Skip to main content
NCBI home page
Dementia & Neuropsychologia logoLink to Dementia & Neuropsychologia
. 2025 Sep 1;19:e20240243. doi: 10.1590/1980-5764-DN-2024-0243

Efficacy of medications in controlling cognitive dysfunction in Alzheimer’s : a systematic review

Eficácia de medicamentos no controle da disfunção cognitiva em Alzheimer: uma revisão sistemática

Sâmia Moreira de Andrade 1, Ítalo Sávio Mendes Rodrigues 2, Luís Marcelo Vieira Rosa 3, Rodrigo Luís Taminato 4, Gustavo Alves Andrade dos Santos 5,6,7
PMCID: PMC12377826  PMID: 40860505

ABSTRACT

Dementia is one of the biggest global health crises of the 21st century. It is known that Alzheimer’s disease (AD) is the most common cause of dementia. Therefore, developing drugs with the potential to alter disease progression has been a priority.

Objective:

This study aims to review the efficacy and safety of drugs for AD.

Methods:

Based on the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) document, a systematic review was carried out in different databases. The Alzheimer’s Disease Assessment Scale (ADAS-Cog) was used as the primary outcome. The risk of bias was checked using the Risk of Bias in Randomized Trials (RoB 2).

Results:

A systematic review resulted in 64 articles which were included in the analysis. The main medications discussed were: donepezil, which demonstrated a significant improvement in cognitive function, with good tolerability, although it has limitations in patients with swallowing difficulties. Transdermal patches showed similar effectiveness and were recently approved. Galantamine showed benefits on cognitive function, with good tolerability. Rivastigmine was effective and presented in transdermal form with similar efficacy to capsules, but had mainly gastrointestinal adverse effects. Pioglitazone showed no significant results initially, but some studies suggest benefits in patients with AD associated with type II diabetes mellitus.

Conclusion:

The studies reviewed indicate that, although some current medications such as donepezil, galantamine, and rivastigmine have modest, well-established benefits in clinical practice, many new agents have not yet demonstrated significant efficacy in modifying AD progression.

Keywords: Alzheimer Disease, Cognitive Dysfunction, Clinical Trial

INTRODUCTION

Dementia is one of the biggest global health crises of the 21st century. Currently, more than 50 million people live with dementia worldwide 1 . It is predicted that, by 2050, the prevalence of dementia will double in Europe and triple globally, with this estimate being three times higher when based on a biological (rather than clinical) definition of Alzheimer’s disease 2 . It is known that Alzheimer’s disease (AD) is the most common cause of dementia, responsible for 60–80% of cases, and is characterized by the deterioration of cognition, function and behavior, generally starting with memory loss of recent events. Elevated levels of β-amyloid (Aβ), which form extracellular senile plaques, and hyperphosphorylated tau (p-tau), which aggregates intracellularly as neurofibrillary tangles, are found in the brain tissues of AD patients, these being the main pathological characteristics 1,3 .

Although the symptoms present in AD can be temporarily alleviated by detailed care and medication, there are no specific measures to prevent or cure Alzheimer’s disease 4 . Current therapeutic agents for dementia related to Alzheimer’s disease temporarily improve symptoms but do not alter the course of the underlying disease. Interventions aimed at removing amyloid plaques are believed to slow the clinical progression of Alzheimer’s disease. Positively, an anti-amyloid antibody (aducanumab) has received accelerated approval from the Food and Drug Administration 5 .

Still, current AD treatment with donepezil, galantamine, rivastigmine, and memantine is symptomatic only and offers modest benefits. Therefore, the development of drugs with the potential to alter disease progression has been a priority. An increasing number of clinical trials have emerged to test the efficacy of potential therapies aimed at treating AD, with β-amyloid having been the main focus for more than 30 years. However, highly promising medicines have recently failed to demonstrate clinical benefits in phase III trials, making it necessary for these data to be synthesized and disseminated 6 . Therefore, in the present review, we will discuss the efficacy in relation to cognitive dysfunction as well as the safety of potential agents tested in clinical trials in Alzheimer’s disease.

METHODS

Protocol

The protocol used followed the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) document 7 .

Eligibility criteria

The guiding question was: “What is the efficacy and safety profile of medications used or under investigation for cognitive dysfunction in Alzheimer’s disease?” For this, the acronym PICO was used: Population (Patients with Alzheimer’s), Intervention (therapeutic intervention or maintenance of therapy), Comparison or Control (between therapies used or control group), and Outcomes (stabilization or delay in the decline of cognition, function and behavior).

Randomized or non-randomized clinical trials carried out with patients with or probably diagnosed with Alzheimer’s disease were eligible, following the fourth edition of the Mental Disorders Diagnostics and Statistics Manual (DSM-IV) and the National Association of Nervous and Communicative Disorders and Stroke/ Alzheimer’s Disease Institute of Standards (NINCDS) 8 . Complete articles published in English were included, without time limits.

Exclusion criteria: duplicate articles in the databases; review articles, meeting summaries or case reports/series; non-human studies; studies without specification of the therapeutic regimen and studies that did not use the Cognitive Subscale of the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) to assess the effectiveness of treatment.

Sources of information

The databases used were Medical Literature Analysis and Retrieval System Online—Medline (via the United States National Library of Medicine—PubMed), Latin American and Caribbean Health Sciences Literature (Lilacs), Scientific Electronic Library Online (SciELO), Excerpta Medica Database (EMBASE), Cochrane Central Register of Controlled Trials (CENTRAL) and Google Scholar. All references were selected until February 17, 2024.

Paper search

The search strategy was adapted for each database, with the descriptors chosen through the list of Health Sciences Descriptors (DeCS, for Lilacs), Medical Subject Headings (Mesh, for Medline and CENTRAL) and EMTREE (for EMBASE); LILACS: Alzheimer’s Disease AND clinical trial; PubMed: (((Alzheimer’s Disease) AND (Clinical trial)) AND (efficiency)) NOT (review); CENTRAL: “Alzheimer’s disease” AND “clinical trial”; EMBASE: alzheimer AND (‘disease’/exp OR disease) AND ‘therapy’ AND ‘clinical trial’; SciELO: ((Alzheimer Disease) AND (treatment) OR (therapeutic)).

Study selection

Two researchers independently selected the articles, with discrepancies eliminated by a third reviewer. With the help of the Rayyan platform (http://rayyan.qcri.org), titles and abstracts were evaluated, in which previously selected studies of interest were read in full to confirm their inclusion.

Data collection process

Data extraction was performed by three reviewers. The variables described were: year of publication, study design, treatment regimen, duration of follow-up, efficacy, safety, side effects and comparator.

To assess efficacy, the Cognitive Subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog) was adopted as the primary clinical outcome. It is one of the most commonly used cognitive scales in clinical trials and is considered the ‘gold standard’ for evaluating anti-dementia treatments 9 .

Bias risk assessment

Two independent reviewers assessed the risk of bias using the Risk of Bias in Randomized Trials (RoB 2), a tool for analyzing randomized studies 10 . For non-randomized studies, the tool used was the Risk of Bias in Non-Randomized Studies of Interventions (ROBINS-I) 11 . The risk of bias graphs was created using the robvis tool 12 .

RESULTS

The search in the databases resulted in 3,638 articles (Figure 1). Initially, 183 duplicate articles were excluded from the databases. After screening, 185 articles were selected for full reading, of which 64 were included in the qualitative analysis.

Figure 1. Article selection flowchart (papers).

Figure 1

Open in a new tab

Therefore, the importance of synthesizing the results found so far to guide new investigations stands out. Figure 2 shows the result of the risk of bias assessment, where it is possible to observe that the majority of selected studies presented a low risk of bias, indicating that they present good quality of the evidence presented, indicating that the analysis and conclusions are less likely to be distorted by systematic errors or external influences.

