jpad journal

AND option

OR option



S.L Lowe1, C. Duggan Evans2, S. Shcherbinin2, Y.-J. Cheng2, B.A. Willis2, I. Gueorguieva3, A.C. Lo2, A.S. Fleisher2, J.L. Dage2,4, P. Ardayfio2, G. Aguiar3, M. Ishibai5, G. Takaichi5, L. Chua1, G. Mullins2, J.R. Sims2 on behalf of AACD Investigators


1. Eli Lilly and Company, Lilly Singapore, Singapore; 2. Eli Lilly and Company, Indianapolis, Indiana, USA; 3. Eli Lilly and Company, Bracknell, UK; 4. Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA; 5. Eli Lilly Japan, K.K., Kobe, Japan.

Corresponding Author: John R. Sims, Eli Lilly and Company, Lilly Corporate Center DC 1532, Indianapolis, IN, 46285, Telephone: 317-655-2206,e-mail:

J Prev Alz Dis 2021;4(8):414-424
Published online September 21, 2021,



Background: Donanemab (LY3002813) is an IgG1 antibody directed at an N‑terminal pyroglutamate of amyloid beta epitope that is present only in brain amyloid plaques.
Objectives: To assess effects of donanemab on brain amyloid plaque load after single and multiple intravenous doses, as well as pharmacokinetics, safety/tolerability, and immunogenicity.
Design: Phase 1b, investigator- and patient-blind, randomized, placebo-controlled study.
Setting: Patients recruited at clinical research sites in the United States and Japan.
Participants: 61 amyloid plaque-positive patients with mild cognitive impairment due to Alzheimer’s disease and mild-to-moderate Alzheimer’s disease dementia.
Intervention: Six cohorts were dosed with donanemab: single dose 10-, 20- or 40- mg/kg (N = 18), multiple doses of 10-mg/kg every 2 weeks for 24 weeks (N = 10), and 10- or 20-mg/kg every 4 weeks for 72 weeks (N=18) or placebo (N = 15).
Measurements: Brain amyloid plaque load, using florbetapir positron emission tomography, was assessed up to 72 weeks. Safety was evaluated by occurrence of adverse events, magnetic resonance imaging, electrocardiogram, vital signs, laboratory testing, neurological monitoring, and immunogenicity.
Results: Treatment with donanemab resulted in rapid reduction of amyloid, even after a single dose. By 24 weeks, amyloid positron emission tomography mean changes from baseline for single donanemab doses in Centiloids were: -16.5 (standard error 11.22) 10-mg/kg intravenous; 40.0 (standard error 11.23) 20 mg/kg intravenous; and -49.6 (standard error 15.10) 40-mg/kg intravenous. Mean reduction of amyloid plaque in multiple dose cohorts by 24 weeks in Centiloids were: 55.8 (standard error 9.51) 10-mg/kg every 2 weeks; -50.2 (standard error 10.54) 10-mg/kg every 4 weeks; and -58.4 (standard error 9.66) 20-mg/kg every 4 weeks. Amyloid on average remained below baseline levels up to 72 weeks after a single dose of donanemab. Repeated dosing resulted in continued florbetapir positron emission tomography reductions over time compared to single dosing with 6 out of 28 patients attaining complete amyloid clearance within 24 weeks. Within these, 5 out of 10 patients in the 20 mg/kg every 4 weeks cohort attained complete amyloid clearance within 36 weeks. When dosing with donanemab was stopped after 24 weeks of repeat dosing in the 10 mg every 2 weeks cohort, florbetapir positron emission tomography reductions were sustained up to 72 weeks. For the single dose cohorts on day 1, dose proportional increases in donanemab pharmacokinetics were observed from 10 to 40 mg/kg. Dose proportional increases in pharmacokinetics were also observed at steady state with the multiple dose cohorts. Donanemab clearance was comparable across the dose levels. Mean donanemab elimination-half-life following 20 mg/kg single dose was 9.3 days with range of 5.6 to 16.2 days. Greater than 90% of patients had positive treatment-emergent antidrug antibodies with donanemab. However, overall, the treatment-emergent antidrug antibodies did not have a significant impact on pharmacokinetics. Donanemab was generally well tolerated. Amongst the 46 participants treated with donanemab, the following amyloid-related imaging abnormalities, common to the drug class, were observed: 12 vasogenic cerebral edema events (12 [19.7%] patients), 10 cerebral microhemorrhage events (6 [13.0%] patients), and 2 superficial siderosis events (2 [4.3%] patients).
Conclusions: Single and multiple doses of donanemab demonstrated a rapid, robust, and sustained reduction up to 72 weeks in brain amyloid plaque despite treatment-emergent antidrug antibodies detected in most patients. Amyloid-related imaging abnormalities were the most common treatment-emergent event.

Key words: Alzheimer’s disease, amyloid plaque, donanemab, florbetapir PET, immunogenicity.



The deposition of amyloid-beta peptide (Aβ) is essential to the pathophysiology and progression of Alzheimer’s disease (AD) (1), and thereby has led to the discovery and development of active and passive immunotherapies with mechanisms of action that reduce Aβ accumulation in the brain (2). Some of the initial active immunotherapies targeted at brain amyloid plaques were associated with a high rate of unacceptable adverse events in clinical trials (e.g., meningoencephalitis (3).
Donanemab (LY3002813) is an immunoglobulin IgG1 antibody directed at an N-terminal pyroglutamate Aβ epitope that is present only in brain amyloid plaques. Donanemab was developed to remove existing amyloid plaques through microglial-mediated phagocytosis. Administration of the murine surrogate of donanemab in aged amyloid precursor protein transgenic mice resulted in dose-dependent plaque reduction without microhemorrhage liability (4). In the first-in-human single-dose and multiple-dose, placebo-controlled, dose-escalation Phase 1a study, donanemab 10-mg/kg was associated with 40–50% reductions in amyloid plaque deposits in amyloid-positive patients with mild cognitive impairment (MCI) due to AD or mild to moderate AD dementia (5). Overall, donanemab was generally well tolerated up to 10-mg/kg in this Phase 1a study. The most common treatment-emergent adverse events among 51 donanemab-treated participants were mild-to-moderate infusion reactions (6 of 37 patients with AD who had IV dosing) and asymptomatic cerebral microhemorrhage (2 out of 51 donanemab treated participants). No cases of vasogenic cerebral edema (ARIA-E) were reported. Approximately, 90% of participants developed anti-drug antibodies at 3 months following a single intravenous dose (5).
Based on the positive safety and pharmacodynamic (PD) findings from the Phase 1a study (5), a second Phase 1 study was initiated with donanemab in patients with MCI due to AD or mild to moderate AD. The overall goal of this Phase 1b study was to determine whether different dosing regimens (single-dose, dosing frequency, and chronic dosing for maximal PD effect) could mitigate immunogenicity, potential immune safety issues and produce sustained amyloid reduction. The primary objective was to assess the effect of donanemab on brain plaque load using florbetapir positron emission tomography (PET) imaging. The secondary objectives were to assess the safety, pharmacokinetics (PK), immunogenicity, and cognitive function effects of donanemab following single intravenous (IV) and multiple IV doses.



Study Design and Treatment

This Phase 1b study was conducted between December 22, 2015 and July 08, 2020 at 8 clinical research centers in the United States and Japan among patients with MCI due to AD or mild to moderate AD (6, 7). The study was a 3-part, patient- and investigator-blind, randomized within cohort, placebo-controlled, parallel-group, single- and multiple-dose study. Each of the 6 cohorts was designed to include approximately 6 (single dose) or 9 (multiple dose) patients treated with donanemab and 2 to 3 patients treated with placebo. Patients in Cohorts 1–3 were each administered a single, IV dose of donanemab (Cohort 1: 10-mg/kg, Cohort 2: 20-mg /kg, Cohort 3: 40-mg/kg) or placebo (Supplemental Figure 1). Follow-up was 72 weeks (Cohorts 1 and 2) or 24 weeks (Cohort 3). Patients in Cohort 4 were each administered multiple IV doses of donanemab (10-mg/kg) or placebo every 2 weeks (Q2W) for up to 24 weeks followed by a 48-week follow-up period to obtain amyloid clearance and safety data. Patients in Cohorts 5 and 6 were each administered multiple IV doses of donanemab (Cohort 5: 10-mg/kg ; Cohort 6: 20-mg/kg) or placebo every 4 weeks (Q4W) for up to 72 weeks followed by a 12-week follow-up period.

Study Population

The study enrolled men or nonfertile women ≥50 years of age with evidence of memory impairment on the Free and Cued Selective Reminding Test with Immediate Recall (FCSRT-IR, picture version; <27 for free recall), a Mini–Mental State Examination (MMSE) score of 16 to 30, a Clinical Dementia Rating (CDR) of 0.5 to 2 and memory box score ≥0.5, and a florbetapir PET scan consistent with the presence of amyloid pathology (as determined using visual assessments and composite standardized uptake value ratio [SUVr] cut-points). The florbetapir F 18 interpretation method used for the eligibility decision included quantification as an adjunct to a visual assessment. The PET imaging core lab was responsible for performing both visual and quantitative analysis of the florbetapir F 18 images. All patients had gradual and progressive change in memory function reported by the patients themselves or informants over a period of more than 6 months. Patients with contraindication for magnetic resonance imaging (MRI), presence of more than four microhemorrhages on MRI, or history or evidence on MRI of macrohemorrhage were excluded. In addition to US patients, Japanese patients were included in this study to explore the safety and PK of donanemab in patients of Japanese decent.

Study Evaluations

Florbetapir PET scans were performed at baseline and at 12, 24, 36, 48, and 72 weeks after starting treatment to estimate mean change in amyloid plaques. Calculation of SUVr with cerebellum reference region was as described previously (8). The latter SUVr values were converted to Centiloid units (9). Volumetric measurements were obtained from structural (3D T1-weighted) MR images acquired at screening and at 24, 48, and 72 weeks. Volume and atrophy were assessed in multiple brain regions including whole brain, lateral ventricles, and hippocampus.
Apolipoprotein E (APOE) genotyping was performed at baseline to determine genetic variants that may influence response to treatment.
Emergence of antibodies against donanemab was evaluated to asses the immunogenicity risk. Antidrug antibodies (ADAs) were detected using an affinity capture elution (ACE) Bridge assay validated at BioAgilytix Labs in Durham, North Carolina, USA. The ACE Bridge immunogenicity assay was developed based on published methods (10-13). Serum for determination of ADAs was collected at screening/baseline and then at regular intervals throughout the study period.
Safety in the study was assessed at regular intervals with MRIs, electrocardiograms, safety laboratory tests (clinical chemistry, hematology, and urinalysis), physical/neurological examinations, and by monitoring the occurrence of adverse events, vital signs, and immunogenicity. In addition, the Columbia Suicide Severity Rating Scale (child version) and (if applicable) the Self-Harm Supplement Form were completed prior to dosing and at most study visits.
Cognition was assessed at screening or baseline for all patients using the CDR, the MMSE, the FCSRT-IR, the Alzheimer’s Disease Assessment Scale Cognitive Subscale (ADAS-Cog-14), the Alzheimer’s Disease Cooperative Study-Mild Cognitive Impairment-Activities of Daily Living, 24-item questionnaire (ADCS-MCI-ADL-24), and the Neuropsychological test battery (NTB). Additionally, these assessments were also performed at 24, 48, and 72 weeks after starting treatment or at the end of the study (eg, Week 24 for Cohort 3) or upon early discontinuation.

Bioanalytical Methods

Serum and CSF samples were evaluated for donanemab using a validated enzyme-linked immunosorbent assay method at Covance Laboratories in Chantilly, Virginia, USA. The lower and upper limit of quantification for the serum assay was 200 ng/mL and 5000 ng/mL, respectively. During validation, the inter-assay accuracy (% relative error) ranged from -1.5%–7.0% and -2.9–5.3% and the inter-assay precision (% relative standard deviation) was 4.0–9.7% and 5.2–8.7%.

Pharmacokinetic and Pharmacodynamic Analyses

Serum PK parameter estimates were calculated by standard noncompartmental methods using Phoenix WinNonlin Version 6.3 (Certara L.P., Raleigh, North Carolina, USA). Parameters estimated after IV administration included maximum observed drug concentration (Cmax), area under the concentration versus time curve (AUC) from time 0 to time infinity (AUC(0-∞)), and terminal half-life (t1/2). Mean plasma concentration versus time profiles and summary statistics of PK parameter estimates by treatment group were generated. To evaluate the potential effect of anti-donanemab antibodies on PK, observed trough donanemab concentrations were plotted by dose separately with time-matched anti-donanemab antibody results. A sample collection time window of 168–672 hours (1–4 weeks) and 168–1344 hours (1–8 weeks) from the most recent dose was used to identify trough concentrations for the Q2W and Q4W dosing regimens, respectively. Samples of CSF and serum were collected at baseline and approximately 72 hours following donanemab administration for the single dose cohorts or at baseline and approximately 72 hours following the dose administered at Week 24 for the multiple dose cohorts and assessed for donanemab concentration. These concentrations were compared to calculate a CSF:serum concentration ratio.
Composite SUVr from florbetapir scans were analyzed to estimate change (14) in amyloid burden. Furthermore, those SUVr values were converted to the Centiloid scale, a standardized methodology to quantify amyloid burden from PET scans (9).

Statistical Analysis

This study intended to enroll approximately 72 patients, a sample size that is customary for studies evaluating safety, PK, and/or PD parameters. Based on prior clinical trials conducted by the sponsor, randomizing 6 patients to each donanemab dose was expected to provide approximately 90% power to detect 17% mean florbetapir SUVr reduction of a dose compared to placebo without multiple comparison adjustment.
The demographic variables, other baseline characteristics, and safety parameters were summarized using standard descriptive statistics. Safety analyses were conducted for all enrolled patients, whether or not they completed all protocol requirements.
PD analyses were conducted on the full analysis set, which included all data from all randomized patients receiving at least one dose of the investigational product according to the treatment the patients actually received. The PD measures included florbetapir PET scans in Centiloid units and were analyzed using a mixed model repeated measure (MMRM) with fixed effects of treatment doses, study visit, interaction between treatment and visit, baseline amyloid PET scan (Centiloid unit), and APOE-ε4 status (carrier /non-carrier) as covariate adjustment. An unstructured covariance matrix was used to model the within-subject variance-covariance errors.
Immunogenicity evaluation was based on antibody formation, that was summarized over time. Treatment-emergent ADAs (TE-ADAs) were defined as those with a titer 2-fold (1 dilution) greater than the minimum required dilution if no ADAs were detected at baseline or those with a 4-fold (2 dilutions) increase in titer compared to baseline if ADAs were detected at baseline. The minimum required dilution of the ADA assay was 1:5.
Cognitive outcomes (CDR, MMSE, FSCRT-IR, ADAS-Cog-11, ADCS-MCI-ADL-24, and NTB) were analyzed using a MMRM with baseline cognitive measures as a baseline covariate, fixed-effects of dose, visit, the dose-visit interaction, and appropriate covariance structures for model convergence. Statistical analyses were performed using SAS EG 9.4 software.



Demographics and Baseline Characteristics

For patients receiving at least 1 dose of study drug, the demographic and baseline characteristics were generally balanced across the treatment groups (Table 1). A total of 61 patients (donanemab, n = 46; placebo, n = 15) participated in this study. Patients were male (n =27) and female (n = 34) with a mean age of 73.2 years (range: 54 to 90 years). Forty-three (70.5%) patients were non-Japanese and 18 (29.5%) patients were Japanese. At baseline, the mean MMSE total score was 21.1 (Standard Deviation [SD] = 4.04) and the mean florbetapir PET Centiloid units was 104.5 (SD = 32.77). Seventy-seven percent (47 of 61) of patients were APOE-ε4 carriers (11 homozygotes and 36 heterozygotes).

Table 1. Demographic and Baseline Characteristics

*Data from the single dose, Q2W, and Q4W placebo arms were pooled; Abbreviations: APOE = apolipoprotein E; MMSE = Mini–Mental State Examination; N = number of patients; n = number of patients in a subgroup; PET = positron emission tomography; Q2W = every 2 weeks; Q4W = every 4 weeks; SD = standard deviation.



