β-amyloid PET neuroimaging: A review of radiopharmaceutical development

Alzheimer's disease (AD) is a neurodegenerative disease characterized by deposition of amyloid-β plaques that occurs even before symptoms of brain failure are clinically detectable. Whereas previously the diagnosis of AD was only routinely based on clinical assessment, an improvement over the past few years in imaging biomarkers has now led to reconsider the core of the AD diagnostic pathway. Therefore, positron emission tomography (PET) radiotracers for the in vivo imaging of amyloid plaques have been the focus of intense research. Many chemical compounds, mostly derived from the chemistry of amyloid histological staining dyes, have permitted to obtain promising brain amyloid radiopharmaceuticals. Three of them have been approved by the FDA and European regulatory bodies. The present review focuses on the development of these compounds not only as a suitable imaging biomarker to improve AD diagnosis, but also to evaluate new potential therapy.     

PET amyloid-beta imaging in preclinical Alzheimer's disease

Alzheimer's disease (AD) is the leading cause of dementia, accounting for 60-70% of all cases [Hebert et al., 2003, 1]. The need for effective therapies for AD is great. Current approaches, including cholinesterase inhibitors and N-methyl-d-aspartate (NMDA) receptor antagonists, are symptomatic treatments for AD but do not prevent disease progression. Many diagnostic and therapeutic approaches to AD are currently changing due to the knowledge that underlying pathology starts 10 to 20 years before clinical signs of dementia appear [Holtzman et al., 2011, 2]. New therapies which focus on prevention or delay of the onset or cognitive symptoms are needed. Recent advances in the identification of AD biomarkers now make it possible to detect AD pathology in the preclinical stage of the disease, in cognitively normal (CN) individuals; this biomarker data should be used in the selection of high-risk populations for clinical trials. In vivo visualization of AD neuropathology and biological, biochemical or physiological confirmation of the effects of treatment likely will substantially improve development of novel pharmaceuticals. Positron emission tomography (PET) is the leading neuroimaging tool to detect and provide quantitative measures of AD amyloid pathology in vivo at the early stages and follow its course longitudinally. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.     

Centiloid scale analysis for 18F-THK5351 PET imaging in Alzheimer’s disease

PurposeA standardized method for quantification is required for analyzing PET data, but such standards have not been established for tau PET imaging. The Centiloid scale has recently been proposed as a standard method for quantifying amyloid deposition on PET imaging. Therefore, the present study aimed to apply the Centiloid scale to ¹⁸F-THK5351 PET imaging in Alzheimer’s disease (AD).MethodsWe acquired ¹⁸F-THK5351 PET, ¹¹C-PiB PET, and MR images from 47 cognitively normal (CN) individuals and 28 patients with AD with mild to moderate dementia. PET images were spatially normalized to Montreal Neurological Institute space. The PET signals were then normalized using the signal in the reference volume of interest (VOI). Target VOI for specific ¹⁸F-THK5351 retention in AD was extracted by voxel-wise comparison of PET images between the 47 CN individuals and 16 AD patients with moderate dementia. Scale anchor points were defined by the CN individuals as 0-anchor points and by that of the average of the typical AD patients as 100-anchor points.ResultsSpecific retention of ¹⁸F-THK5351 was predominant in the angular gyrus, inferior temporal cortex, and parieto-occipital regions in patients with AD. Standardized uptake value ratio (SUVR) of 1.227 and 1.797 were defined as 0- and 100-anchor points, respectively. ¹⁸F-THK5351 PET data could be expressed using the Centiloid scale, with the SUVR of the ¹⁸F-THK5351 PET images converted to Centiloid using our VOI, the standard Centiloid reference VOI, and the following equation: Centiloid = 169.0 × SUVR–204.6.ConclusionCentiloid methods can be applied to tau PET imaging using ¹⁸F-THK5351.     