Figure 2. General assessment of the risk of bias of the studies.

Figure 2

Open in a new tab

Table 1 exemplifies the medications reported in different Randomized Clinical Trials for mild to moderate Alzheimer’s Disease, which will be discussed in specific topics in this review. Among the 68 medications, the most evaluated were donepezil (n=8), galantamine (n=5) and rivastigmine (n=3), which are medications already used in clinical practice for the treatment of Alzheimer’s 13 . A direct comparison between these medications is also reported in Table 2 to facilitate comparison between them.

Table 1. Medicines evaluated in the present study.

Medicine Number of publications
Donepezil 7
Galantamine 5
Rivastigmine 3
Pioglitazone 2
Doxycycline 2
Rifampicin 2
Resveratrol 2
Metrifonate 2
Acetyl-L-carnitine (ALCAR) 1
Saffron 1
Tulrampator (S47445) 1
Fisostigmine 1
Cerebrolysin 1
Tacrine 1
Eptastigmine 1
Diclofenac 1
Misoprostol 1
PF-05212377 (SAM-760) 1
Scyllo-Inositol (ELND005) 1
Semagacestat 1
Huperzine A 1
Tideglusibe 1
Sodium selenate 1
Capric/Caprylic Acid Triglycerides 1
Vitamin D2 1
ABT-288 1
Simvastatin 1
Atomoxetine 1
Benfotiamine 1
Docosahexaenoic acid 1
Bexarotene 1
Hydroxychloroquine 1
Levetiracetam 1
Masupirdine 1
Rotigotine 1
Tarenflurbil 1
NeuroAiD™ (MLC601) 1
Octohydroaminoacridine 1
Velnacrine 1
EHT0202 (Etazolate hydrochloride) 1
Vitamin B 1
MK-7622 1
Edonerpic maleate (T-817MA) 1
Idalopirdine 1
UB-311 1
SB-742457 1
Omega-3 1
Tramiprosate 1
Velnacrine 1
Blarcamesine 1
Alphoscerate 1
Posiphen 1
Open in a new tab

Table 2. Pharmacological comparison between the most cited medications in the literature*.

Drug Pharmacological
class		 Starting dose and maximum dose Route
of administration		 Efficiency
Donepezil Acetylcholinesterase (iAChE) inhibitors Starting dose:5 mg once a day (at night, before bed).Maximum dose:10 mg once a day (for mild to moderate Alzheimer’s).23 mg once daily (for moderate to severe Alzheimer’s, in patients who have tolerated 10 mg for at least 3 months). Oral Donepezil has demonstrated modest improvements in cognition in patients with mild to moderate Alzheimer’s disease. Its effect is symptomatic, that is, it temporarily improves cognitive functions, but does not stop the progression of the disease.
Rivastigmine Acetylcholinesterase (iAChE) inhibitors and butyrylcholinesterase (BuChE) inhibitors Oral route (capsules or oral solution)Starting dose: 1.5 mg twice a dayMaximum dose: 6 mg twice a day (12 mg/day)

Transdermal route (skin patch)Initial dose: 4.6 mg/24h (1 patch per day)Maximum dose: 13.3 mg/24h (for patients who tolerate 9.5 mg/24h for at least 4 weeks).		 Oral or transdermal Rivastigmine has proven efficacy in the treatment of mild to moderate Alzheimer’s disease and dementia associated with Parkinson’s disease. Its effect is symptomatic, that is, it temporarily improves cognition and functionality, but does not stop the progression of the disease.
Galantamine Acetylcholinesterase inhibitors and nicotinic allosteric modulators Oral route (capsules or oral solution)Starting dose: 4 mg twice a dayMaximum dose: 12 mg twice a day (24 mg/day)

Transdermal route (skin patch)Initial dose: 5 mg/24h (1 patch per day)Maximum dose: 10 mg/24h		 Oral or transdermal Galantamine is effective in treating mild to moderate Alzheimer’s disease, improving cognition, functionality and neuropsychiatric symptoms. Its dual mechanism (acetylcholinesterase inhibition + nicotinic modulation) provides additional benefits over other acetylcholinesterase inhibitors.
Open in a new tab

Note: *This table addresses a comparison of cognitive effectiveness in Alzheimer’s disease between medications commonly indicated for the disease.

DISCUSSION

The studies evaluated were published between 1994 and 2025, demonstrating that clinical research on Alzheimer’s disease is an important topic that continues to this day. In fact, Alzheimer’s disease is the most common cause of dementia, which is considered one of the biggest global health crises of the 21st century 1 .

Recognition of the entire pathophysiological process involved in the onset and progress of AD should serve as the basis for the pharmacological treatment of Alzheimer’s disease. In this sense, many hypotheses about the causes and possible treatments have been established, some have already been discarded and others are in the confirmation phase. It is believed that the entire neurodegenerative process is triggered by a series of reactions involving neurotransmitters, proteins, and other molecules, some of which were previously unknown. Some elements such as lifestyle, age and comorbidities, in addition to genetic aspects, can make meaning, as long as there is some type of relationship with the disease 14 . Below, we will discuss each medication found in this review individually and in detail.

Donepezil

Donepezil is a centrally acting, rapid and reversible acetylcholinesterase inhibitor. By binding to acetylcholinesterase, it inhibits the hydrolysis of acetylcholine, thus increasing the availability of this neurotransmitter in synapses and improving cholinergic transmission 15 . The FDA approved its marketing, currently the most used medication in the treatment of dementia and cognitive symptoms in Alzheimer’s disease 16 .

The first Randomized Clinical Trials (RCTs), carried out by Rogers and colleagues in 1996 and 1998 17,18 , demonstrated that cognitive function, based on the ADAS-Cog scale, significantly improved in the 5 and 10 mg/day donepezil groups compared with the placebo in the initial 12 weeks and extended up to 24 weeks. Other clinical trials confirmed this benefit, demonstrating that this medication is effective and well tolerated 19-21 . Despite being effective, this oral medication has some limitations such as difficulty in administration when the patient is unable to swallow 22 . Therefore, it becomes necessary to develop new pharmaceutical formulations to deliver the medicine to the patient. To this end, transdermal donepezil IPI-30 patches (87.5 mg/25 cm2 of IPI-301) were tested, demonstrating similar effects to the 5 mg donepezil tablet on patients’ cognitive function after 24 weeks. The use of patches was associated with a greater number of adverse events, however mild, such as pruritus or erythema, which demonstrates safety and efficacy for patients with mild to moderate AD when compared to oral donepezil 23 . Interestingly, in relation to cognition, donepezil demonstrated a better effect when compared to galantamine, with both drugs being well tolerated, although galantamine presented more gastrointestinal adverse events than donepezil 24 . Positively, in March 2022, the FDA approved the first transdermal system for the administration of donepezil in patients with mild, moderate and severe AD 25 .

Post-treatment adverse events include: nausea, diarrhea, anorexia, vomiting, associated with cholinergic side effects, as well as headache, urinary tract infection, dizziness, agitation, insomnia, confusion, depression and anxiety 17-19 . Still, studies show that donepezil has good safety, as well as efficacy.

Galantamine

In RCTs, they demonstrated that galantamine presented significant benefits on cognitive function at doses of 16, 18, 24 and 36 mg/day 26,27 . The dose of 4 mg twice daily during weeks 1–4 and 8 mg twice daily during weeks 5–13 also showed positive results with safety and tolerability comparable to donepezil 28 . The study by Wilcock et al. 28 reported superior efficacy of galantamine in maintaining cognition and similar safety and tolerability compared to donepezil, suggesting that galantamine should be considered in the initial and long-term treatment of patients with mild to moderate Alzheimer’s disease. In fact, this drug, like donepezil, acts by inhibiting acetylcholinesterase. Additionally, galantamine exerts a positive modulation on nicotinic acetylcholine receptors, which can enhance the release of this neurotransmitter 29 .

