Open access
Abstract
Alzheimer's disease (AD) is the leading cause of dementia, characterized by neuropathological features such as amyloid-β (Aβ) plaques, neurofibrillary tau tangles, and neurodegeneration. Immunotherapy offers a promising potentially disease-modifying treatment for AD. We review recent advances in AD immunotherapy, specifically focusing on Aβ, tau, and neuroinflammation-targeted approaches, and gain insights from randomized controlled trials to propose disease-modifying directions.
1 Introduction
Alzheimer's disease (AD) is a severe neurodegenerative disorder characterized by progressive cognitive function deficits, ultimately impairing daily quality of life. The deposition of amyloid-β (Aβ) peptides into senile plaques outside neurons and the presence of neurofibrillary tangles (NFT) composed of hyperphosphorylated tau (pTau) protein inside neurons are the predominant histopathological features of AD (Long and Holtzman 2019). In addition, there is growing evidence that neuroinflammation plays a significant role in the early stages of AD progression (Smirnov and Galasko 2022).
Immunotherapy has gained attention as a promising approach to modify the course of AD (Høilund-Carlsen et al. 2023). This therapy encompasses two fundamental approaches: stimulating the immune system to generate its antibodies through vaccines (active immunization) or administering foreign antibodies directly (passive immunization). The recent accelerated approval of two anti-Aβ antibodies, aducanumab and lecanemab, by the US Food and Drug Administration (FDA) was considered to be a significant advancement in "disease-modifying therapy for AD." However, it has sparked controversy (Zhang et al. 2023).
This review aims to provide context for recent advances in immunotherapies targeting Aβ, tau, and neuroinflammation, elucidating their mechanisms in AD. The literature review on AD immunotherapy spans from inception to October 2023, incorporating sources such as PubMed, meeting abstracts, and Alzforum.org. The search focused on English-language publications. Clinical trials related to AD immunotherapy are identified through a search on ClinicalTrials.gov using the keywords "Alzheimer's disease immunotherapy," with exclusion criteria for "terminated" trials and “completed” trials with negative results. We will also explore the pros and cons of each therapeutic approach. Additionally, we will highlight the most recent developments and offer insights into the future of AD immunotherapy.
2 Immunotherapy targeting Aβ
Extensive genetic studies have supported the causative role of Aβ accumulation in AD pathogenesis. Consequently, anti-Aβ immunotherapies gained much attention in the AD research community. Currently, active immunity vaccines targeting Aβ, namely ABvac 40, ACI-24, and UB-311 (Table 1), have advanced to Phase 2 clinical trials. And passive immunotherapies targeting Aβ immunity are in development and have progressed to late-stage clinical trials involving antibodies: ABBV-916, aducanumab, donanemab, Gantenerumab, lecanemab, remternetug, solanezumab (Table 1). Among them, both aducanumab and lecanemab have received FDA approval.
2.1 ABvac40
ABvac40 is the first active vaccine targeting the C terminus of Aβ40 peptide, which comprises multiple replicates of the short C-terminal fragments of Aβ40 (Aβ33-40). Terminal Aβ-directed antibodies at the C-terminus generated by ABvac40 can provide protection against N-terminus truncated and/or modified Aβ peptides, such as pyroglutamate-3 Aβ, which is described as highly toxic and readily aggregate (Lacosta et al. 2018).
2.2 ACI-24
ACI-24 is a liposome vaccine designed to elicit an antibody response against aggregated Aβ peptides without concomitant pro-inflammatory T cell activation, which was based on the truncated Aβ-15 serial sandwiched between palmitoylated lysine at either end and anchored into the surface of liposomes. Preclinical studies have shown that subcutaneous injection of ACI-24 into double-transgenic mice with APPxPS1 reduces amyloid and improves memory, and produces high-titer antibodies against AβIgG1 and IgG2b (Muhs, Hickman et al. 2007). In a Phase 2 clinical study, ACI-24 produced a significant IgM antibody response but a low IgG titer. Cerebrospinal fluid (CSF) levels of Aβ40 and Aβ42 were elevated from baseline, indicating target binding, but amyloid Positron Emission Computed Tomography (PET) was not altered.
2.3 Aducanumab
Aducanumab (Aduhelm, BIIB037) is a fully human IgG1 monoclonal antibody that exhibits high affinity against a conformational epitope found on Aβ. It specifically binds to aggregated forms of Aβ rather than monomer. In the brain, BIIB037 preferentially binds to parenchymal amyloid over vascular amyloid (Soderberg et al. 2023).
In 2021 aducanumab received accelerated approval from the US FDA (Sevigny et al. 2016; Knopman et al. 2021). However, FDA approval is controversial because of the therapeutic effects on cognitive ability that barely meet the clinical endpoint and are limited to specific subsets of patients. Of note, the FDA’s approval of aducanumab was based on the drug’s ability to reduce amyloid plaques detected through PET scans, under the assumption that this intervention would be “reasonably likely to predict a clinical benefit to patients”. In particular, the 2 identically designed phase 3 trials of aducanumab [EMERGE (NCT02484547) and ENGAGE (NCT02477800)] were terminated prematurely, with subsequent analyses on a larger data set producing contradictory results (Budd Haeberlein et al. 2022). Data from the EMERGE trial demonstrated a statistically significant change across all four primary and secondary clinical endpoints. In contrast, the ENGAGE trial failed to meet both its primary and secondary endpoints. A dose and time-dependent reduction in pathophysiological markers of AD was observed in both trials (Budd Haeberlein et al. 2022). A meta-analysis of clinical trials has shown that there is no statistically significant effect of Aβ removal on cognition, even with the use of aducanumab (Ackley et al. 2021). FDA required the company to verify clinical benefits through a post-approval (phase 4) trial.
2.4 Donanemab
Donanemab, also known as N3pG, is a humanized IgG1 monoclonal antibody developed from mouse mE8-IgG2a. Donanemab recognizes pyroglutamate, which forms aggregates in amyloid plaques, and removes it from the brain. Early results from phase 1 and phase 2 clinical studies provide some compelling evidence that donanemab can reduce the burden of amyloid and tau proteins (Zhang and Song 2017).
