The manifestation of the symptoms of Alzheimer’s disease usually begins in individuals of over 65 years and consists of a progressive neurodegenerative disorder, which is responsible for cognitive, behavioral and various functional abnormalities [1]. The pathogenesis and progression of the disease are associated with the appearance of amyloid plaques and neurofibrillary tangles, with consequent loss of synapses and neurons [2]. Amyloid-β peptide constitutes the plaques, whereas tau protein is involved in the production of the tangles [3]. Among all the neurodegenerative disorders, Alzheimer’s disease has the highest incidence and affects 47 million people in the world [1-4]. Unfortunately, the occurrence of Alzheimer’s disease is destined to increase in the future, due to the overall aging of the world population [1-4]. One important consideration is that the prevalences of biologically defined Alzheimer disease and clinically defined probable Alzheimer disease differ significantly, up to 3 folds [5].

Currently, there are two types of therapeutic approaches for the treatment of Alzheimer’s disease: (I) the so-called disease-modifying therapies (DMTs), which are designed to avoid and/or postpone the onset of the illness, or at least to retard the progression of the clinical course of the malady; (II) medications/drugs for the improvement of cognition and/or the neuropsychiatric manifestations affecting the symptomatic stages of the disease, in order to enhance the memory and amending at least partially the compromised behavior of the patients.

Previous clinical trials mainly targeted the amyloid-β peptide in subjects with the advanced clinical course of the disease [3]. Even though pharmaceutical industries invested billions of dollars for the development of drugs, clinical testing failed to provide efficacious medications for the treatment of patients with Alzheimer’s disease [6, 7]. Small drugs and immunotherapies did not exhibit significant clinical benefits in patients, when compared with placebo controls [6-10]. In addition, high levels of toxicities were reported in a number of clinical trials [6-10]. A retrospective study analyzed clinical trials conducted from 2002 to 2012 [6]. In that period, there were 244 medications tested in 413 trials, which comprised 124 phase I, 206 phase II and 83 phase III clinical studies. Among 244 drugs, only one was approved to be introduced in the market, which constitutes an approval success rate of 0.4% over an entire decade [6].

There are several factors that may account for the exceedingly high rate of failure in producing efficient medications for the treatment of Alzheimer’s disease. For instance, the majority of clinical trials used to enroll patients with an advanced course of the disease and, probably, it was already too late to achieve an effective therapeutic intervention [6, 7]. Another possible cause for therapeutic setbacks is most likely related to the consistency of amyloid plaques, which have been present probably for a decade, by the time the early symptoms of the illness become apparent in the patient [8-10]. Naturally, the presence of amyloid plaque during the asymptomatic period contributes to the production of bigger amyloid deposits in the brain of symptomatic patients and, ultimately, in neuronal death [8-10]. Last, but not least, the biology of Alzheimer’s disease is still not sufficiently characterized, in order to develop effective medications. On these grounds, the treatments may not be directed against the correct target and/or the doses may not be sufficient, along with other parameters of the clinical protocols, which are probably not particularly accurate [6, 7].

This article provides an overview of the different drugs that have been used in phase III clinical trials for the treatment of patients with Alzheimer’s disease in the last two years. In this respect, a major emphasis has been placed on the assessment of the therapeutic efficacy among the participants of the trials. Phase I clinical trials are mainly focused on the evaluation of toxicity and other possible adverse effects, rather than determining eventual clinical benefits in patients. For this reason, drugs that are still in early phase clinical trials will not be discussed in this review. There are other reviews on Alzheimer's Disease therapeutics development pipeline [11].

The improvement of therapeutic interventions for the treatment of patients with Alzheimer’s disease is at the top of the agenda both for clinicians and pharmaceutical industries. In this respect, the collection and analysis of various clinical data is essential for the elaboration of new protocols and/or the development of improved therapeutics for the treatment of the disease. Patients are monitored during the clinical trials with positron emission tomography (PET) and/or detection of biomarkers that are present in cerebrospinal fluids [6-8, 8-10]. This section describes the list of medications that were utilized in phase III and phase II clinical trials, which are either completed, or currently active and not recruiting new patients. Table 1 shows a summary of the drugs that were applied in phase III clinical trials, whereas the medications used in phase II clinical trials are listed in Table 2.