Among 276 patients screened, 61 patients satisfied entry criteria and were enrolled into the study (7, 7, and 4 patients were randomized to the 10-mg/kg, 20-mg/kg, and 40-mg/kg single dose cohorts respectively; 10 patients were randomized to the 10-mg/kg Q2W for 24 weeks cohort and 8 and 10 patients were randomized to the 10-mg/kg Q4W and 20-mg/kg Q4W cohorts respectively). For simplicity, all patients receiving placebo were pooled into one group. Main reasons for screen failure were not meeting threshold criteria for amyloid PET (40 of 154 patients; 26.0%), cognition (MMSE/FCSRT-IR; 33 of 154 patients; 21.4%), and microhemorrhage greater than 4 on MRI (16 of 154 patients; 10.4%). Of the 61 patients who received at least 1 dose of study treatment, 46 (75.4%) patients completed the study (Supplemental Figure 2). Fifteen patients did not complete the study, which included 6 due to investigator decision (3 in the 10-mg/kg Q4W cohort and 3 in the 20-mg/kg Q4W cohort); 5 due to the patient’s withdrawal of consent (1 in the 10-mg/kg single dose cohort, 1 in the 10-mg/kg Q2W cohort, 1 in the 10-mg/kg Q4W cohort, 1 in the 20-mg/kg Q4W cohort, and 1 placebo); 3 patients discontinued due to adverse events (ARIA-E [20-mg/kg Q4W cohort], hypertensive crisis [20-mg/kg Q4W cohort] and myocardial infarction, considered a serious adverse event, resulting in death [placebo Q4W cohort]); and 1 patient was lost to follow-up (20-mg/kg single dose cohort).

Florbetapir Positron Emission Tomography – Centiloid Scale and Standardized Uptake Value Ratio

Single and multiple doses of donanemab showed a consistent reduction from baseline in cerebral amyloid (Centiloid units) observed by PET from Week 12 through Week 72 (Figure 1). At Week 24, amyloid PET least squares mean Centiloid changes from baseline for single donanemab doses were: -16.5 (standard error [SE] = 11.22) 10-mg/kg IV; -40.0 (SE = 11.23) 20-mg/kg IV; and -49.6 (SE = 15.10) 40-mg/kg IV. In contrast, in the placebo group there was no significant reduction in florbetapir PET at 72 weeks (90.9 Centiloids at 72 weeks compared to 104.4 Centiloids at baseline). Corresponding Centiloid changes for multiple doses at Week 24 included: -55.8 (SE = 9.51) 10-mg/kg Q2W; -50.2 (SE = 10.54) 10-mg/kg Q4W; and -58.4 (SE = 9.66) 20-mg/kg Q4W. Patients in the 20 mg/kg Q4W cohort tended to achieve greater plaque reduction earlier in the study than patients in either of the 10 mg/kg multiple dose cohorts (Figures 1 and 2). After dosing, a sustained reduction of brain amyloid level without significant reaccumulation for up to 72 weeks was observed across all single- and multiple-dose cohorts.

Figure 1. LS mean change of florbetapir PET scans from baseline (Centiloid units) through Week 72 following single and multiple dosing of IV donanemab

Error bars = SE; *Treatment duration of 24 weeks; Abbreviations: IV = intravenous; LS mean = least squares mean; N = number of patients; PET = positron emission tomography; Q2W = every 2 weeks; Q4W = every 4 weeks; SE = standard error.

igure 2. Cerebral amyloid over time as measured by quantitative amyloid PET imaging (florbetapir SUVr). Absolute Centiloid value as calculated from SUVr

*Treatment duration of 24 weeks; Notes: Color indicates APOE-ε4 status and symbol indicates ADA titer of ≥1:5120. The black dashed horizontal line indicates threshold Centiloid value for being amyloid positive; Abbreviations: APOE = apolipoprotein E; LY = LY3002813 (donanemab); PET = positron emission tomography; Q2W = every 2 weeks; Q4W = every 4 weeks; SUVr = standardized uptake value ratio.


The change in absolute Centiloid value did not appear to be influenced by APOE-ε4 status with no clear association between presence of the APOE-ε4 allele and florbetapir PET response (Figure 2). TE-ADAs (see below) also appeared not to impact the reduction in amyloid as some participants with high TE-ADA titers (≥1:5120) still had a reduction in amyloid in this study (Figure 2).
Overall, 2 participants in single-dose cohorts (1 in 20-mg /kg and 1 in 40-mg /kg) and 9 participants in the multiple-dose cohorts (2 in 10mg/kg Q2W; 2 in 10-mg /kg Q4W; and 5 in 20-mg /kg Q4W) achieved complete amyloid clearance status based on a threshold 24.1 Centiloid value. Most participants achieving amyloid clearance starting at 12 or 24 weeks remained amyloid negative for the duration of their florbetapir PET measurements.
Reduction in cerebral amyloid (Centiloid units) and SUVr changes from baseline were visually comparable between non-Japanese and Japanese patients (Supplemental Figure 3).

Single- and Multiple-Dose Serum and Cerebrospinal Fluid PK

Dose proportional increases were observed in both Cmax and exposure (AUC) following single and multiple doses. Single doses of 10, 20, and 40 mg/kg had measurable donanemab concentration for at least 56 days post-dose with elimination t1/2 of approximately 10 days. Multiple doses resulted in either no (10 mg/kg Q4W) or very limited exposure accumulation (10 mg/kg Q2W; 20 mg/kg Q4W). PK parameters for single and multiple dose cohorts are summarized in Supplemental Tables 1 and 2, respectively. Single dose PK characteristics were similar between Japanese and non-Japanese participants, albeit based on small sample size (5 patients who are Japanese out of 18 patients given donanemab). Quantifiable concentrations were detected in CSF samples collected from patients treated with single and multiple donanemab doses with CSF to serum concentration ratio of approximately 0.2% across all patients and dose levels.

Table 2. Treatment-Emergent Adverse Events

*Data from the single dose Q2W and Q4W placebo arms were pooled; †One patient reported 2 SAEs; Abbreviations: ARIA = amyloid-related imaging abnormalities; CNS = central nervous system; E = vasogenic cerebral edema; H = cerebral microhemorrhage; N = number of patients; n = number of patients in a group; Q2W = every 2 weeks; Q4W = every 4 weeks; SAE = serious adverse event; TEAE = treatment emergent adverse event.


Treatment-emergent Antidrug Antibodies and Effect on Donanemab Serum Concentration

Postbaseline, 46 donanemab-treated participants were evaluable for TE-ADAs. Except for 1 patient in the 10-mg/kg single-dose cohort, all other 45 patients randomized to donanemab developed TE-ADAs. All 6 treatment groups randomized to single or multiple IV administration of donanemab exhibited distinctly higher TE-ADA titers relative to the placebo group. No relationship between dose and TE-ADA was identified in this study. The overall incidence of TE-ADA and titer dynamics were similar for each dose group. The majority of participants exhibited TE-ADAs 3 months after the first dose of donanemab, which returned to or towards baseline after discontinuation of treatment. All 45 donanemab-treated TE-ADA-positive participants were also positive for neutralizing antibody (Nab) to donanemab. Maximum titers for TE-ADA+ participants ranged from 1:10–1:327680 with a median maximum titer of 1:2560. A total of 17 out of 46 of AD patients exposed to donanemab developed high titers (≥1:5120).
To evaluate the potential effect of the kinetics (onset and duration) of TE-ADA on donanemab PK after multiple dosing in the 10 mg/kg Q2W, 10 mg/kg Q4W and 20 mg/kg Q4W cohorts, the observed trough drug concentrations were plotted by dose with ADA results (time-matched with PK) for each visit. Based on graphical analyses, overall there did not appear to be a significant effect of TE-ADAs on the PK of donanemab despite the high incidence of TE-ADAs. Observed trough concentrations among TE-ADA+, NAb+ samples (N=59) appeared similar to those that were TE- ADA- (N=54) across all multiple dose groups (one sample was TE-ADA+, NAb-). Exceptions were observed following 20 mg/kg Q4W beyond Week 48 (Figure 3) where mean trough donanemab concentrations of TE-ADA+, NAb+ samples appeared lower compared with those earlier than Week 48. However, these observations are based on a small number of trough samples, namely Week 48 (5 samples), Week 60 (5 samples), and Week 72 (4 samples). Specific individual participants associated with these lower trough samples were identified to graphically evaluate any effect of titer value on low trough donanemab concentrations. Out of these participants with lower than previous trough samples, there were 2 participants with concentrations below the limit of quantification and low titers, as well as 2 participants with low but quantifiable concentrations and high titers (selected data shown in Supplemental Figure 4).

Figure 3. Serum trough concentrations with available time matched PK and TE ADA evaluable data in the 10 mg/kg Q2W, 10 mg/kg Q4W, and 20 mg/kg Q4W cohorts

Note: Dashed line represents BQL (0.2 µg/mL); Abbreviations: BQL = below the limit of quantification; N = number of patients; NAb = neutralizing antidrug antibody; PK = pharmacokinetics; Q2W = every 2 weeks; Q4W = every 4 weeks; TE-ADA = treatment emergent antidrug antibody.

Figure 4. Least squares mean atrophy on A) whole brain volume, B) average hippocampal volume, and C) lateral ventricle volume (mm3) per study intervention group at 72 weeks

Abbreviations: Q2W = every 2 weeks; Q4W = every 4 weeks; p-values are versus placebo



A total of 7 serious adverse events among 6 patients were reported. Of these, 1 patient (randomized to placebo) discontinued from the study because of a SAE of death due to myocardial infarction (considered not drug-related by the investigator). One of the SAEs, intermittently symptomatic ARIA-E was considered drug-related (20-mg/kg Q4W cohort). The remaining 5 SAEs were considered not drug-related by the investigator.
A total of 223 treatment-emergent adverse events (TEAEs) across all cohorts were reported in this study, regardless of causality (Table 2). Of 61 patients, 55 patients (90.2%) reported least 1 TEAE (generally mild to moderate in severity) and 24 (39.3%) reported at least 1 study drug-related TEAE. The most common TEAE of ARIA-E was experienced by 12 out of 46 donanemab-treated patients with AD and occurred in all donanemab-dosing cohorts except the 10-mg/kg single-dose cohort. The most common study drug-related TEAEs after a single dose of study drug were ARIA-E (n = 4) and cerebral microhemorrhage (n = 4). The most common study drug-related TEAEs in the Q2W- and Q4W-dose cohorts were ARIA-E (n = 2 and n = 6, respectively) and cerebral microhemorrhage (n = 2 and n = 3, respectively).
One infusion-related reaction was reported in 1 patient in the 10-mg/kg Q2W cohort. An additional event of hypertensive crisis had timing consistent with an infusion-related reaction. Three patients discontinued the study prematurely due to an AE: fatal myocardial infarction (placebo Q4W cohort), mild hypertensive crisis (20-mg/kg Q4W cohort), and mild ARIA-E (20-mg/kg Q4W cohort). The patients with hypertensive crisis and ARIA-E both recovered after approximately 20 mins and 8 weeks , respectively. There were no clinically significant changes in other safety assessments, including vital signs, safety laboratories, electrocardiograms, and neurological examinations. Overall, all safety analyses showed no clinically relevant differences between non-Japanese and Japanese patients.


Overall, ARIA-E events occurred in 12 of the 46 donanemab-treated patients of whom 2 were symptomatic with mild to moderate symptoms (headache, confusion, hyper-somnolence, and nausea) (Table 2). All patients with ARIA-E were discontinued from study drug as per protocol. All ARIA-E events (including symptoms) resolved following dose discontinuation. All events were considered drug-related.
There were 10 events of cerebral microhemorrhage among 6 of the 46 donanemab-treated patients (Table 2). The majority of cerebral microhemorrhage events (9 of 10) were considered drug-related. Superficial siderosis was reported for 1 patient in the 10-mg/kg Q4W cohort and 1 patient in the 20-mg/kg Q4W cohort. Macrohemorrhage was not observed.

Volumetric Magnetic Resonance Imaging (vMRI)

Overall, administration of donanemab did not result in consistent significant reductions in whole brain volume or hippocampal brain volume nor were there consistent significant increases in lateral ventricular volume when compared to placebo (Figure 4 and Supplemental Figure 5). The changes in whole brain, hippocampal, and ventricular volume were generally numerically greater at 72 weeks with donanemab treatment compared to placebo. However, there was no dose response in the changes, and there were no significant changes in most donanemab treatment cohorts.

Cognition and Function

Across all dose groups, there were no significant changes from baseline in any of the cognitive measures with donanemab treatment (data not shown).



This Phase 1b study was a randomized, placebo-controlled, single- and multiple-dose study in patients with MCI due to AD or mild to moderate AD (amyloid detected by a positive florbetapir scan). PD, PK, immunogenicity, safety, and tolerability of single and multiple IV doses of donanemab were assessed. The main findings in this study were that:
1) single and multiple doses of donanemab up to 40 mg and 20-mg/kg Q4W, respectively, reduced amyloid plaque deposits in patients with AD; 5 out of 10 patients in the 20 mg/kg Q4W cohort attained complete amyloid clearance within 36 weeks
2) the observed amyloid plaque lowering by donanemab was rapid, robust, and sustained
3) nearly all donanemab-treated patients developed anti-drug antibodies, however, there was no overall significant effect of the antibodies on the PK of donanemab for the duration of the study, given the observed linear PK
4) donanemab was generally well tolerated with manageable ARIA-E events that resolved completely upon treatment discontinuation.

A reduction in cerebral amyloid plaque has also been reported with other anti-amyloid monoclonal antibodies, like gantenerumab, lecanemab, and aducanumab (15-18). The findings of a rapid and dose-dependent reduction in cerebral amyloid plaque after donanemab treatment extend those of a previous ascending dose donanemab study (5), which demonstrated a similar reduction in cerebral amyloid at 10 mg/kg (the highest dose administered in that study). A novel finding in this study is that a significant reduction in cerebral amyloid plaque was observed, even after single doses of donanemab, and the reduction was sustained up to 72 weeks after the single dose. Importantly, the rate of the observed amyloid plaque lowering was rapid, with a greater than 50 Centiloid reduction observed after 24-weeks of multiple-dose donanemab treatment. Furthermore, complete amyloid clearance, as measured by florbetapir PET, was observed for 5 of 10 patients (50.0%) treated with 20-mg/kg Q4W donanemab. This result was sustained through 18 months.
Notably, these robust effects of donanemab on cerebral amyloid were observed in the background of a high incidence of TE-ADAs. Although nearly all donanemab-treated patients developed anti-drug antibodies, there did not appear to be a clinically meaningful effect of the antibodies on the PK of donanemab. However, further analysis are planned where these and other longitudinal data will be analysed via population PK analyses with immunogenicity evaluated as a potential covariate. Despite the background of high TE-ADAs, the PK after single and multiple doses of donanemab were linear from 10- to 40-mg/kg. This result extends the dose range from the earlier Phase 1a study, where the PK of donanemab appeared to be non-linear in nature (5). The reason for this nonlinearity was unclear, and it was speculated that it might be attributed to either donanemab target-mediated disposition and/or anti-drug antibodies impacting PK (5). In this study, the high incidence of anti-drug antibodies was not associated with a high incidence of infusion-related reactions or hypersensitivity reactions (including anaphylaxis).
Donanemab was generally well tolerated with ARIA-E reported as the most common adverse event, which completely resolved upon treatment discontinuation. The incidence of ARIA-E (12 of 46 donanemab-treated patients; 26.1%) was within the range of rates of ARIA-E observed with other amyloid lowering antibodies (19). Several studies with amyloid-lowering therapies have shown a reduction in brain volume and/or an increase in ventricular volume with treatment (20-23). There were no consistent significant changes in vMRI measurements in this study. However, vMRI was an exploratory endpoint in the study and the sample size was small, thus the effect of donanemab on brain volume will need to be more fully addressed in larger clinical studies.
There was no statistically significant effect of donanemab on cognition and function at any dose level or dosing regimen, although this is not unexpected given the small sample size and range of disease stages from MCI to moderate AD dementia enrolled in this study. In contrast, a larger, clinically and pathologically more homogenous Phase 2 trial TRAILBLAZER-ALZ (NCT03367403) met the prespecified primary endpoint of change from baseline to 76 weeks in the Integrated Alzheimer’s Disease Rating Scale with a statistically significant slowing of decline by 32% relative to placebo. Donanemab-treated patients also showed consistent improvements in all prespecified secondary endpoints measuring cognition and function compared to placebo but did not reach nominal statistical significance on every secondary endpoint (24).