Slow dose escalation appears to improve the tolerability of galantamine, minimizing the incidence and severity of adverse events. The incidence of adverse events in the galantamine groups presented as gastrointestinal symptoms was low and the majority of adverse events were mild, such as nausea (13% [33/261]), vomiting (6% [15/261]), dizziness (5% [13/261]) and anorexia (4% [11/261]) 26,27 .

Rivastigmine

Rivastigmine also acts as an inhibitor of the enzyme acetylcholinesterase, in addition to inhibiting butyrylcholinesterase. Since these enzymes are responsible for the degradation of acetylcholine, their use guarantees a greater concentration of this neurotransmitter in the synapse, thus improving communication between neurons and consequently cognition 30 .

RCTs demonstrate that rivastigmine provides benefits at doses of 1–4 mg/day with visible results in the first six months, which increased after 12 months. Increasing to higher doses (6–12 mg/day) was not associated with an increase in mortality risk 31,32 . This medication was also evaluated with another pharmaceutical formulation, where patients received a patch with 9.5 mg/24 h (10 cm2) of rivastigmine once a day compared to a capsule twice a day (12 mg/day). Positively, considering the efficacy parameters under consideration, both treatments demonstrated similar performance at Week 24 33 . Rivastigmine in patch form significantly reduces the levels of the enzyme butyrylcholinesterase, closely related to the reduction of acetylcholine in the synaptic cleft, when compared to the oral form, demonstrating the advantages of transdermal use, in addition to reducing the risk of drug interactions 34 .

The most common adverse symptoms were gastrointestinal, e.g. nausea, vomiting, diarrhea and anorexia. Other less frequent adverse events included confusion and agitation, decreased appetite, dizziness, weight loss, hypertension and itching at the application site 31-33 .

Pioglitazone

Pioglitazone is an efficient PPARγ agonist, thus presenting anti-inflammatory properties that can prevent problems with cognitive deterioration 35 . Individuals with mild-moderate Alzheimer’s who received 15 mg pioglitazone tablets or placebo per day, increased from one tablet per week to three tablets per day to reach a maximum dose of 45 mg pioglitazone/day showed no improvement on the ADAS-Cog scale or any other clinical outcome. The researchers did not rule out the possibility that the lack of a statistically significant treatment effect was related to the small sample size. Interestingly, even though this is a medication for the treatment of diabetes, its administration for 18 months did not promote significant changes in blood glucose levels even in non-diabetic individuals 36 . On the other hand, another clinical trial, this time carried out in patients with AD associated with type II diabetes mellitus, demonstrated that its daily use at a dose of 15–30 mg was sufficient to promote cognitive and functional improvements and stabilization of the disease in diabetic patients with AD 37 . The limited number of RCTs makes it difficult to reach a broader conclusion, especially because there is a divergence in the results found in the studies. However, to date, we cannot rule out the possibility of a positive effect of pioglitazone on the cognitive function of patients with AD, and future investigations are needed to better explore its effects. Its most common adverse effect was edema, which is already a widely recognized effect for this medication. Still, this adverse effect was tolerated without discontinuation of study medication 36,37 .

Doxycycline and rifampicin

Doxycycline was evaluated in combination with rifampicin. While doxycycline inhibits the translation of messenger RNA (mRNA) into proteins, rifampicin acts to inhibit bacterial RNA polymerase 38,39 . Although these drugs have long been used as antibiotics, recently, studies have shown that they are neuroprotective in models of neurodegenerative diseases and brain injuries, mainly due to their anti-inflammatory and antiapoptotic effects 40,41 . Patients with mild-moderate AD received daily oral doses of doxycycline 200 mg and rifampicin 300 mg or placebo for three months. Positively, this combination showed a smaller decline in ADAS-cog score at six months when compared to the placebo group, without showing a statistically significant difference in the percentages of patients who presented adverse events 42 . However, another study carried out over a 12-month period of treatment with doxycycline 100 mg twice a day + rifampicin 300 mg a day did not demonstrate statistical significance in the decline/deterioration of cognitive function in patients with AD compared to placebo 43 . Therefore, conflicting data prevents a conclusion about its effectiveness, requiring further future investigations. Adverse effects were: anorexia, sleep disturbances, nausea, weight loss and diarrhea 42,43 .

Resveratrol

Resveratrol is marketed as a phytonutrient and is considered neuroprotective 44 . Patients with AD who received placebo or resveratrol 500 mg orally once a day (with dose escalation in 500 mg increments every 13 weeks, ending with 1,000 mg twice daily) showed no improvement or delay in decline in function cognitive 45 . Furthermore, the use of 5 mg of resveratrol per dose administered twice a day in liquid form also did not reach statistical significance in relation to this parameter 46 . These studies indicate that resveratrol is not capable of slowing cognitive decline in patients with AD. Despite this, its use is safe and well tolerated, without adverse effects 45,46 .

Metrifonate

Metrifonate is also an inhibitor of the acetylcholinesterase enzyme, and is currently marketed as an anti-parasitic 47 . Monitoring patients with AD for 18 months using metrifonate (5 mg/kg of body weight for two weeks and 4.9 mg/kg for one week) revealed that this medication was able to reduce the decline in cognition 48 . This fact was confirmed in a subsequent study using the following treatment regimens:

  • dose of 40/50 mg of metrifonate: 40 mg in patients weighing less than 65 kg and 50 mg in patients weighing 65 kg (i.e. equivalent to approximately 0.65 mg/kg/day);

  • 60/80 mg dose of metrifonate: 60 mg in patients weighing 565 kg and 80 mg in patients weighing 565 kg (i.e., equivalent to approximately 1.0 mg/kg/day);

  • placebo.

In this case, ADAS-cog was significantly improved in the 60/80 mg and 40/50 mg dose groups, compared to placebo 49 .

Its reported adverse effects were: dizziness, restlessness, slight and gradual decrease in hemoglobin, hematocrit and red blood cell count, chest discomfort, atrial fibrillation, headache and hiccups. However, these events were rare and did not require adjustment of the metrifonate dose or discontinuation of treatment 48,49 .

Medications with potential use in Alzheimer’s disease

Analysis of the listed medications and their clinical studies can provide insight into the development of treatments for AD and the potential impact of these medications on delaying cognitive decline. Among these medicines, the following stand out:

  • Physostigmine 50 : Acetylcholinesterase inhibitor, which promotes the increase in acetylcholine, as well as donepezil;

  • Cerebrolysin 51 : It is a mixture of peptides and amino acids with neuroprotective properties;

  • Tacrine 52 : It was one of the first acetylcholinesterase inhibitors approved for the treatment of AD. Although it has shown modest benefits, tacrine has been taken off the market in many places due to its hepatic side effects;

  • Eptastigmine 53 : This medication is also an acetylcholinesterase inhibitor;

  • Benfotiamine 54 : It is a synthetic form of vitamin B1 (thiamine) that has been studied for its neuroprotective potential. Evidence on its effectiveness in treating AD is still limited, and more studies are needed to determine its impact;

  • Rotigotine 55 : It is a dopamine agonist used mainly for Parkinson’s disease;

  • Octohydroaminoacridine 56 : A compound with acetylcholinesterase inhibitory properties, with initial studies indicating possible benefits in AD. However, more research is needed to confirm its effectiveness;

  • Idalopirdine 57 : An inhibitor of acetylcholinesterase and the serotonin receptor. Studies have shown a modest effect on cognitive function, but the evidence is not enough for a clear consensus;

  • SB-742457 20 : It is an acetylcholinesterase inhibitor with distinct properties, but available data is limited and does not support a significant benefit compared to established treatments;

  • Velnacrine 58 : An acetylcholinesterase inhibitor that has had some initial success, but clinical use has been limited due to concerns about side effects and the availability of safer, more effective alternatives;

  • Blarcamesine 59 : SIGMAR1 (sigma non-opioid intracellular receptor 1) agonists in the central nervous system (CNS). It showed delayed clinical progression by 49.8% at 48 weeks on the pre-specified ADAS-Cog primary cognitive endpoint, with no side effects;

  • Alphoscerate 60 : This is a phospholipid containing choline, which is a precursor to acetylcholine. This treatment has been shown to be safe and effective in improving cognitive function in study subjects with mild cognitive impairment, but further studies are needed to consolidate this research.