Neuropathological correlates of amyloid PET imaging in Down syndrome

Down syndrome (DS) results in an overproduction of amyloid‐β (Aβ) peptide associated with early onset of Alzheimer's disease (AD). DS cases have Aβ deposits detectable histologically as young as 12–30 years of age, primarily in the form of diffuse plaques, the type of early amyloid pathology also seen at pre‐clinical (i.e., pathological aging) and prodromal stages of sporadic late onset AD. In DS subjects aged >40 years, levels of cortical Aβ deposition are similar to those observed in late onset AD and in addition to diffuse plaques involve cored plaques associated with dystrophic neurites (neuritic plaques), which are of neuropathological diagnostic significance in AD. The purpose of this review is to summarize and discuss findings from amyloid PET imaging studies of DS in reference to postmortem amyloid‐based neuropathology. PET neuroimaging applied to subjects with DS has the potential to (a) track the natural progression of brain pathology, including the earliest stages of amyloid accumulation, and (b) determine whether amyloid PET biomarkers predict the onset of dementia. In addition, the question that is still incompletely understood and relevant to both applications is the ability of amyloid PET to detect Aβ deposits in their earliest form.     

Amyloid PET: Its diagnostic potential compared to FDG

Amyloid PET using high-affinity ligands for fibrillary amyloid is providing high specificity and sensitivity for detection of Alzheimer's disease (AD) even before onset of dementia. Most current published data have been acquired using 11C-Pittsburgh Compound B (PIB). However, due to the extremely short half-life of 11C, PIB is available only in some research laboratories. This limitation will be overcome by 18F-labeled ligands which are currently undergoing formal clinical trials as amyloid imaging agents and are expected to become commercially available for clinical use in the near future. Compared to FDG, which demonstrates regional metabolic deficits in AD and late-stage mild cognitive impairment (MCI), amyloid imaging is expected to provide higher sensitivity for early detection of AD. By detecting amyloid, it is providing information that is complementary to clinical symptoms, while FDG-PET is more closely related to dementia severity and cognitive symptoms. Current data suggest that a negative amyloid PET scan is likely to rule out AD with more than 90% certainty, while a positive scan in a dementia patient or a patient with amnestic MCI indicates a very high likelihood of AD. There is still uncertainty about the clinical significance of positive amyloid scans in elderly normal controls (10 to 40% depending on age and selection criteria).     

Saliva levels of Abeta1-42 as potential biomarker of Alzheimer's disease: a pilot study

Background  

Simple, non-invasive tests for early detection of degenerative dementia by use of biomarkers are urgently required. However, up to the present, no validated extracerebral diagnostic markers for the early diagnosis of Alzheimer disease (AD) are available. The clinical diagnosis of probable AD is made with around 90% accuracy using modern clinical, neuropsychological and imaging methods. A biochemical marker that would support the clinical diagnosis and distinguish AD from other causes of dementia would therefore be of great value as a screening test. A total of 126 samples were obtained from subjects with AD, and age-sex-matched controls. Additionally, 51 Parkinson's disease (PD) patients were used as an example of another neurodegenerative disorder. We analyzed saliva and plasma levels of β amyloid (Aβ) using a highly sensitive ELISA kit.     

Amelioration of amyloid load by anti-Abeta single-chain antibody in Alzheimer mouse model

Parenteral immunization of transgenic mouse models of Alzheimer disease (AD) with synthetic amyloid beta-peptide (Abeta) prevented or reduced Abeta deposits and attenuated their memory and learning deficits. A clinical trial of immunization with synthetic Abeta, however, was halted due to brain inflammation, presumably induced by a toxic Abeta, T-cell- and/or Fc-mediated immune response. Another issue relating to such immunizations is that some AD patients may not be able to raise an adequate immune response to Abeta vaccination due to immunological tolerance or age-associated decline. Because peripheral administration of antibodies against Abeta also induced clearance of amyloid plaques in the model mice, injection of humanized Abeta antibodies has been proposed as a possible therapy for AD. By screening a human single-chain antibody (scFv) library for Abeta immunoreactivity, we have isolated a scFv that specifically reacts with oligomeric Abeta as well as amyloid plaques in the brain. The scFv inhibited Abeta amyloid fibril formation and Abeta-mediated cytotoxicity in vitro. We have tested the efficacy of the human scFv in a mouse model of AD (Tg2576 mice). Relative to control mice, injections of the scFv into the brain of Tg2576 mice reduced Abeta deposits. Because scFvs lack the Fc portion of the immunoglobulin molecule, human scFvs against Abeta may be useful to treat AD patients without eliciting brain inflammation.     