Single and multiple doses of donanemab demonstrated a rapid and robust reduction in brain amyloid plaque. Single and multiple doses of donanemab yielded sustained amyloid plaque reduction without evidence of significant reaccumulation when measured at 72 weeks. The presence of ADAs were consistent with previous studies, and events of ARIA were manageable. These findings support donanemab dosing up to 1400 mg (approximately 20 mg/kg) Q4W in the TRAILBLAZER-ALZ phase 2 study (NCT03367403), TRAILBLAZER-EXT extension study (NCT04437511), the TRAILBLAZER-ALZ 2 Phase 3 study (NCT04640077) and the planned TRAILBLAZER-ALZ 3 study.


Acknowledgments: Data analyses were performed by Eli Lilly and Company. Writing support was provided by Teresa Tartaglione, PharmD (Synchrogenix, a Certara Company, Wilmington, DE, USA) and Paula Hauck, PhD (Eli Lilly and Company).

Funding: This work was supported by Eli Lilly and Company. The sponsors of the study were involved in the design and conduct of the study as well as the collection, analysis, and interpretation of data; in the preparation of the manuscript; and in the review or approval of the manuscript.

Conflict of Interest: JLD – previous employee and minor stockholder of Eli Lilly and Company; currently at Indiana University School of Medicine. All other authors are employees and minor stockholders of Eli Lilly and Company.

Ethical Standards: The study protocol was reviewed and approved by the ethics review board for each of the study sites. The studies were conducted according to Good Clinical Practice, consensus ethics principles derived from international ethics guidelines, including the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines, ICH GCP Guideline [E6], and applicable laws and regulations. Patients and/or patients’ legally acceptable representatives provided written informed consent before undergoing study procedures.

Open Access: This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.





1. Karran E, Mercken M, De Strooper B. The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov. 2011 Aug 19;10(9):698-712. 10.1038/nrd3505
2. Cummings J, Lee G, Ritter A, Sabbagh M, Zhong K. Alzheimer’s disease drug development pipeline: 2019. Alzheimers Dement (N Y). 2019;5:272-293. 10.1016/j.trci.2019.05.008
3. Gilman S, Koller M, Black RS, et al. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology. 2005 May 10;64(9):1553-62. 10.1212/01.WNL.0000159740.16984.3C
4. Demattos RB, Lu J, Tang Y, et al. A plaque-specific antibody clears existing beta-amyloid plaques in Alzheimer’s disease mice. Neuron. 2012 Dec 6;76(5):908-20. 10.1016/j.neuron.2012.10.029
5. 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. 10.1002/trc2.12112
6. Albert MS, DeKosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011 May;7(3):270-9. 10.1016/j.jalz.2011.03.008
7. McKhann GM. Changing concepts of Alzheimer disease. JAMA. 2011 Jun 15;305(23):2458-9. 10.1001/jama.2011.810
8. Barthel H, Gertz HJ, Dresel S, et al. Cerebral amyloid-beta PET with florbetaben (18F) in patients with Alzheimer’s disease and healthy controls: a multicentre phase 2 diagnostic study. Lancet Neurol. 2011 May;10(5):424-35. 10.1016/S1474-4422(11)70077-1
9. Navitsky M, Joshi AD, Kennedy I, et al. Standardization of amyloid quantitation with florbetapir standardized uptake value ratios to the Centiloid scale. Alzheimers Dement. 2018 Dec;14(12):1565-1571. 10.1016/j.jalz.2018.06.1353
10. Bourdage JS, Cook CA, Farrington DL, Chain JS, Konrad RJ. An Affinity Capture Elution (ACE) assay for detection of anti-drug antibody to monoclonal antibody therapeutics in the presence of high levels of drug. J Immunol Methods. 2007 Oct 31;327(1-2):10-7. 10.1016/j.jim.2007.07.004
11. Butterfield AM, Chain JS, Ackermann BL, Konrad RJ. Comparison of assay formats for drug-tolerant immunogenicity testing. Bioanalysis. 2010 Dec;2(12):1961-9. 10.4155/bio.10.136
12. Chen YQ, Pottanat TG, Carter QL, et al. Affinity capture elution bridging assay: A novel immunoassay format for detection of anti-therapeutic protein antibodies. J Immunol Methods. 2016 Apr;431:45-51. 10.1016/j.jim.2016.02.008
13. Sloan JH, Conway RG, Pottanat TG, et al. An innovative and highly drug-tolerant approach for detecting neutralizing antibodies directed to therapeutic antibodies. Bioanalysis. 2016 Oct;8(20):2157-68. 10.4155/bio-2016-0161
14. Clark CM, Schneider JA, Bedell BJ, et al. Use of florbetapir-PET for imaging beta-amyloid pathology. JAMA. 2011 Jan 19;305(3):275-83. 10.1001/jama.2010.2008
15. Bohrmann B, Baumann K, Benz J, et al. Gantenerumab: a novel human anti-Abeta antibody demonstrates sustained cerebral amyloid-beta binding and elicits cell-mediated removal of human amyloid-beta. J Alzheimers Dis. 2012;28(1):49-69. 10.3233/JAD-2011-110977
16. Ostrowitzki S, Deptula D, Thurfjell L, et al. Mechanism of amyloid removal in patients with Alzheimer disease treated with gantenerumab. Arch Neurol. 2012 Feb;69(2):198-207. 10.1001/archneurol.2011.1538
17. Sevigny J, Chiao P, Bussiere T, et al. The antibody aducanumab reduces Abeta plaques in Alzheimer’s disease. Nature. 2016 Sep 1;537(7618):50-6. 10.1038/nature19323
18. Swanson CJ, Zhang Y, Dhadda S, et al. DT-01-07: Treatment of early AD subjects with BAN2401, an anti-Aβ protofibrial monoclonal antibody, significantly clears amyloid plaque and reduces clinical decline. Alzheimer’s & Dementia. 2018;14(7S_Part_31):P1668-P1668.
19. Tolar M, Abushakra S, Hey JA, Porsteinsson A, Sabbagh M. Aducanumab, gantenerumab, BAN2401, and ALZ-801-the first wave of amyloid-targeting drugs for Alzheimer’s disease with potential for near term approval. Alzheimers Res Ther. 2020 Aug 12;12(1):95. 10.1186/s13195-020-00663-w
20. Sur C, Kost J, Scott D, et al. BACE inhibition causes rapid, regional, and non-progressive volume reduction in Alzheimer’s disease brain. Brain. 2020 Dec 1;143(12):3816-3826. 10.1093/brain/awaa332
21. Zimmer JA, Shcherbinin S, Devous MD, Sr., et al. Lanabecestat: Neuroimaging results in early symptomatic Alzheimer’s disease. Alzheimers Dement (N Y). 2021;7(1):e12123. 10.1002/trc2.12123
22. Novak G, Fox N, Clegg S, et al. Changes in Brain Volume with Bapineuzumab in Mild to Moderate Alzheimer’s Disease. J Alzheimers Dis. 2016;49(4):1123-34. 10.3233/JAD-150448
23. Swanson CJ, Zhang Y, Dhadda S, et al. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Abeta protofibril antibody. Alzheimers Res Ther. 2021 Apr 17;13(1):80. 10.1186/s13195-021-00813-8
24. Mintun MA, Lo AC, Duggan Evans C, et al. Donanemab in Early Alzheimer’s Disease. N Engl J Med. 2021 Mar 13. 10.1056/NEJMoa2100708



M.B. Usman1,*, S. Bhardwaj2, S. Roychoudhury3, D. Kumar4, A. Alexiou5,6, P. Kumar7, R.K. Ambasta7, P. Prasher8, S. Shukla9, V. Upadhye10, F.A. Khan11, R. Awasthi12, M.D. Shastri13, S.K. Singh14, G. Gupta15, D.K. Chellappan16, K. Dua9,17, S.K. Jha18, J. Ruokolainen19, K.K. Kesari19,20, S. Ojha21, N.K. Jha18


1. Department of Life Sciences, School of Basic Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh, India; 2. Department of Biotechnology, HIMT, CCS University, Greater Noida, UP, India; 3. Department of Life Science and Bioinformatics, Assam University, Silchar, India; 4. Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Sec 125, Noida, India; 5. Novel Global Community Educational Foundation, Hebersham, 2770 NSW, Australia; 6. AFNP Med Austria, Wien, Austria; 7. Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University (Formerly DCE), Delhi, India; 8. Department of Chemistry, University of Petroleum & Energy Studies, Energy Acres, Dehradun, India; 9. Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Ultimo NSW 2007, Australia; 10. Centre of Research for Development (CRD4), Parul Institute of Applied Sciences, Parul University, Vadodara-391760, Gujrat, India; 11. Department of Stem Cell Biology, Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia; 12. Amity Institute of Pharmacy, Amity University Uttar Pradesh, Noida, India; 13. School of Pharmacy and Pharmacology, University of Tasmania, Hobart, Australia; 14. School of Pharmaceutical Sciences, Lovely Professional University, Phagwara 144411, Punjab, India; 15. School of Pharmacy, Suresh Gyan Vihar University, Jagatpura, Mahal Road, Jaipur, India; 16. Department of Life Sciences, School of Pharmacy, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia; 17. Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, 2007 New South Wales, Australia; 18. Department of Biotechnology, School of Engineering & Technology, Sharda University, Greater Noida, Uttar Pradesh, India; 19. Department of Applied Physics, School of Science, Aalto University, Espoo, Finland; 20. Department of Bioproducts and Biosystems, School of Chemical Engineering, Aalto University, Espoo, Finland; 21. Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain 17666, United Arab Emirates; * These authors contributed equally to this work

Corresponding Author: Dr. Niraj Kumar Jha, Assistant Professor, Department of Biotechnology, School of Engineering & Technology (SET), Sharda University, Knowledge Park III, Greater Noida, Uttar Pradesh-201310, India, Email:;, Tel: +91-7488019194, ORCID:; Dr. Shreesh Ojha, Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, UAE University, PO Box – 17666, Al Ain, UAE, E-mail:, Tel: +971-3-7137524, ORCID:

J Prev Alz Dis 2021;4(8):534-551
Published online September 15, 2021,



Alzheimer’s disease (AD) is a global health concern owing to its complexity, which often poses a great challenge to the development of therapeutic approaches. No single theory has yet accounted for the various risk factors leading to the pathological and clinical manifestations of dementia-type AD. Therefore, treatment options targeting various molecules involved in the pathogenesis of the disease have been unsuccessful. However, the exploration of various immunotherapeutic avenues revitalizes hope after decades of disappointment. The hallmark of a good immunotherapeutic candidate is not only to remove amyloid plaques but also to slow cognitive decline. In line with this, both active and passive immunotherapy have shown success and limitations. Recent approval of aducanumab for the treatment of AD demonstrates how close passive immunotherapy is to being successful. However, several major bottlenecks still need to be resolved. This review outlines recent successes and challenges in the pursuit of an AD vaccine.

Key words: Alzheimer’s disease, amyloid plaque, passive immunotherapy, active immunotherapy, monoclonal antibody.



Alzheimer’s disease (AD) is a brain disorder characterized by progressive, chronic neurodegenerative symptoms, such as memory loss, cognitive disabilities, and dementia. The global prevalence rates of dementia among people over 85 years and people over 60 years are 20% and 6%, respectively (1). AD is the most common form of dementia among aging individuals in North America and western Europe. It can lead to a decrease in cognitive function, judgment, decision-making, and language abilities among people over 65 years of age (2, 3). Gradual neurodegeneration in the cortex and hippocampus explains the continued loss of memory and dementia observed in patients with AD. This degenerative process can last for up to 25 years after the initial symptoms appear (4).
AD is a significant global health issue associated with a significant economic burden. The global AD prevalence is 24 million, with the United States (US) alone having nearly 5.5 million cases, including 200,000 cases of early-onset AD (2). According to the World Health Organization, an estimated 81.1 million people will have AD by 2040. Unfortunately, the number of people with the disease is projected to multiply in every 20 years (5, 6). AD is the fifth leading cause of death among elderly people globally and sixth in the US (7). While it ranks third in terms of total health care costs in the US after cancer and cardiovascular disease, it is projected to surpass the two diseases in terms of mortality rate and overall financial burden on US health care in the next two decades (8, 9). Approximately $172 billion is spent annually on AD-related healthcare costs (10).
AD, like other neurodegenerative disorders, is a proteinopathy, in that it arises due to protein misfolding or failure of certain peptides to adopt their usual functional and conformational state. Misfolding results in protein accumulation (and/or fibril formation), gain of toxic function, or loss of function. The major causes of protein misfolding include genetic mutations, exposure to external or internal toxins, impairments in the posttranslational modification machinery, and oxidative damage. AD is characterized by the pathological accumulation of two forms of proteinaceous inclusions: the extracellular amyloid beta (Aβ) plaques that develop during the initial disease phase and intracellular neurofibrillary tangles that manifest at later stages (11, 12).
Although we now have a deeper understanding of the pathological features of AD, several questions related to its complex pathways remain unanswered. At present, no single theory has accounted for the various risk factors leading to the pathological and clinical manifestations of dementia-type AD (3, 13). Treatment options targeting various molecules that play essential roles in the development of the disease have been unsuccessful due to multiple drawbacks (14, 15). However, these failures have led to a better understanding of the disease and a shift in focus toward preventive approaches that can avert or delay disease onset (5, 7, 16). One of the major therapeutic avenues being explored currently is immunotherapy, which involves manipulation of the immune system by suppressing, inducing, or enhancing its activity in vivo. Immunotherapy or vaccination against AD-specific peptides inspired considerable optimism in preventing or treating AD through an adaptive immune response (7, 16). Vaccines or immunotherapies for AD utilize the power of the immune system to attack the body’s own proteins or molecules that seem to be dangerous. Despite the practical challenges and decade of disappointments, hopes for Alzheimer’s vaccine are increasing again. Moreover, the enticing allure of being able to curtail the disease through vaccination makes the idea very appealing and worth striving for (16, 17). This review explores the recent successes and challenges in the pursuit of developing an AD vaccine.


Pathophysiology and Molecular Concept of AD

AD was first described in 1907 by the German physician, Alois Alzheimer (18). This discovery was ensued by many studies that led to various discoveries and hypothesis on the disease. While the exact cause of AD remains unknown, the most widely acknowledged hypothesis involves abnormal processing of the β-amyloid precursor protein (AβPP), resulting in the overproduction of or reduced clearance of amyloid β-protein (Aβ) in the cortex (19). AβPP, the progenitor molecule of Aβ, is a membrane-bound protein that plays crucial roles in the regulation of neuronal survival, synaptic stabilization and plasticity, cell adhesion, and neuritic outgrowth formation (20, 21). Under normal circumstances, α-secretase cleaves the large AβPP molecule at the middle of the Aβ sequence. In AD, the β-secretase-mediated endoproteolytic cleavage of AβPP generates the primary N-terminal cut, while γ-secretase generates pathogenic Aβ fragments. The length of the deadly Aβ peptide fragments can be determined from the exact site of γ-secretase cleavage. Although β- and γ-secretases are active throughout a person’s lifetime, their undesirable effects on Aβ production are observed in individuals aged ≥60 years (22, 23). The two major forms of Aβ peptides are the 40-residue (Aβ1-40) and 42-residue (Aβ1-42) moieties, which are considered more pathogenic due to their higher aggregation tendency, longer length, and higher quantity in amyloid plaques incases of sporadic and early-onset AD (4, 24). Aβ peptides, like other proteins, have N and C terminals; the N-terminal constitutes the hydrophilic domain with 1-28 residues that are mostly charged, while the C-terminal domain is completely hydrophobic with 29–40 or 29–42 residues. Aβ42, when produced, assumes a beta-pleated structure that clumps to form fibrils that are insoluble in the extracellular space. Over time, amyloid plaques are formed by the deposition of complement protein, microglia, and reactive astrocytes (11, 25). Amyloid plaque formation results in a cascade of neuropathogenic events characterized by neurotoxicity, local inflammation, neuronal apoptosis, complement activation, and disruption of calcium homeostasis, ultimately leading to cognitive decline and AD manifestations. Aβ impairs neuronal function even before its deposition in amyloid plaques. Similarly, Aβ oligomers induce hyperphosphorylation of microtubule-associated protein tau (cytoskeletal protein), leading to the formation of insoluble intracellular neurofibrillary tangles and consequent tauopathy that affects neuronal function (26-28). Hence, the two abnormal protein deposits, amyloid plaques and neurofibrillary tangles, result in the pathophysiological, clinical, and microscopic manifestations of AD (Figure 1).