In summary, many of these medications have shown some initial evidence of potential benefit in the treatment of AD, but the limited number of studies and variability in results make it difficult to draw definitive conclusions. Research remains essential to determine which treatments are most effective and safe for slowing the cognitive decline associated with AD.

Other medications that have not been shown to be effective in reducing cognitive decline in Alzheimer’s disease

The development of treatments for AD is an active field of research, and many medications and supplements have been studied with the hope of slowing cognitive decline. However, some of these treatments have not demonstrated significant effectiveness in clinical trials. Among these medications and supplements that did not present clear benefits in reducing cognitive decline in AD, the following stand out:

  • Acetyl-L-carnitine (ALCAR) 61 : This supplement has been studied for its neuroprotective properties and potential cognitive effect. However, the results were inconclusive, and there was insufficient evidence to support its use as an effective treatment for AD;

  • Saffron 62 : Studies on saffron (Crocus sativus) have shown mixed results. Although some initial research suggested a potential benefit, the overall evidence was not sufficient to recommend its clinical use;

  • Tulrampator (S47445) 63 : An AMPA receptor modulator studied for AD. Studies have not shown significant benefits in terms of slowing cognitive decline;

  • Diclofenac/misoprostol 64 : A non-steroidal anti-inflammatory drug (NSAID) in combination with misoprostol. It did not show clear benefits in the treatment of AD, with the combination not demonstrating efficacy;

  • PF-05212377 (SAM-760) 65 : A beta-secretase inhibitor investigated for AD. Clinical results did not show significant positive effects in the treatment of AD;

  • Scyllo-Inositol (ELND005) 66 : A compound studied for its potential effect in modulating the formation of amyloid plaques. Trials have not shown substantial clinical benefits;

  • Semagacestat 67 : A gamma-secretase inhibitor that has not demonstrated efficacy in delaying cognitive decline and has been associated with adverse effects;

  • Huperzine A 68 : A plant-derived acetylcholinesterase inhibitor. Despite some promising initial studies, the evidence was not sufficient to support its large-scale use in AD;

  • Tideglusib 69 : An inhibitor of the enzyme glycogen synthase kinase-3 beta (GSK-3β). Studies have not shown significant benefits on cognitive function;

  • Sodium selenate 70 : A selenium supplement studied for its potential neuroprotective effect. The results did not indicate clear benefits in AD;

  • Capric/Caprylic Acid Triglycerides 71 : These triglycerides are used as a supplement to improve cognitive function. Studies have not provided robust evidence of efficacy for AD;

  • Vitamin D2 72 : Although vitamin D plays an important role in general health, studies have not shown that vitamin D2 supplementation has a significant effect on cognitive decline in AD;

  • ABT-288 73 : A glutamate receptor antagonist. Studies have not demonstrated clear benefits in AD;

  • Simvastatin 74 : A medication used to reduce cholesterol, with some theory about a neuroprotective effect. However, studies have not shown benefits for cognitive decline;

  • Atomoxetine 75 : A norepinephrine reuptake inhibitor used for attention deficit hyperactivity disorder (ADHD). Studies have not shown benefits in AD;

  • Docosahexaenoic acid 76 : An omega-3 fatty acid studied for its possible neuroprotective effects. The evidence was not sufficient to recommend its use in AD;

  • Bexarotene 77 : A retinoid investigated for its ability to reduce amyloid plaques. Studies have not shown clear benefits on cognitive function;

  • Hydroxychloroquine 78 : An antimalarial drug studied for its anti-inflammatory effects. Research has not demonstrated significant benefits in AD;

  • Levetiracetam 79 : An anticonvulsant investigated for possible neuroprotective effects. Studies have shown no significant impact on cognitive decline;

  • Masupirdine 80 : A drug with neuroprotective properties investigated for AD. No clear benefits found in studies;

  • Tarenflurbil 81 : An anti-inflammatory investigated for AD, but results did not show significant clinical benefits;

  • NeuroAiD™ (MLC601) 82 : A compound supplement investigated for AD, but studies have not shown robust evidence of efficacy;

  • Iclepertin (425809) 83 : An N-methyl D-Aspartate (NMDA) receptor modulator, with studies that have not indicated clear benefits in AD;

  • Etazolate hydrochloride (EHT0202) 84 : A medication studied for AD, but has not shown significant benefits on cognitive function;

  • Vitamin B 85 : Reference to a complex of vitamins from group B. Studies have not shown significant effects on AD;

  • MK-7622 86 : A GSK-3β inhibitor investigated for AD but has not demonstrated clinical efficacy;

  • Edonerpic maleate (T-817MA) 87 : A compound studied with the expectation of a neuroprotective effect. The results were not positive;

  • UB-311 88 : A therapeutic vaccine investigated for AD, but studies have not shown significant benefits;

  • Omega-3 89 : Omega-3 fatty acids are often studied for various neurological conditions. However, the evidence for efficacy in AD has not been conclusive;

  • Tramiprosate 90 : An anti-amyloid agent investigated for AD but has not shown clear benefits in clinical trials;

  • Posiphen 91 : This molecule is an analogue of phenylbutyrate and an inhibitor of amyloid precursor protein (APP). Its main mechanism of action involves reducing the production of the APP protein and, consequently, its metabolites, including amyloid-β peptide (Aβ), which is implicated in the pathogenesis of Alzheimer’s disease (AD). Despite being safe and well tolerated, there were no significant changes in the total ADAS-cog scores.

These examples highlight the complexity and challenges in researching new treatments for Alzheimer’s disease. Most of these medications and supplements have failed to demonstrate a significant impact on disease progression in clinical studies, reflecting the continued need for research to find effective therapeutic options.

Study limitations

This study has some methodological limitations that may have influenced the results obtained. First, the inclusion and exclusion criteria adopted may have restricted the inclusion of studies that evaluated the use of memantine, a widely used drug approved for the treatment of Alzheimer’s disease, as well as the recently approved lecanemab and donanemab. Although these exclusions were based on previously defined criteria, we recognize that the inclusion of these drugs could provide a more comprehensive view of the available therapeutic options. In addition, the choice to use only the ADAS-Cog scale as the main cognitive outcome may have limited the inclusion of studies that employed other widely recognized measures, such as the Mini-Mental State Examination (MMSE). Although the MMSE is frequently used, its sensitivity and specificity for detecting subtle cognitive changes in moderate to severe stages of Alzheimer’s disease were considered insufficient for the objectives of this review. Finally, although the review was updated until February 2025, new studies and drug approvals continue to emerge. Therefore, the inclusion of more recent data on innovative treatments may be considered in future updates of this study.