A phase 3 TRAILBLAZER-ALZ 2 study (NCT04437511) enrolled 1736 participants with early symptomatic AD 【Mild Cognitive Impairment (MCI)/mild dementia】 with amyloid and low/medium or high tau pathology based on PET imaging. Treatment with donanemab significantly decelerated cognitive and functional decline in individuals with early symptomatic AD when compared to the placebo group (Lowe et al. 2021, Sims et al. 2023). Among individuals with low to medium tau levels, donanemab demonstrated a 36.0% slowing of clinical progression as measured by Clinical Dementia Rating scale sum of boxes (CDR-SB), and 35.1% slowing as measured by integrated Alzheimer Disease Rating Scale (Sims et al. 2023). The TRAILBLAZER-ALZ-3 trial is testing donanemab in asymptomatic individuals between 65 and 80 years old who have evidence of elevated brain Aβ. The study will run for 3 years, with a clinical primary outcome of time to clinical progression as measured by clinical dementia rating scale global score (CDR-GS) (NCT05026866).
2.5 Lecanemab
Lecanemab (Lecanemab-irmb, BAN2401, mAb158) is the humanized IgG1 antibody derived from the mouse monoclonal antibody mAb158, which selectively binds to soluble Aβ aggregates (oligomers and protofibrils) (Soderberg et al. 2023). Soluble Aβ has been demonstrated to be more neurotoxic than monomers or insoluble fibrils. Lecanemab is believed to target the most toxic pathological amyloid species (Dyck et al. 2023).
In the phase 3 clinical trial (NCT03887455) of 1795 participants with 1:1 ratioassigned to receive lecanemab or placebo, lecanemab slowed CDR-SB decline by 27% at 18 months compared to placebo, suggesting that treatment with lecanemab over 18 months resulted in a slowdown in cognitive and functional decline, equivalent to delaying disease-related clinical progression by 4–5 months over the course of 1.5 years (Dyck et al. 2023). In addition to meeting all primary and secondary outcomes of cognition and function, lecanemab treatment also yielded differences in AD biomarkers, including CSF, plasma, and PET measures of tau, indicating a downstream pathophysiologic effect of Aβ plaque removal. In fact, two-thirds of people in the treatment group were negative for amyloid PET at 18 months. Tau PET showed a significant slowdown in tangle accumulation in the medial temporal lobe, andtrend level slowdown in other brain regions. The astrocytosis biomarker glial fibrillary acidic protein (GFAP) decreased after treatment, and the Aβ42/40 ratio increased in CSF and plasma Aβ42/40, especially in CSF, and p-tau181 decreased in both. Safety concern was raised especially in APOEε4 homozygote carriers, with amyloid-related imaging abnormalities (ARIA) with edema or effusions detected in 32.6% of treated participants compared with 3.8% in the placebo group. About a quarter of the participants developed symptoms, which were usually mild and transient (Dyck et al. 2023). A large ongoing immunotherapy trial, AHEAD (NCT04468659) is testing lecanemab in participants with preclinical AD as well as in individuals with an intermediate level of Aβ accumulation (Rafii et al. 2023).
On January 6, 2023, lecanemab received approval via the Accelerated Approval pathway by the FDA, based on evidence of its effect on the surrogate endpoint of amyloid removal in the phase 3 trial (Larkin 2023). On July 19, the FDA announced that lecanemab had transitioned to traditional approval.
2.6 UB-311
UB-311 is a synthetic peptide vaccine that binds helper T cell epitopes to Aβ1-14 sequence, packaged in a proprietary vaccine delivery system. This approach is designed to stimulate T-helper type 2 modulation of immune responses rather than T-adductor type 1 pro-inflammatory responses and to avoid autoimmune responses. UB-311 was safe, well tolerated and produced a robust immune response. In the phase 2 study, in the UB-311 group, an antibody response rate of 97% was observed and continued to be 93% at the end of the study (Yu et al. 2023). In May 2022, the US FDA granted fast-channel status to UB-311 for the treatment of AD, facilitating accelerated development and review.
2.7 Others
ABBV-916 is a monoclonal antibody to Aβ. It recognizes N-terminal truncated Aβ modified with pyroglutamate at position 3 (N3), a form that is aggregated in amyloid plaques (Zhang et al. 2023). Its specificity is similar to donanemab and remternetug. The aim of these antibodies is to remove amyloid plaques quickly and completely.
Gantenerumab is a fully human IgG1 antibody and binds to the N-terminal and central amino acids of the conformational epitope on the Aβ fibrils. It works intensively to break down and degrade amyloid plaques by recruiting microglia and activating phagocytosis. Two phase 3 trials, GRADUATE I and II, with subcutaneous gantenerumab in subjects with MCI and mild AD, did not meet the primary endpoint of slowing the clinical decline in cognitive impairment (Yadollahikhales and Rojas 2023). Solanezumab and Gantenerumab are being evaluated by the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) in a Phase 2/3 trial aimed at preventing dementia in 210 people (Zhang et al. 2023).
Remternetug (LY3372993, N3pG-Abeta mAb) is an in-development monoclonal antibody, which recognizes the pyroglutamate form of Aβ in amyloid plaques. Remternetug induced a high clearance of amyloid load (Zhang et al. 2023).
Solanezumab is a humanized monoclonal IgG1 antibody directed against the mid-domain of the Aβ peptide. It recognizes soluble monomeric, not fibrillary Aβ. The therapeutic rationale is that it may provide benefit by sequestering Aβ, shifting equilibria between different species of Aβ, and removing small soluble species of Aβ that are directly toxic to synaptic function. In patients with mild to moderate AD, solanezumab failed to significantly slow the rate of cognitive decline and brain atrophy (Doody et al. 2014; Honig, Vellas et al., 2018). In a Phase 3 trial involving patients with preclinical AD, solanezumab did not slow cognitive decline over 240 weeks compared to placebo (Sperling, Donohue et al. 2023).
2.8 Advantages and limitations
In the last 20 years, based on the identification of Aβ plaques as the hallmark pathology of AD (Zhang and Song 2017) and the amyloid cascade hypothesis (Hardy and Higgins 1992), targeting-Aβ strategies have been the main therapeutic strategies for AD treatment (Song et al. 2022). These approaches include active immunization against Aβusing specific antigens and passive immunization by direct administration of Aβ-specific antibodies (Sun et al. 2021). Aducanumab and lecanemab, the first effective disease-modifying therapies for AD, were recently approved by the US FDA through an accelerated approval pathway. It’s an important milestone for AD research.
