Evaluating the efficacy and safety of Alzheimer's disease drugs: A meta-analysis and systematic review.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Dementia severity was assessed mainly through cognitive function, psychobehavioral symptoms, and daily living ability. Currently, there are not many drugs that can be selected to treat mild to moderate AD, and the value of drugs remains controversial. OBJECTIVE: The aim of this study is to quantitatively evaluate the efficacy and safety of cholinesterase inhibitors (ChEIs), memantine, and sodium oligomannate (GV-971) in the treatment of patients with AD. Additionally, molecular docking analysis will be used to investigate the binding affinities of donepezil, galantamine, rivastigmine, and memantine with key receptor proteins associated with AD, including beta-amyloid (Abeta), microtubule-associated protein (MAP), apolipoprotein E4 (APOE4), and Mitofusin-2 (MFN2), to further validate the results of the meta-analysis. METHODS: We obtained clinical trials characterized by randomization, placebo control, and double-blinded methodologies concerning ChEIs, memantine, and GV-971. Statistical analysis was performed using Review Manager Version 5.4 software. Molecular docking was also conducted to evaluate the results. RESULTS: All drugs improved the cognitive function, with the effect value ranging from -1.23 (95% CI -2.17 to -0.30) for 20 mg memantine to -3.29 (95% CI -4.14 to -2.45) for 32 mg galantamine. Although 32 mg galanthamine and GV-971 did not improve the clinicians' Global Impression of Change scale, other drugs showed significant results compared with placebo. On NPI, only 10 mg of donepezil and 24 mg of galantamine had improvement effects. On ADCS/ADL, only 20 mg memantine and 900 mg GV-971 had no significant difference from the placebo. Donepezil 5 mg and GV-971 900 mg did not increase the drug withdrawal rates due to various reasons or adverse reactions when compared to the placebo. Donepezil demonstrated superior binding to the protein and exhibited greater efficacy compared to other drugs. CONCLUSION: ChEIs, memantine, and GV-971 all can slow the progression of AD but have different effects on respective assessments. Donepezil and GV-971 were relatively well tolerated.

Harnessing memantine in Alzheimer's disease therapy through inhibition of microtubule affinity-regulating kinase: Mechanistic insights.

Alzheimer's disease (AD) is one of the neurodegenerative disorder that primarily affects memory, thinking, and behavior, eventually leading to severe cognitive impairment. Therapeutic management of AD is urgently needed to improve the quality and lifestyle of patients. Tau phosphorylating kinases are considered attractive therapeutic targets. Microtubule affinity-regulating kinase 4 (MARK4) is directly linked with pathological phosphorylations of tau, highlighting its role in the therapeutic targeting of AD. The current manuscript shows the MARK4 inhibitory effect of Memantine (MEM), a drug used in treating AD. We have performed fluorescence based binding measurements, enzyme inhibition assay, docking and molecular dynamics (MD) simulations to understand the binding of of MARK4 and MEM and subsequent inhibition in the kinase activity. A 100 ns MD simulations provided a detailed analysis of MARK4-MEM complex and the role of potential critical residues in the binding. Finally, this study provides molecular insights into the therapeutic implication of MEM in AD therapeutics. We propose MEM effectively inhibits MARK4, it may be implicated in the development of targeted and efficient treatments for AD.

Combination strategy employing BACE1 inhibitor and memantine to boost cognitive benefits in Alzheimer's disease therapy.