The sponsor is Avanir Pharmaceuticals. AVP-786 stands for deuterated (d6)-dextromethorphan/quinidine, which is a small molecule designed to function as Sigma 1 receptor against and NMDA receptor antagonist [12]. Deuteration and the presence of quinidine increase the plasma half-life of dextromethorphan and facilitate the penetration of the compound into the brain. Specifically, deuterium and quinidine slow down the hepatic metabolism of dextromethorphan.

AVP-786 was utilized in the phase III NCT02442765 clinical trial to calm agitation in patients with dementia of the Alzheimer’s disease type. The trial involved 410 patients that were divided into three groups. AVP-786 was administered orally twice a day at two different doses for a total period of 12 weeks. The two doses were not specified. A third group of patients were treated with an unspecified dose of placebo, twice a day for a period of 12 weeks.

AVP-923 consists of dextromethorphan-quinidine and was utilized in a phase II clinical trial to control agitation in 200 patients with Alzheimer’s disease-related dementia [12]. AVP-923 was well tolerated by the patients, who exhibited a reduction of agitation. This finding prompted FDA to approve the use of AVP-786 in the NCT02442765 phase III clinical trial.

The sponsor is Axsome Therapeutics, Inc. AXS-05 is a small molecule designed to improve neuropsychiatric symptoms by calming agitation, which functions as Sigma-1 receptor agonist and NMDA receptor antagonist. The status of this phase III clinical trial is completed and involved 366 patients with Alzheimer’s disease-related dementia.

The participants in the clinical trial were divided into three groups: one active treatment group received AXS-05, a second active treatment group received Bupropion, whereas a control group was treated with the corresponding dose of placebo. The compounds were administered orally for 5 weeks. The dosage and the frequency of the treatments were not specified by the investigators.

ClinicalTrials.gov identifier: NCT03887455. The sponsor is Eisai Inc., with the collaboration of Biogen. The status of this phase III clinical trial is recruiting and will involve 1566 patients with early stage Alzheimer’s disease. BAN2401 is an anti-amyloid monoclonal antibody designed to reduce beta-amyloid deposits in the brain. A previous phase IIb clinical trial was conducted for the treatment of 800 patients with early Alzheimer’s disease (see ClinicalTrials.gov identifier: NCT01767311, in the phase II clinical trials section). In the phase III clinical trial protocol, BAN2401 will be administered biweekly as i.v. infusions, for 18 months, at a dose of 10 mg/Kg. The treatment will be followed by an extension period up to 45 months, with the same regimen. The study design also includes a placebo control.

ClinicalTrials.gov identifier: NCT03605667. The sponsor is Biohaven Pharmaceuticals, Inc., with the collaboration of Alzheimer's Disease Cooperative Study (ADCS). The status of this phase III clinical trial is active and not recruiting and involves 350 patients with mild to moderate Alzheimer’s disease. BHV-4157 is a small molecule designed to function as neuroprotective agent, by reducing the synaptic levels of glutamate (https://www.alzforum.org/therapeutics/troriluzole).

BHV-4157 is administered orally, every day, at a dose of 280 mg, for 48 weeks. Patients have been divided into two groups: one group is receiving active treatment, whereas the second group is receiving the equivalent dose of a placebo.

ClinicalTrials.gov identifier: NCT02565511. The sponsor is Novartis Pharmaceuticals, with the collaboration of Banner Alzheimer's Institute, the National Institute on Aging (NIA), Alzheimer's Association and Amgen. The status of this phase III clinical trial is active and not recruiting and involves 480 participants, who are at risk of developing the clinical symptoms of Alzheimer's disease. CAD106 is also termed amilomotide and consists of a vaccine against amyloid deposits. CAD106 contains multiple copies of the Aβ1-6 peptide, which are assembled into virus-like particles. CAD106 was designed to elicit the production of antibodies against amyloid proteins, without inducing inflammatory T cell activation [22]. CNP520 is also termed umibecestat and is a small molecule that targets the beta secretase cleaving enzyme (BACE)-1 [23].

Doses of CAD106 (450 µg) and Alum (450 µg) are injected intramuscularly at week 1, 7, 13 and quarterly thereafter. A placebo is administered with the same modality. The active treatment group is also receiving oral doses of 50 mg of CNP520, whereas the control group is receiving a placebo also for CNP520. The frequency of CNP520 administration was not specified by the investigators.

ClinicalTrials.gov identifier: NCT03131453. The sponsor is Novartis Pharmaceuticals, with the collaboration of Amgen and Banner Alzheimer's Institute. The status of this phase III clinical trial is active and not recruiting and involves 1145 participants at risk for the onset of clinical symptoms of Alzheimer's Disease. CNP520 is a small molecule designed to inhibit BACE-1, which regulates the proteolytic processing of APP [23].