How was this milestone achieved? Identifying the correct targets was crucial. The success is also attributable to advances in AD biomarkers. It’s important to use PET or CSF measures to select patients and measure biological effects. The use of PET or CSF measures of Aβ and tau as primary inclusion criteria ensures that AD is the cause of patients’ clinical syndrome. Amyloid PET has proven to be a valuable biomarker for assessing treatment response, enabling the identification of clinically relevant effects of anti-Aβ therapies. Recent phase 3 trials of lecanemab and donanemab have clearly demonstrated this relationship. The hypothesis that removing amyloid would reasonably predict clinical benefit underpinned the FDA’s controversial accelerated approval of aducanumab and less controversial accelerated approval of lecanemab for early AD. Selecting the appropriate population at the right stage of disease is also important. The lecanemab trial participants were generally at an earlier disease stage, as per enrollment criteria mandating less severe short-term memory impairments.
Although aducanumab and lecanemab have received traditional regulatory approval, several challenges remain in the clinical translation of anti-amyloid agents. Firstly, which Aβ species should be targeted? First-generation agent bapineuzumab targeted the N-terminus of aggregated Aβ, while second-generation agents like crenezumab, gantenerumab, and solanezumab were developed to target non-plaque Aβ species. Third-generation agents, such as lecanemab (high-affinity antibodies against soluble Aβ oligomers and protofibrils) and aducanumab/donanemab (targeting plaque Aβ), were also developed (Yadollahikhales and Rojas 2023). The first and second-generation agents did not demonstrate significant changes in cognition (Doody et al. 2014; Ostrowitzki et al. 2022). The trials of lecanemab, aducanumab and donanemab demonstrated clinical efficacy, indicating oligomers, protofibrils and plaques might be the ideal targets. However, during the disease continuum, there is possibly a mixed format of Aβ, even at the early stage, thus targeting a single format of Aβ might not be the best choice.
Secondly, how can the safety of Aβ immunotherapy be modified? ARIAs are defined as a spectrum of image abnormalities detected on different MRI sequences, which are serious side-effect of Aβ immunotherapy. ARIAs include focal cerebral edema/effusion (ARIA-E) and hemosiderin accumulation (ARIA-H, a marker of previous microbleeds). The third-generation agents also prompted safety concerns (Alhazmi and Albratty 2022). Data from EMERGE, TRAILBLAZER-ALZ, and Clarity AD trials showed that the incidence of ARIA was 41.3%, 38.9%, and 26.6% in patients treated with the most effective dose of aducanumab, donanemab, and lecanemab, respectively (Yadollahikhales and Rojas 2023). ARIA is especially a safety concern for APOEε4 homozygote carriers, thus testing APOE status is helpful at the beginning of these trials. Three deaths were reported in lecanemab-treated patients who developed intracerebral hemorrhage after the primary trial was completed (Reish et al. 2023). Further understanding of the Aβ-mediated AD pathophysiology and more specific anti-Aβ antibodies are needed (Zhang et al. 2023). However, a substantial gap remains between experimental and clinical studies, highlighting the need for greater emphasis on toxicology and safety.
Thirdly, how can we enhance the effectiveness of Aβ immunotherapy? The blood-brain barrier (BBB) presents a formidable challenge for peripherally administered antibodies engaging targets within the central nervous system (CNS) (Wang et al. 2018). Studies estimated that the BBB excludes 99.9% of the dose of peripherally administered antibodies (Nisbet et al. 2017). Researchers developed nanoparticles (Mulvihill et al. 2020), adeno-associated virus vector (Selles et al. 2023) and low-intensity ultrasound (Leinenga et al. 2021, Chen et al. 2022) to enhance the delivery of antibodies through BBB. Studies reported that the use of these vectors with Aβ antibodies could enhance the selectivity and permeability of antibodies in the CNS at lower dose (Mulvihill et al. 2020), but also decrease amyloid deposits and attenuate cognitive function deficits (Liu et al. 2020, Xie et al. 2020, Kong et al. 2022, Jung et al. 2023, Selles et al. 2023).
Fourthly, when should the intervention begin? Recently, a consensus has emerged in favor of early intervention, prompting a shift in the focus of AD clinical trials from secondary to primary prevention (Zhang et al. 2023). However, the ideal timing for administering anti-Aβ therapeutics remains uncertain. Conducting trials in AD is challenging due to the long time required to observe the transition from preclinical to clinical stages of AD. To illustrate, recent trials in secondary prevention for autosomal dominant AD, assessing the efficacy of anti-amyloid agents such as solanezumab and gantenerumab, did not succeed in slowing cognitive decline. This could be attributed to the inadequacy of the treatment period or variations in Aβ pathogenesis between sporadic AD and familial AD (Salloway et al. 2021). The optimal duration of therapy is still unclear (Ramanan and Day 2023). In addition, numerous concerns exist regarding the most appropriate trial design for evaluating preventive treatments in healthy, asymptomatic individuals. This is particularly pertinent given the potential for unforeseen financial burdens and the consideration of antibodies that could cause ARIA (Joseph-Mathurin et al. 2022).
3 Immunotherapy targeting tau
Tau is a microtubule associated protein involved in the polymerization and assembly of microtubules. The aggregated and hyperphosphorylated tau protein is one of the main drivers of neurodegeneration in AD. The emergence of insoluble tau pathology coincides with the onset of clinical symptoms of AD and strongly predicts patterns of clinical decline (Sanchez et al. 2021, Samudra et al. 2023). Tau is another theoretically important AD therapeutic target. But to date no disease-modifying therapies targeting tau are approved by the US FDA for the treatment of AD. Currently there are a number of tau-directed trials underway at various phases (Table 2).
3.1 AADvac1
The first anti-tau vaccine, AADvac1, uses a peptide containing one of the epitopes of the DC8E8 antibody, 294KDNIKHVPGGGS305, conjugated to keyhole limpet hemocyanin (KLH) along with aluminum hydroxide as an adjuvant (Zheng et al. 2016; Plotkin and Cashman 2020). This approach seeks to generate antibodies that block aberrant tau-tau interactions. Studies in transgenic rat models showed that AADvac1 resulted in decreases in abnormally phosphorylated tau, tau oligomers and cerebral neurofibrillary pathology (Yanamandra et al. 2013).
AADvac1was tested in phase 1 clinical trials (NCT01850238) and its follow-up open-label trial (NCT02031198), which showed acceptable safety and effective immunogenicity (Novak et al. 2017, 2018; Novak et al. 2019). Then it advanced to a Phase 2 study (NCT02579252). The preliminary findings of Phase 2 study showed positive immunogenicity (98.2% of patients produced specific anti-tau antibodies) (Novak et al. 2021). Tau biomarkers and neurofilament light chain (NfL) biomarkers indicate significant slowing of neurodegenerative progression (Vaz and Silvestre 2020). The excellent results of Phase 2 study may lead its progression to Phase 3.