RATIONALE: The ß-secretase BACE1 initiates amyloid-ß (Aß) generation and represents a long-standing prime therapeutic target for the treatment of Alzheimer's disease (AD). However, BACE1 inhibitors tested to date in clinical trials have yielded no beneficial outcomes. In fact, prior BACE1 inhibitor trials targeted at ~ 50-90% Aß reductions in symptomatic or prodromal AD stages have ended in the discontinuation due to futility and/or side effects, including cognitive worsening rather than expected improvement at the highest dose. OBJECTIVES: We tested whether a combination strategy with the selective BACE1 inhibitor GRL-8234 and the FDA-approved symptomatic drug memantine may provide synergistic cognitive benefits within their safe dose range. METHODS: The drug effects were evaluated in the advanced symptomatic stage of 5XFAD mice that developed extensive cerebral Aß deposition. RESULTS: Chronic combination treatment with 33.4-mg/kg GRL-8234 and 10-mg/kg memantine, but not either drug alone, rescued cognitive deficits in 5XFAD mice at 12 months of age (the endpoint after 60-day drug treatment), as assessed by the contextual fear conditioning, spontaneous alternation Y-maze and nest building tasks. Intact baseline performances of wild-type control mice on three cognitive paradigms demonstrated that combination treatment did not augment potential cognitive side effects of individual drugs. Biochemical and immunohistochemical examination showed that combination treatment did not synergistically reduce the ß-amyloidogenic processing of amyloid precursor protein or Aß levels in 5XFAD mouse brains. CONCLUSIONS: A combination strategy with BACE1 inhibitors and memantine may be able to increase the effectiveness of individual drugs within their safe dose range in AD therapy.

Memantine versus Ginkgo biloba Extract: A Comparative Study on Cognitive Dysfunction Treatment in a Novel Rat Model.

Extracellular senile plaques and intraneuronal neurofibrillary tangles are two devastating brain proteinopathies that are indicative of Alzheimer's disease, the most prevalent type of dementia. Currently, no effective medications are available to stop or reverse Alzheimer's disease. Ginkgo biloba extract, commonly referred to as EGb 761, is a natural product made from the leaves of the G. biloba tree. It has long been demonstrated to have therapeutic benefits in Alzheimer's disease. The current study assessed the beneficial effects of EGb 761 against Alzheimer's disease in comparison with memantine, a standard treatment for Alzheimer's disease. The scopolamine-heavy metals mixture rat Alzheimer's disease model is a newly created model to study the effects of EGb 761 oral therapy on cognitive performance and other Alzheimer's disease-like changes over a 28-day experimental period. This new Alzheimer's disease model provides better criteria for Alzheimer's disease hallmarks than the conventional scopolamine model. The EGb 761 reversed memory and learning deficits induced by the scopolamine-heavy metals mixture. These outcomes were linked to a more pronounced inhibitory effect on acetylcholinesterase, caspase-3, hippocampal amyloid-beta protein (Aß1 - 42), phosphorylated tau protein counts, and proinflammatory cytokines (tumor necrosis factor-α and interleukin-1ß) compared to the memantine-treated group. Furthermore, EGb 761 treatment considerably reduced lipid peroxidation (malondialdehyde) and improved reduced glutathione levels compared to memantine. Our results suggest EGb 761's potential in treating central nervous system disorders. It's a promising candidate for future Alzheimer's disease therapeutic exploration. This study also highlights the need for future research to focus on the positive benefits of herbal medicines.

[Use of antipsychotics in patients with dementia in Spain: Comparison with prescription of acetylcholinesterase inhibitors and memantine and analysis of associations]. / Uso de antipsicóticos en los pacientes con demencia en España: comparación con la prescripción de los inhibidores de la acetilcolinesterasa y de la memantina, y análisis de las asociaciones.

OBJECTIVE: We have analyzed the prevalence of antipsychotics in patients with dementia in Spain, their age distribution and the influence of treatment with IACEs and memantine on their prescription. METHOD: Descriptive, retrospective and cross-sectional study of the 2017 BIFAP database in over 65 years of age with dementia. Prescriptions of antipsychotics, IACEs and memantine were collected. For antipsychotics were also collected, the duration of treatment and time from dementia diagnosis to prescription. RESULTS: A total of 1,327,792 subjects were retrieved, 89,464 (6.73%) with dementia. Antipsychotics were prescribed in 31.76%; by frequency: quetiapine (58.47%), risperidone (21%) and haloperidol (19.34%). Prescriptions of IACEs and memantine were clustered in those younger than 84 years and antipsychotics in those older than 85 (P<.001). Antipsychotics were maintained for a mean of 1174.5 days. In 26.4% of cases they were prescribed alone, OR 0.61 (95% CI: 0.59-0.62), in 35.85% associated with IACEs, OR 1.26 (95% CI: 1.22-1.30) and in 42.4% with memantine, OR 1.69 (95% CI: 1.62-1.78) (P<.000). From the diagnosis of dementia, 461 days (±1576.5) elapsed when isolated drugs were prescribed; 651 days (±1574.25) associated with IACEs and 1224 (±1779) with memantine. CONCLUSIONS: One third of patients with dementia were prescribed antipsychotics, mostly atypical, more frequently in those older than 85 years and for prolonged periods. IACEs and memantine were associated with the risk of antipsychotic prescription, but paradoxically, with prolonged time to onset.