CNP520 is administered orally on a daily basis. The participants have been divided into three cohorts: one group receives 50 mg dose of CNP520, a second group is treated with a 15 mg dose of CNP520, whereas a third group of participants receives a placebo. The placebo dosage was not specified. The trial is event-driven and it will last at least 60 months, with the possibility of an extension up to a maximum of 84 months.

ClinicalTrials.gov identifier: NCT02670083. The sponsors are Roche and Genentech. The number of participants is 813 patients with prodromal to mild Alzheimer’s disease. Crenezumab is an anti-amyloid β antibody [13]. Fifty percent of the participants are receiving intravenous injections of crenezumab, whereas the remaining fifty percent of patients are treated with intravenous injections of placebo. Both treatments are administered every 4 weeks, for a total of 100 weeks. No clinical results have been posted yet on the ClinicalTrials.gov site. A previous phase II clinical trial utilized crenezumab and placebo control in 91 patients with mild-to-moderate progression of the disease [13]. The treatment was well tolerated by the patients [13]. However, the phase II trial did not meet the primary endpoint. Probably, the dose of crenezumab was not sufficient for an efficient treatment of the disease. This finding prompted for subsequent clinical studies with higher doses of crenezumab to be tested in patients with an earlier stage of the disease. This new clinical protocol was utilized in the current phase III clinical trial.

On January 30th, 2019, Roche announced the decision to discontinue the crenezumab phase III clinical trial. Although the treatment was safe in patients, the analysis conducted by the Independent Data Monitoring Committee indicated that crenezumab was not likely to provide significant clinical benefits among the participants in the trial.

Crenezumab has been shown to reduce the level of oligomeric amyloid beta protein in CSF [24].

ClinicalTrials.gov identifier: NCT02956486. The sponsor is Eisai Co., Ltd., with the collaboration of Biogen. The status of this phase III clinical trial is active and not recruiting and involves 950 patients with early Alzheimer’s disease. E2609 is a small molecule designed to inhibit the beta secretase cleaving enzyme (BACE)-1, in order to reduce the production of the amyloid precursor protein (APP) [25].

E2609 is administered orally, at a daily dose of 50 mg, for a total period of 24 months. A group of patients is receiving a placebo treatment, with the same dosage. The patients that will complete the first stage of the core study will continue the treatment, with daily doses of 50 mg, for other 24 months.

ClinicalTrials.gov identifier: NCT02913664. The sponsor is University of Texas Southwestern Medical Center, with the collaboration of Texas Health Resources, University of Kansas Medical Center, Washington University School of Medicine, Pennington Biomedical Research Center and Michigan State University. The status of this phase III clinical trial is active and not recruiting and involves 513 senior individuals that are at risk for Alzheimer’s disease and/or vascular dementia. The risk factors that have been included in the clinical trial comprise physical inactivity, high blood pressure and hyperlipidemia. Losartan is an angiotensin II receptor blocker, amlodipine is a calcium channel blocker, whereas atorvastatin reduces the leves of lipids in the blood.

One group of patients is taking part in supervised aerobic training for a period of 2 years, while is receiving the regular doctor’s recommendation for the control of high blood pressure and the presence of lipids in the blood. A second group of patients is receiving losartan and amlodipine to reduce systolic blood pressure below 130mmHg, in combination with supervised aerobic training for a period of 2 years. The placebo group is receiving the standard care for the management of blood pressure and hyperlipidemia, in addition to stretching exercise.

ClinicalTrials.gov identifiers: NCT02051608 and NCT01224106. Roche is the sponsor for the two trials, which are currently active and not recruiting. The NCT02051608 trial involves 389 participants with mild Alzheimer’s disease, whereas the NCT01224106 trial has enrolled 799 patients with prodromal Alzheimer's disease. Gantenerumab is an anti-amyloid monoclonal antibody. No clinical results have been posted yet on the ClinicalTrials.gov site.

For the NCT02051608 trial, patients are receiving either a subcutaneous injection every 4 weeks of gantenerumab, or a subcutaneous injection every 4 weeks of placebo. Treatments will be conducted for a total of 104 weeks. Pharmacokinetics will be monitored for 152 weeks. Patients will be kept under observation for possible adverse effects for 7 years, after the conclusion of the trial.