Figure 1. Neurobiology of Alzheimer’s disease


Although the amyloid hypothesis suggests that Aβ deposition and plaque formation are the first steps in the pathogenesis of AD, the relationship between amyloid burden and cognitive symptoms remains unclear. Similarly, the order and timing of amyloidosis and other processes of AD that result in the clinical onset of dementia are not well understood (12). Moreover, the failure of different therapeutic approaches in preventing Aβ aggregation or production raises questions about the hypothesis. So far, there has not been a single successful treatment based on the amyloid hypothesis (3). Recent studies point to the protective and anti-microbial roles of Aβ peptides along with increased formation of tau-positive tangles in AD cell lines, rodent models, and nematodes. In some cases, Aβ is produced in response to bacterial and neurotoxic fungal infection, indicating its neuroprotective role (29). Hence, overproduction of Aβ may be due to downstream immune dysregulation and not the disease process itself.
AD can be divided into two types based on symptom onset: (i) late-onset or sporadic AD is the most common type of AD, in which a majority of patients are diagnosed after 65years of age, and its incidence increases with age (30, 31) and (ii) early-onset AD accounts for 1–2% of AD cases and is characterized by symptom presentation before the age of 65 years (32, 33). Early-onset AD is also referred to as autosomal-dominant AD as it results from mutations in the following genes: amyloid precursor protein (APP) (chromosome 21), presenilin 1/PSEN1(chromosome 14), and presenilin 2/PSEN2 (chromosome 1). Mutations in these genes can lead to abnormal Aβ processing, its excessive accumulation, and consequently, AD with complete penetrance (12). The age of clinical onset of autosomal-dominant AD is influenced by genetic background and is similar among different generations in a family (34, 35). While dominantly inherited mutations have no significant role in sporadic AD, polymorphisms in the apolipoprotein E gene (ε4 allele) increase the risk of developing AD, particularly in females (36, 37). Increasing evidence shows that sporadic and autosomal-dominant AD share pathophysiological features (12, 32).
Modified vaccine formulations use Aβ-specific sequences and epitope-based DNA, while emerging vaccine candidates target other proteins and molecules involved in AD etiology.


Vaccines and Immunotherapies for AD

Most immunotherapies and vaccines directly or indirectly target Aβ42 peptides to elicit an appropriate immune response (anti-Aβ antibodies) that will not only clear the Aβ deposits, but also help in improving cognitive and functional abilities (38). Immunotherapy related to AD may be divided into two forms: injection of Aβ42-containing antigens is termed active immunotherapy (vaccination), whereas passive immunotherapy involves administering preformed antibodies against the Aβ42 peptide (such as monoclonal antibodies) (24). Thus, an immunotherapeutic approach involves active injection of Aβ-based immunogens or passive infusion of Aβ-specific antibodies (Figure 2).

Figure 2. Classification of Alzheimer’s disease immunotherapy and hypothetical mechanisms of anti-Aβ antibody action

Active Immunotherapy

In active immunotherapy, patients are injected with a purified form of an antigen, usually coupled with a different protein carrier or adjuvant that helps in the optimization of the immune response. Active AD vaccines are aimed at eliciting an appropriate immune response that clears accumulated proteins. While active immunotherapy has the potential to generate long-term polyclonal antibodies through short-term administration of vaccines at a limited cost, it may cause inconsistent immune responses and long-lasting adverse reactions, especially in older people with low immune competence (25, 39). Most active vaccine trials involve the administration of Aβ42 antigenic peptides. However, more recent studies make use of small Aβ peptides, their DNA sequences, or prime-boost approaches to elicit the anti-Aβ antibody production. This is usually achieved through B-cell activation while avoiding T-cell activation, which may cause autoimmunity (24, 39). As the presence of Aβ plaques is common across different forms of AD, the Aβ peptide is a notable target across immunotherapeutic approaches.

Mechanism of Anti-Aβ Antibodies

Anti-Aβ antibodies are versatile in nature owing to the intrinsic diversity of the human immune system. This versatility is necessary because of the uncertainty about the role of Aβ in physiological conditions and lack of knowledge of the pathogenic forms of Aβ (40). The mechanism by which anti-Aβ antibodies are transported into the central nervous system (CNS) is not well understood. However, it is thought to involve the lymphatic system, passive diffusion through perivascular spaces, and leaky areas in the CNS within the blood-brain barrier (BBB). Consequently, only a small fraction of antibodies in the peripheral circulation is detectable in the CNS (25).
Three hypotheses have been formulated to outline the mechanisms by which anti-Aβ antibodies achieve plaque clearance and reduce AD symptoms (Figure 2). First, anti-Aβ antibodies bind directly to the peptides in the senile plaques, protofibrils, fibrils, or oligomers to destabilize their aggregates and eventually disrupt them (direct action hypothesis). Second, specific antibodies would bind to Aβ plaques and trigger phagocytosis mediated by microglial cells and Fc receptors (41). Third, specific antibodies do not cross the BBB, but bind to and remove the Aβ molecules circulating in the plasma. This generates a concentration gradient that leads to the efflux of Aβ molecules from the brain to the plasma (peripheral sink hypothesis) (14). Most AD vaccine studies prioritize the reduction in senile plaques in the brain by active immunization, which can stimulate the production of anti-Aβ antibodies (38, 42, 43).
Anti-Aβ antibodies are also involved in several other mechanisms that contribute to Aβ reduction or clearance. For instance, antibodies can interact with and alter the transport system of Aβ that includes the receptor for advanced glycation end products (RAGE), the influx channel for Aβ in the CNS, and efflux via the low-density lipoprotein receptor. Theoretically, antibodies that block RAGE could enhance reduction in Aβ levels in the cerebrospinal fluid (CSF) by hindering their transport from the blood (44, 45). While some antibodies may interfere with the interaction between Aβ and other molecules, thereby reducing toxicity, others could act as signals that induce or reduce inflammation by binding to receptors on immune effectors. Further, when antibodies enter the synaptic cleft between neurons or are internalized by neurons, they can alter the cell-to-cell transmission of Aβ and its aggregates (46).

First- and Next-Generation Active Vaccines

Active vaccines aim to stimulate the patient’s immune system to prevent or reduce amyloidosis and restore cognitive and functional abilities. It is commonly believed that immunotherapy must start when the two common features amyloid plaques and neurofibrillary tangles are not obvious. Efforts to develop active AD vaccines have been punctuated by drawbacks, which have led to the evolution of vaccine generations (Table 1).

Table 1. Summary of active vaccines of AD in clinical trial stage

First-generation active vaccines

AD immunotherapy research began with a major breakthrough published by Schenk et al., who demonstrated that active immunization with Aβ42 and an immune-stimulating adjuvant improved cognition in transgenic mice (47). They also showed prevention of or reduction in β-amyloid plaque formation in transgenic mice overexpressing human APP. This discovery led to the rapid development of a first-generation active vaccine called AN-1792.
AN-1792, the first anti-Aβ immunotherapy candidate, consists of aggregated human Aβ42 coupled to a saponin-based adjuvant (QS-21). It elicits an immunological response against the host Aβ42, which can improve cognition and reduce plaque burden (48). The phase 1 trial showed evidence of the tolerability and safety of the vaccine. Moreover, anti-Aβ42 antibodies developed by the recipient patients could recognize the β-amyloid plaque in the extracellular space and the β-amyloid within the blood vessels of the brain. The antibodies were also selective and did not cross-react with native full-length APP or other physiological components (43). Amyloid clearance is facilitated by the solubilization of Aβ42, leading to its exit from the brain through the perivascular pathway. Vaccination also resulted in reduced hippocampal tau pathology mediated by a decrease in tau phosphorylation and inhibition of inflammatory processes that result in neurodegeneration (49-51). Approximately 20% of the vaccinated patients developed antibody titers above the present therapeutic cut-off level (52, 53). However, despite the desirable outcomes, AN-1792 clinical trials were halted in phase 2, owing to adverse inflammatory reactions resulting in subacute meningoencephalitis in nearly 6% of the patients and one death. Subsequent follow-up studies attributed these consequences to the activation of proinflammatory T helper (Th)-1 cell-mediated responses that result in autoimmunity (25, 54). Inflammatory infiltrates in the CNS of the deceased patient were mainly CD8+ cells; to a lesser extent, CD4+, CD3+, and CD5+ cells; and rarely CD7+ cells. In contrast, the patient tested negative for T cytotoxic markers such as CD16 and CD57, turbidimetric immunoassay, granzymes, and B lymphocytes (54). The Aβ42 epitopes are located in the carboxyl-terminal and central region of the Aβ peptide (55). These findings were supported by studies conducted to develop next-generation vaccines containing only B-cell epitopes (primarily located in the N-terminal region of the Aβ peptide). As vaccines that induce only humoral or Th2-mediated responses aim to avoid the undesirable inflammatory effects of Th1 stimulation (Table 1), next-generation vaccines usually contain B-cell epitopes as antigenic determinants coupled to an appropriate adjuvant (56-59).

Next-generation active vaccines

Next-generation active vaccines target the N-terminal regions of Aβ peptides (B-cell epitope) to stimulate humoral immune responses.
ACC-001: ACC-001 (VanutideCridificar) contains1-7 amino acid-long N-terminal Aβ peptide fragments connected to a carrier protein (CRM197) via a surface-active saponin adjuvant (QS-21). The CRM197 carrier protein is a nontoxic Diphtheria toxin mutant (60, 61). ACC-001 elicits an Aβ-specific B-cell response without the adverse T-cell response recorded following AN-1792 administration (62). A phase 1, single ascending dose trial of ACC-001 showed safety and tolerability, which paved the way for phase 2, multiple ascending dose studies (61) conducted in Europe ( Identifier: NCT00479557), US ( Identifier: NCT00498602), and Japan. These trials involved administration of different doses of the vaccine (3, 10, and 30μg) with or without the adjuvant. The patients who received doses of ACC-001+QS-21 adjuvant showed sustained anti-Aβ IgG titers and consistently higher peaks. While no case of meningoencephalitis was reported, few patients showed side effects such as insignificant microhemorrhage, treatment-related vasogenic edema, local injection reaction, and headache (61,62). Phase 2a extension studies carried out in these countries showed that long-term exposure to ACC-001+ QS-21 was well-tolerated and gave the highest anti-Aβ IgG titer compared to other regimens (63). However, the phase 2 trial of this vaccine was aborted in 2014 owing to adverse effects linked to autoimmune responses, lack of efficacy, and case of treatment-related angina pectoris recorded in a patient who received ACC-001 (30μg) + QS-21 (62, 64).
AD01, AD02, AD03: While AD01 and AD02 contain Aβ1-6 (B-cell epitope) peptides that mimic the N-terminal region of Aβ42 coupled with an Alum adjuvant, AD03 consists of N-terminal-truncated and pyroglutamated Aβ conjugated with an Aluma djuvant (58). Phase 1 trials of AD01/ AD02 have been announced to be completed by AFFiRiS (Wien, Austria). So far, the trial has demonstrated safety of AD02 and its ability to stabilize cognitive parameters based on a potential correlation between cognitive function and post-vaccination antibody levels; however, these data have not yet been published (58). Phase 2 trials of AffitopeAD02 have been performed in patients with early-onset AD; however, these trials were terminated due limited efficacy and adverse side effects (64). AFFiRiS also conducted a phase 1 trial usingAD03 (58). However, the follow-up study was aborted due to organizational reasons (65, 66).
ACI-24: ACI-24 is based on tetra-palmitoylated amyloid 1–15 peptide in β conformation coupled with liposomes containing monophosphorylated lipid A as an adjuvant. ACI-24 aims to induce antibodies specific to the beta-sheet conformation, thereby targeting Aβ1-15 (67). It is similar to the liposomal vaccine against Aβ1-15, which showed the ability to restore memory defects and reduced plaques in mice (67, 68). Having achieved the desired outcomes in the preclinical trial, a combined phase1/2a clinical trial was initiated (67, 69). The trial compared vaccine doses of 10,100, 300, and 1000 µg/ml to placebo; the dose was administered subcutaneously for the first year, followed by an additional 1 or 2 years. The primary outcomes included tolerability, safety, and serum titers of anti-Aβ42 IgG antibodies. The secondary outcomes included biomarker measures such as T-cell activation measures; magnetic resonance imaging (MRI)-based volumetry; and tau, phospho-tau, and Aβ levels in the CSF. ACI-24 was the first anti-Aβ vaccine to be examined for the treatment of AD patients with Down’s syndrome. The study involved subcutaneous injection of ACI-24 in 24 patients (age: 35–55 years). The study ended in June 2020 and reported positive outcomes and no serious adverse effects. The AC Immune registered additional phase 2 trial in the same syndrome by May 2020, it was set to commence in October 2020 and designed to enroll 72 patients aged 40–50 years who had only brain amyloid deposition without dementia. The primary outcome measures include safety parameters and incidence of adverse events such as suicidal ideation, heart rate, and changes in blood pressure studied for up to 2 years. The secondary outcome measures include changes in cognitive and behavioral measures, levels of amyloid and tau in the blood, neurodegeneration, blood Aβ antibody titers, and levels of amyloid and tau in the brain as determined by positron emission tomography (PET). The trial is projected to end in October 2024 (70).
CAD-106 (Novartis): Novartis’s CAD-106 is composed of multiple copies of B-cell epitope (Aβ1-6) fragments as the immunogenic sequence, attached to a carrier with 180 copies of bacteriophage QB protein coat as an adjuvant (57, 69). The formulation stimulates Aβ-specific antibodies unique to the N-terminus, while avoiding T-cell autoimmune responses (57). As the vaccine could reduce Aβ plaques in APP transgenic mice in a preclinical trial, a phase 1 trial was conducted among patients with mild AD. The trial showed reasonable antibody response and evidence of safety, with no meningoencephalitis, autoimmunity, or other adverse reactions (71). Although phase 2 trials showed adequate antibody production in 75% of the patients without the adverse effects observed in the AN-1792 trials, there was no significant difference between the control and treated groups (71). Phase 2a randomized control trials and two open extension studies showed effective antibody response in approximately 64% of the treated patients. There were sustained anti-Aβ IgG titers in extension versus core studies. Although there was no evidence of Aβ-specific T-cell response or vasogenic edema, a few patients showed intracerebral hemorrhage and imaging abnormalities corresponding to amyloid-related microhemorrhage (57). The phase 2/3 clinical trial (GENERATION 1) sponsored by Novartis Pharmaceuticals was initiated in 2015. It aimed to investigate whether CAD-106 and CNP520, an inhibitor of aspartyl protease beta-secretase or beta-site APP cleaving enzyme, can stall the onset and progression of clinical symptoms in cognitively unimpaired individuals with two APOE4 genes. The clinical trial consists of 1340 enrolled patients and is set to end in 2024. While half of the participants will receive CAD-106 injections four times a year, the other half will receive 50 mg CNP520 once daily; the outcomes in both groups will be compared to that of an age-matched placebo group (72). An additional phase 2/3 prevention study (GENERATION 2) was initiated in August 2017, which enrolled 2000 heterozygous carriers with evidence of brain amyloid protein (age 65–70 years) or homozygous ApoE4 carriers. Patients were randomized to one of three groups: while groups 1 and 2 are given one capsule of CNP520 (group 1: 15 mg; group 2: 50 mg) daily for 60–84 months, group 3 is given one capsule of placebo daily. The GENERATION 1 and 2 trials of CNP520 were both prematurely terminated by the sponsors in July 2019, owing to worsening of cognitive abilities in the treatment groups (73). A phase 3 trial is expected to show whether CAD-106 is more effective than placebo in delaying AD symptoms among individuals with genetic susceptibility to AD. Therefore, CAD-106 remains the only vaccine to advance to phase 3 trials and was selected for an AD prevention initiative (API) in theAPOEε4 homozygote study (39).
Lu AF20513: Lu AF20513 consists of three B-cell epitopes (Aβ1-12) attached to two Th epitopes obtained from tetanus toxoid P2 and P30 (74). The formulation is designed to activate memory Th cells present in majority of the population immunized with the conventional tetanus vaccine, thereby enhancing response against Aβ1-12 in elderly people. The phase 1 study aimed to determine the tolerability and safety of multiple immunizations of the drug. The trial enrolled 24 patients with a recent MRI consistent with an AD diagnosis and Aβ antibodies in the CSF. Multiple shots of either low-, medium-, or high-dose Lu AF20513 were administered to the participants. Although the study aimed to evaluate the safety, tolerability, and antibody titers for around 2 years, the study was terminated on account of new efficacy data from another study (59).
UB-311: UB-311 contains synthetic Aβ1-14 (B-cell epitope) coupled with CpG/Alum as an adjuvant (58). A novel form of the vaccine contains two synthetic Aβ targeting peptides, each of which is conjugated with different Th epitopes and designed in a Th2-based delivery system (56). A successful phase 1 trial led to the advancement to phase 2. The recruitment for this trial is now complete, and the outcomes show early evidence of safety and immunogenicity (59).
V-950: V-950 is a multivalent vaccine containing Aβ1-15 coupled with Alum/ISCOMATRIX as an adjuvant. Although a phase 1 study was initiated to determine its safety, tolerability, and immunogenicity, the study was suspended for unknown reasons (69).
Anti-tau Vaccines: Given the failure of vaccine candidates that target Aβ to provide the desired results in clinical trials, recent efforts seek to include tau protein as another target antigen in preventing or controlling AD.
ACI-35: ACI-35 is a liposomal vaccine based on a synthetic human tau protein sequence phosphorylated at S396 and S404 (75); phase 1 trials to study ACI-35 are ongoing (64, 76).
AADvac1: AADvac1 contains synthetic peptides that mimic the naturally occurring truncated and misfolded tau protein, conjugated with keyhole limpet hemocyanin and aluminum hydroxide as adjuvants (77). AADvac1 is formulated to elicit antibodies against the pathological tau protein, prevent the aggregation or progression of the tau protein aggregates, and thereby hinder the spread of the pathology and the disease. A phase 1 trial was conducted in patients with mild-to-moderate AD. A 24-month, randomized, placebo-controlled, parallel group, double-blind, multi-center, phase 2 study aimed at assessing the safety and efficacy of AADvac1 in patients with mild AD (ADAMANT) is ongoing. Patients with pathological tau protein and/or hippocampal atrophy and CSF amyloid were enrolled in the phase 2 trial, in which they would be given 11 vaccinations within a period of 11 months. Although the study was set to conclude in summer 2019 (77), the results are yet to be published.
Given the failures and practical uncertainties associated with several peptide vaccines in clinical trials, new formulations that do not require adjuvant-like peptides such as DNA vaccines, epitope/protein-based vaccines, and the prime-boost approach have been developed (Table 2).