Dispensing of antineoplastic medications and their impact on the dispensing of anti-dementia drugs for adults aged ≥60 years: A cohort study.

History of cancer has been associated with decreased risk of dementia, but it is unclear if this is due to the use of antineoplastic medications. Participants were 442,795 adults aged ≥60 years, of whom 235,841 (53.26 %) were women. Those dispensed antineoplastic medications during 2012-2013 had lower odds of being dispensed an anti-dementia drug between 2015 and 2021 (age/sex-adjusted OR = 0.60, 95%CI = 0.55-0.66). The dispensing of antineoplastic medications was associated with an adjusted hazard ratio of 0.72 (95%CI = 0.65-0.80) of subsequent dispensing of an anti-dementia drug. Understanding the mechanisms that support this association may contribute to the introduction of novel approaches to dementia prevention.

Memantine: Updating a rare success story in pro-cognitive therapeutics.

The great potential for NMDA receptor modulators as druggable targets in neurodegenerative disorders has been met with limited success. Considered one of the rare exceptions, memantine has consistently demonstrated restorative and prophylactic properties in many AD models. In clinical trials memantine slows the decline in cognitive performance associated with AD. Here, we provide an overview of the basic properties including pharmacological targets, toxicology and cellular effects of memantine. Evidence demonstrating reductions in molecular, physiological and behavioural indices of AD-like impairments associated with memantine treatment are also discussed. This represents both an extension and homage to Dr. Chris Parson's considerable contributions to our fundamental understanding of a success story in the AD treatment landscape.

Memantine Improves Memory and Neurochemical Damage in a Model of Maple Syrup Urine Disease.

Maple Syrup Urine Disease (MSUD) is a metabolic disease characterized by the accumulation of branched-chain amino acids (BCAA) in different tissues due to a deficit in the branched-chain alpha-ketoacid dehydrogenase complex. The most common symptoms are poor feeding, psychomotor delay, and neurological damage. However, dietary therapy is not effective. Studies have demonstrated that memantine improves neurological damage in neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. Therefore, we hypothesize that memantine, an NMDA receptor antagonist can ameliorate the effects elicited by BCAA in an MSUD animal model. For this, we organized the rats into four groups: control group (1), MSUD group (2), memantine group (3), and MSUD + memantine group (4). Animals were exposed to the MSUD model by the administration of BCAA (15.8 µL/g) (groups 2 and 4) or saline solution (0.9%) (groups 1 and 3) and treated with water or memantine (5 mg/kg) (groups 3 and 4). Our results showed that BCAA administration induced memory alterations, and changes in the levels of acetylcholine in the cerebral cortex. Furthermore, induction of oxidative damage and alterations in antioxidant enzyme activities along with an increase in pro-inflammatory cytokines were verified in the cerebral cortex. Thus, memantine treatment prevented the alterations in memory, acetylcholinesterase activity, 2',7'-Dichlorofluorescein oxidation, thiobarbituric acid reactive substances levels, sulfhydryl content, and inflammation. These findings suggest that memantine can improve the pathomechanisms observed in the MSUD model, and may improve oxidative stress, inflammation, and behavior alterations.

Compounding and Characterization of Oral Disintegrating Films Containing Memantine Hydrochloride for Geriatrics.