In conclusion, medications such as donepezil, galantamine and rivastigmine have demonstrated significant efficacy in improving cognitive function in patients with AD. In turn, other medications have limited or inconclusive evidence: pioglitazone, despite its potential anti-inflammatory effects, has not demonstrated a clear benefit in cognitive improvement, although it may have positive effects in specific subgroups, such as patients with AD and type II diabetes. The combination of doxycycline and rifampicin has shown mixed results, with some evidence of effect, but no definitive conclusions. Metrifonate has shown a positive impact on cognition in some studies, but adverse effects and limited availability make widespread clinical application difficult. Finally, other investigated medications and supplements demonstrated a lack of proven efficacy, such as: acetyl-L-carnitine, turmeric, tulrampator, and scyllo-Inositol, did not show clear benefits in slowing cognitive decline in AD. Study results were inconclusive or did not show statistically significant efficacy. Medications such as semagacestat and bexarotene have also failed to demonstrate a positive impact on cognitive function, and some have been associated with additional adverse effects. Regarding safety and tolerability, among treatments that did not demonstrate significant efficacy, many were well tolerated, with adverse effects that were generally mild and self-limited. However, the lack of consistent efficacy prevents these medications from being recommended for clinical use in AD. Still, the lack of robust evidence for many treatments reflects the need for more research to find effective and safe therapies.

Footnotes

Funding: none.

DATA AVAILABILITY STATEMENT

All data sets were generated or analyzed in the current study.