Table 2. Summary of some active vaccines at preclinical stage


DNA Vaccines (genetic vaccines): These are considered as third-generation vaccines; they are constructed by inserting a gene of interest or target gene (Aβ) into an expression vector. The construct is then introduced into a host, which expresses the protein of interest that elicits an immune response in the recipient host (78). DNA vaccines have been found to elicit both humoral and cellular immune responses characterized by Th2 cell stimulation and IgG1 antibody generation in animals (79). The vaccine formulations employ the concept of fusion with immune-modulatory sequences, such as the pan-human leucocyte antigen DR-binding peptide (PADRE) sequence, a non-self Th-cell epitope being used together with other modulators or by itself (7, 80, 81). The vaccine formulation demonstrated evidence of induction of an Aβ-specific immune response without the undesired cytotoxic response.
Some epitope vaccines are obtained from the fusion of Aβ with immunomodulatory sequences such as PADRE, which are either attached to adjuvants or incorporated into chimeric vaccines, such as virus-like particles. The formulation shows good immunogenicity, induction of humoral immune response, and Th2 modulation (58, 82, 83). Vaccines based on recombinant viruses encode an Aβ-specific epitope. However, they are costly and may have adverse effects due to the generation of antibodies with altered epitope specificities (84).
The prime-boost approach seeks to enhance the immune response by administering priming doses (like synthetic peptides) followed by booster doses (like DNA vaccines). This delivery approach facilitates the expansion and selection of B cells with a high degree of affinity for the target gene. Further, the initial boost stimulates T-cell generation, while the second boost activates regulatory T cells that help in the Aβ-specific T-cell-mediated prevention of autoimmune reactions (85, 86).


Passive Immunotherapy

Passive immunotherapy involves the administration of preformed antibodies to stimulate the immune system. These antibodies are either derived from humanized murine monoclonal antibodies (mAbs) or naturally occurring polyclonal antibodies obtained from various young healthy donors (intravenous immunoglobulin [IVIG]). Humanized mAbs are derived from non-human sources and have their protein sequences modified to increase similarity with naturally produced human antibodies, whereas fully human mAbs are obtained using phage display or transgenic mice to avoid the side effects of human antibodies (93). Unlike active immunotherapy, passive immunotherapy ensures consistent antibody titer volumes (through infusion of known amount of antibody) and rapid antibody clearance. Drawbacks of the therapy include repeated infusion of antibodies, high cost of production, BBB penetration, proper selection of antigen targets, and generation of an immune response to the injected antibodies (67,94). The antibodies injected into human subjects have different modes of action based on their antigenic targets (Table 3).

Table 3. Summary of monoclonal antibodies (mAbs) with their targets and current statuses

Mechanisms of Action of Anti-Aβ Monoclonal Antibodies

Monoclonal antibodies (mAbs) originate from a single clone of a unique parent cell and bind to a single epitope given their monovalent affinity. For the treatment of AD, various mAbs have been designed to target various epitopes of Aβ species (95) and are administered either subcutaneously or through intravenous infusions.
Monoclonal antibody action begins with binding to a specific antigenic epitope, which triggers an effector function mediated by the Fc portion of the mAb (96). While one hypothesis suggests that mAb binding to amyloid initiates a cascade of processes resulting in complement activation and macrophage-mediated phagocytosis, another suggests that the peripheral sink leads to the efflux of Aβ from the CNS (see mechanism of anti-Aβ antibody and Figure 2 and 3). However, the first hypothesis is based on the assumption that mAbs enter the CNS in sufficient amounts and enhance the phagocytic action of resident microglia or infiltrating monocytes (97). This hypothesis is not widely acknowledged because only 0.1% of the mAbs cross the BBB; the failures of these agents can be linked to poor CNS penetration (67). A novel approach targets receptors on the BBB to induce active transport of the antibodies into the CNS or deliver the gene encoding the antibodies (98).
A recent approach for mAbs is targeting pyroglutamate-3 Aβ, which may be considered as a seed of Aβ aggregation owing to its neurotoxicity and resistance to degradation (93). A preclinical study showed that passive immunization with mAbs reduces plaque deposits while minimizing vaccination side effects (99,100). Another approach involves targeting the N-terminus of Aβ, which could be the most effective way of removing aggregated Aβ (98).

Figure 3. Alzheimer’s disease immunotherapy or anti-Aβ vaccines associated adverse effects

Monoclonal Antibodies in Clinical Trials


Bapineuzumab was the first mAb developed for passive immunotherapy in AD; it entered testing after the failure of the AN-1792 trial. It is a humanized mAb (IgG1) targeting the Aβ N-terminus (Aβ1-5), which binds to and clears fibrillar Aβ42 as well as amyloid plaques. A 12-month, phase 1, single ascending dose trial of 0.5, 1.5, or 5 mg/kg of bapineuzumab showed safety and tolerability in patients with mild-to-moderate AD (101). The phase 2 study involved intravenous administration of either 0.15, 0.5, 0.1, or 2 mg/kg of bapineuzumab in 124 patients with the same form of AD; vasogenic edema was recorded, especially among APOEε4 carriers (102). APOEε4 is one of the alleles of polymorphic apolipoprotein E involved in cholesterol metabolism. It is associated with an increased risk of late-onset AD and Aβ production (103). Given differences in the incidence of vasogenic edema between APOEε4 carriers and non-carriers, phase 3 trials included separate protocols for the two. The mAb was intravenously administered to 2452 patients with mild-to-moderate symptoms in two 18-month phase 3 trials. The results of the two large, multi-center, randomized, double-blind, placebo-controlled, parallel group phase 3 studies did not match the expected outcomes, which were largely negative. Although there was a small reduction in the CSF tau level, there were no significant differences between the bapineuzumab-treated groups and placebo-treated control group (104). The adverse effects included significant vasogenic edema and intracerebral microhemorrhages, referred to as amyloid-related imaging abnormalities with parenchymal edema (ARIA-E) and hemorrhage (ARIA-H), respectively. These conditions could be detected by MRI even when lower doses were administered to APOEε4 carriers (105). Other adverse effects include neuropsychiatric and gastrointestinal symptoms, headache, and confusion. The bapineuzumab trial was terminated because of these side effects and lack of clinical efficacy (94, 106).


Solanezumab (Eli Lilly) is another humanized IgG1mAb that binds to monomeric, soluble, and toxic Aβ species at the mid-region of the peptide (Aβ16-26) (107). After its apparent success in improving cognitive deficits in transgenic mice, a phase 1 trial of solanezumab at doses of 0.5, 1.5, 4.0, or 10.0 mg/kg in 19 patients with mild-to-moderate AD and healthy volunteers showed good tolerability without any MRI evidence of microhemorrhage, vasogenic edema, or inflammation (108, 109). No adverse events were observed in a multiple-dose study involving 33 patients with mild-to-moderate AD taking 400 mg/month intravenous solanezumab. However, pharmacodynamic biomarker studies showed changes in plasma and CSF levels of Aβ40 and Aβ42. The phase 2 study involved administering 100–1600 mg/month of solanezumab to patients with mild-to-moderate AD. The drug showed a good safety profile and adequate tolerability even at high doses; although the dose-dependent increases in Aβ (Aβ40 and Aβ42) levels in the plasma and CSF indicate mobilization of Aβ from the senile plaques in the brain, there was no change in cognitive function (110). Double-blind, placebo-controlled phase 3 studies (EXPEDITION-1 and EXPEDITION-2) were conducted with over 2000 patients with mild-to-moderate AD who were administered a drug dose of 400 mg/month. Subgroup analysis in the EXPEDITION-1 trial revealed a 34% reduction in cognitive decline in patients with mild AD. The incidences of ARIA-E and ARIA-H in the treatment and placebo groups across the two studies were not significantly different (107). Consequently, Lilly launched the phase 3 (EXPEDITION-3) trial on 2100 patients with brain amyloid burden and mild AD. Although the secondary outcome of this trial slightly favored the drug, solanezumab had no effect on Aβ and tau PET biomarkers; therefore, its development was discontinued (111). Nonetheless, given the drug’s good safety profile and encouraging performance in mild AD cases, it was considered as a candidate in two secondary prevention studies. One prevention study was conducted by the Dominantly Inherited Alzheimer’s Network Trials Unit (DIAN-TU) in 2012. The study was targeted at 210 asymptomatic and very mildly symptomatic carriers of APP, PSEN1, and PSEN2 mutations. The study began as a two-year, phase 2 biomarker study and later proceeded to phase 3 registration with endpoint measurement of cognition after 4 years of treatment. The dose was 400 mg/month initially, which was increased to 1600 mg/month halfway through the trial. However, as the trial did not meet its primary endpoint and there was no reasonable treatment-related change on the DIAN multivariate cognitive endpoint, it was considered to have failed (112).
The other prevention study was initiated by the Alzheimer’s Disease Cooperative as a three-year trial in February 2014. The study recruited 1150 very mildly symptomatic or asymptomatic patients (age: 65 years or more) and investigated biomarker-based evidence of brain amyloid deposition. Solanezumab or placebo was administered intravenously once every four weeks and the drug dose was increased from 400 to 1600 mg/month in June 2017. This trial is expected to continue until mid-2020 (113). Therefore, solanezumab is being evaluated for treatment in patients with mild AD and for prevention in cognitively normal individuals at risk of AD (NCT02008357) and those with familial AD mutations (NCT01760005) (114, 115).


Gantenerumab (Hoffman-La, Roche/Ganentech) is the first fully human anti-Aβ mAb(IgG1) that binds specifically to the fibrillar form of Aβ (116). Gantenerumab is a conformational protein that binds to epitopes expressed on Aβ fibrils at the N-terminal (3-12) and central (18-27) amino acids of Aβ. Therefore, the antibody shows a higher affinity for Aβ oligomers and fibrils than for Aβ monomers (116). Gantenerumab significantly reduced Aβ plaques in transgenic mice by mobilizing microglia and hindering the formation of new plaques without altering plasma Aβ levels (116).
Four phase 1 trials in 308 patients conducted internationally showed safety, tolerability, and reduction in brain amyloid plaques in a dosage-dependent manner; however, ARIA remains a major concern. A phase 2 trial was started by Roche in 2010, consisting of 360 participants receiving subcutaneous gantenerumab injections (105 or 225 mg). The study was later expanded into a multinational, 159-center, phase 2/3 registration trial called SCarlet RoAD and recruited 799 participants. Double-blind, placebo-controlled, phase 2/3 studies conducted on Aβ-PET-positive patients with prodromal AD were terminated due to lack of efficacy and incidence of ARIA that increased in a dose-dependent and APOEε4 genotype-dependent manner; this was subsequently converted to an open extension study (117). Participants of SCarlet RoAD who became part of the open-label extension study were administered up to 1200 mg subcutaneous gantenerumab, and slow titration resulted in less ARIA-E (118). Although the open-label trial was set to continue until July 2020, it was later reported to have failed futility analysis (119). GRADUATE-1 and GRADUATE-2 are two new phase 3, double-blind, placebo-controlled studies initiated in 2018, each with the goal of recruiting 760 patients with Aβ pathology and prodromal-to-mild AD; the target enrollment was later raised to 1016 in 2020 (14). The participants will be administered up to 1020 mg subcutaneous gantenerumab or placebo for 2 years. The trial might be completed in 2023. Gantenerumab together with solanezumab are being tested by DIAN-TU for prevention of AD in a phase 2/3 trial for 210 individuals at risk of AD due to autosomal-dominant APP, PSEN1, and PSEN2 mutations (114, 115). The researchers increased the dosage of the two drugs and began a two-year, phase 2 biomarker study. The trial failed to meet its primary endpoint as gantenerumab did not provide reasonable treatment-related changes on the DIAN multivariate cognitive endpoint (114).


Crenezumab (Genetech/Hoffman-La Roche) was obtained from a mouse antibody and modified to a novel human IgG4mAb that binds to pentameric oligomeric forms of Aβ oligomers, plaques, and fibrils. It also promotes disaggregation while hindering aggregation (120). Phase 1 studies in patients with mild-to-moderate AD reported no case of ARIA-E in either single dose or multiple ascending doses (121). A phase 2, double-blind, placebo-controlled study of patients with mild-to-moderate AD did not report sufficient efficacy (122). A smaller phase 2 imaging study (BLAZE) also failed to show cognitive or clinical benefits of the drug, while a double-blind, placebo-controlled phase 1b trial reported adverse effects like ARIA-H. Currently, a phase 3, double-blind, placebo-controlled study (NCT02670083) is being conducted on Aβ-PET-positive patients with prodromal-to-mild AD to evaluate higher doses of crenezumab (39). As part of the API, crenezumab has also been tested in secondary prevention trials in cognitively normal PSEN1 mutation carriers from the world’s largest early-onset AD kindred in Columbia (NCT01998841) (123).