Soluble Amyloid Precursor Protein 770 Is Released from Inflamed Endothelial Cells and Activated Platelets: A NOVEL BIOMARKER FOR ACUTE CORONARY SYNDROME*

Most Alzheimer disease (AD) patients show deposition of amyloid β (Aβ) peptide in blood vessels as well as the brain parenchyma. We previously found that vascular endothelial cells express amyloid β precursor protein (APP) 770, a different APP isoform from neuronal APP695, and produce Aβ. Since the soluble APP cleavage product, sAPP, is considered to be a possible marker for AD diagnosis, sAPP has been widely measured as a mixture of these variants. We hypothesized that measurement of the endothelial APP770 cleavage product in patients separately from that of neuronal APP695 would enable discrimination between endothelial and neurological dysfunctions. Using our newly developed ELISA system for sAPP770, we observed that inflammatory cytokines significantly enhanced sAPP770 secretion by endothelial cells. Furthermore, we unexpectedly found that sAPP770 was rapidly released from activated platelets. We also found that cerebrospinal fluid mainly contained sAPP695, while serum mostly contained sAPP770. Finally, to test our hypothesis that sAPP770 could be an indicator for endothelial dysfunction, we applied our APP770 ELISA to patients with acute coronary syndrome (ACS), in which endothelial injury and platelet activation lead to fibrous plaque disruption and thrombus formation. Development of a biomarker is essential to facilitate ACS diagnosis in clinical practice. The results revealed that ACS patients had significantly higher plasma sAPP770 levels. Furthermore, in myocardial infarction model rats, an increase in plasma sAPP preceded the release of cardiac enzymes, currently used markers for acute myocardial infarction. These findings raise the possibility that sAPP770 can be a useful biomarker for ACS.     

Diagnosed Mild Cognitive Impairment Due to Alzheimer’s Disease with PET Biomarkers of Beta Amyloid and Neuronal Dysfunction

The aim of this study is to identify mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) using amyloid imaging of beta amyloid (Aβ) deposition and FDG imaging of reflecting neuronal dysfunction as PET biomarkers. Sixty-eight MCI patients underwent cognitive testing, [11C]-PIB PET and [18F]-FDG PET at baseline and follow-up. Regions of interest were defined on co-registered MRI. PIB distribution volume ratio (DVR) was calculated using Logan graphical analysis, and the standardized uptake value ratio (SUVR) on the same regions was used as quantitative analysis for [18F]-FDG. Thirty (44.1%) of all 68 MCI patients converted to AD over 19.2±7.1 months. The annual rate of MCI conversion was 23.4%. A positive Aβ PET biomarker significantly identified MCI due to AD in individual MCI subjects with a sensitivity (SS) of 96.6% and specificity (SP) of 42.1%. The positive predictive value (PPV) was 56.8%. A positive Aβ biomarker in APOE ε4/4 carriers distinguished with a SS of 100%. In individual MCI subjects who had a prominent impairment in episodic memory and aged older than 75 years, an Aβ biomarker identified MCI due to AD with a greater SS of 100%, SP of 66.6% and PPV of 80%, compared to FDG biomarker alone or both PET biomarkers combined. In contrast, when assessed in precuneus, both Aβ and FDG biomarkers had the greatest level of certainty for MCI due to AD with a PPV of 87.8%. The Aβ PET biomarker primarily defines MCI due to AD in individual MCI subjects. Furthermore, combined FDG biomarker in a cortical region of precuneus provides an added diagnostic value in predicting AD over a short period.     