REFERENCES

  • 1.Porsteinsson AP, Isaacson RS, Knox S, Sabbagh MN, Rubino I. Diagnosis of Early Alzheimer’s Disease: Clinical Practice in 2021. J Prev Alzheimers Dis. 2021;8(3):371–86. doi: 10.14283/jpad.2021.23. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Scheltens P, De Strooper B, Kivipelto M, Holstege H, Chételat G, Teunissen CE, et al. Alzheimer’s disease. Lancet. 2021;397(10284):1577–90. doi: 10.1016/S0140-6736(20. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Zhang XX, Tian Y, Wang ZT, Ma YH, Tan L, Yu JT. The epidemiology of Alzheimer’s disease modifiable risk factors and prevention. J Prev Alzheimers Dis. 2021;8(3):313–21. doi: 10.14283/jpad.2021.15. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Li X, Feng X, Sun X, Hou N, Han F, Liu Y. Global, regional, and national burden of Alzheimer’s disease and other dementias, 1990-2019. Front Aging Neurosci. 1990;10(14):937486. doi: 10.3389/fnagi.2022.937486. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388(1):9–21. doi: 10.1056/NEJMoa2212948. [DOI] [PubMed] [Google Scholar]
  • 6.Vaz M, Silvestre S. Alzheimer’s disease: Recent treatment strategies. Eur J Pharmacol. 2020;887:173554. doi: 10.1016/j.ejphar.2020.173554. [DOI] [PubMed] [Google Scholar]
  • 7.Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097. doi: 10.1371/journal.pmed.1000097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Li DD, Zhang YH, Zhang W, Zhao P. Meta-analysis of randomized controlled trials on the efficacy and safety of donepezil, galantamine, rivastigmine, and memantine for the treatment of Alzheimer’s Disease. Front Neurosci. 2019;15(13):472. doi: 10.3389/fnins.2019.00472. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Kueper JK, Lizotte DJ, Montero-Odasso M, Speechley M, Alzheimer’s Disease Neuroimaging Initiative Cognition and motor function: The gait and cognition pooled index. PLoS One. 2020;11(19):e0238690. doi: 10.1371/journal.pone.0238690. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898. doi: 10.1136/bmj.l4898. [DOI] [PubMed] [Google Scholar]
  • 11.Sterne JA, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016;355:4919. doi: 10.1136/bmj.i4919. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.McGuinness LA, Higgins JPT. Risk-of-bias VISualization (robvis): An R package and Shiny web app for visualizing risk-of-bias assessments. Res Synth Methods. 2021;12(1):55–61. doi: 10.1002/jrsm.1411. [DOI] [PubMed] [Google Scholar]
  • 13.Pathak C, Kabra UD. A comprehensive review of multi-target directed ligands in the treatment of Alzheimer’s disease. Bioorg Chem. 2024;144:107152. doi: 10.1016/j.bioorg.2024.107152. [DOI] [PubMed] [Google Scholar]
  • 14.Santos GAA. Santos GAA. Pharmacological Treatment of Alzheimer’s Disease. Cham: Springer; 2022. Introduction. [DOI] [Google Scholar]
  • 15.Pooladgar P, Sakhabakhsh M, Taghva A, Soleiman-Meigooni S. Donepezil beyond Alzheimer’s disease? A narrative review of therapeutic potentials of donepezil in different diseases. Iran J Pharm Res. 2022;21(1):e128408. doi: 10.5812/ijpr-128408. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Zhang X, Lian S, Zhang Y, Zhao Q. Efficacy and safety of donepezil for mild cognitive impairment: A systematic review and meta-analysis. Clin Neurol Neurosurg. 2022;213:107134. doi: 10.1016/j.clineuro.2022.107134. [DOI] [PubMed] [Google Scholar]
  • 17.Rogers SL, Friedhoff LT. The efficacy and safety of donepezil in patients with Alzheimer’s disease: results of a US multicentre, randomized, double-blind, placebo-controlled trial. Dementia. 1996;7(6):293–303. doi: 10.1159/000106895. [DOI] [PubMed] [Google Scholar]
  • 18.Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer’s disease. Neurology. 1998;50(1):136–45. doi: 10.1212/wnl.50.1.136. [DOI] [PubMed] [Google Scholar]
  • 19.Rogers SL, Doody RS, Pratt RD, Ieni JR. Long-term efficacy and safety of donepezil in the treatment of Alzheimer’s disease: final analysis of a US multicentre open-label study. Eur Neuropsychopharmacol. 2000;10(3):195–203. doi: 10.1016/s0924-977x(00. [DOI] [PubMed] [Google Scholar]
  • 20.Maher-Edwards G, Dixon R, Hunter J, Gold M, Hopton G, Jacobs G, et al. SB-742457 and donepezil in Alzheimer disease: a randomized, placebo-controlled study. Int J Geriatr Psychiatry. 2011;26(5):536–44. doi: 10.1002/gps.2562. [DOI] [PubMed] [Google Scholar]
  • 21.Seltzer B, Zolnouni P, Nunez M, Goldman R, Kumar D, Ieni J, et al. Efficacy of donepezil in early-stage Alzheimer disease: a randomized placebo-controlled trial. Arch Neurol. 2004;61(12):1852–6. doi: 10.1001/archneur.61.12.1852. [DOI] [PubMed] [Google Scholar]
  • 22.Passeri E, Elkhoury K, Morsink M, Broersen K, Linder M, Tamayol A, et al. Alzheimer’s disease: treatment strategies and their limitations. Int J Mol Sci. 2022;23(22):13954. doi: 10.3390/ijms232213954. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Han HJ, Park MY, Park KW, Park KH, Choi SH, Kim HJ. A multinational, multicenter, randomized, double-blind, active comparator, phase III clinical trial to evaluate the efficacy and safety of donepezil transdermal patch in patients with Alzheimer’s disease. J Clin Neurol. 2022;18(4):428–36. doi: 10.3988/jcn.2022.18.4.428. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Jones RW, Soininen H, Hager K, Aarsland D, Passmore P, Murthy A, et al. A multinational, randomised, 12-week study comparing the effects of donepezil and galantamine in patients with mild to moderate Alzheimer’s disease. Int J Geriatr Psychiatry. 2004;19(1):58–67. doi: 10.1002/gps.1038. [DOI] [PubMed] [Google Scholar]
  • 25.Nunes D, Loureiro JA, Pereira MC. Drug delivery systems as a strategy to improve the efficacy of FDA-approved Alzheimer’s drugs. Pharmaceutics. 2022;14(11):2296. doi: 10.3390/pharmaceutics14112296. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Tariot PN, Solomon PR, Morris JC, Kershaw P, Lilienfeld S, Ding C. A 5-month, randomized, placebo-controlled trial of galantamine in AD. The Galantamine USA-10 Study Group. Neurology. 2000;54(12):2269–76. doi: 10.1212/wnl.54.12.2269. [DOI] [PubMed] [Google Scholar]
  • 27.Wilkinson D, Murray J. Galantamine: a randomized, double-blind, dose comparison in patients with Alzheimer’s disease. Int J Geriatr Psychiatry. 2001;16(9):852–7. doi: 10.1002/gps.409. [DOI] [PubMed] [Google Scholar]
  • 28.Wilcock G, Howe I, Coles H, Lilienfeld S, Truyen L, Zhu Y, et al. A long-term comparison of galantamine and donepezil in the treatment of Alzheimer’s disease. Drugs Aging. 2003;20(10):777–89. doi: 10.2165/00002512-200320100-00006. [DOI] [PubMed] [Google Scholar]
  • 29.Marucci G, Buccioni M, Ben DD, Lambertucci C, Volpini R, Amenta F. Efficacy of acetylcholinesterase inhibitors in Alzheimer’s disease. Neuropharmacology. 2021;1(190):108352. doi: 10.1016/j.neuropharm.2020.108352. [DOI] [PubMed] [Google Scholar]
  • 30.Dhillon S. Rivastigmine transdermal patch: a review of its use in the management of dementia of the Alzheimer’s type. Drugs. 2011;71:1209–31. doi: 10.2165/11206380-000000000-00000. [DOI] [PubMed] [Google Scholar]
  • 31.Farlow M, Anand R, Messina J, Jr, Hartman R, Veach J. A 52-week study of the efficacy of rivastigmine in patients with mild to moderately severe Alzheimer’s disease. Eur Neurol. 2000;44(4):236–41. doi: 10.1159/000008243. [DOI] [PubMed] [Google Scholar]
  • 32.Karaman Y, Erdoğan F, Köseoğlu E, Turan T, Ersoy AO. A 12-month study of the efficacy of rivastigmine in patients with advanced moderate Alzheimer’s disease. Dement Geriatr Cogn Disord. 2005;19(1):51–6. doi: 10.1159/000080972. [DOI] [PubMed] [Google Scholar]
  • 33.Zhang ZX, Hong Z, Wang YP, He L, Wang N, Zhao ZX, et al. Rivastigmine patch in Chinese patients with probable Alzheimer’s disease: A 24-week, randomized, double-blind parallel-group study comparing rivastigmine patch (9.5 mg/24 h) with capsule (6 mg twice daily) CNS Neurosci Ther. 2016;22(6):488–96. doi: 10.1111/cns.12521. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Santos GAA, Canineu PR, Gonçalves ID, Pardi PC. Influence of Rivastigmine transdermal on butyrylcholinesterase levels in patients with Alzheimer’s disease. Dement Neuropsychol. 2011;5(4):332–6. doi: 10.1590/S1980-57642011DN05040012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Ramkalawan H, Wang YZ, Hurbungs A, Yang YF, Tian FF, Zhou WB, et al. Pioglitazone, PPARγ agonist, attenuates experimental autoimmune neuritis. Inflammation. 2012;35(4):1338–47. doi: 10.1007/s10753-012-9447-4. [DOI] [PubMed] [Google Scholar]