Ponezumab (Pfizer Inc.) is a humanized IgG2mAb designed to recognize the C-terminus of Aβ40 (Aβ30-40) (124). It elicits lower immune effector functions than IgG1. Although phase 1 trials showed a good safety profile without evidence of ARIA, CSF antibody levels were poor. The development of ponezumab was halted when two consecutive phase 2 studies revealed no clinical efficacy (125).


BAN2401 (Biogen/Eisai) is a humanized IgG1mAb that selectively binds, clears, or neutralizes the large soluble Aβ protofibrils. A multi-center phase 1 trial comprised a randomized, double-blind, placebo-controlled study to assess the safety, tolerability, pharmacokinetics, immunogenicity, and pharmacodynamic response to repeated intravenous infusions of BAN2401 (up to 10 mg/kg every 2 weeks for 4 months) in 80 subjects with mild AD and mild cognitive impairment due to AD. While the tolerability of BAN2401 at all the tested doses was good, dosage-dependent increases in ARIA-H and ARIA-E were observed in the treatment and placebo groups. Although the serum elimination half-life was short (7 days) and there was no clear effect on CSF biomarkers, the antibodies entered the CSF and showed dose-dependent exposure (126). A phase 1/2a study of the drug showed adequate tolerability with no cases of ARIA-E (127). Consequently, an 18-month phase 2b trial recruited 856 participants with prodromal-to-mild AD to evaluate the safety, tolerability, and efficacy of BAN2401 at five different intravenous dosages. The study revealed a 47% reduction in cognitive decline and a 93% reduction in brain amyloid with the highest antibody dose (10 mg/kg) administered twice monthly. MRI reports in the highest dose group revealed ARIA in only 10% of the participants and in less than 15% of those with ApoE4 (128). Eisai began a phase 3 trial known as Clarity AD in March 2019, and enrolled 1566 patients with early symptomatic AD across 250 sites in the world. Participants will receive 10 mg/kg drug or placebo every 2 weeks for a period of 18 months, followed by a two-year open-label extension. Changes in Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) at 18 months and the brain amyloid subscale constitute the primary and secondary outcomes, respectively. The trial will continue till 2024. The Alzheimer’s Clinical Trial Consortium began a large BAN2401 phase 3 study, co-funded by Eisai and National Institute of Health (NIH) (AHEAD 3-45). The trial was expected to start in July 2020 and recruit 1400 people who would be divided into two sub-studies. A3 will consist of 400 participants with sub-threshold amyloid levels, and BAN2401 (5 mg/kg titrated to 10 mg/kg) or placebo will be administered every month for 216 weeks; changes in brain amyloid PET at week 216 will constitute the primary outcome. A45 will comprise 1000 participants with amyloid-positive PET scans; BAN2401 (titrated to 10 mg/kg) will be administered at two-week intervals for 96 weeks, followed by a dose of 10 mg/kg every 4 weeks for 216 weeks. A change from baseline in the Preclinical Alzheimer Cognitive Composite 5 score at week 216 constitutes the primary outcome, while changes in brain amyloid PET and cognitive function constitute the secondary outcomes (128).


Aduhelm (Neurimmune/Biogen) is another fully human IgG1mAb that selectively binds to soluble Aβ aggregates and insoluble fibrils (129).The drug was developed by screening libraries of B-memory cells from healthy elderly individuals for reactivity against aggregated Aβ. The analog of aducanumab has been shown to cross the BBB in transgenic mice; dose-dependent reductions in soluble and insoluble Aβ have also been observed in mice (129). A 12-month phase 1b trial conducted on patients with Aβ-PET-positive prodromal-to-mild AD showed evidence of a dose- and time-dependent reduction in brain fibrillar Aβ. However, the ARIA-E incidence among APOEε4 carriers was high (129). Two identical 18-month phase 3 studies were launched based on the success of the phase 1b trial. These trials sought to evaluate the efficacy of monthly doses of aducanumab in improving cognitive and functional abilities. Although only the data related to doses of 1, 3, and 10 mg/kg were reported, the drug appeared to reduce decline in a dose-dependent manner. Exploratory analyses showed that instances of ARIA-E increased with ApoE4 carriage and dosage (55% inApoE4 homozygotes at 10 mg/kg); these instances occurred in the initial phase of the trial and were later resolved (130).
The development study on patients with mild-to-moderate AD began in Japan in May 2015, with a phase 1 trial of increasing doses up to 6 mg/kg. Later, a phase 3 trial with two efficacy trials was initiated:221AD301ENGAGE and 221AD302EMERGE. 221AD301 ENGAGE enrolled 1350 patients with mild AD or mild cognitive impairment due to AD, as determined by a positive amyloid PET scan. The study, set to continue until 2022, aimed at comparing placebo with monthly infusions of one of the three doses of aducanumab over a period of 18 months. 221AD302 EMERGE, identical to ENGAGE, was conducted at 131 sites in North America with 1350 additional patients. In 2016, Biogen published and presented PRIME data, indicating that a dose titration schedule mitigated ARIA-E and announced its usage in phase 3 (131). However, in March 2019, Biogen and Eisai announced a plan for termination of all aducanumab trials based on an interim analysis that suggested that ENGAGE and EMERGE would miss their primary endpoints; the drug was subsequently removed from the pipeline (132). Interestingly, in October 2019, Biogen faulted the futility analysis and subsequent analysis showed that EMERGE achieved its primary endpoint. Although ENGAGE did not meet the primary endpoint, some exploratory analysis suggested a slow decline in the subgroup that received 10 or more doses of 10 mg/kg.
Following some interactive sessions with the Food and Drug Administration (FDA), Biogen announced plans to apply for regulatory approval of aducanumab in the US and to re-engage eligible patients from the EMERGE, ENGAGE, and PRIME trials with renewed dosing and observations (133).
In January 2020, Biogen launched a phase 3b open-label study called EMBARK, targeting 2400 previous aducanumab trial participants who will receive monthly injections of 10 mg/kg for 2 years. EMBARK has the same endpoints for efficacy as EMERGE and ENGAGE, while biomarker endpoints consist of tauPET, amyloidPET, volumetric MRI, and CSF in a subset of participants. The study is expected to end in 2023.
Biogen submitted the license application in July 2020, demanding priority review (134), and later applied for approval in Japan and the European Union. In November 2020, the FDA advisory committee cited weaknesses in efficacy and voted against approval, while recommending a confirmatory trial. In April 2021, the committee renewed its argument against approval with complaints from public citizens (135). Ultimately, the FDA approved aducanumab in June 2021 under its accelerated approval pathway that requires reasonable likelihood of a meaningful clinical benefit, substantial evidence of effect on an intermediate marker, and phase 4 evidence for such a benefit to be gathered in a subsequent trial after the marketing license has been granted (136).


Intravenous Immunoglobulin (IVIG)

IVIG is closely related to passive immunotherapy. It involves the intravenous administration of naturally occurring polyclonal antibodies obtained from the plasma of thousands of healthy young donors. IVIG has already been used as replacement therapy in various clinical conditions, such as certain forms of cancers, immunodeficiency syndromes, and hematological and autoimmune disorders. IVIG primarily contains IgG antibodies, only about 0.5% of which bind to Aβ. The use of IVIG as a potential treatment for AD began in 2002 when human pooled antibodies were shown to have strong affinity for Aβ fibrils and neurotoxic oligomers, while weakly interacting with its monomeric form (16, 137). Moreover, IVIG has some immunomodulatory effects pertinent to the treatment of AD. Early trials of IVIG revealed some benefits in reducing cognitive decline, paving the way for further studies. A phase 2 open-label IVIG trial revealed symptomatic benefits, and a futility study of Gammagard IVIG (Baxter) conducted on patients with mild-to-moderate AD showed positive cognitive scores (25). Baxter and the US funded the phase 3 trial of Gammagard IVIG to determine its efficacy and safety among patients with mild-to-moderate AD. Baxter announced that the primary endpoint for this study was not achieved; the trial has now been discontinued (138).
Grifols conducted a pilot study that involved plasma removal and replacement with Albutein in seven patients with mild-to-moderate AD (7). This procedure was performed twice weekly with a follow-up period of 6 months. Grifols concluded that this is a feasible approach for AD treatment. In 2017, Grifols conducted a phase 2 trial using the same approach and measured similar parameters as the pilot, involving 20 sham-treated and 19 actively treated patients with mild-to-moderate AD. A sawtooth pattern for plasma Aβ40/Aβ42 was seen in the treatment group, while both groups showed similar incidence of adverse events. Grifols’ recent Alzheimer Management by Albumin Replacement (AMBAR) study was a multi-center, randomized, double-blind, placebo-controlled study involving 496 patients with mild-to-moderate AD treated for 14 months. This approach is under phase 3 trial in Europe, while a phase 2 trial in the US is investigating the effect of plasmapheresis with albumin replacement and IVIG. The treatment groups were divided into a sham-treated control group and three treatment groups: plasmapheresis with albumin replacement, plasmapheresis with low dose albumin and IVIG, and plasmapheresis with high-dose albumin and IVIG (139). Changes in the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scores between baseline and the endpoint constitute the primary outcome measures. The secondary measures include changes in functional, cognitive, and behavioral tests; measures of disease progression; changes in CSF total tau, p-tau, Aβ40, and Aβ42 levels; changes in plasma Aβ40 and Aβ42 levels; and changes in brain structure and brain glucose metabolism. Subjects in the treatment groups showed 50–75% less worsening of ADAS-Cog scores and 42–70% less worsening of ADCS-ADL scores than control subjects. In addition, pooled data from treated subjects showed that the average decline in ADAS-Cog and ADCS-ADL scores in the treatment group were 66% and 52% lower, respectively, then in the control group. Although some patients with mild AD showed slower disease progression, sham-treated patients with mild AD unexpectedly showed a similar pattern. Grifols reported significant differences in memory, processing speed, quality of life, and language between the control and high albumin/high IVIG treatment groups. Moreover, actively treated patients with moderate AD demonstrated better memory and quality of life than their sham-treated counterparts. Similarly, actively treated patients with mild AD showed better outcomes in language and processing speed tasks than their control counterparts. However, some instances of mild adverse events were noted during high-volume plasma exchange. While the outcomes of AMBAR are promising, some important gaps need to be addressed: mechanism(s) leading to reduction in disease progression; effectiveness of the approach in mild AD as in moderate AD; necessity of including IVIG in the protocol; and how ApoE genotype, age, and sex influence the treatment response (140).


Adverse effects of anti-Aβ vaccines

Importantly, both passive and active Aβ immunization elicit CNS inflammation, and can also induce cerebral microhaemorrhage and vasogenic oedema in the already inflamed milieu (141). With the administration of vaccine/antibodies against Aβ, many factors have led to compromised efficacy of immunotherapy in clinical trials. These adverse effects include brain cerebral amyloid angiopathy (CAA), microhemorrhage and meningoencephalitis, which have led to the suspension of clinical trials (Figure 3). Furthermore, patients with AD have well-established neurotic plaques, which are obstacles for a successful vaccine-mediated immune response. Aβ peptide production leads to the activation of the innate immune response marked by activated microglia and elevated levels of complement protein, together they are known to release chemokines and proinflammatory cytokines. Moreover, endogenous sugars can modify Aβ fibrils to advanced glycation end products (AGEs), resulting in proinflammatory signal transduction pathways pertaining to the overproduction of reactive oxygen species and upregulation of AGE receptors. These pathological events constitute a secondary inflammatory response to the early aggregation of Aβ peptides. When the vaccine is administered, the Aβ–antibody complex activates the complement system and microglia, eliciting inflammation in the CNS. Furthermore, activation of T-lymphocytes triggers an adaptive immune response. T-lymphocytes insinuate the brain parenchyma and damage the neural tissue, which is the primary cause of aseptic meningoencephalitis reported in many immunotherapy clinical trials. Moreover, mobilization of Aβ plaques may be an additional concern. As Aβ species cross the BBB, there is a potential risk of neurotoxicity from the brain to the periphery (141). Aβ monomers readily aggregate into oligomers and then into fibrils with β-pleated sheet structures. Aβ oligomers are reported to be more neurotoxic than other Aβ species. Aβ toxicity can be reduced by targeting Aβ oligomers in the early stages rather than plaques. Additionally, current clinical trials based on Aβ-based immunotherapies target Aβ aggregates and do not affect the amount of soluble Aβ. An AN1972 active immunization study reported that increased concentrations of detergent-soluble and water-soluble forms of Aβ in the brain are linked to reduced Aβ plaque load. A series of events such as this aids the formation of Aβ oligomers, which may cause damage to neurons during Aβ clearance (141). This effect of immunotherapy is a significant safety concern and must be investigated.


Conclusion and Future Perspectives

After a decade of disappointment in AD prevention through vaccination against Aβ, some vaccine candidates have entered phase 3 clinical trials, while other approaches are in preclinical trials. One of the challenges related to vaccination is its timing. It is now clear that vaccination must start early because plaque removal at later stages does not curtail the progression of the disease, possibly due to progressive tau aggregation. Thus, amyloid removal at pre-symptomatic stages can avert the clinical onset of AD. However, determining the appropriate time for commencement of vaccination is quite challenging. Another point of concern in vaccination is anti-Aβ specificity and antibody titer volumes. Therefore, future studies should evaluate the appropriate timing for vaccination, pathogenic Aβ specificity, and optimization of the titer for antibody response.
Currently, passive immunotherapy appears more promising than active vaccination. The recent approval of aducanumab by the FDA, albeit with some controversies, demonstrates the potential of passive immunotherapy. One of the advantages of passive immunotherapy is that mAbs are amenable to dose and specificity modulation. However, the challenges of short-term antibody effects, low improvement in cognition, and instances of ARIA constitute bottlenecks that need to be addressed.
Given the complex pathophysiology of AD, it is necessary to re-strategize future research in both active and passive immunotherapy. Combination therapy may help in targeting tau protein and Aβ protein, while specific formulations may be beneficial in individuals with specific APOE genotypes, immune phenotypes, and/or Aβ strains. Thus, considering inter-individual differences could improve the prospects of immunotherapeutic prevention of AD.


Author’s contributions: NKJ and SO conceptualized the study and hypotheses. MBU, SB, SR, DK, AA and SKS performed literature search. NKJ draw the schemes and drafted the artwork. GG, DKC, KD, JR and KKK drafted the tables. NKJ, and other authors contributed significantly in editing the manuscript. PK, RKA, PP, SS, VU, FAK, RA, SKJ and MDS significantly contributed during revision. All authors read, edited and approved the manuscript.

Acknowledgements: The authors would like to express their gratitude to the unknown referees for carefully reading the paper and giving valuable suggestions.

Conflict of Interest: The authors declare that they have no conflict of interest.

Consent for publication: All authors have read the final version of the manuscript and have given their consent for publication.