AZD2184: a radioligand for sensitive detection of β-amyloid deposits

The presence of β‐amyloid plaques in brain is a hallmark of Alzheimer’s disease (AD) and serves as a biomarker for confirmation of diagnosis postmortem. Positron emission tomography (PET) radioligands such as Pittsburgh compound B ([¹¹C]‐2‐(3‐fluoro‐4‐methylamino‐phenyl)‐benzothiazol‐6‐ol) (PIB) binds selectively to β‐amyloid and are promising new tools supporting the clinical diagnoses of AD. In addition, such methodology may be useful for evaluation of new drugs aiming at reduction of amyloid plaque load. The objective of this study is to develop a new amyloid selective PET radioligand with higher signal‐to‐background ratio when compared with existing amyloid PET ligands. The lead compound, AZD2184, (2‐[6‐(methylamino)pyridin‐3‐yl]‐1,3‐benzothiazol‐6‐ol) was found to have high affinity for amyloid fibrils in vitro (K_d: 8.4 ± 1.0 nM). Two minutes after i.v. administration in rats, about 1% of the dose was in brain. In vitro autoradiography on cortical brain sections from amyloid‐beta precursor protein/presenilin 1 (APP/PS1) mice and AD patients showed that while [³H]AZD2184 and [³H]PIB are mutually displaceable, [³H]AZD2184 displays a higher signal‐to‐background ratio primarily by virtue of lower background binding levels. The ratio of binding ability in prefrontal cortex (high plaque load) to subcortical white matter (background) was 4.5 for [³H]AZD2184 and 0.8 for [³H]PIB at 1 nM. In adjacent cortical sections from APP/PS1 mouse as well as from AD cortical tissue, [³H]AZD2184 and antibodies to human β‐amyloid labeled identical structures. In vivo administration of [³H]AZD2184 to APP/PS1 mice further showed that [³H]AZD2184 labels amyloid deposits with low non‐specific background binding. Taken together, the pre‐clinical profile of AZD2184 in relation to the reference ligand PIB, suggests that ¹¹C‐labeled AZD2184 is a potential radioligand for PET‐visualization of β‐amyloid deposits in the living human brain.     

Tritium-labeled (E,E)-2,5-bis(4′-hydroxy-3′-carboxystyryl)benzene as a probe for β-amyloid fibrils

Accumulation of Aβ in the brains of Alzheimer disease (AD) patients reflects an imbalance between Aβ production and clearance from their brains. Alternative cleavage of amyloid precursor protein (APP) by processing proteases generates soluble APP fragments including the neurotoxic amyloid Aβ40 and Aβ42 peptides that assemble into fibrils and form plaques. Plaque-buildup occurs over an extended time-frame, and the early detection and modulation of plaque formation are areas of active research. Radiolabeled probes for the detection of amyloid plaques and fibrils in living subjects are important for noninvasive evaluation of AD diagnosis, progression, and differentiation of AD from other neurodegenerative diseases and age-related cognitive decline. Tritium-labeled (E,E)-1-[³H]-2,5-bis(4′-hydroxy-3′-carbomethoxystyryl)benzene possesses an improved level of chemical stability relative to a previously reported radioiodinated analog for radiometric quantification of Aβ plaque and tau pathology in brain tissue and in vitro studies with synthetic Aβ and tau fibrils.     

OAB-14, a bexarotene derivative,improves Alzheimer's disease-related pathologies and cognitive impairments by increasing β-amyloid clearance in APP/PS1 mice

The pathogenesis of Alzheimer's disease (AD) is complex, though the clinical failures of anti-AD candidates targeting Aβ production (such as β- and γ-secretase inhibitors) make people suspect the Aβ hypothesis, in which the neurotoxicity of Aβ is undoubtedly involved. According to studies, >95% of AD patients with sporadic AD are primarily associated with abnormal Aβ clearance. Therefore, drugs that increase Aβ clearance are becoming new prospects for the treatment of AD. Here, the novel small molecule OAB-14, designed using bexarotene as the lead compound, significantly alleviated cognitive impairments in amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mice after administration for 15?days or 3?months. OAB-14 rapidly cleared 71% of Aβ by promoting microglia phagocytosis and increasing IDE and NEP expression. This compound also attenuated the downstream pathological events of Aβ accumulation, such as synaptic degeneration, neuronal loss, tau hyperphosphorylation and neuroinflammation in APP/PS1 mice. Moreover, OAB-14 had no significant effect on body weight or liver toxicity after acute and chronic treatment. OAB-14 was well tolerated and its maximum-tolerated dose in mice was >4.0?g/kg. Based on these findings, OAB-14 represents a promising new candidate for AD treatment.     