  • 36.Geldmacher DS, Fritsch T, McClendon MJ, Landreth G. A randomized pilot clinical trial of the safety of pioglitazone in treatment of patients with Alzheimer disease. Arch Neurol. 2011;68(1):45–50. doi: 10.1001/archneurol.2010.229. [DOI] [PubMed] [Google Scholar]
  • 37.Sato T, Hanyu H, Hirao K, Kanetaka H, Sakurai H, Iwamoto T. Efficacy of PPAR-γ agonist pioglitazone in mild Alzheimer disease. Neurobiol Aging. 2011;32(9):1626–33. doi: 10.1016/j.neurobiolaging.2009.10.009. [DOI] [PubMed] [Google Scholar]
  • 38.Singh S, Khanna D, Kalra S. Minocycline and doxycycline: more than antibiotics. Curr Mol Pharmacol. 2021;14(6):e301221191269. doi: 10.2174/1874467214666210210122628. [DOI] [PubMed] [Google Scholar]
  • 39.Mosaei H, Zenkin N. Inhibition of RNA polymerase by rifampicin and rifamycin-like molecules. EcoSal Plus. 2020;9(1):101128. doi: 10.1128/ecosalplus.ESP-0017-2019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Amaral L, Santos NAG, Sisti FM, Bel ED, Santos AC. The antibiotic doxycycline mimics the NGF signaling in PC12 cells: A relevant mechanism for neuroprotection. Chem Biol Interact. 2021;341:109454. doi: 10.1016/j.cbi.2021.109454. [DOI] [PubMed] [Google Scholar]
  • 41.Zhu L, Yuan Q, Zeng Z, Zhou R, Luo R, Zhang J, et al. Rifampicin suppresses amyloid-β accumulation through enhancing autophagy in the hippocampus of a lipopolysaccharide-induced mouse model of cognitive decline. J Alzheimers Dis. 2021;79(3):1171–84. doi: 10.3233/JAD-200690. [DOI] [PubMed] [Google Scholar]
  • 42.Loeb MB, Molloy DW, Smieja M, Standish T, Goldsmith CH, Mahony J, et al. A randomized, controlled trial of doxycycline and rifampin for patients with Alzheimer’s disease. J Am Geriatr Soc. 2004;52(3):381–7. doi: 10.1111/j.1532-5415.2004.52109.x. [DOI] [PubMed] [Google Scholar]
  • 43.Molloy DW, Standish TI, Zhou Q, Guyatt G. A multicenter, blinded, randomized, factorial controlled trial of doxycycline and rifampin for treatment of Alzheimer’s disease: the DARAD trial. Int J Geriatr Psychiatry. 2013;28(5):463–70. doi: 10.1002/gps.3846. [DOI] [PubMed] [Google Scholar]
  • 44.Rahman MH, Akter R, Bhattacharya T, Abdel-Daim MM, Alkahtani S, Arafah MW, et al. Resveratrol and neuroprotection: impact and its therapeutic potential in Alzheimer’s disease. Front Pharmacol. 2020;11:619024. doi: 10.3389/fphar.2020.619024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Turner RS, Thomas RG, Craft S, van Dyck CH, Mintzer J, Reynolds BA, et al. A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease. Neurology. 2015;85(16):1383–91. doi: 10.1212/WNL.0000000000002035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Zhu CW, Grossman H, Neugroschl J, Parker S, Burden A, Luo X, et al. A randomized, double-blind, placebo-controlled trial of resveratrol with glucose and malate (RGM) to slow the progression of Alzheimer’s disease: A pilot study. Alzheimers Dement (N Y) 2018;4(1):609–16. doi: 10.1016/j.trci.2018.09.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Singh A, Jha A. Cholinesterase inhibitors used for the management of Alzheimer’s disease: A review. J Pharm Res Int. 2021;33(60A):121–28. doi: 10.9734/jpri/2021/v33i60A34463. [DOI] [Google Scholar]
  • 48.Becker RE, Colliver JA, Markwell SJ, Moriearty PL, Unni LK, Vicari S. Double-blind, placebo-controlled study of metrifonate, an acetylcholinesterase inhibitor, for Alzheimer disease. Alzheimer Dis Assoc Disord. 1996;10(3):124–31. doi: 10.1097/00002093-199601030-00003. [DOI] [PubMed] [Google Scholar]
  • 49.Dubois B, McKeith I, Orgogozo JM, Collins O, Meulien D. A multicentre, randomized, double-blind, placebo-controlled study to evaluate the efficacy, tolerability and safety of two doses of metrifonate in patients with mild-to-moderate Alzheimer’s disease: the MALT study. Int J Geriatr Psychiatry. 1999;14(11):973–82. [PubMed] [Google Scholar]
  • 50.Thal LJ, Ferguson JM, Mintzer J, Raskin A, Targum SD. A 24-week randomized trial of controlled-release physostigmine in patients with Alzheimer’s disease. Neurology. 1999;52(6):1146–52. doi: 10.1212/wnl.52.6.1146. [DOI] [PubMed] [Google Scholar]
  • 51.Ruether E, Husmann R, Kinzler E, Diabl E, Klingler D, Spatt J, et al. A 28-week, double-blind, placebo-controlled study with Cerebrolysin in patients with mild to moderate Alzheimer’s disease. Int Clin Psychopharmacol. 2001;16(5):253–63. doi: 10.1097/00004850-200109000-00002. [DOI] [PubMed] [Google Scholar]
  • 52.Knapp MJ, Knopman DS, Solomon PR, Pendlebury WW, Davis CS, Gracon SI. A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer’s disease. JAMA. 1994;271(13):985–91. [PubMed] [Google Scholar]
  • 53.Imbimbo BP, Troetel WM, Martelli P, Lucchelli F. A 6-month, double-blind, placebo-controlled trial of eptastigmine in Alzheimer’s disease. Dement Geriatr Cogn Disord. 2000;11(1):17–24. doi: 10.1159/000017208. [DOI] [PubMed] [Google Scholar]
  • 54.Gibson GE, Luchsinger JA, Cirio R, Chen H, Franchino-Elder J, Hirsch JA, et al. Benfotiamine and cognitive decline in Alzheimer’s disease: results of a randomized placebo-controlled phase IIa clinical trial. J Alzheimers Dis. 2020;78(3):989–1010. doi: 10.3233/JAD-200896. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Koch G, Motta C, Bonnì S, Pellicciari MC, Picazio S, Casula EP, et al. Effect of rotigotine vs placebo on cognitive functions among patients with mild to moderate Alzheimer disease: a randomized clinical trial. JAMA Netw Open. 2020;3(7):e2010372. doi: 10.1001/jamanetworkopen.2020.10372. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Xiao S, Wang T, Ma X, Qin Y, Li X, Zhao Z, et al. Efficacy and safety of a novel acetylcholinesterase inhibitor octohydroaminoacridine in mild-to-moderate Alzheimer’s disease: a Phase II multicenter randomised controlled trial. Age Ageing. 2017;46(5):767–73. doi: 10.1093/ageing/afx045. [DOI] [PubMed] [Google Scholar]
  • 57.Wilkinson D, Windfeld K, Colding-Jorgensen E. Safety and efficacy of idalopirdine, a 5-HT6 receptor antagonist, in patients with moderate Alzheimer’s disease (LADDER): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 2014;13(11):1092–9. doi: 10.1016/S1474-4422(14. [DOI] [PubMed] [Google Scholar]
  • 58.Zemlan FP. Velnacrine for the treatment of Alzheimer’s disease: a double-blind, placebo-controlled trial. The Mentane Study Group. J Neural Transm. 1996;103(8):1105–16. doi: 10.1007/BF01291795. [DOI] [PubMed] [Google Scholar]
  • 59.Macfarlane S, Grimmer T, Teo K, O’Brien TJ, Woodward M, Grunfeld J, et al. Blarcamesine for the treatment of Early Alzheimer’s Disease: Results from the ANAVEX2-73-AD-004 Phase IIB/III trial. J Prev Alzheimers Dis. 2025;12(1):100016. doi: 10.1016/j.tjpad.2024.100016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Jeon J, Lee SY, Lee S, Han C, Park GD, Kim SJ, et al. Efficacy and safety of choline alphoscerate for amnestic mild cognitive impairment: a randomized double-blind placebo-controlled trial. BMC Geriatr. 2024;24(1):774. doi: 10.1186/s12877-024-05366-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Thal LJ, Calvani M, Amato A, Carta A. A 1-year controlled trial of acetyl-l-carnitine in early-onset AD. Neurology. 2000;55(6):805–10. doi: 10.1212/wnl.55.6.805. [DOI] [PubMed] [Google Scholar]
  • 62.Akhondzadeh S, Sabet MS, Harirchian MH, Togha M, Cheraghmakani H, Razeghi S, et al. A 22-week, multicenter, randomized, double-blind controlled trial of Crocus sativus in the treatment of mild-to-moderate Alzheimer’s disease. Psychopharmacology. 2010;207:637–643. doi: 10.1007/s00213-009-1706-1. [DOI] [PubMed] [Google Scholar]
  • 63.Bernard K, Gouttefangeas S, Bretin S, Galtier S, Robert P, Holthoff-Detto V, et al. A 24-week double-blind placebo-controlled study of the efficacy and safety of the AMPA modulator S47445 in patients with mild to moderate Alzheimer’s disease and depressive symptoms. Alzheimers Dement. 2019;5(1):231–40. doi: 10.1016/j.trci.2019.04.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.Scharf S, Mander A, Ugoni A, Vajda F, Christophidis N. A double-blind, placebo-controlled trial of diclofenac/misoprostol in Alzheimer’s disease. Neurology. 1999;53(1):197–201. doi: 10.1212/wnl.53.1.197. [DOI] [PubMed] [Google Scholar]