For the NCT01224106 trial, patients are receiving subcutaneous injections of either gantenerumab at 105 mg or 225 mg, or the corresponding dose of placebo. In the first part of the trial, the injections are administered every 4 weeks for approximately 2 years. At the end of the first part of the trial, the participants will have the option to continue the treatment for other 2 years. Upon completion of the second part of the trial, the patients will receive subcutaneous injections of gantenerumab at 105 mg, 225 mg, or up to 1200 mg, every 4 weeks for three years.

Previous phase III clinical trials did not produce clinical benefits in patients [15]. Nevertheless, a dose-dependent reduction in the standardized uptake value ratio (SUVR) of brain amyloid beta was observed among the participants. This finding is likely to suggest that higher doses of gantenerumab might lead to some clinical benefits in patients, which prompted for the activation of the two aforementioned phase III clinical trials (NCT02051608 and NCT01224106).

It is also part of ClinicalTrials.gov identifier: NCT01760005, which also includes solanezumab. The sponsor is Washington University School of Medicine, in collaboration with Eli Lilly and Company, Hoffmann-La Roche, Alzheimer's Association, National Institute on Aging (NIA), Avid Radiopharmaceuticals, Accelerating Medicines Partnership (AMP) and Janssen, LP. The status of this phase II/III clinical trial is active and not recruiting. Gantenerumab and solanezumab are anti-amyloid monoclonal antibodies [15, 26, 27] and were utilized in a phase II and phase III clinical protocols, respectively. The phase II/III clinical trial enrolled 490 individuals carrying a genetic mutation that is associated with Alzheimer’s disease [28]. The participants were therefore either at risk, or were already diagnosed with an early onset of Alzheimer’s disease at the time of the trial. Gantenerumab was administered every 4 weeks by subcutaneous injections at escalating doses, whereas solanezumab was injected intravenously every 4 weeks at escalating doses. Fifty percent of patients received the same doses of placebo controls for the two therapeutic agents.

ClinicalTrials.gov identifier: NCT02293915. The sponsor is Shanghai Green Valley Pharmaceutical Co., Ltd. The status of this phase III clinical trial is completed and involved 818 patients with mild to moderate Alzheimer's disease. GV-971 is a small molecule designed to inhibit the aggregation of amyloid deposits. The active treatment group received oral administration of 900 mg GV-971 twice a day for a total period of 24 weeks. The corresponding dose of placebo was administered to the patients of the control group. The drug was approved by Chiense regulatory authority for clinical use in Nov 2019.

ClinicalTrials.gov identifier: NCT01767909. The title of this phase III trial is SNIFF, which is the acronym for the “study of nasal insulin in the fight against forgetfulness”. The sponsor is the University of Southern California. This trial involves 240 patients either with amnestic mild cognitive impairment, or mild Alzheimer’s disease. Insulin is a metabolic agent, which might act as a cognitive enhancer by optimizing cell signaling and by promoting neurogenesis in the brain [16-18]. Insulin can be easily introduced into the central nervous system through a simple intranasal administration [16-18]. The treatment of patients with amnestic mild cognitive impairment is a phase II trial, whereas the treatment of patients with mild Alzheimer’s disease is a phase III trial. No clinical results have been posted yet on the ClinicalTrials.gov site.

A previous phase II clinical trial conducted on 173 patients either with mild cognitive impairment, or Alzheimer’s disease showed that intranasal administration of insulin was safe (clinicaltrials.gov identifier: NCT00438568) [18]. No substantial variation in levels of cerebrospinal fluid biomarkers was reported among patients treated with insulin. However, some alterations in amyloid β42 levels and in the ratio of tau protein versus amyloid β42 were observed in the cerebrospinal fluid of a number of patients, which were correlated with detectable positive changes in memory and function [18]. The patients of the placebo control group exhibited reduced fludeoxyglucose F 18 uptake in the parietotemporal, frontal, precuneus and cuneus regions [18]. These findings suggested extending the intranasal insulin treatment period both in patients with amnestic mild cognitive impairment and in patients with mild Alzheimer’s disease [18]. This new protocol was utilized in the current clinical trial (NCT01767909).

ClinicalTrials.gov identifier: NCT02817906. The sponsor is Intra-Cellular Therapies, Inc. The status of this phase III clinical trial is terminated, following an interim analysis that indicated futility. However, the termination of the clinical trial was not related to adverse effects in patients, as compound was well tolerated.