Distribution and binding of 18F-labeled and 125I-labeled analogues of ACI-80, a prospective molecular imaging biomarker of disease: a whole hemisphere post mortem autoradiography study in human brains obtained from Alzheimer's disease patients

One of the major pathological landmarks of Alzheimer's disease and other neurodegenerative diseases is the presence of amyloid deposits in the brain. The early non-invasive visualization of amyloid is a major objective of recent diagnostic neuroimaging approaches, including positron emission tomography (PET), with an eye on follow-up of disease progression and/or therapy efficacy. The development of molecular imaging biomarkers with binding affinity to amyloid in the brain is therefore in the forefront of imaging biomarker and radiochemistry research. Recently, a dodecamer peptide (amino acid sequence=QSHYRHISPAQV; denominated D1 or ACI-80) was identified as a prospective ligand candidate, binding with high ex vivo affinity to L-Aβ-amyloid (K(d): 0.4 μM). In order to assess the ligand's capacity to visualize amyloid in Alzheimer's disease (AD), two (125)I labeled and three (18)F labeled analogues of the peptide were synthesized and tested in post mortem human autoradiography experiments using whole hemisphere brain slices obtained from deceased AD patients and age matched control subjects. The (18)F-labeled radioligands showed more promising visualization capacity of amyloid that the (125)I-labeled radioligands. In the case of each (18)F radioligands the grey matter uptake in the AD brains was significantly higher than that in control brains. Furthermore, the grey matter: white matter uptake ratio was over ~2, the difference being significant for each (18)F-radioligands. The regional distribution of the uptake of the various radioligands systematically shows a congruent pattern between the high uptake regions and spots in the autoradiographic images and the disease specific signals obtained in adjacent or identical brain slices labeled with histological, immunohistochemical or autoradiographic stains for amyloid deposits or activated astrocytes. The present data, using post mortem human brain autoradiography in whole hemisphere human brains obtained from deceased AD patients and age matched control subjects, support the visualization capacity of the radiolabeled ACI-80 analogues of amyloid deposits in the human brain. Further studies are warranted to explore the usefulness of the (18)F-labeled analogues as in vivo molecular imaging biomarkers in diagnostic PET studies.     

突变和修饰β淀粉样蛋白与阿尔茨海默病

淀粉样蛋白级联假说是阿尔茨海默病(Alzheimer's disease,AD)病因学的核心,但在过去几年中,靶向淀粉样斑块并未实现成功的免疫治疗.最近几年,不同形式的β淀粉样蛋白(Aβ)引起人们的关注.本文总结了关于早发性AD患者大脑中不同Aβ突变体和散发性AD患者大脑中已经鉴定出的经过酶切及修饰产生的不同形式Aβ的...     

综述:β分泌酶1调控机制在阿尔茨海默病早期发病中的作用

β-淀粉样蛋白(Aβ)在脑内的沉积被认为是阿尔茨海默病(AD)发病的始动因素之一．β-淀粉样蛋白前体蛋白裂解酶1(BACE1)是Aβ产生过程中重要的蛋白酶．BACE1在细胞内的表达与成熟受多种因素调节．BACE1与缺血缺氧、炎症应激等多种AD早期的分子病理变化相关,BACE1、Aβ及其相关细胞因子可能成为体液生物学标记物,为临床早期诊断AD提供新的手段．     

Alzheimer Disease—No Target for Statin Treatment. A Mini Review

Nosologically, Alzheimer disease (AD) is not a single disorder. A minority of around 400 families worldwide can be grouped as hereditary in origin, whereas the majority of all Alzheimer cases (approx. 25 million worldwide) are sporadic in origin. In the pathophysiology of the latter type, a number of susceptibility genes contribute to the disease among which are allelic abnormalities of the apolipoprotein E4 gene pointing to a link between disturbed cholesterol metabolism and sporadic AD. Cholesterol is a main component of membrane composition enriched in microdomains and is functionally linked to the proteolytic processing of amyloid precursor protein (APP). In sporadic AD, a marked diminution of both membrane phospholipids and cholesterol has been found. Evidence has been provided that high plasma cholesterol may protect from AD. In contrast to these well documented abnormalities observed in AD patients, it was assumed that an elevated cholesterol concentration might favour the generation of β-amyloid and, thus, AD. However, a series of in vitro-and in vivo-studies did not provide evidence for the assumption that an enhanced cholesterol concentration increased βA4-production. A harsh reduction of membrane cholesterol only caused a “beneficial” effect of APP metabolism. However, this experimentally induced condition may not be compatible to sporadic AD. The application of statins in sporadic AD did not yield results to assume that this therapeutic strategy may prevent or treat successfully sporadic AD. Dedicated to Professor John P. Blass.     

