brain microenvironment, enhance the efficacy of Aβ immunotherapy, and facilitate the realization of long-term cognitive benefits [72].

Antibody-related determinants

The intrinsic properties of anti-Aβ antibodies, including Aβ clearance capacity, clearance rate, and propensity to induce ARIA, represent critical determinants of cognitive recovery following immunotherapy. Aβ clearance efficiency and rate determine the speed at which neurotoxic signaling is terminated, thus influencing the magnitude and timing of cognitive benefits [24, 25]. In addition, ARIA-related adverse effects frequently result in dose reduction or treatment interruption, impairing long-term cognitive outcomes [10]. Preclinical studies in AD mouse models have revealed that brain shuttle antibodies improve brain exposure, accelerate Aβ clearance, and mitigate ARIA risks, thereby enhancing cognitive recovery [73]. These properties represent key determinants for optimizing immunotherapeutic efficacy.

Mechanisms underlying cognitive recovery

As the primary pathological substances of AD, Aβ is excessively produced and/or inadequately cleared in this condition, leading to its accumulation in the brain [74]. This over-accumulation disrupts local immune homeostasis [75, 76], impairs neurovascular and synaptic functions [77, 78], suppresses neural regeneration and mitochondrial activity in neurons [79, 80], and interferes with cross-talks between neurons and glial cells [81]. The clearance of Aβ may facilitate brain repair and the reconstruction of neural networks through several potential mechanisms, ultimately improving cognitive function.

Alleviation of neuroinflammation

Aβ accumulation in the brain activates microglia and astrocytes, triggering neuroinflammation [82, 83]. After Aβ clearance, microglia shift their metabolism from glycolysis to oxidative phosphorylation, improving energy efficiency and promoting a phenotypic switch from pro-inflammatory (M1) to anti-inflammatory (M2) states, specifically from a pro-inflammatory (M1) type to an anti-inflammatory (M2) type [84]. M2 microglia secrete anti-inflammatory cytokines such as IL-10 and TGF-β, which reduce inflammation [85] and promote neuron repair [86]. Following Aβ clearance, M1 microglia decrease significantly, along with lower levels of pro-inflammatory cytokines like TNF-α, IL-1β, and IL-6 [85], leading to reduced neurotoxicity and neuronal damage [87].

Recovery of neurovascular function

Aβ deposition not only affects neurons but also disrupts the neurovascular unit (NVU) [88], leading to vascular dysfunction that impacts the energy supply and homeostasis of both neuronal and glial cells [88, 89]. Aβ clearance restores endothelial nitric oxide synthase (eNOS) activity and increases nitric oxide (NO) release [90], inducing microvessel dilation and inhibiting platelet aggregation, thereby improving local cerebral blood flow. Expression of tight junction proteins such as Claudin-5 and Occludin in endothelial cells is also restored, reducing vascular leakage [91]. Aβ accumulation adversely affects key cellular components of the BBB, including pericytes, thus compromising its integrity [48]. Following Aβ clearance, BBB integrity is restored, limiting infiltration of peripheral inflammatory cells and harmful substances and ultimately protecting neurons from further damage [92].

Restoration of synaptic function

Aβ deposition impairs synaptic function by disrupting presynaptic neurotransmitter release [93], postsynaptic receptor regulation [94], calcium homeostasis [95], and by promoting microglia-mediated synapse elimination [96–98]. Clearance of Aβ facilitates synaptic recovery, evidenced by a 40–60% increase in hippocampal dendritic spine density and restored expression of key synaptic proteins including synaptophysin, GAP-43, and PSD-95 [86, 87]. This is accompanied by recovered long-term potentiation and enhanced synaptic plasticity [99]. Aβ clearance reduces complement receptor expression on microglia, limiting excessive synapse phagocytosis [100], and promotes a shift of astrocytes from a reactive (A1) to a supportive (A2) phenotype. A2 astrocytes release GDNF, further supporting synapse maturation and functional recovery [101].

Neuronal regeneration

Aβ accumulation triggers oxidative stress that disrupts the neuronal microenvironment and suppresses neurogenesis [87, 102]. Mechanistically, Aβ induces reactive oxygen species (ROS) overproduction, leading to lipid peroxidation and disrupted ionic homeostasis, which further exacerbates neuronal damage [103, 104], and creates a self-perpetuating cycle of oxidative injury and Aβ deposition [105, 106]. Clearance of Aβ attenuates this cycle by reducing ROS levels and enhancing endogenous antioxidant capacity, thereby alleviating oxidative damage [107]. Moreover, Aβ overload upregulates senescence markers in neural stem/progenitor cells (NSPCs), impairing their differentiation into neurons and astrocytes [108]. Following Aβ removal, hippocampal NSPCs in the dentate gyrus regain proliferative and differentiation potential [109], supporting the integration of new neurons into existing circuits and contributing to the recovery of learning and memory functions.