Memantine hydrochloride is commonly prescribed for Alzheimer's disease and vascular dementia. However, the drug is only available in tablet form, a dosage form which is difficult for geriatrics to swallow. This problem is especially difficult for those patients diagnosed with Alzheimer's. This study was therefore aimed to develop and characterize an oral disintegrating film containing memantine hydrochloride using different types and concentrations of polymers. Using the solvent casting method, twelve formulations were developed, which involved manipulations on the type and concentration of the polymer. Afterwards, six formulations were selected to undergo characterization tests. These tests evaluated the films' tensile strength, Young's Modulus, percent elongation, folding endurance, disintegration and dissolution time, content uniformity, moisture loss, and moisture uptake. Polymers such as polyvinyl alcohol, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, and pullulan gum were respectively incorporated at different concentrations. The study found that only hydroxypropyl methylcellulose and polyvinyl alcohol formulations developed into acceptable oral disintegrating films. Formulation E (hydroxypropyl methylcellulose 50-mg/film), which exhibited optimal mechanical strength, fast disintegration and dissolution, and excellent content uniformity, was identified as the best formula. Although polyvinyl alcohol showed higher mechanical strength, hydroxypropyl methylcellulose films were better at fulfilling the optimal characteristics of an oral disintegrating film. The study showed that the mechanical strength increased proportionally to the polymer concentration in the polyvinyl alcohol film. However, for the hydroxypropyl methylcellulose film, the mechanical strength increased only when hydroxypropyl methylcellulose's concentration was increased from a 40-mg/film to a 50-mg/film but decreased with a 60-mg/film. To summarize, orally disintegrating films containing memantine hydrochloride was developed, characterized, and reasoned to have high potential to be marketed and to increase medication compliance among geriatrics suffering from Alzheimer's disease.

[Russian experience in using a combination of fixed doses of donepezil and memantine in the treatment of Alzheimer's disease as an observational non-interventional multicenter program]. / Rossiiskii opyt primeneniya kombinatsii fiksirovannykh doz donepezila i memantina v terapii bolezni Al'tsgeimera v ramkakh nablyudatel'noi neinterventsionnoi mnogotsentrovoi programmy.

OBJECTIVE: To evaluate the efficacy, safety, and compliance to therapy with Mioreol, first used as part of routine clinical practice in patients with moderate-to-severe dementia due to AD. MATERIAL AND METHODS: The study was conducted as a non-interventional observational program. The work was performed on a group of 48 patients with moderate-to-severe AD aged from 60 to 90 years (median age 74 [69; 77]). The therapeutic dose of Mioreol was 10 mg donepezil + 20 mg memantine, the drug was taken orally, once a day at the same time, regardless of meals. The duration of the course of therapy was 24 weeks. The effects of the drug were assessed using the MMSE, ADAS-Cog, NPI, and CGI scales before the start of therapy and by the end of 12 and 24 weeks of treatment. RESULTS: The use of Mioreol in six-month therapy of AD patients with moderate-to-severe dementia improved not only cognitive but also a wide range of non-cognitive mental disorders. There was an improvement in the CGI-C scale in more than 50% of included patients, positive dynamics on the ADAS-cog scale (6.5 points reduction in total score) and reduction of non-cognitive mental disorders on the NPI scale (4 points reduction in total score). CONCLUSION: Fixed-dose combination therapy with Mioreol is an effective and well-tolerated treatment option for patients with moderate-to-severe AD. A combination of fixed-dose therapeutic doses of donepezil and memantine is potentially more appropriate than the simultaneous use of two recommended drugs for the treatment of AD, which will improve treatment adherence in patients with moderate to severe AD.

Dementia: Management and Controversies in Management.

Dementia management requires individualized patient encounters that focus on education and realistic expectations. Numerous vitamins and supplements are promoted for memory enhancement, but they lack evidence to support their use. Nonpharmacotherapy should be used through all stages of dementia. Common initial pharmacotherapy includes cholinesterase inhibitors and memantine, with use guided by dementia type, tolerability, patient goals, and disease stage. Assessment of benefit should incorporate caregiver input, functional improvements, behavioral symptoms, and tolerability. Management length is individualized. When a drug is discontinued, physicians should evaluate the patient for early worsening of cognitive or functional symptoms. Newer treatments, such as aducanumab, can reduce beta-amyloid plaques, but evidence for cognitive improvements is lacking; these treatments also are expensive and patient access is limited, resulting in barriers to widespread use. As dementia progresses, patients often develop behavioral and psychological symptoms, which are challenging for patients and caregivers. Nonpharmacotherapy is the first-line treatment for behavioral and psychological symptoms of dementia. Use of antipsychotics and benzodiazepines should be limited unless symptoms are placing the patient or others in imminent danger. Pharmacotherapy for these symptoms should be individualized, often requiring trials of various therapeutic options.