ITI-007 is a 5-HT2A antagonist for the modulation of the dopamine receptor, which was designed to calm agitation in 177 patients with dementia and/or Alzheimer’s disease. The active treatment group received an oral administration of 9 mg of ITI-007 for a total period of 4 weeks, whereas the control group received an analogous dose of a placebo. The reason of the clinical inefficacy in patients was not determined.

ClinicalTrials.gov identifier: NCT02346201. The sponsor is Johns Hopkins Bloomberg School of Public Health, with the collaboration of the National Institute on Aging (NIA). The status of this phase III clinical trial is active and not recruiting and involves 200 patients with a not specified stage of Alzheimer’s disease.

Methylphenidate is a small molecule designed to decrease the neuropsychiatric symptoms that are related to apathy in patients with Alzheimer’s disease [29-31]. The biological function of methylphenidate consists of inhibiting the dopamine transporter, which removes the dopamine from the synaptic cleft to place it back into the neuronal cytosol.

Methylphenidate is administered orally at a total daily dose of 20 mg, over a period of 6 months. Each patient of the active treatment group is receiving two 5 mg tablets, twice a day. The patients of the control group receive an analogous dose of the placebo.

ClinicalTrials.gov identifier: NCT03031184. The sponsor is the University of Sussex, with the collaboration of Norwich Clinical Trials Unit, University of East Anglia, University of Cambridge, University College of London, London School of Economics and Political Science, University of Manchester, University of Newcastle Upon-Tyne, Birmingham and Solihull Mental Health NHS Foundation Trust, Alzheimer's Society and The Centre for Dementia Studies, Brighton and Sussex Medical School and SPFT. The status of this phase III clinical trial is active and not recruiting and involves 222 patients with Alzheimer’s disease and agitated behavior.

Mirtazapine is a small molecule that antagonizes the alpha-1 adrenergic receptor and was designed to function as an antidepressant [32-34]. Mirtazapine is administered orally. The active treatment groups received a daily dose of 15 mg for the first two weeks. The dose escalates to 30 mg per day for 4 weeks. If no adverse effects are observed, the dose will be increased to a daily dose of 45 mg until the completion of the trial, which will last for a total of 12 weeks. The control group pf patents is receiving the same dosage of a placebo.

ClinicalTrials.gov identifier: NCT01953601. The status of the trial is terminated. The sponsors are Merck Sharp & Dohme Corp. Verubecestat is an anti-amyloid agent, which inhibits the beta secretase cleaving enzyme BACE-1. This phase III trial assessed the safety and efficacy of the compound in 1454 patients with prodromal Alzheimer's disease [19]. The trial was discontinued due to severe adverse effects observed among the patients, such as falls and injuries, suicidal ideation, rash, sleep disorder, weight loss and hair-color change [20]. In addition, no clinical benefit was observed among the participants that were treated with verubecestat. Probably, the dose of the medication was not sufficient. However, the dosage of verubecestat cannot be increased in a new trial, because of its elevated levels of toxicity in patients.

ClinicalTrials.gov identifier: NCT01872598. The sponsor is AB Science. The status of this phase III clinical trial is active and not recruiting and involves 721 patients with mild to moderate Alzheimer’s disease. Masitinib is a small molecule. which was designed to function as an anti-inflammatory through the modulation of the activity of mast cells [35].

Masitinib is administered orally twice a day, over a period of 6 months. There are three active treatment groups at different doses:

1. Masitinib fixed dose (4.5 mg/kg/day).
2. Masitinib fixed dose (3 mg/kg/day)
3. Masitinib at 4.5 mg/kg/day for the first three months of treatment, which will be increased to 6 mg/kg/day for the remaining three months.

Two groups of patients are treated with a placebo either at a fixed dose, or with escalating doses as described above. The fixed dose was not specified by the investigators.

ClinicalTrials.gov identifier: NCT02351882. The sponsor is Sunnybrook Health Sciences Centre. Nabilone is a cannabinoid-derived small molecule that was designed to control neuropsychiatric symptoms and calm agitation [36, 37]. The status of this phase III clinical trial is completed and involved 38 patients with moderate to severe Alzheimer’s disease with agitation [38-40].

Nabilone was administered orally. The active treatment group of patients received daily doses of nabilone for 6 weeks, followed by one-week washout treatment with a placebo. At the end of the washout period, the active treatment group received a further 6 weeks treatment. The nabilone doses were not specified by the investigators. The control group of patients received a placebo for the entire duration of the clinical trial (13 weeks).