Extracellular matrix (ECM) remodelling

Aβ deposition initiates the degradation of the ECM through the activation of matrix metalloproteinases 2 and 9 (MMP-2/9), which breakdowns the key ECM components, compromises the stability of the neuronal microenvironment and disrupts the interactions between neurons and glial cells [110].

Aβ clearance leads to the restoration of ECM components, such as proteoglycans and fibronectin, creating a favorable microenvironment for neuronal and synaptic repair. It could facilitate cognitive function recovery [111]. The remodelling of the ECM plays a crucial role in restoring intercellular signalling by inhibiting excessive activation of complement proteins [112], reducing the over-pruning of synapses by microglia [100, 113], and maintaining normal interactions between neurons and glial cells.

Metabolic restoration

Excessive Aβ accumulation of inhibits the activity of respiratory chain complexes, ultimately leading to a reduction in ATP production [114]. Furthermore, Aβ suppresses the function of GLUT1 and GLUT3 transporters to reduce glucose uptake by neurons [115], while Aβ downregulates hexokinase activity to hinder the initiation of glycolysis and adversely affects normal energy metabolism in the brain [116]. Mitochondria serve as the energy factories of cells. Aβ clearance restores the activity of respiratory chain complexes, increases ATP production, recovers mitochondrial function, and promotes the efficiency of cellular energy metabolism [114]. Aβ clearance also enhance glucose uptake in the brain. The restoration of glycolytic function in neurons provides adequate energy support for their normal functioning [116].

Reconstruction of neural networks

Aβ deposition at early stage could induce abnormal excitability in the hippocampal DG and CA3 region [117], which is manifested as interictal discharges (IEDs) observed in electroencephalogram (EEG) recordings [118]. This accumulation within the precuneus, a central node of the default mode network (DMN), results in a disruption of connectivity between the DMN and parietal/temporal lobes, and impairments in memory encoding capabilities. Employing techniques such as functional magnetic resonance imaging (fMRI), studies have demonstrated that there is an enhancement in functional connectivity among various brain regions and improved recovery of cognitive and behavioral functions after Aβ clearance [119].

Future directions and optimization strategies

Extended treatment duration

The current clinical trials investigating immunotherapy targeting Aβ in AD have produced certain findings, but the impact on delaying cognitive decline in patients remains limited [5–8, 10]. This limitation may be attributed to various factors during the treatment process, including intervention duration, disease stage, genetics and aging. It is suggested that an 18-month observation period is insufficient to observe cognitive benefits [25]. Currently available monoclonal antibody treatments can only reduce brain Aβ levels below negative thresholds within this timeframe, which does not allow for a comprehensive evaluation of cognitive benefits. Therefore, extending the observation period is essential. Besides, drug treatment should be maintained throughout the extended observation period. Evidence shows that discontinuing therapy after Aβ plaque clearance leads to Aβ rebound and cognitive decline [4, 8, 120], likely due to the ongoing production of Aβ in the brain. The 48-month PRIME extension study of aducanumab found that sustained treatment beyond 18 months was associated with continued Aβ reduction and slower cognitive decline [27]. Prolonged intervention may thus provide additional benefit by preventing plaque re-accumulation [8]. Extended treatment does not imply continuous dosing; instead, it involves intermittent dosing guided by scheduled monitoring intervals. Donanemab uses a “treatment stopping protocol”: therapy halts when amyloid PET shows plaque levels below a predefined threshold [4]. Most patients reach this point within 6–12 months, potentially reducing costs. However, Aβ re-accumulates at a rate of 2.4–3.3 CL per year [4, 8, 29, 121], necessitating regular monitoring and resumption of treatment upon reaching the threshold. To determine optimal treatment and observation duration, integrating PET imaging with genomics, proteomics, and cognitive assessments is recommended [122, 123]. This strategy may balance cost-effectiveness with cognitive outcomes. Additionally, real-world data post-approval should be monitored, enabling large-scale evaluation of long-term cognitive effects [7].