3.2 Bepranemab
Bepranemab (UCB0107, UCB 0107, antibody D) is a humanized monoclonal IgG4 antibody. It targets the mid-region of tau (aa 235–246), before the microtubule binding region (MTBR). It will more effectively impede the cell-to-cell spread of pathogenic, aggregated tau compared to N-terminally targeted anti-tau antibodies. In vivo, bepranemab may inhibit tau aggregation and the spread of tau pathology (Roberts et al. 2020).
A Phase 1 randomized controlled trial (RCT) (NCT03464227) showed no drug-related adverse events or changes in safety results. In June 2021, a Phase 2 RCT (NCT04867616) to evaluate the efficacy, safety, and tolerability of bepranemab in patients with MCI or mild AD began recruitment. The study will run until November 2025.
3.3 E2814
E2814 is a humanized monoclonal IgG1 antibody targeting the MTBR of tau, which is the main NFT component (Roberts et al. 2020). This antibody binds to extracellular tau, thereby preventing the intercellular spread of pathological tau aggregates and mediating the clearance of microglia.
A Phase 1 RCT of E2814 was completed in August 2020. The most frequent side effects were headache, nausea, and vomiting. In June 2021, a Phase 1/2 trial (NCT04971733) began to assess safety and target engagement in people with dominantly inherited AD. In November 2021, amendments were made to the study design of Dominantly Inherited Alzheimer Network Trial Unit, which incorporated the usage of the anti-Aβ antibody lecanemab. This Phase 1/2 RCT (NCT05269394) will enroll 168 participants with normal cognition, MCI, or mild dementia. The potential benefits of the anti-tau antibody E2814 will be tested while an anti-amyloid antibody lecanemab is given as a background therapy. The study will run through 2027.
3.4 JNJ-63733657
JNJ-63733657 is a humanized IgG1 monoclonal antibody which recognizes the MTBR of tau. It has high affinity for tau phosphorylated at residue 217 and more potently interferes with propagation of pathogenic aggregated tau between cells. JNJ-63733657 was reported to eliminate pathogenic tau "seeds" in a cell-based assay and inhibit the spread of tau pathology in a mouse model (news from AAT-AD/PD Focus Meeting 2018).
Two Phase 1 RCTs evaluating the safety and tolerability of JNJ-63733657 observed no safety concerns, and the most prevalent complaints included back pain and headaches. In January 2021, a Phase 2 trial (NCT04619420) started on 420 individuals with early AD symptoms and a positive tau PET scan. The trial will run until 2025.
3.5 Semorinemab
Semorinemab (RO7105705, MTAU9937A, RG6100) is a humanized IgG4 monoclonal antibody that binds to the N-terminus of both monomeric and oligomeric tau. Treatment with the antibody reduced brain pathology in P301L mice in a dose dependent manner (Ayalon et al. 2021).
Phase 1 study of semorinemab in 74 volunteers showed no serious adverse events (Ayalon et al. 2021). In 2017, a Phase 2 study TAURIEL in 457 people with prodromal or probable AD showed that Semorinemab did not meet the primary or secondary endpoints (Teng et al. 2022). In February 2019, another Phase 2 trial AURIET (NCT03828747) in 272 people with moderate AD, confirmed by amyloid positivity on PET or CSF testing, and moderate dementia. In 2021, it was announced that semorinemab showed a 43.6% slowing of decline on the ADAS-Cog11 co-primary endpoint, but there were no other positive cognitive or functional outcomes. In November, the company reported at the Clinical Trials on AD (CTAD) that the treatment did not change tangle accumulation measured by GTP1 PET. A decision on a Phase 3 RCT will depend on additional data from LAURIET's ongoing long-term extension study and biomarker measurements.
3.6 Others
ACI-35 is another active immunotherapy vaccine targeted the pathological conformers of hyperphosphorylated tau. The vaccine contains 16 copies of a synthetic tau recognizing the pathological phosphorylation residues S396 and S404 of tau. APNmAb005 is a humanized monoclonal anti-tau IgG antibody that reacts with tau aggregates in early AD cases, but not with tangles and neurofilaments that form later in the disease (Tai et al. 2022). Lu AF87908 is a humanized murine IgG1 monoclonal antibody against tau protein phosphorylated at serine 396 and 404. Humanized antibodies bind to phosphorylated tau in the brains of patients with AD and primary tau after death, blocking the aggregation of brain extracts (Helboe et al. 2022). MK-2214 is an anti-pSer413 tau monoclonal antibody. It could reduce hyperphosphorylated tau proteins, tau oligomers, tangle formation, and synaptic loss (Umeda et al. 2015). PNT001 is a monoclonal antibody directed against tau cis-isomers phosphorylated by threonine 231 (Galas et al. 2006; Hamdane et al. 2006). PRX005 is an anti-tau IgG1 humanized antibody that binds with high affinity to the R1, R2, and R3 repeats within MTBR. It could inhibit the binding of tau protein to heparin sulfate proteoglycan and protect rat cortical neurons from tau toxicity (Katsinelos et al. 2018). They are underway at clinical trial Phase 1.
3.7 Advantages and limitations
Up to now, 2 tau vaccines and 9 anti-tau antibodies have entered RCT for the treatment of AD. And none of the 11 drugs reached a phase 3 RCT.
Although the development of anti-tau antibodies is not as advanced as the anti-Aβ, the following points can help improve the results of future attempts. Questions need to be answered, regarding the choice of the immunogen, the site of action of anti-tau antibodies (intracellular or extracellular) and the epitope of tau protein to be targeted, as well as mechanism of action and safety (Panza et al. 2023). First, therapeutic targets related to tau should be chosen with greater precision to mitigate potential adverse events and should be tailored to the disease's stage and subtype. It is possible to achieve more clinical effects by designing different aspects of multi-targeted therapy strategies for different forms of intracellular and extracellular tau proteins. Second, the pathogenesis of AD encompasses amyloid and tau pathology, so combinations of antibodies could potentially be used to slow AD progression. Studies suggest that a multi-target approach is likely to be more central and effective in controlling disease progression, offering superior efficacy, safety, and specificity (Dujardin et al. 2022, Jung et al. 2023, Zhang et al. 2023). In one trial (NCT05269394), the potential benefits of an anti-tau antibody (E2814) will be tested while an antiamyloid antibody (lecanemab) is given as a background therapy.