Consumption of drugs for Alzheimer's disease on the Brazilian private market.

OBJECTIVE: To analyze the consumption of drugs for Alzheimer's disease on the Brazilian private market and its geographical distribution from 2014 to 2020. METHODS: National data from the Brazilian National System of Controlled Product Management were used, regarding sales of donepezil, galantamine, rivastigmine, and memantine from January 2014 to December 2020. Sales data were used as a proxy for drug consumption and expressed as defined daily dose/1,000 inhabitants/year at national, regional, federative unit and microregion levels. RESULTS: Drug consumption went from 5,000 defined daily doses/1,000 inhabitants, in 2014, to more than 16,000/1,000 inhabitants, in 2020, and all federative units showed positive variation. The Brazilian Northeast had the highest cumulative consumption in the period but displayed microregional disparities while the North region had the lowest consumption. Donepezil and memantine were the most consumed drugs, with the highest growth in consumption from 2014 to 2020. CONCLUSION: The consumption of medicines indicated to treat Alzheimer's disease tripled in Brazil between 2014 and 2020, which may relate to the increase in the prevalence of the disease in the country, greater access to health services, and inappropriate use. This challenges managers and healthcare providers due to population aging and the increased prevalence of chronic-degenerative diseases.

Memantine administration prevented chorea movement in Huntington's disease: a case report.

BACKGROUND: Huntington's disease is an autosomal dominant inherited disorder characterized by personality changes (such as irritability and restlessness) and psychotic symptoms (such as hallucinations and delusions). When the personality changes become noticeable, involuntary movements (chorea) also develop. The disease is caused by the CAG repeat expansion in the coding region of the HTT gene, and the diagnosis is based on the presence of this expansion. However, there is currently no effective treatment for the progression of Huntington's disease and its involuntary motor symptoms. Herein, we present a case in which memantine was effective in treating the chorea movements of Huntington's disease. CASE PRESENTATION: A 75-year-old Japanese woman presented to the hospital with involuntary movements of Huntington's disease that began when she was 73 years old. In a cerebral blood flow test (N-isopropyl-p-iodoamphetamine-single-photon emission computed tomography), decreased blood flow was observed in the precuneus (anterior wedge) and posterior cingulate gyrus. Usually, such areas of decreased blood flow are observed in patients with Alzheimer's-type dementia. So, we administered memantine for Alzheimer's-type dementia, and this treatment suppressed the involuntary movements of Huntington's disease, and the symptoms progressed slowly for 7 years after the onset of senility. In contrast, her brother died of complications of pneumonia during the course of Huntington's disease. CONCLUSIONS: We recorded changes in parameters such as the results of the N-isopropyl-p-iodoamphetamine-single-photon emission computed tomography and gait videos over 7 years. Treatment with memantine prevented the chorea movement and the progression of Huntington's disease. We believe this record will provide clinicians with valuable information in diagnosing and treating Huntington's disease.

Behavioural Variant Frontotemporal Dementia due to CCNF Gene Mutation: A Case Report.