Personalized treatment

Precision medicine represents a significant trend in contemporary medical development [124]. In alignment with the principles of precision medicine, AD treatment should be individualized to account for patient-specific differences by formulating customized treatment plans [125]. Key determinants influencing the efficacy of AD treatments include the presence or absence of risk genes, such as APOE ε4 [44], as well as the current stage [56]. Future research must prioritize the integration of these multifaceted factors into a unified, comprehensive framework. This involves creating multifactorial treatment models that simultaneously consider a patient’s genetic profile, disease stage, specific biomarker burden (Aβ and Tau), and other co-pathologies like vascular contributions or neuroinflammation [2]. This approach aims to develop multifactorial treatment models and strategies that optimize cognitive recovery for individual patients.

Early intervention

As mentioned above, early intervention is beneficial for slowing cognitive decline in early-stage AD [4]. The prerequisite for early intervention is early diagnosis [126]. Current research focuses on the detection of Aβ and tau protein biomarkers in blood and CSF, enabling early screening for AD [127]. Future studies should prioritize developing accessible, accurate diagnostic indicators for identifying AD during initial Aβ accumulation, facilitating personalized treatment plans [126]. For individuals with moderate to severe AD, whether the Aβ burden in the brain should be reduced to lower levels remains ongoing debate [3, 128]. To mitigate downstream neurodegenerative processes triggered by Aβ, “early intervention” remains essential. It emphasizes removing Aβ from the brain as soon as possible [4]. However, patients with moderate to severe AD face a higher risk of severe ARIA and gain little or no cognitive benefit from this Aβ monoclonal antibody therapy [10]. This lack of efficacy may be attributed to extensive neuronal loss, which likely prevents the reconstruction of cognitive neural circuits [40]. Future research should not only focus on clearing Aβ from the brains of patients with moderate to severe AD but also aim at targeting downstream tau pathology and promoting neuronal regeneration and neural circuit reconstruction, thereby maximizing potential cognitive benefits for these individuals [2].

In addition to early pharmacological intervention, non-pharmacological approaches are also critical [129]. These include lifestyle improvements such as following a Mediterranean diet, engaging in regular aerobic exercise, participating in social and cognitive activities, and managing risk factors like hypertension and diabetes [129–131]. Such non-pharmacological early intervention measures have been proven to effectively reduce the risk of AD [132, 133].

Combination therapy

Current single-target therapies such as anti-Aβ monoclonal antibodies only modestly improve cognitive function, likely due to persistent neuronal damage and circuit disruption [4–6, 118]. To achieve meaningful clinical benefits, combination strategies that simultaneously enhance Aβ clearance and provide neuroprotection are needed [2]. Promising approaches include neuroprotective agents targeting tau pathology, oxidative stress, neuroinflammation, aging and energy metabolism [134–139], as well as circuit repair strategies such as neuromodulation techniques [140, 141], and endogenous neurogenesis promotion [140, 142]. Notably, integrating holistic anti-aging interventions (e.g., senolytics, young plasma infusion, gut microbiota transplantation) with anti-Aβ therapies could synergistically mitigate systemic aging-driven neurodegeneration [139, 143–147]. Although early-phase trials of some neuroprotective agents show short-term cognitive improvement [144–146, 148], their long-term efficacy requires validation. Furthermore, therapeutic strategies targeting increased Aβ production—such as BACE1 and γ-secretase inhibitors—have failed to show significant cognitive benefits in clinical trials [149, 150]. This lack of efficacy is primarily attributed to the essential physiological roles of these enzymes, which limit the therapeutic window due to mechanism-based toxicities [151, 152]. Whether low-dose BACE1 or γ-secretase inhibitors, combined with other disease-modifying therapies, can improve outcomes remains unclear and requires further investigation. Future research should focus on large-scale clinical evaluations of neuroprotective agents and circuit-based interventions, including their integration with Aβ monoclonal antibody therapies in coordinated regimens [2].

Next-generation antibody platforms and emerging immunotherapies

Beyond the strategies outlined above, continuous optimization of antibody-based therapeutic platforms represents a pivotal direction for maximizing the long-term cognitive benefits of Aβ immunotherapy. Brain Shuttle antibodies enhance brain penetration, promote faster and more thorough Aβ clearance, and mitigate the occurrence of ARIA-related adverse events, thereby improving the overall benefit–risk profile and facilitating cognitive recovery [73]. Moreover, emerging immunomodulatory approaches, including CAR-astrocyte [153], CAR-monocytes [154], CAR-T cell therapy [155], and immune rejuvenation strategies [156], exhibit substantial potential to remodel the brain’s immune microenvironment, enhance Aβ catabolism, and alleviate pathological neuroinflammation. The rational integration of these next-generation modalities is expected to further augment cognitive preservation and broaden the therapeutic landscape for AD.

Competing interests

The authors declare no competing interests.