4 Immunotherapy targeting neuroinflammation
In addition to tau and Aβ pathologies, neuroinflammation plays a crucial role in exacerbating AD progression (Leng and Edison 2021). Microglia is thought to play an important role in neuro-immune response and inflammation in the CNS. Aβ and phosphorylated tau protein could be recognized by receptors such as Toll-like receptor 4 (TLR-4) on the surface of microglia, promoting the release of inflammatory factors in AD brains. The inflammatory factors, in turn, increase the formation of Aβ deposits and NFT, thus creating a vicious cycle that exacerbates the disease process. A number of disease-modifying therapeutics in current AD clinical trials is attempting to target neuroinflammation (Cummings et al. 2022) (Table 3).
4.1 AL002
AL002 is a humanized monoclonal IgG1 antibody which binds the microglial receptor triggering receptor expressed on myeloid cells 2 (TREM2) and induces microglia proliferation. In APP/PS1 mice or 5XFAD mice, AL002 injection was able to recognize mouse TREM2 and double the number of CD11b-positive microglia, which expressed more pro-inflammatory and repair genes, halving nearby amyloid deposits and improving cognitive performance (Wang et al. 2020).
The Phase 1 trial showed the antibody was well tolerated and no serious adverse events were noted. In January 2021, the Phase 2 INVOKE-2 study (NCT04592874) started enrolling 265 people with early AD. Because some serious adverse events were found in people with two copies of the ApoE4 allele, the company amended the protocol to exclude them. No additional related serious adverse events were subsequently reported (Jan 2023 company presentation). The trial will run through the end of 2023.
4.2 Gamunex
This immunoglobulin preparation (Intravenous Immunoglobulin (IVIg), Human Albumin Combined with Flebogamma) is used in obstetric indications to prevent and treat blood conditions related to rhesus factor incompatibility. It is one of several IVIg products being tested clinically as an AD treatment following Phase 1 and 2 results for Baxter Healthcare's IVIg product, Gammagard™.
A multicenter Phase 2/3 trial (NCT01561053) compared three doses of 5% human albumin plus 5% immunoglobulin to placebo delivered intravenously in 350 people with mild to moderate AD. The results showed that albumin with IVIg was associated with less deleterious changes in subcortical structures and less metabolic decline compared to the typical progression of AD. This effect was more marked in the group treated with high albumin + IVIg (Cuberas-Borros et al. 2022).
4.3 Pepinemab
Pepinemab is a humanized IgG4 monoclonal antibody which neutralizes semaphorin 4D (sema4D). Sema4D binds to receptors on glia and activates inflammatory cytokine release, thereby inhibits axon extension and oligodendrocyte migration, and disrupts the BBB (Luque et al. 2018). According to data presented at the 2020 AAT-AD/PD conference, Sema4D was elevated in human postmortem brain of Huntington’s disease (HD) and AD. In preclinical work, pepinemab slowed brain atrophy and improved some behaviors in the HD mouse model (Southwell et al. 2015).
Pepinemab has both Orphan Drug and Fast-Track designation for HD from the FDA. In May 2020, Vaccinex registered a Phase 1/2 trial of this drug (NCT04381468) in early AD. It will run through February 2024.
4.4 Others
Four anti-neuroinflammation antibodies are still in phase 1 RCT. CpG 1018 is a proprietary immune adjuvant made up of short, unmethylated cytosine-phosphate-guanine oligodeoxynucleotides (CpG ODNs). Its components mimic bacterial DNA to activate innate immunity through binding to the toll-like receptor 9 (TLR9), which is an important regulator of microglia.,Studies showed that CpG oligodeoxynucleotides treatment activated microglia, and then stimulated clearance of amyloid pathology and improved performances on cognitive tests in mouse and monkey models (Scholtzova et al. 2009; 2014; 2017; Patel et al. 2021).
The humanized IgG1 antibody IBC-Ab002 inhibits an immune checkpoint protein called programmed death ligand, aka PD-L1, stimulating the immune system. In preclinical efficacy studies, a single antibody dose improved cognitive performance one month later in 5xFAD, DM-HTau (K257T/P301S), and PS19 (p301S Tau) mice (AAIC poster).
TB006 is a humanized monoclonal antibody against Galectin-3, which involved in microglia activation and Aβ aggregation (Boza-Serrano et al. 2019). In preclinical evaluation TB006 has been shown to significantly reduce Aβ/Tau protein aggregation and neuroinflammation by inhibiting Galectin-3 (Tao et al. 2020).
AL044 is an antibody targeting MS4A, a brain immune checkpoint molecule and a genetic risk factor for late-onset AD (Ma et al. 2019). Some MSA4 family members could regulate TREM2 receptor activity, suggesting a role for these proteins in the microglia response to AD pathology (Deming et al. 2019).
4.5 Advantages and limitations
The neuroinflammation molecular targets are challenging because they have a dynamic role in relation to AD development and progression. They can have both detrimental and beneficial roles (Dujardin et al. 2022). In addition, the complicated communication between multiple cell types coordinates both innate and adaptive immune responses (Zhou et al. 2020, Zeng et al. 2023). For example, the activation of TREM2 may be an effective treatment strategy during the early stages of AD that are defined by amyloid pathology, but it is not clear if it will work at the symptomatic stage of AD when tau pathology is present. Clinical trials with TREM2 agonist antibodies have entered phase 2 (NCT04592874) in early AD, so more data will emerge soon.
Another possible therapeutic target that influences microglial responses to AD pathologies is APOE. APOE expression influences cross-talk between microglia and astrocyte to coordinate innate immune responses to AD pathologies (McAlpine et al. 2021). Therapeutic reduction of APOE4 protein significantly protected against tau pathology and associated neurodegeneration, decreased neuroinflammation, and preserved synaptic density (Litvinchuk et al. 2021, Wang et al. 2021, Koutsodendris et al. 2023). Thus, therapeutic strategies that aim to reduce APOE expression may be most effective in modulating neuroinflammatory responses that contribute to amyloid and tau-mediated neurodegeneration.
Fully unravelling the interplay between the various facets of the immune system and AD pathology at different disease stages is crucial for developing potent immunotherapies for AD.