BACKGROUND: Frontal, temporal lobe dementia (FTD) and amyotrophic lateral sclerosis (ALS) are fatal neurodegenerative diseases. Studies have found that CCNF mutations have been found in patients with familial and sporadic ALS and FTD. Behavioural variant frontotemporal dementia (bvFTD) is a clinical syndrome characterized by progressive deterioration of personality, social behaviour, and cognitive function, which is most closely related to genetic factors. As the early symptoms of bvFTD are highly heterogeneous, the condition is often misdiagnosed as Alzheimer's disease or psychiatric disorders. In this study, a bvFTD patient had a CCNF gene mutation, which led to ubiquitinated protein accumulation and ultimately caused neurodegenerative disease. Genetic detection should be improved urgently for bvFTD patients and family members to provide a clinical reference for early diagnosis of frontotemporal dementia. CASE PRESENTATION: In this case, the patient was 65 years old with an insidious onset, early-onset memory loss, a significant decline in the episodic memory, an early AD diagnosis, and oral treatment with donepezil hydrochloride for 3 years with poor efficacy, followed by a change to oral memantine hydrochloride tablets, which controlled the condition for several months. His medication was switched to sodium oligomannate capsules, and his condition was gradually controlled, but no significant improvement was observed. After spontaneous drug withdrawal, the patient's condition progressed rapidly; therefore, he visited our hospital and underwent neuropsychological tests for moderate to severe cognitive impairment. AD cerebrospinal fluid markers showed no significant abnormalities, and cranial MRI revealed frontotemporal lobe atrophy and decreased hippocampal volume. Genetic testing for the presence of the CCNF gene revealed a c.1532C > A (p. T511N) heterozygous variant, which might be a diagnostic criterion for bvFTD. Therefore, the patient's symptoms recurred after transient improvement with the combination of donepezil, oral memantine hydrochloride tablets, and sodium oligomannate, but his overall condition was improved compared to that before, and this treatment regimen was continued to observe changes during the follow-up. CONCLUSION: The early clinical manifestations of bvFTD are complex and variable, and the condition is easily misdiagnosed, thus delaying treatment. Therefore, for patients with a high clinical suspicion of FTD, in addition to a detailed understanding of their medical history and family history and improvement of relevant examinations, genetic testing should be performed as early as possible to help confirm the diagnosis. For diseases closely related to genes, genetic testing of other family members should be optimised as much as possible to allow early diagnosis and intervention and guide fertility in the next generation.

Memantine Improves the Disturbed Glutamine and γ-Amino Butyric Acid Homeostasis in the Brain of Rats Subjected to Experimental Autoimmune Encephalomyelitis.

Glutamine (Gln), glutamate (Glu), and γ-amino butyric acid (GABA) are essential amino acids for brain metabolism and function. Astrocyte-derived Gln is the precursor for the two most important neurotransmitters in the central nervous system (CNS), which are the excitatory neurotransmitter Glu and the inhibitory neurotransmitter GABA. In addition to their roles in neurotransmission, these amino acids can be used as alternative substrates in brain metabolism that enable metabolic coupling between astrocytes and neurons in the glutamate-glutamine cycle (GGC). The disturbed homeostasis of these amino acids within the tripartite synapse may be involved in the pathogenesis of various neurological diseases. Interactions between astrocytes and neurons in terms of Gln, Glu, and GABA homeostasis were studied in different phases of experimental allergic encephalomyelitis (EAE) in Lewis rats. The results of the study showed a decrease in the transport (uptake and release) of Gln and GABA in both neuronal and astrocyte-derived fractions. These effects were fully or partially reversed when the EAE rats were treated with memantine, a NMDA receptor antagonist. Changes in the expression and activity of selected glutamine/glutamate metabolizing enzymes, such as glutamine synthase (GS) and phosphate-activated glutaminase (PAG), which were affected by memantine, were observed in different phases of EAE. The results suggested perturbed homeostasis of Gln, Glu, and GABA during EAE, which may indicate alterations in neuron-astrocyte coupling and dysfunction of the tripartite synapse. Memantine appears to partially regulate the disturbed relationships between Gln, Glu, and GABA.

A causal inference study: The impact of the combined administration of Donepezil and Memantine on decreasing hospital and emergency department visits of Alzheimer's disease patients.