Tau PET Imaging for Staging of Alzheimer's Disease in Down Syndrome

Alzheimer's disease (AD) pathology and early‐onset dementia develop almost universally in Down syndrome (DS). AD is defined neuropathologically by the presence of extracellular plaques of aggregated amyloid β protein and intracellular neurofibrillary tangles (NFTs) of aggregated hyperphosphorylated tau protein. The development of radiolabeled positron emission tomography (PET) ligands for amyloid plaques and tau tangles enables the longitudinal assessment of the spatial pattern of their accumulation in relation to symptomatology. Recent work indicates that amyloid pathology develops 15–20 years before neurodegeneration and symptom onset in the sporadic and autosomal dominant forms of AD, while tau pathology correlates more closely with symptomatic stages evidenced by cognitive decline and dementia. Recent work on AD biomarkers in DS illustrates similarities between DS and sporadic AD. It may soon be possible to apply recently developed staging classifications to DS to obtain a more nuanced understanding of the development AD in DS and to provide more accurate diagnosis and prognosis in the clinic.     

Association between acetylcholinesterase and β-amyloid peptide in Alzheimer's cerebrospinal fluid

The altered expression of acetylcholinesterase (AChE) in the brains of patients with Alzheimer's disease (AD) has raised much interest of late. Despite an overall decrease in the AD brain, the activity of AChE increases around β-amyloid plaques and indeed, the β-amyloid peptide (Aβ) can influence AChE levels. Such evidence stimulated our interest in the possibility that the levels of AChE and amyloid might vary together in AD. We previously found that the different AChE forms present in both the brain and in the cerebrospinal fluid (CSF) of AD patients varied in conjunction with abnormal glycosylation. Thus, the alterations in glycosylation are correlated with the accumulation of a minor subspecies of AChE monomers. We also recently analysed whether long-term exposure to the cholinesterase inhibitor (ChE-I) donepezil influences the AChE species found in AD CSF. The marked increase in CSF-AChE activity in AD patients following long-term treatment with donepezil was not paralleled by a rise in this subset of light variants. Hence, the correlation with the levels of CSF-Aβ is unique to these AChE species in patients receiving such treatment. The aim of this report is to review the links between AChE and β-amyloid, and to discuss the significance of the responses of the distinct AChE species to ChE-I during the treatment of AD.     

Évaluation quantitative préliminaire du 18F-FDDNP en TEP/TDM dans la maladie d’Alzheimer,en utilisant différentes régions de référence

IntroductionAlzheimer's disease (AD) is the leading cause of dementia in the world. His current treatment is symptomatic. New therapies, aimed at slowing the neurodegenerative process, are actually under study. Early detection of AD as also the evaluation of new generation of neuroprotectors drugs is essential. For this reason, markers of amyloid plaques and neurofibrillary lesions have been developed including ¹⁸F-FDDNP.MethodsTwo patients and two controls were included in this preliminary study. They were submitted to a PET/CT with ¹⁸F-FDDNP. Data acquisition was performed in a list mode during 90 minutes. We used a cerebral atlas to create ROI, after co registration with a perfusion PET template, and we estimated the distribution volume ratio (DVR) using two different reference regions: the cerebellum and the white matter. We calculated a simplified index of quantification (SUVr) using a single 10 minutes acquisition frame.ResultsWe found an increased DVR in temporal lobes (amygdala) (1.23–1.40 in patients vs 1.06–1.31 in controls, with cerebellum as reference region) and fronto-basal regions (1.48–1.30 in patients vs 1.16–1.23 in controls with the same reference region and 1.25–1.18 in patients vs 1.13–1.19 in controls with white matter as reference region). SUVr calculated between 50 and 60 minutes after injection was highly correlated to DVR values (correlation coefficient 0.93). The SUVr difference between patients and controls was more important with cerebellum rather than white matter as reference region (26% in amygdala).ConclusionThis is a very preliminary study due to the low number of subjects included. However, the results obtained suggest the feasibility of brain ROI segmentation and the DVR-SUVr calculation using an anatomical atlas.     

阿尔茨海默病免疫治疗的临床研究进展

阿尔茨海默病免疫治疗以淀粉样蛋白Aβ或tau蛋白为治疗靶点。通过疫苗刺激产生靶标抗体的主动免疫或直接给予抗体的被动免疫,可减轻AD病理改变,有望延缓或阻止AD病程进展。动物研究显示了广阔的治疗前景,临床免疫治疗的部分药物已完成III期试验,但未达到预期效果。综述近年来免疫治疗AD的临床研究进展。