  • 65.Fullerton T, Binneman B, David W, Delnomdedieu M, Kupiec J, Lockwood P, et al. A Phase 2 clinical trial of PF-05212377 (SAM-760) in subjects with mild to moderate Alzheimer’s disease with existing neuropsychiatric symptoms on a stable daily dose of donepezil. Alzheimers Res Ther. 2018;10(1):38. doi: 10.1186/s13195-018-0368-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66.Salloway S, Sperling R, Keren R, Porsteinsson AP, van Dyck CH, Tariot PN, et al. A phase 2 randomized trial of ELND005, scyllo-inositol, in mild to moderate Alzheimer disease. Neurology. 2011;77(13):1253–62. doi: 10.1212/WNL.0b013e3182309fa5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.Doody RS, Raman R, Farlow M, Iwatsubo T, Vellas B, Joffe S, et al. A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N Engl J Med. 2013;369:341–50. doi: 10.1056/NEJMoa1210951. [DOI] [PubMed] [Google Scholar]
  • 68.Rafii MS, Walsh S, Little JT, Behan K, Reynolds B, Ward C, et al. A phase II trial of huperzine A in mild to moderate Alzheimer disease. Neurology. 2011;76(16):1389–94. doi: 10.1212/WNL.0b013e318216eb7b. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Lovestone S, Boada M, Dubois B, Hüll M, Rinne JO, Huppertz HJ, et al. A phase II trial of tideglusib in Alzheimer’s disease. J Alzheimers Dis. 2015;45(1):75–88. doi: 10.3233/JAD-141959. [DOI] [PubMed] [Google Scholar]
  • 70.Malpas CB, Vivash L, Genc S, Saling MM, Desmond P, Steward C, et al. A phase IIa randomized control trial of vel015 (sodium selenate) in mild-moderate Alzheimer’s disease. J Alzheimers Dis. 2016;54(1):223–32. doi: 10.3233/JAD-160544. [DOI] [PubMed] [Google Scholar]
  • 71.Henderson ST, Morimoto BH, Cummings JL, Farlow MR, Walker J. A placebo-controlled, parallel-group, randomized clinical trial of AC-1204 in mild-to-moderate Alzheimer’s disease. J Alzheimers Dis. 2020;75(2):547–57. doi: 10.3233/JAD-191302. [DOI] [PubMed] [Google Scholar]
  • 72.Stein MS, Scherer SC, Ladd KS, Harrison LC. A randomized controlled trial of high-dose vitamin D2 followed by intranasal insulin in Alzheimer’s disease. J Alzheimers Dis. 2011;26(3):477–84. doi: 10.3233/jad-2011-110149. [DOI] [PubMed] [Google Scholar]
  • 73.Haig GM, Pritchett Y, Meier A, Othman AA, Hall C, Gault LM, et al. A randomized study of H3 antagonist ABT-288 in mild-to-moderate Alzheimer’s dementia. J Alzheimers Dis. 2014;42(3):959–71. doi: 10.3233/JAD-140291. [DOI] [PubMed] [Google Scholar]
  • 74.Sano M, Bell KL, Galasko D, Galvin JE, Thomas RG, van Dyck CH, et al. A randomized, double-blind, placebo-controlled trial of simvastatin to treat Alzheimer disease. Neurology. 2011;77(6):556–63. doi: 10.1212/WNL.0b013e318228bf11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75.Mohs RC, Shiovitz TM, Tariot PN, Porsteinsson AP, Baker KD, Feldman PD. Atomoxetine augmentation of cholinesterase inhibitor therapy in patients with Alzheimer disease: 6-month, randomized, double-blind, placebo-controlled, parallel-trial study. Am J Geriatr Psychiatry. 2009;17(9):752–9. doi: 10.1097/JGP.0b013e3181aad585. [DOI] [PubMed] [Google Scholar]
  • 76.Geleijnse JM, Giltay EJ, Kromhout D. Effects of n-3 fatty acids on cognitive decline: a randomized, double-blind, placebo-controlled trial in stable myocardial infarction patients. Alzheimers Dement. 2012;8(4):278–87. doi: 10.1016/j.jalz.2011.06.002. [DOI] [PubMed] [Google Scholar]
  • 77.Cummings JL, Zhong K, Kinney JW, Heaney C, Moll-Tudla J, Joshi A, et al. Double-blind, placebo-controlled, proof-of-concept trial of bexarotene Xin moderate Alzheimer’s disease. Alzheimers Res Ther. 2016;8:4. doi: 10.1186/s13195-016-0173-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78.Van Gool WA, Weinstein HC, Scheltens P, Walstra GJ. Effect of hydroxychloroquine on progression of dementia in early Alzheimer’s disease: an 18-month randomised, double-blind, placebo-controlled study. Lancet. 2001;358(9280):455–60. doi: 10.1016/s0140-6736(01. [DOI] [PubMed] [Google Scholar]
  • 79.Vossel K, Ranasinghe KG, Beagle AJ, La A, Ah Pook K, Castro M, et al. Effect of levetiracetam on cognition in patients with Alzheimer disease with and without epileptiform activity: a randomized clinical trial. JAMA Neurol. 2021;78(11):1345–54. doi: 10.1001/jamaneurol.2021.3310. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80.Nirogi R, Ieni J, Goyal VK, Ravula J, Jetta S, Shinde A, et al. Effect of masupirdine (SUVN-502) on cognition in patients with moderate Alzheimer’s disease: A randomized, double-blind, phase 2, proof-of-concept study. Alzheimers Dement (N Y) 2022;8(1):e12307. doi: 10.1002/trc2.12307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 81.Green RC, Schneider LS, Amato DA, Beelen AP, Wilcock G, Swabb EA, et al. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial. Jama. 2009;302(23):2557–64. doi: 10.1001/jama.2009.1866. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 82.Pakdaman H, Harandi AA, Hatamian H, Tabatabae M, Delavar Kasmaei H, Ghassemi A, et al. Effectiveness and safety of MLC601 in the treatment of mild to moderate Alzheimer’s disease: a multicenter, randomized controlled trial. Dement Geriatr Cogn Dis Extra. 2015;5(1):96–106. doi: 10.1159/000375295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 83.Wunderlich G, Blahova Z, Garcia M, Jessen F. Efficacy and safety of the novel GlyT1 inhibitor BI 425809 in Alzheimer’s dementia: a randomized controlled trial. Alzheimers Res Ther. 2023;15:24. doi: 10.1186/s13195-023-01163-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 84.Vellas B, Sol O, Snyder PJ, Ousset PJ, Haddad R, Maurin M, et al. EHT0202 in Alzheimer’s disease: a 3-month, randomized, placebo-controlled, double-blind study. Curr Alzheimer Res. 2011;8(2):203–12. doi: 10.2174/156720511795256053. [DOI] [PubMed] [Google Scholar]
  • 85.Aisen PS, Schneider LS, Sano M, Diaz-Arrastia R, Dyck CHV, Weiner MF, et al. High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial. Jama. 2008;300(15):1774–83. doi: 10.1001/jama.300.15.1774. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 86.Voss T, Li J, Cummings J, Farlow M, Assaid C, Froman S, et al. Randomized, controlled, proof-of-concept trial of MK-7622 in Alzheimer’s disease. Alzheimers Dement (N Y) 2018;4(1):173–81. doi: 10.1016/j.trci.2018.03.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 87.Schneider LS, Thomas RG, Hendrix S, Rissman RA, Brewer JB, Salmon DP, et al. Safety and efficacy of edonerpic maleate for patients with mild to moderate Alzheimer disease: a phase 2 randomized clinical trial. JAMA Neurol. 2019;76(11):1330–9. doi: 10.1001/jamaneurol.2019.1868. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 88.Yu HJ, Dickson SP, Wang PN, Chiu MJ, Huang CC, Chang CC, et al. Safety, tolerability, immunogenicity, and efficacy of UB-311 in participants with mild Alzheimer’s disease: a randomised, double-blind, placebo-controlled, phase 2a study. EBioMedicine. 2023;94:104665. doi: 10.1016/j.ebiom.2023.104665. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 89.Chiu CC, Su KP, Cheng TC, Liu HC, Chang CJ, Dewey ME, et al. The effects of omega-3 fatty acids monotherapy in Alzheimer’s disease and mild cognitive impairment: a preliminary randomized double-blind placebo-controlled study. Prog Neuro-Psychopharmacol Biol Psychiatry. 2008;32(6):1538–44. doi: 10.1016/j.pnpbp.2008.05.015. [DOI] [PubMed] [Google Scholar]
  • 90.Aisen PS, Gauthier S, Ferris SH, Saumier D, Haine D, Garceau D, et al. Tramiprosate in mild-to-moderate Alzheimer’s disease–a randomized, double-blind, placebo-controlled, multi-centre study (the Alphase Study) Arch of Med Sci. 2011;7(1):102–11. doi: 10.5114/aoms.2011.20612. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 91.Galasko D, Farlow MR, Lucey BP, Honig LS, Elbert D, Bateman R, et al. medRxiv. 2024. A multicenter, randomized, double-blind, placebo-controlled ascending dose study to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamic (PD) effects of Posiphen in subjects with Early Alzheimer’s Disease. 2024.03.20.24304638. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

All data sets were generated or analyzed in the current study.

Articles from Dementia & Neuropsychologia are provided here courtesy of Academia Brasileira de Neurologia

RESOURCES