Alzheimer's disease is the most common type of dementia that currently affects over 6.5 million people in the U.S. Currently there is no cure and the existing drug therapies attempt to delay the mental decline and improve cognitive abilities. Two of the most commonly prescribed such drugs are Donepezil and Memantine. We formally tested and confirmed the presence of a beneficial drug-drug interaction of Donepezil and Memantine using a causal inference analysis. We applied doubly robust estimators to one of the largest and high-quality medical databases to estimate the effect of two commonly prescribed Alzheimer's disease (AD) medications, Donepezil and Memantine, on the average number of hospital or emergency department visits per year among patients diagnosed with AD. Our results show that, compared to the absence of medication scenario, the Memantine monotherapy, and the Donepezil monotherapy, the combined use of Donepezil and Memantine treatment significantly reduces the average number of hospital or emergency department visits per year by 0.078 (13.8%), 0.144 (25.5%), and 0.132 days (23.4%), respectively. The assessed decline in the average number of hospital or emergency department visits per year is consequently associated with a substantial reduction in medical costs. As of 2022, according to the Alzheimer's Disease Association, there were over 6.5 million individuals aged 65 and older living with AD in the US alone. If patients who are currently on no drug treatment or using either Donepezil or Memantine alone were switched to the combined used of Donepezil and Memantine therapy, the average number of hospital or emergency department visits could decrease by over 613 thousand visits per year. This, in turn, would lead to a remarkable reduction in medical expenses associated with hospitalization of AD patients in the US, totaling over 940 million dollars per year.

Treatment of Alzheimer's Disease: Beyond Symptomatic Therapies.

In an ever-increasing aged world, Alzheimer's disease (AD) represents the first cause of dementia and one of the first chronic diseases in elderly people. With 55 million people affected, the WHO considers AD to be a disease with public priority. Unfortunately, there are no final cures for this pathology. Treatment strategies are aimed to mitigate symptoms, i.e., acetylcholinesterase inhibitors (AChEI) and the N-Methyl-D-aspartate (NMDA) antagonist Memantine. At present, the best approaches for managing the disease seem to combine pharmacological and non-pharmacological therapies to stimulate cognitive reserve. Over the last twenty years, a number of drugs have been discovered acting on the well-established biological hallmarks of AD, deposition of ß-amyloid aggregates and accumulation of hyperphosphorylated tau protein in cells. Although previous efforts disappointed expectations, a new era in treating AD has been working its way recently. The Food and Drug Administration (FDA) gave conditional approval of the first disease-modifying therapy (DMT) for the treatment of AD, aducanumab, a monoclonal antibody (mAb) designed against Aß plaques and oligomers in 2021, and in January 2023, the FDA granted accelerated approval for a second monoclonal antibody, Lecanemab. This review describes ongoing clinical trials with DMTs and non-pharmacological therapies. We will also present a future scenario based on new biomarkers that can detect AD in preclinical or prodromal stages, identify people at risk of developing AD, and allow an early and curative treatment.

Psychopharmacological Medication Use in Frontotemporal Dementia at the Time of Diagnosis: Comparison with Alzheimer's Disease.

BACKGROUND: Due to the significant presence of neuropsychiatric symptoms in patients with frontotemporal dementia (FTD) spectrum disorders, psychiatric misdiagnoses, diagnostic delay, and use of psychiatric treatments are common prior to the FTD diagnosis. Furthermore, treatment of diagnosed FTD patients mainly relies on off-label psychopharmacological approaches. Currently, limited real-world data are available regarding the actual use of psychopharmacological medications in FTD. OBJECTIVE: To evaluate psychopharmacological medication use at the time of FTD diagnosis. METHODS: Psychopharmacological medication use was evaluated in a Finnish FTD cohort containing 222 FTD patients, including the major clinical disease phenotypes (behavioral, language, and motor variants) and genetic patients carrying the C9orf72 repeat expansion. A cohort of 214 Alzheimer's disease (AD) patients was used as a neurodegenerative disease reference group. RESULTS: Active use of psychopharmacological medications at the time of diagnosis was significantly more common in FTD compared to AD, especially in the case of antidepressants (26.1% versus 15.0%, OR = 2.01, p = 0.008), antipsychotics (23.9% versus 9.3%, OR = 3.15, p < 0.001), and mood-stabilizers (6.3% versus 1.9%, OR = 2.93, p = 0.085; not statistically significant), whereas the use of cholinesterase inhibitors or memantine was nearly nonexistent in FTD patients. Female gender and behavioral variant of FTD phenotype alongside with depressive and psychotic symptoms were the most prominent factors associating with the use of these medications among the FTD spectrum patients. CONCLUSION: Use of off-label psychopharmacological medication and polypharmacy is substantially common at the time of FTD diagnosis. This likely reflects the challenges in using symptom-driven treatment approaches, especially prior to the eventual diagnosis.