1. LoGiudice D, & Watson R. Dementia in older people: an update. Internal Medicine Journal 2014; 44(11):1066–1073.
2. Mayeux R, & Stern Y. Epidemiology of Alzheimer disease. Cold Spring Harbor Perspectives in Medicine 2012; 2(8):a006239.
3. Jha NK, Jha SK, Kar R, Nand P, Swati K & Goswami VK. Nuclear Factor-Kappa β as a therapeutic target for Alzheimer’s disease. J Neurochemistry 2019; 150(2):113-137. doi:10.1111/jnc.14687
4. Uversky VN. Intrinsic Disorder in Proteins Associated with Neurodegenerative Diseases. In: Ovádi J., Orosz F. (eds) Protein Folding and Misfolding: Neurodegenerative Diseases. Focus on Structural Biology, vol 2009; 7. Springer, Dordrecht.
5. Imtiaz B, Tolppanen AM, Kivipelto M, Soininen H. Future directions in Alzheimer’s disease from risk factors to prevention. Biochemical Pharmacology 2014; 88(4):661–670.
6. Sosa-Ortiz AL, Acosta-Castillo I,Prince MJ. Epidemiology of dementias and Alzheimer’s disease. Archives of Medical Research 2012; 43(8):600–608.
7. Alves RP, Yang MJ, Batista MT, Ferreira LC. Alzheimer’s disease: is a vaccine possible?. Brazilian JMedical Biological Research 2014; 47(6):438–444.×20143434
8. Alzheimer’s Association. 2012 Alzheimer’s disease facts and figures. Alzheimer’s &Dementia: The Journal of the Alzheimer’s Association (2012; 8(2):131–168.
9. Hallock P, Thomas MA. Integrating the Alzheimer’s disease proteome and transcriptome: a comprehensive network model of a complex disease. Omics: AJournal of Integrative Biology 2012;16(1-2):37–49.
10. Reitz C, Mayeux R. Alzheimer disease: epidemiology, diagnostic criteria, risk factors and biomarkers. Biochemical Pharmacology 2014; 88(4): 640–651.
11. Henderson VW. Alzheimer’s disease: Review of hormone therapy trials and implications for treatment and prevention after menopause. J Steroid Biochem and Mol Biol 2014; 142:99–106.
12. Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. The New England Journal of Medicine 2012; 367(9):795–804.
13. Jack CR, Jr KnopmanDS, Jagust WJ, ShawLM, Aisen PS, Weiner MW, Petersen RC &Trojanowski JQ. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. The Lancet Neurology 2010; 9(1):119–128.
14. Panza F, Lozupone M, Seripa D, Imbimbo BP. Amyloid-β immunotherapy for alzheimer disease: Is it now a long shot?. Annals of Neurology 2019; 85(3):303–315.
15. Haass C. New hope for Alzheimer disease vaccine. Nature medicine 2002; 8(11):1195–1196.
16. Schnabel J. Vaccines:Chasing the dream. Nature 2011; 475(7355):S18–S19. doi:10.1038/475s18a
17. Sterner RM, Takahashi PY & Yu Ballard AC. Active Vaccines for Alzheimer Disease Treatment. Journal of the American Medical Directors Association 2016; 17(9):862.e11–862.e15. doi:10.1016/j.jamda.2016.06.009
18. Alzheimer A, Stelzmann RA, Schnitzlein HN Murtagh FR. An English translation of Alzheimer’s 1907 paper, “Uber eineeigenartigeErkankung der Hirnrinde”. Clinical Anatomy (New York, N.Y.) 1995; 8(6):429–431.
19. Hardy J,Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science (New York, N.Y.) 2002; 297(5580):353–356.
20. Mattson MP. Pathways towards and away from Alzheimer’s disease. Nature 2004; 430(7000):631–639.
21. Van Gassen G, Annaert W, Van Broeckhoven C. Binding partners of Alzheimer’sdisease proteins: are they physiologically relevant? Neurobiol Dis 2000; 7(3):135– 151.
22. Price JL, Morris JC. Tangles and plaques in nondemented aging and “preclinical” Alzheimer’s disease. Annals of Neurology 1999; 45(3):358–368.<358::aid-ana12>;2-x
23. Berg L, McKeel DW, Jr Miller JP, Storandt M, Rubin EH, Morris JC, Baty J, Coats M, Norton J, Goate AM, Price JL, Gearing M, Mirra SS &Saunders AM. Clinicopathologic studies in cognitively healthy aging and Alzheimer’s disease: relation of histologic markers to dementia severity, age, sex, and apolipoprotein E genotype. Archives of Neurology 1998; 55(3): 326–335.
24. Lambracht-Washington D & Rosenberg RN. Advances in the development of vaccines for Alzheimer’s disease. Discov Med 2013; 15(84):319-326.
25. Lannfelt L, Relkin NR & Siemers ER. Amyloid-ß-directed immunotherapy for Alzheimer’s disease. Journal of Internal Medicine 2014; 275(3):284–295. doi:10.1111/joim.12168
26. Jin M, Shepardson N, Yang T, Chen G, Walsh D & Selkoe DJ. Soluble amyloid beta-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. Proceedings of the National Academy of Sciences, U.S.A 2011; 108(14):5819–5824.
27. Oddo S, Caccamo A, Tran L, Lambert MP, Glabe CG, Klein WL & La Ferla FM. Temporal profile of amyloid-beta (Abeta) oligomerization in an in vivo model of Alzheimer disease. A link between Abeta and tau pathology. The Journal of Biological Chemistry 2006; 281(3):1599–1604.
28. Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ &Selkoe DJ. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 2002; 416(6880):535–539.
29. Kumar DK, Choi SH, Washicosky KJ, Eimer WA, Tucker S, Ghofrani J, Lefkowitz A, McColl G, Goldstein LE, Tanzi RE & Moir RD. Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease. Science Translational Medicine 2016; 8(340):340ra72.
30. Kukull WA, Higdon R, Bowen JD, McCormick WC, Teri L, Schellenberg GD, van Belle G, Jolley L & Larson EB. Dementia and Alzheimer disease incidence: a prospective cohort study. Archives of Neurology 2002; 59(11):1737–1746.
31. Launer LJ, Andersen K, Dewey ME, Letenneur L, Ott A, et al. Rates and risk factors for dementia and Alzheimer’s disease: results from EURODEM pooled analyses. EURODEM Incidence Research Group and Work Groups. European Studies of Dementia. Neurology 1999; 52(1):78–84.
32. Cruchaga C, Haller G, Chakraverty S, Mayo K, Vallania FL, Mitra RD, et al. Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer’s disease families. PloS one 2012; 7(2):e31039.
33. Campion D, Dumanchin C, Hannequin D, Dubois B, Belliard S, Puel M, Thomas-Anterion C, et al. Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. American Journal of Human Genetics 1999; 65(3):664–670.
34. Wijsman EM, Daw EW, Yu X, Steinbart EJ, Nochlin D, Bird TD & Schellenberg GD. APOE and other loci affect age-at-onset in Alzheimer’s disease families with PS2 mutation. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics: The official publication of the International Society of Psychiatric Genetics 2005; 132B(1):14–20.
35. Lopera F, Ardilla A, Martínez A, Madrigal L, Arango-Viana JC, Lemere CA, Arango-Lasprilla JC et al. Clinical features of early-onset Alzheimer disease in a large kindred with an E280A presenilin-1 mutation. JAMA 1997; 277(10):793–799.
36. Bretsky PM, Buckwalter JG, Seeman TE, Miller CA, Poirier J, Schellenberg GD, Finch CE & Henderson VW. Evidence for an interaction between apolipoprotein E genotype, gender, and Alzheimer disease. Alzheimer Disease and Associated Disorders 1999; 13(4):216–221.
37. Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijn CM. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA 1997; 278(16):1349–1356.
38. Evans CF, Davtyan H, Petrushina I, Hovakimyan A, Davtyan A, Hannaman D, Cribbs DH, Agadjanyan MG & Ghochikyan A. Epitope-based DNA vaccine for Alzheimer’s disease: translational study in macaques. Alzheimer’s &Dementia: The Journal of the Alzheimer’s Association 2014; 10(3):284–295.
39. van Dyck CH. Anti-Amyloid-β Monoclonal Antibodies for Alzheimer’s Disease: Pitfalls and Promise. Biological Psychiatry 2018; 83(4):311–319.
40. Abramov E, Dolev I, Fogel H, Ciccotosto GD, Ruff E & Slutsky I. Amyloid-beta as a positive endogenous regulator of release probability at hippocampal synapses. Nature Neuroscience 2009; 12(12):1567–1576.
41. Wilcock DM, Munireddy SK, Rosenthal A, Ugen KE, Gordon MN, Morgan D. Microglial activation facilitates Abeta plaque removal following intracranial anti-Abeta antibody administration. Neurobiology of Disease 2004; 15(1):11–20.
42. Weiner HL, Frenkel D. Immunology and immunotherapy of Alzheimer’s disease. Nature Reviews Immunology 2006; 6(5):404–416. doi:10.1038/nri1843
43. Hock C, Konietzko U, Papassotiropoulos A, Wollmer A, Streffer J, von Rotz RC, Davey G, Moritz E, Nitsch RM. Generation of antibodies specific for beta-amyloid by vaccination of patients with Alzheimer disease. Nature Medicine 2002; 8(11):1270–1275.
44. Zlokovic BV. Clearing amyloid through the blood-brain barrier. Journal of Neurochemistry 2004; 89(4):807–811.
45. Deane R, Du Yan S, SubmamaryanRK, LaRue B, Jovanovic S, Hogg E, Welch D, et al. RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nature Medicine 2003; 9(7):907–913.
46. Arbel M, Yacoby I, Solomon B. Inhibition of amyloid precursor protein processing by beta-secretase through site-directed antibodies. Proceedings of the National Academy of Sciences U.S.A 2005; 102(21):7718–7723.
47. Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 1999; 400(6740):173–177.
48. Bayer AJ, Bullock R, Jones RW, Wilkinson D, Paterson KR, Jenkins L, Millais SB, Donoghue S. Evaluation of the safety and immunogenicity of synthetic Abeta42 (AN1792) in patients with AD. Neurology 2005; 64(1):94–101.
49. Zotova E, Bharambe V, Cheaveau M, Morgan W, Holmes C, Harris S, Neal JW, Love S, Nicoll JA &Boche D. Inflammatory components in human Alzheimer’s disease and after active amyloid-β42 immunization. Brain: AJournal of Neurology 2013; 136(Pt 9):2677–2696.
50. Serrano-Pozo A, William CM, Ferrer I, Uro-Coste E, Delisle MB, Maurage CA, Hock C, Nitsch RM, Masliah E, Growdon JH, Frosch MP & Hyman BT. Beneficial effect of human anti-amyloid-beta active immunization on neurite morphology and tau pathology. Brain: A Journal of Neurology 2010; 133(Pt 5):1312–1327.
51. Boche D, Zotova E, Weller RO, Love S, Neal JW, Pickering RM, Wilkinson D, Holmes C & Nicoll JA. Consequence of Abeta immunization on the vasculature of human Alzheimer’s disease brain. Brain: AJournal of Neurology 2008; 131 (Pt12):3299–3310.
52. Gilman S, Koller M, Black RS, Jenkins L, Griffith SG, Fox NC, Eisner L, Kirby L, Rovira MB, et al. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interruptedtrial. Neurology 2005; 64(9):1553–1562.
53. Orgogozo JM, Gilman S, Dartigues JF, Laurent B, Puel M, Kirby LC, Jouanny P, Dubois B, Eisner L, et al. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology 2003; 61(1):46–54.
54. Ferrer I, Rovira MB, Guerra MLS, Rey MJ & Costa-Jussá F. Neuropathology and Pathogenesis of Encephalitis following Amyloid β Immunization in Alzheimer’s Disease. Brain Pathology 2004; 14(1):11–20. doi:10.1111/j.1750-3639.2004.tb00493.x
55. Cribbs DH, Ghochikyan A, Vasilevko V, Tran M, Petrushina I, Sadzikava N, Babikyan D, Kesslak P, Kieber-Emmons T, Cotman CW &Agadjanyan MG. Adjuvant-dependent modulation of Th1 and Th2 responses to immunization with beta-amyloid. International Immunology 2003; 15(4):505–514.
56. Wang CY, Wang PN, Chiu MJ, Finstad CL, Lin F, Lynn S, Tai YH, De Fang X, et al. UB-311, a novel UBITh® amyloid β peptide vaccine for mild Alzheimer’s disease. Alzheimer’s &Dementia (New York, N. Y.) 2017; 3(2):262–272.
57. Farlow MR, Andreasen N, Riviere ME, Vostiar I, Vitaliti A, SovagoJ, Caputo A, Winblad B & Graf A. Long-term treatment with active Aβ immunotherapy with CAD106 in mild Alzheimer’s disease. Alzheimer’s Research & Therapy 2015; 7(1):23.
58. Davtyan H, Bacon A, Petrushina I, Zagorski K, Cribbs DH, Ghochikyan A &Agadjanyan MG. Immunogenicity of DNA- and recombinant protein-based Alzheimer Disease epitope vaccines.Human Vaccines & Immunotherapeutics 2014; 10(5):1248–1255. doi:10.4161/hv.27882.
59. Mantile, F., & Prisco, A. Vaccination against β-Amyloid as a Strategy for the Prevention of Alzheimer’s Disease. Biology, 2020; 9(12), 425. doi:10.3390/biology9120425
60. Mamikonyan G, Necula M, Mkrtichyan M, Ghochikyan A, PetrushinaI, Movsesyan N, Mina E, Kiyatkin A, Glabe CG, Cribbs DH &Agadjanyan MG. Anti-A beta 1-11 antibody binds to different beta-amyloid species, inhibits fibril formation, and disaggregates preformed fibrils but not the most toxic oligomers. The Journal of Biological Chemistry 2007; 282(31):2 2376–22386.
61. Arai H, Suzuki H, Yoshiyama T. Vanutidecridificar and the QS-21 adjuvant in Japanese subjects with mild to moderate Alzheimer’s disease: results from two phase 2 studies. Curr Alzheimer Res 2015; 12(3):242-254. doi:10.2174/1567205012666150302154121. PMID: 25731629.
62. Pasquier F, Sadowsky C, Holstein A, Leterme G, Peng Y, Jackson N, Fox NC, et al. Two Phase 2 Multiple Ascending-Dose Studies of VanutideCridificar (ACC-001) and QS-21 Adjuvant in Mild-to-Moderate Alzheimer’s Disease. Journal of Alzheimer’s Disease: JAD 2016; 51(4):1131–1143.
63. Hull M, Sadowsky C, Arai H, Le Prince Leterme G, Holstein A, Booth K, Peng Y, Yoshiyama T, Suzuki H, Ketter N, Liu E & Ryan JM. Long-Term Extensions of Randomized Vaccination Trials of ACC-001 and QS-21 in Mild to Moderate Alzheimer’s Disease. Current Alzheimer research 2017; 14(7):696–708.
64. Godyń J, Jończyk J, Panek D &Malawska B. Therapeutic strategies for Alzheimer’s disease in clinical trials. Pharmacological Reports: PR 2016; 68(1):127–138.
65. Kwan, P., Konno, H., Chan, K. Y., & Baum, L. Rationale for the development of an Alzheimer’s disease vaccine. Human Vaccines & Immunotherapeutics. 2019. doi:10.1080/21645515.2019.1665453
66. Schneeberger A, Hendrix S, Mandler M, Ellison N, Bürger V, Brunner M, Frölich L, et al. Results from a Phase II Study to Assess the Clinical and Immunological Activity of AFFITOPE® AD02 in Patients with Early Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease 2015; 2(2):103–114.
67. Lemere CA. Immunotherapy for Alzheimer’s disease: hoops and hurdles. Molecular Neurodegeneration 2013; 8(1):36. doi:10.1186/1750-1326-8-36
68. Muhs A, Hickman DT, Pihlgren M, Chuard N, Giriens V, MeerschmanC, van der Auwera I, van Leuven F, et al. Liposomal vaccines with conformation-specific amyloid peptide antigens define immune response and efficacy in APP transgenic mice. Proceedings of the National Academy of Sciences (U.S.A.) 2007; 104(23): 9810–9815.
69. Yu YZ & Xu Q. Prophylactic immunotherapy of Alzheimer’s disease using recombinant amyloid-β B-cell epitope chimeric protein as subunit vaccine. Human Vaccines &Immunotherapeutics 2016; 12(11):2801–2804.
70. Last updated 08 October 2020
71. Winblad B, Andreasen N, Minthon L, Floesser A, Imbert G, Dumortier T, Maguire RP, et al. Safety, tolerability, and antibody response of active Aβ immunotherapy with CAD106 in patients with Alzheimer’s disease: randomised, double-blind, placebo-controlled, first-in-human study. The Lancet Neurology 2012; 11(7):597–604.