5 Conclusion
The recent success of phase 3 clinical trials involving the anti-Aβ monoclonal antibodies lecanemab and donanemab marks a significant milestone in AD research. Ongoing progress in understanding the cellular and molecular factors impacting AD pathogenesis will result in the discovery of new effective targets for AD treatment (Srivastava et al. 2019, Rai et al. 2020). More accurate disease models such as brain organoids are also required to test the preclinical effects of candidate drugs (Cazzaniga, et al. 2022), which could bridge the gap between basic research and the clinical practice (Chen et al. 2022; Zhang et al. 2023). Accurate biomarkers are essential to identify individuals in the preclinical stage of AD, enabling early intervention to prevent or slow down disease progression (Self and Holtzman 2023). And the development of innovative drug delivery systems that integrate multiple therapeutic targets in preclinical stages would be more potent and cost-effective. In particular, the therapeutic targets should be more specific to avoid possible AEs and should address the disease stage and subtype (Tijms et al. 2024). These solutions could facilitate the exploration and development of a more refined immunotherapy for AD.
Availability of data and materials
The data are available on request from the corresponding author.
References
Ackley SF, Zimmerman SC, Brenowitz WD, et al. Effect of reductions in amyloid levels on cognitive change in randomized trials: instrumental variable meta-analysis. BMJ. 2021;372:n156.
Alhazmi HA, Albratty M. An update on the novel and approved drugs for Alzheimer disease. Saudi Pharm J. 2022;30(12):1755–64.
Ayalon G, Lee SH, Adolfsson O, et al. Antibody semorinemab reduces tau pathology in a transgenic mouse model and engages tau in patients with Alzheimer’s disease. Sci Transl Med. 2021;13(593):eabb2639.
Boza-Serrano A, Ruiz R, Sanchez-Varo R, et al. Galectin-3, a novel endogenous TREM2 ligand, detrimentally regulates inflammatory response in Alzheimer’s disease. Acta Neuropathol. 2019;138(2):251–73.
Budd Haeberlein S, Aisen PS, Barkhof F, et al. Two randomized phase 3 studies of Aducanumab in Early Alzheimer’s disease. J Prev Alzheimers Dis. 2022;9(2):197–210.
Cazzaniga A, Fedele G, Castiglioni S, et al. The presence of blood-brain barrier modulates the response to magnesium salts in human brain organoids. Int J Mol Sci. 2022;23(9):5133.
Chen J, Liao S, Xiao Z, et al. The development and improvement of immunodeficient mice and humanized immune system mouse models. Front Immunol. 2022;13: 1007579.
Chen L, Cruz E, Oikari LE, et al. Opportunities and challenges in delivering biologics for Alzheimer’s disease by low-intensity ultrasound. Advanced Drug Delivery Rev. 2022;189:114517.
Cuberas-Borros G, Roca I, Castell-Conesa J, et al. Neuroimaging analyses from a randomized, controlled study to evaluate plasma exchange with albumin replacement in mild-to-moderate Alzheimer’s disease: additional results from the AMBAR study. Eur J Nucl Med Mol Imaging. 2022;49(13):4589–600.
Cummings J, Lee G, Nahed P, et al. Alzheimer’s disease drug development pipeline: 2022. Alzheimers Dement (N Y). 2022;8(1):e12295.
Deming Y, Filipello F, Cignarella F, et al. The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer’s disease risk. Sci Transl Med. 2019;11(505):eaau2291.
Doody RS, Thomas RG, Farlow M, et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med. 2014;370(4):311–21.
Dujardin P, Vandenbroucke RE, Hoecke LV. Fighting fire with fire: the immune system might be key in our fight against Alzheimer’s disease. Drug Discovery Today. 2022;27(5):1261–83.
Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer’s disease. New England J Med. 2023;388(1):9–21.
Galas MC, Dourlen P, Begard S, et al. The peptidylprolyl cis/trans-isomerase Pin1 modulates stress-induced dephosphorylation of Tau in neurons. Implication in a pathological mechanism related to Alzheimer disease. J Biol Chem. 2006;281(28):19296–304.
Hamdane M, Dourlen P, Bretteville A, et al. Pin1 allows for differential Tau dephosphorylation in neuronal cells. Mol Cell Neurosci. 2006;32(1–2):155–60.
Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science. 1992;256(5054):184–5.
Helboe L, Rosenqvist N, Volbracht C, et al. Highly specific and sensitive target binding by the humanized pS396-Tau Antibody hC10.2 across a wide spectrum of Alzheimer’s disease and primary tauopathy postmortem brains. J Alzheimers Dis. 2022;88(1):207–28.
Honig LS, Vellas B, Woodward M, et al. Trial of Solanezumab for Mild Dementia Due to Alzheimer's Disease. N Engl J Med. 2018;378(4):321–30.
Høilund-Carlsen PF, Revheim ME, Costa T, et al. Passive Alzheimer’s immunotherapy: a promising or uncertain option? Ageing Res Rev. 2023;90:101996.
Joseph-Mathurin N, Llibre-Guerra JJ, Li Y, et al. Amyloid-related imaging abnormalities in the DIAN-TU-001 trial of Gantenerumab and Solanezumab: lessons from a trial in dominantly inherited Alzheimer disease. Ann Neurol. 2022;92(5):729–44.
Jung M, Lee S, Park S, et al. A therapeutic nanovaccine that generates anti-amyloid antibodies and amyloid-specific regulatory T cells for Alzheimer’s disease. Adv Mater (Deerfield Beach, Fla). 2023;35(3):e2207719.
Katsinelos T, Zeitler M, Dimou E, et al. Unconventional secretion mediates the trans-cellular spreading of Tau. Cell Rep. 2018;23(7):2039–55.
Knopman DS, Jones DT, Greicius MD. Failure to demonstrate efficacy of aducanumab: an analysis of the EMERGE and ENGAGE trials as reported by Biogen, December 2019. Alzheimers Dement. 2021;17(4):696–701.
Kong C, Yang EJ, Shin J, et al. Enhanced delivery of a low dose of aducanumab via FUS in 5×FAD mice, an AD model. Transl Neurodegen. 2022;11(1):57.
Koutsodendris N, Blumenfeld J, Agrawal A, et al. Neuronal APOE4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits. Nat Aging. 2023;3(3):275–96.
Lacosta AM, Pascual-Lucas M, Pesini P, et al. Safety, tolerability and immunogenicity of an active anti-Abeta(40) vaccine (ABvac40) in patients with Alzheimer’s disease: a randomised, double-blind, placebo-controlled, phase I trial. Alzheimers Res Ther. 2018;10(1):12.
Larkin HD. Lecanemab gains FDA approval for early Alzheimer disease. JAMA. 2023;329(5):363.
Leinenga G, Koh WK, Gotz J. A comparative study of the effects of Aducanumab and scanning ultrasound on amyloid plaques and behavior in the APP23 mouse model of Alzheimer disease. Alzheimers Res Ther. 2021;13(1):76.