The results have been published and indicated that the use of nabilone is safe and effective in controlling agitation in patients with Alzheimer’s disease [38-40]. In addition, nabilone had beneficial effects in increasing appetite and reducing pain among the active treatment group of participants of the clinical trial.

ClinicalTrials.gov identifier: NCT02992132. The sponsor is ACADIA Pharmaceuticals Inc. The status of this phase II trial is completed and involved 111 patients with probable Alzheimer’s disease, according to the guidelines of the National Institute on Aging-Alzheimer's Association (NIA-AA). Pimavanserin is a serotonin-boosting antipsychotic that functions as an inverse agonist of the 5-HT2A receptor, which was initially utilized for the treatment of patients affected by Parkinson's disease-derived hallucinations and delusions [41]. Subsequently, the compound was applied for the control of agitation and aggression in patients with Alzheimer’s disease [42, 43]. No results have been posted yet for this trial on clinicaltrials.gov.

A previous phase II clinical trial conducted in the U.K. for the treatment of patients with Alzheimer’s disease showed that pimavanserin had no detrimental effects on cognition or motor function measures, however, no substantial benefit was reported among the majority of the participants in the trial after a period of 12 weeks [44]. The investigators considered two possible interpretations for the lack of clinical benefits: either the effects of the compound are transient, or a worsening of the conditions of the placebo group affected the final outcome of the study. Interestingly, pimavanserin treatment exhibited significant benefits in patients with more severe psychotic symptoms [43]. On these grounds, longer periods of treatment were proposed.

For the phase II NCT02992132 clinical trial, the patients were divided into three groups. Two groups received active treatment, whereas the third group was treated with placebo. The two active treatment groups utilized two daily doses of pimavanserin, which was administered orally. Each day a group received two tablets of 17 mg, for a total of 34 mg, whereas the other group was treated with two tablets of 10 mg, for a total of 20 mg. The entire treatment lasted 12 weeks.

ClinicalTrials.gov identifier: NCT02008357. The sponsor is Eli Lilly and Company, with the collaboration of the Alzheimer's Therapeutic Research Institute. Solanezumab is an anti-amyloid monoclonal antibody. This phase III clinical trial is testing the efficacy of solanezumab in slowing down the progression of cognitive impairment in a cohort of 1150 elderly individuals, who exhibit signs of amyloid plaque formation, but do not have the symptoms of Alzheimer's disease-induced cognitive impairment, or dementia yet. Solanezumab is injected intravenously every 4 weeks for a total of 240 weeks at doses ranging from 400 to 1600 mg per injection. A group of patients is only receiving the same dosage of placebo. No results have been posted yet for this trial on clinicaltrials.gov.

A previous phase III clinical trial utilized solanezumab at a dose of 400 mg per injection, but no benefit was observed among the patients in terms of improvement of cognition and functional ability [21]. Probably, this previous phase III trial failed, because the dose of solanezumab was not sufficient to elicit clinical benefits in patients. Therefore, the dose of solanezumab was increased in the protocol of the current phase III clinical trial, which started on February 28, 2014 and will be completed on July 22, 2022 (NCT02008357).

Solanezumab is also part of ClinicalTrials.gov identifier: NCT01760005, which includes gantenerumab. See above about gantenerumab for details about NCT01760005.

A recent phase I clinical study utilized focused ultrasound for the transient opening of the blood-brain-barrier in patients with Alzheimer’s disease to enhance the therapeutic effects of aducanumab infusions [45]. Aducanumab is a monoclonal antibody against amyloid-beta (Aβ). Three patients were enrolled in the study. Focused ultrasound was selectively administered in a region of the brain of patients with Alzheimer’s disease, who received infusions of aducanumab once a month, for a total period of six months. Fluorine-18 florbetaben positron-emission tomography was used to assess the overall reduction of Aβ levels among the participants of the trial. In all cases, the region of the brain that was treated with focused ultrasound exhibited lower levels of Aβ than the untreated contralateral hemisphere of the brain. Safety evaluations and cognitive tests were conducted over a period ranging from 30 to 180 days post-treatment. Magnetic resonance imaging (MRI) was used to direct low-intensity focused ultrasound. In addition to Alzheimer’s disease [46-49], focused ultrasound may be utilized to enhance the efficiency of therapeutic agents for the treatment of other neurodegenerative diseases, such as brain tumors [50-52], Parkinson’s disease [53] and amyotrophic lateral sclerosis [54].