72. Lopez C, Tariot PN., Caputo A, Langbaum JB, Liu F, et al. The Alzheimer’s Prevention Initiative Generation Program: Study design of two randomized controlled trials for individuals at risk for clinical onset of Alzheimer’s disease. Alzheimer’s & dementia (New York, N. Y.), 2019; 5, 216–227.
73. 20 Dec 2019
74. Davtyan H, Ghochikyan A, Hovakimyan A, Petrushina I, Yu J, Flyer D, Madsen PJ, Pedersen LO, Cribbs DH &Agadjanyan MG. Immunostimulant patches containing Escherichia coli LT enhance immune responses to DNA- and recombinant protein-based Alzheimer’s disease vaccines. Journal of Neuroimmunology 2014; 268(1-2):50–57.
75. Theunis C, Crespo-Biel N, Gafner V, Pihlgren M, López-Deber MP, Reis P, Hickman DT, et al. Efficacy and safety of a liposome-based vaccine against protein Tau, assessed in tau.P301L mice that model tauopathy. PloS one 2013; 8(8):e72301.
76. Grüninger F. Invited review: Drug development for tauopathies. Neuropathology and Applied Neurobiology 2015; 41(1):81–96.
77. 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;6:63–69.
78. RobinsonHL & Pertmer TM. DNA vaccines for viral infections: basic studies and applications. Advances in Virus Research 2000; 55:1–74.
79. Martins YA, Tsuchida CJ, Antoniassi P &Demarchi IG. Efficacy and Safety of the Immunization with DNA for Alzheimer’s Disease in Animal Models: A Systematic Review from Literature. Journal of Alzheimer’s Disease Reports 2017; 1(1):195–217. doi:10.3233/adr-170025
80. Ghochikyan A, Davtyan H, Petrushina I, Hovakimyan A, Movsesyan N, Davtyan A, Kiyatkin A, Cribbs DH & Agadjanyan MG. Refinement of a DNA based Alzheimer’s disease epitope vaccine in rabbits. Human Vaccines & Immunotherapeutics 2013; 9(5):1002–1010.
81. Movsesyan N, Ghochikyan A, Mkrtichyan M, Petrushina I, Davtyan H, Olkhanud PB, et al. Reducing AD-Like Pathology in 3xTg-AD Mouse Model by DNA Epitope Vaccine — A Novel Immunotherapeutic Strategy. PLoS ONE 2008; 3(5):e2124. doi:10.1371/journal.pone.0002124
82. Bach P, Tschäpe JA, Kopietz F, Braun G, Baade JK, Wiederhold KH, Staufenbiel M, Prinz M, Deller T, Kalinke U, Buchholz CJ & Müller UC. Vaccination with Abeta-displaying virus-like particles reduces soluble and insoluble cerebral Abeta and lowers plaque burden in APP transgenic mice. Journal of Immunology (Baltimore, Md.:1950) 2009; 182(12):7613–7624.
83. Petrushina, I, Ghochikyan A, Mktrichyan M, Mamikonyan G, Movsesyan N, Davtyan H, Patel A, Head E, Cribbs DH &Agadjanyan MG. Alzheimer’s disease peptide epitope vaccine reduces insoluble but not soluble/oligomeric Abeta species in amyloid precursor protein transgenic mice. The Journal of Neuroscience :The official Journal of the Society for Neuroscience 2007; 27(46):12721–12731.
84. Zou J, Yao Z, Zhang G, Wang H, Xu J, Yew DT & Forster EL. Vaccination of Alzheimer’s model mice with adenovirus vector containing quadrivalent foldable Abeta(1-15) reduces Abeta burden and behavioral impairment without Abeta-specific T cell response. Journal of the Neurological Sciences 2008; 272(1-2):87–98.
85. Lambracht-Washington D, Qu BX, Fu M, Anderson LD, Jr Eagar TN, Stüve O & Rosenberg RN. A peptide prime-DNA boost immunization protocol provides significant benefits as a new generation Aβ42 DNA vaccine for Alzheimer disease. Journal of Neuroimmunology 2013; 254(1-2):63–68.
86. Kim H-D, Jin J-J, Maxwell JA & Fukuchi K. Enhancing Th2 immune responses against amyloid protein by a DNA prime-adenovirus boost regimen for Alzheimer’s disease. Immunology Letters 2007; 112(1):30–38. doi:10.1016/j.imlet.2007.06.006
87. Rosenberg RN, Fu M &Lambracht-Washington D. Active full-length DNA Aβ42 immunization in 3xTg-AD mice reduces not only amyloid deposition but also tau pathology. Alzheimer’s Research & Therapy 2018; 10(1). doi:10.1186/s13195-018-0441-4
88. Davtyan H, Chen WW, Zagorski K, Davis J, Petrushina I, Kazarian K, Cribbs DH, Agadjanyan MG, Blurton-Jones M &Ghochikyan A. MultiTEP platform-based DNA epitope vaccine targeting N-terminus of tau induces strong immune responses and reduces tau pathology in THY-Tau22 mice. Vaccine 2017; 35(16):2015–2024.
89. Matsumoto Y, Niimi N & Kohyama K. Development of a New DNA Vaccine for Alzheimer Disease Targeting a Wide Range of Aβ Species and Amyloidogenic Peptides. PLoS ONE 2013; 8(9):e75203. doi:10.1371/journal.pone.0075203
90. Xing XN, Zhang WG, Sha S, Li Y, Guo R, Wang C & Cao YP. Amyloid β 3-10 DNA vaccination suggests a potential new treatment for Alzheimer’s disease in BALB/c mice. Chinese Medical Journal 2011; 124(17):2636–2641.
91. Olkhanud PB, Mughal M, Ayukawa K, Malchinkhuu E, Bodogai M, Feldman N, Rothman S, Lee JH, Chigurupati S, Okun E, Nagashima K, Mattson MP & Biragyn A. DNA immunization with HBsAg-based particles expressing a B cell epitope of amyloid β-peptide attenuates disease progression and prolongs survival in a mouse model of Alzheimer’s disease. Vaccine 2012; 30(9):1650–1658.
92. Qu B, Boyer PJ, Johnston SA, Hynan LS & Rosenberg RN. Abeta42 gene vaccination reduces brain amyloid plaque burden in transgenic mice. Journal of the Neurological Sciences 2006; 244(1-2):151–158.
93. Prins ND & Scheltens P. Treating Alzheimer’s disease with monoclonal antibodies: current status and outlook for the future. In Alzheimer’s Research & Therapy 2013; 5(6):56.
94. Panza F, Solfrizzi V, Imbimbo BP, Tortelli R, Santamato A &LogroscinoG. Amyloid-based immunotherapy for Alzheimer’s disease in the time of prevention trials: the way forward. In Expert Review of Clinical Immunology 2014; 10(3):405–419.
95. Moreth J, Mavoungou C &Schindowski K. Passive anti-amyloid immunotherapy in Alzheimer’s disease: What are the most promising targets? In Immunity & Ageing 2013; 10(1):18.
96. Morgan D. Immunotherapy for Alzheimer’s disease. In Journal of Internal Medicine 2011; 269(1):54–63).
97. Bard F, Cannon C, Barbour R, Burke R-L, Games D, Grajeda H, Guido T, Hu K, et al. Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nature Medicine 2000; 6(8):916–919.
98. Montoliu-Gaya L & Villegas S. Aβ-Immunotherapeutic strategies: a wide range of approaches for Alzheimer’s disease treatment. Expert Reviews in Molecular Medicine 2016; 18.
99. Frost JL, Liu B, Kleinschmidt M, Schilling S, Demuth H-U &Lemere CA. Passive Immunization against Pyroglutamate-3 Amyloid-β Reduces Plaque Burden in Alzheimer-Like Transgenic Mice: A Pilot Study. Neurodegenerative Diseases 2012; 10(1-4):265–270.
100. Venkataramani V, Wirths O, Budka H, Härtig W, Kovacs GG & Bayer TA. Antibody 9D5 Recognizes Oligomeric Pyroglutamate Amyloid-β in a Fraction of Amyloid-β Deposits in Alzheimer’s Disease without Cross-Reactivity with other Protein Aggregates. Journal of Alzheimer’s Disease 2012; JAD29(2):361–371.
101. Black RS, Sperling RA, Safirstein B, Motter RN, Pallay A, Nichols A & Grundman M. A single ascending dose study of bapineuzumab in patients with Alzheimer disease. Alzheimer Disease and Associated Disorders 2010; 24(2):198–203.
102. Sperling R, Salloway S, Brooks DJ, Tampieri D, Barakos J, Fox NC, Raskind M, et al. Amyloid-related imaging abnormalities in patients with Alzheimer’s disease treated with bapineuzumab: a retrospective analysis. Lancet Neurology 2012; 11(3):241–249.
103. Bagyinszky E, Youn YC, An SSA & Kim S. The genetics of Alzheimer’s disease. Clinical Interventions in Aging 2014; 9:535–551.
104. Blennow K, Zetterberg H, Rinne JO, Salloway S, Wei J, Black R, Grundman M, Liu E & for the AAB-001 201/202 Investigators Effect of Immunotherapy With Bapineuzumab on Cerebrospinal Fluid Biomarker Levels in Patients With Mild to Moderate Alzheimer Disease. Archives of Neurology 2012; 69(8):1002–1010
105. Sperling RA, Jack CR, Jr Black SE, Frosch MP, Greenberg SM, Hyman BT, Scheltens P. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimer’s &Dementia: The Journal of the Alzheimer’s Association 2011; 7(4):367–385.
106. Aisen, P.S. Failure After Failure. What Next in AD Drug Development?. J Prev Alzheimers Dis 2019; 6:150.
107. Siemers ER, Sundell KL, Carlson C, Case M, SethuramanG, Liu-Seifert H, Dowsett SA, Pontecorvo MJ, Dean RA &Demattos R. Phase 3 solanezumab trials: Secondary outcomes in mild Alzheimer’s disease patients. Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association 2016; 12(2):110–120.
108. Dodart JC, Bales KR, Gannon KS, Greene SJ, DeMattos RB, Mathis C, DeLong CA, Wu S, Wu X, Holtzman DM & Paul SM. Immunization reverses memory deficits without reducing brain Aβ burden in Alzheimer’s disease model. Nature Neuroscience 2002; 5(5):452–457.
109. Mably AJ, Liu W, Mc Donald JM, Dodart JC, Bard F, Lemere CA, O’Nuallain B & Walsh DM. Anti-Aβ antibodies incapable of reducing cerebral Aβ oligomers fail to attenuate spatial reference memory deficits in J20 mice. In Neurobiology of Disease 2015; 82:372–384.
110. Farlow M, Arnold SE, van Dyck CH, Aisen PS, Joy Snider B, Porsteinsson AP, Friedrich S, et al. Safety and biomarker effects of solanezumab in patients with Alzheimer’s disease. In Alzheimer’s & Dementia 2012; 8(4):261–271.
111. Neurology TL & The Lancet Neurology. Solanezumab: too late in mild Alzheimer’s disease? In The Lancet Neurology 2017; 16(2):97.
112. Topline Result for First DIAN-TU Clinical Trial: Negative on Primary 10 Feb 2020
113. updated May 2020
114. Bateman RJ, Benzinger TL, Berry S, Clifford DB, Duggan C, Fagan AM, Fanning K, et al. The DIAN-TU Next Generation Alzheimer’s prevention trial: Adaptive design and disease progression model. Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association 2017; 13(1):8–19.
115. Sperling RA, Rentz DM, Johnson KA, Karlawish J, Donohue M, Salmon DP & Aisen P. The A4 Study: Stopping AD Before Symptoms Begin? Science Translational Medicine 2014; 6(228):228fs13–fs228fs13.
116. Bohrmann B, Baumann K, Benz J, Gerber F, Huber W, Knoflach F, Messer J, Oroszlan K. Gantenerumab: A Novel Human Anti-Aβ Antibody Demonstrates Sustained Cerebral Amyloid-β Binding and Elicits Cell-Mediated Removal of Human Amyloid-β. Journal of Alzheimer’s Disease: JAD 2012; 28(1):49–69.
117. Ostrowitzki S, Lasser RA, Dorflinger E, Scheltens P, Barkhof F, Nikolcheva T, Ashford E, et al. A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease. Alzheimer’s Research & Therapy 2017; 9(1):1–15.
118. High-Dose Gantenerumab Lowers Plaque Load 13 Dec 2017
119. updated 25 January 2021
120. Ultsch M, Li B, Maurer T, Mathieu M, Adolfsson O, Muhs A, Pfeifer A, Pihlgren M. Structure of Crenezumab Complex with Aβ Shows Loss of β-Hairpin. Scientific Reports 2016; 6:39374.
121. Adolfsson O, Pihlgren M, Toni N, Varisco Y, Buccarello AL, Antoniello K, Lohmann S, et al. An Effector-Reduced Anti-β-Amyloid (Aβ) Antibody with Unique Aβ Binding Properties Promotes Neuroprotection and Glial Engulfment of Aβ. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience 2012; 32(28):9677–9689.
122. Cummings JL, Cohen S, van Dyck CH, Brody M, Curtis C, Cho W, Ward M, et al. ABBY: A phase 2 randomized trial of crenezumab in mild to moderate Alzheimer disease. Neurology 2018; 90(21):e1889–e1897.
123. Tariot PN, Lopera F, Langbaum JB, Thomas RG, Hendrix S, Schneider LS, Rios-Romenets S, et al. The Alzheimer’s Prevention Initiative Autosomal-Dominant Alzheimer’s Disease Trial: A study of crenezumab versus placebo in preclinical PSEN1 E280A mutation carriers to evaluate efficacy and safety in the treatment of autosomal-dominant Alzheimer’s disease, including a placebo-treated noncarrier cohort. Alzheimer’s & dementia (New York, N. Y.) 2018; 4:150–160.
124. Porte SLL, La Porte SL, Bollini SS, Lanz TA, Abdiche YN, Rusnak AS, Ho W.H, et al. Structural Basis of C-terminal β-Amyloid Peptide Binding by the Antibody Ponezumab for the Treatment of Alzheimer’s Disease. In Journal of Molecular Biology 2012; 421(4-5):525–536).
125. Landen JW, Zhao Q, Cohen S, Borrie M, Woodward M, Billing CB, Jr Bales K, Alvey C, McCush F, Yang J, Kupiec JW & Bednar MM. Safety and pharmacology of a single intravenous dose of ponezumab in subjects with mild-to-moderate Alzheimer disease: a phase I, randomized, placebo-controlled, double-blind, dose-escalation study. Clinical Neuropharmacology 2013; 36(1):14–23.
126. Topline Results: 18 Months of BAN2401 Might Work 7 Jul 2018
127. Logovinsky, V., Satlin, A., Lai, R., Swanson, C., Kaplow, J., Osswald, G., Basun, H., & Lannfelt, L. Safety and tolerability of BAN2401–a clinical study in Alzheimer’s disease with a protofibril selective Aβ antibody. Alzheimer’s Research & Therapy 2016 ;8(1), 14.
128. Vellas B, Aisen P. New Hope for Alzheimer’s Disease. J Prev Alzheimers Dis 2021; 8, 238–239.
129. Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, DunstanR, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature 2016; 537(7618):50–56).
130. Aducanumab, Solanezumab, Gantenerumab Data Lift Crenezumab, As Well 10 Aug 2015
131. Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature 2016; 537(7618):50-6. PubMed.
132. Keep Your Enthusiasm? Scientists Process Brutal Trial Data 16 May 2019
133. ‘Reports of My Death Are Greatly Exaggerated.’ Signed, Aducanumab 24 Oct 2019
134. Biogen Asks FDA To Approve Aducanumab 8 Jul 2020
135. Advisory Committee Again Urges FDA to Vote No on Aducanumab 14 Apr 2021
136. Aducanumab Approved to Treat Alzheimer’s Disease 7 Jun 2021
137. Szabo P, Mujalli DM, Rotondi ML, Sharma R, Weber A, Schwarz H-P, Weksler ME & Relkin N. Measurement of anti-beta amyloid antibodies in human blood. Journal of Neuroimmunology 2010; 227(1-2):167–174
138. Relkin NR, Szabo P, Adamiak B, Burgut T, Monthe C, Lent RW, Younkin S, Younkin L, Schiff R & Weksler ME. 18-Month study of intravenous immunoglobulin for treatment of mild Alzheimer disease. Neurobiology of Aging 2009; 30(11):1728–1736.
139. Imbimbo BP, Ippati S, Ceravolo F, Watling M. Perspective: Is therapeutic plasma exchange a viable option for treating Alzheimer’s disease?. Alzheimer’s & Dementia: Translational Research & Clinical Interventions 2020; 6(1):e12004.
140. Loeffler DA. AMBAR, an Encouraging Alzheimer’s Trial That Raises Questions. Frontiers in Neurology, 2020; 11:459.
141. Liu YH, Giunta B, Zhou HD, Tan J, Wang YJ. Immunotherapy for Alzheimer disease: the challenge of adverse effects. Nat Rev Neurol. 2012 Aug;8(8):465-9.