Leng F, Edison P. Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here? Nat Rev Neurol. 2021;17(3):157–72.
Litvinchuk A, Huynh TV, Shi Y, et al. Apolipoprotein E4 reduction with antisense oligonucleotides decreases neurodegeneration in a tauopathy model. Ann Neurol. 2021;89(5):952–66.
Liu R, Yang J, Liu L, et al. An “Amyloid-beta Cleaner” for the treatment of Alzheimer’s disease by normalizing microglial dysfunction. Adv Sci (Weinh). 2020;7(2):1901555.
Long JM, Holtzman DM. Alzheimer disease: an update on pathobiology and treatment strategies. Cell. 2019;179(2):312–39.
Lowe SL, Willis BA, Hawdon A, et al. Donanemab (LY3002813) dose-escalation study in Alzheimer’s disease. Alzheimers Dement (N Y). 2021;7(1):e12112.
Luque MCA, Galuppo MK, Capelli-Peixoto J, et al. CD100 effects in macrophages and its roles in atherosclerosis. Front Cardiovasc Med. 2018;5: 136.
Ma Y, Jun GR, Chung J, et al. CpG-related SNPs in the MS4A region have a dose-dependent effect on risk of late-onset Alzheimer disease. Aging Cell. 2019;18(4): e12964.
McAlpine CS, Park J, Griciuc A, et al. Astrocytic interleukin-3 programs microglia and limits Alzheimer’s disease. Nature. 2021;595(7869):701–6.
Muhs A, Hickman DT, Pihlgren M, et al. Liposomal vaccines with conformation-specific amyloid peptide antigens define immune response and efficacy in APP transgenic mice. Proc Natl Acad Sci U S A. 2007;104(23):9810–5.
Mulvihill JJ, Cunnane EM, Ross AM, et al. Drug delivery across the blood-brain barrier: recent advances in the use of nanocarriers. Nanomedicine (Lond). 2020;15(2):205–14.
Nisbet RM, Van der Jeugd A, Leinenga G, et al. Combined effects of scanning ultrasound and a tau-specific single chain antibody in a tau transgenic mouse model. Brain. 2017;140(5):1220–30.
Novak P, Kovacech B, Katina S, et al. ADAMANT: a placebo-controlled randomized phase 2 study of AADvac1, an active immunotherapy against pathological tau in Alzheimer’s disease. Nat Aging. 2021;1(6):521–34.
Novak P, Schmidt R, Kontsekova E, et al. FUNDAMANT: an interventional 72-week phase 1 follow-up study of AADvac1, an active immunotherapy against tau protein pathology in Alzheimer’s disease. Alzheimers Res Ther. 2018;10(1):108.
Novak P, Schmidt R, Kontsekova E, et al. Safety and immunogenicity of the tau vaccine AADvac1 in patients with Alzheimer’s disease: a randomised, double-blind, placebo-controlled, phase 1 trial. Lancet Neurol. 2017;16(2):123–34.
Novak P, Zilka N, Zilkova M, et al. AADvac1, an active immunotherapy for alzheimer’s disease and non alzheimer tauopathies: an overview of preclinical and clinical development. J Prev Alzheimers Dis. 2019;6(1):63–9.
Ostrowitzki S, Bittner T, Sink KM, et al. Evaluating the safety and efficacy of Crenezumab vs Placebo in adults with early Alzheimer disease: two phase 3 randomized placebo-controlled trials. JAMA Neurol. 2022;79(11):1113–21.
Panza F, Dibello V, Sardone R, et al. Clinical development of passive tau-based immunotherapeutics for treating primary and secondary tauopathies. Expert Opin Investig Drugs. 2023;32(7):625–34.
Patel AG, Nehete PN, Krivoshik SR, et al. Innate immunity stimulation via CpG oligodeoxynucleotides ameliorates Alzheimer’s disease pathology in aged squirrel monkeys. Brain. 2021;144(7):2146–65.
Plotkin SS, Cashman NR. Passive immunotherapies targeting Abeta and tau in Alzheimer’s disease. Neurobiol Dis. 2020;144:105010.
Rafii MS, Sperling RA, Donohue MC, et al. The AHEAD 3–45 study: design of a prevention trial for Alzheimer’s disease. Alzheimers Dement. 2023;19(4):1227–33.
Rai SN, Singh C, Singh A, et al. Mitochondrial dysfunction: a potential therapeutic target to treat Alzheimer’s disease. Mol Neurobiol. 2020;57(7):3075–88.
Ramanan VK, Day GS. Anti-amyloid therapies for Alzheimer disease: finally, good news for patients. Mol Neurodegener. 2023;18(1):42.
Reish NJ, Jamshidi P, Stamm B, et al. Multiple cerebral hemorrhages in a patient receiving Lecanemab and treated with t-PA for stroke. N Engl J Med. 2023;388(5):478–9.
Roberts M, Sevastou I, Imaizumi Y, et al. Pre-clinical characterisation of E2814, a high-affinity antibody targeting the microtubule-binding repeat domain of tau for passive immunotherapy in Alzheimer’s disease. Acta Neuropathol Commun. 2020;8(1):13.
Salloway S, Farlow M, McDade E, et al. A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease. Nat Med. 2021;27(7):1187–96.
Samudra N, Lane-Donovan C, VandeVrede L, et al. Tau pathology in neurodegenerative disease: disease mechanisms and therapeutic avenues. J Clin Invest. 2023;133(12):e168553.
Sanchez JS, Becker JA, Jacobs HIL, et al. The cortical origin and initial spread of medial temporal tauopathy in Alzheimer’s disease assessed with positron emission tomography. Sci Transl Med. 2021;13(577):eabc0655.
Scholtzova H, Chianchiano P, Pan J, et al. Amyloid beta and Tau Alzheimer’s disease related pathology is reduced by Toll-like receptor 9 stimulation. Acta Neuropathol Commun. 2014;2:101.
Scholtzova H, Do E, Dhakal S, et al. Innate immunity stimulation via toll-like receptor 9 ameliorates vascular amyloid pathology in Tg-SwDI mice with associated cognitive benefits. J Neurosci. 2017;37(4):936–59.
Scholtzova H, Kascsak RJ, Bates KA, et al. Induction of toll-like receptor 9 signaling as a method for ameliorating Alzheimer’s disease-related pathology. J Neurosci. 2009;29(6):1846–54.
Self WK, Holtzman DM. Emerging diagnostics and therapeutics for Alzheimer disease. Nat Med. 2023;29(9):2187–99.
Selles MC, Fortuna JTS, Cercato MC, et al. AAV-mediated neuronal expression of an scFv antibody selective for Aβ oligomers protects synapses and rescues memory in Alzheimer models. Mol Ther. 2023;31(2):409–19.
Sevigny J, Chiao P, Bussiere T, et al. The antibody aducanumab reduces Abeta plaques in Alzheimer’s disease. Nature. 2016;537(7618):50–6.
Sims JR, Zimmer JA, Evans CD, et al. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA. 2023;330(6):512–27.
Smirnov D, Galasko D. Dynamics of neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2022;21(4):297–8.
Soderberg L, Johannesson M, Nygren P, et al. Lecanemab, Aducanumab, and Gantenerumab - binding profiles to different forms of amyloid-beta might explain efficacy and side effects in clinical trials for Alzheimer’s disease. Neurotherapeutics. 2023;20(1):195–206.
Song C, Shi J, Zhang P, et al. Immunotherapy for Alzheimer’s disease: targeting beta-amyloid and beyond. Transl Neurodegener. 2022;11(1):18.
Southwell AL, Franciosi S, Villanueva EB, et al. Anti-semaphorin 4D immunotherapy ameliorates neuropathology and some cognitive impairment in the YAC128 mouse model of Huntington disease. Neurobiol Dis. 2015;76:46–56.
Sperling RA, Donohue MC, Raman R, et al. Trial of Solanezumab in Preclinical Alzheimer's Disease. N Engl J Med. 2023;389(12):1096–107.
Srivastava P, Tripathi PN, Sharma P, et al. Design and development of some phenyl benzoxazole derivatives as a potent acetylcholinesterase inhibitor with antioxidant property to enhance learning and memory. Euro J Med Chem. 2019;163:116–35.
Sun BL, Chen Y, Fan DY, et al. Critical thinking on amyloid-beta-targeted therapy: challenges and perspectives. Sci China Life Sci. 2021;64(6):926–37.
Tai HC, Ma HT, Huang SC, et al. The tau oligomer antibody APNmAb005 detects early-stage pathological tau enriched at synapses and rescues neuronal loss in long-term treatments. bioRxiv. 2022. https://doi.org/10.1101/2022.06.24.497452.
Tao CC, Cheng KM, Ma YL, et al. Galectin-3 promotes Abeta oligomerization and Abeta toxicity in a mouse model of Alzheimer’s disease. Cell Death Differ. 2020;27(1):192–209.
Teng E, Manser PT, Pickthorn K, et al. Safety and efficacy of semorinemab in individuals with prodromal to mild Alzheimer disease: a randomized clinical trial. JAMA Neurol. 2022;79(8):758–67.
Tijms BM, Vromen EM, Mjaavatten O, et al. Cerebrospinal fluid proteomics in patients with Alzheimer’s disease reveals five molecular subtypes with distinct genetic risk profiles. Nat Aging. 2024;4(1):33–47.
Umeda T, Eguchi H, Kunori Y, et al. Passive immunotherapy of tauopathy targeting pSer413-tau: a pilot study in mice. Ann Clin Transl Neurol. 2015;2(3):241–55.
Vaz M, Silvestre S. Alzheimer’s disease: recent treatment strategies. Eur J Pharmacol. 2020;887:173554.
Wang C, Xiong M, Gratuze M, et al. Selective removal of astrocytic APOE4 strongly protects against tau-mediated neurodegeneration and decreases synaptic phagocytosis by microglia. Neuron. 2021;109(10):1657-1674 e1657.
Wang Q, Delva L, Weinreb PH, et al. Monoclonal antibody exposure in rat and cynomolgus monkey cerebrospinal fluid following systemic administration. Fluids Barriers CNS. 2018;15(1):10.
Wang S, Mustafa M, Yuede CM, et al. Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer’s disease model. J Exper Med. 2020;217(9):e20200785.
Xie J, Gonzalez-Carter D, Tockary TA, et al. Dual-sensitive nanomicelles enhancing systemic delivery of therapeutically active antibodies specifically into the brain. ACS Nano. 2020;14(6):6729–42.
Yadollahikhales G, Rojas JC. Anti-Amyloid immunotherapies for Alzheimer’s disease: a 2023 clinical Update. Neurotherapeutics. 2023;20(4):914–31.
Yanamandra K, Kfoury N, Jiang H, et al. Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo. Neuron. 2013;80(2):402–14.
Yu HJ, Dickson SP, Wang PN, et al. Safety, tolerability, immunogenicity, and efficacy of UB-311 in participants with mild Alzheimer’s disease: a randomised, double-blind, placebo-controlled, phase 2a study. Ebiomedicine. 2023;94:104665.
Zeng H, Huang J, Zhou H, et al. Integrative in situ mapping of single-cell transcriptional states and tissue histopathology in a mouse model of Alzheimer’s disease. Nat Neurosci. 2023;26(3):430–46.
Zhang Y, Chen H, Li R, et al. Amyloid beta-based therapy for Alzheimer’s disease: challenges, successes and future. Signal Transduct Target Ther. 2023;8(1):248.
Zhang Y, Song W. Islet amyloid polypeptide: another key molecule in Alzheimer’s pathogenesis? Prog Neurobiol. 2017;153:100–20.
Zheng C, Zhou XW, Wang JZ. The dual roles of cytokines in Alzheimer’s disease: update on interleukins, TNF-alpha, TGF-beta and IFN-gamma. Transl Neurodegener. 2016;5:7.
Zhou Y, Song WM, Andhey PS, et al. Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease. Nat Med. 2020;26(1):131–42.
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The authors acknowledge colleagues in our department for critical reading of the manuscript.
Funding
This study was supported by the Key Project of the National Natural Science Foundation of China (U20A20354); Beijing Brain Initiative from Beijing Municipal Science & Technology Commission (Z201100005520016, Z201100005520017); STI2030-Major Projects (No.2021ZD0201802); the National Key Scientific Instrument and Equipment Development Project (31627803); the Key Project of the National Natural Science Foundation of China (81530036).
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Jianping Jia and Wei Qin conceived the idea and framework of the manuscript. Wei Qin, Yana Pang, Shuya Nie wrote the first draft of the manuscript; Wei Qin, Meina Quan and Jianping Jia reviewed and revised the manuscript; Jianping Jia supervised the review; All authors read and approved the final manuscript.
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Correspondence to Jianping Jia.
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