With population aging, Alzheimer's disease (AD) is becoming increasingly prevalent, causing great health and economic burdens worldwide. Despite decades of research, there are still no effective disease-modifying treatments for AD, highlighting the urgent need for more in-depth understanding of the disease-causing mechanisms. The brain serotonin (5-HT) neurotransmission system undergoes structural and functional changes in aging and AD, which contributes to cognitive decline and comorbid mood disturbances. This review discusses the critical involvement of the brain 5-HT system in aging and AD. Existing findings on the changes in projection fiber innervation and receptor/transporter expression in AD are reviewed. Preclinical and clinical progress on the development of 5-HT-modulating drugs for AD and the obstacles faced by these development efforts are discussed. Epigenetic control of the brain 5-HT system and the potential of modulating 5-HT transmission via DNA methylation are also examined.

BackgroundAgitation is a common neuropsychiatric symptom of Alzheimer's disease; however, limited information exists on how measurable changes in agitated behaviors relate to overall caregiver experience. We sought to describe agitated behaviors measured by the Cohen-Mansfield Agitation Inventory (CMAI) score among individuals with Alzheimer's disease living in US community-based settings and experience of their caregivers.MethodsAn online survey was conducted (08/26/2021-09/24/2021) among adult caregivers who lived with and provided unpaid care for an individual with Alzheimer's disease. The 3-part survey involved (1) informed consent and screening; (2) CMAI assessment (total and sub-scores for four agitation factors); (3) characteristics and outcomes of caregivers and individuals with Alzheimer's disease. Descriptive statistics are reported. Association between the CMAI total score and caregiver burden (measured using the Zarit Burden Interview), mental health (measured using the Patient Health Questionnaire 4-item), and work/activity impairment (measured using the Work Productivity and Activity Impairment: Caregiver scale) was estimated using regression models.ResultsA total of 250 caregivers (mean age: 44.5 years; 55.2% male; 86.4% White) completed the survey. Based on the CMAI, 99.6% of individuals with Alzheimer's disease (mean age: 68.6 years; 55.2% male; 83.2% White) experienced ≥1 agitated behavior in the past 2 weeks. Caregivers reported providing an average of 39.1 hours of care per week for individuals with Alzheimer's disease (additional non-paid and paid care provided by other caregivers was 58.8% and 38.4%, respectively); 60.8% of caregivers had a high caregiving burden, 35.2% experienced moderate-to-severe distress, and 68.2/64.0% had impairment in work/daily activities. Agitation among individuals with Alzheimer's disease was associated with significantly poorer caregiver outcomes.ConclusionsIndividuals with Alzheimer's disease frequently experience several different agitated behaviors. Effective management of agitated behaviors is important and has the potential to improve the overall caregiver experience.

BackgroundAmong neuropsychiatric symptoms (NPSs) of Alzheimer's disease (AD), agitation has been shown to occur commonly in the course of AD, overlapping or comorbid with other NPSs.ObjectiveThe proportion of patients with agitation and the severity of agitation appear to differ depending on the neurocognitive stage of AD, and knowledge about the characteristic comorbid symptom pattern may help in elucidation of the underlying mechanism.MethodsAmong 421 clinic-based patients with AD, we re-analyzed the dataset of the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD) to examine the correlations between the scores for agitation and those for other Neuropsychiatric Inventory subscales in each neurocognitive stage of AD (mild, moderate, and severe) classified according to scores in Mini-Mental State Examination.ResultsThe scores for agitation were positively and robustly correlated with the scores for irritability in all stages of AD, and with the scores for anxiety in the moderate and severe stages. The scores for agitation were also correlated with those for sleep disorders in severe AD stage or disinhibition in the moderate AD stage. Multiple regression analysis identified irritability influencing the agitation in moderate and severe stages, and sleep disorders influencing the agitation in the severe stage.ConclusionsAs comorbid NPSs with agitation, characteristic affective, impulsive, and circadian abnormalities may be relevant to generate diverse subsyndromes in AD. Irritability consistently causes agitated behaviors, including refusal to take one's own care, and diurnal rhythm disorder in the severe AD stage may also cause poor acceptance for self-care.

Citalopram is effective in treating agitation in Alzheimer's dementia (AD), but it is associated with cognitive and cardiac risks, likely due to its R-enantiomer. Escitalopram, the S-enantiomer, may be an alternative. In this double-masked randomized (1:1) placebo-controlled trial, we assessed the efficacy and safety of escitalopram in treating agitation in AD after failure of a psychosocial intervention (PSI). Assessments occurred at enrollment, post-PSI (baseline) and at 3, 6, 9 and 12 weeks post-baseline. Settings were 27 community-based centers. The target randomization sample was 392 participants. Participants were adults with AD, a Mini-Mental State Examination Telephone score of 3-20 and significant agitation. PSI non-responders received escitalopram (up to 15 mg per day) or placebo for 12 weeks while continuing PSI. The outcome was the proportion of participants with clinically significant improvement in agitation from baseline at 12 weeks. In total, 173 participants were randomized (84 escitalopram versus 89 placebo; mean ± s.d. age = 78.4 ± 8.7 years; 90 men (52.0%); 127 White (73.4%)). The unadjusted risk difference at 12 weeks was 0.08 (95% confidence interval: -0.21, 0.06). Drug-related QT interval prolongation was observed. Although the randomized sample was smaller than planned, escitalopram was not effective in treating agitation in AD and was associated with cardiac conduction delays. Clinicians need to be cautious in recommending escitalopram as an alternative to citalopram for this condition. ClincialTrials.gov identifier: NCT03108846 .

Dementia describes when a person has cognitive limitations that impede function. Persons with kidney disease are unduly impacted by dementia: up to 87% of the dialysis population has cognitive impairment. In this review, we discuss the diagnosis and management of dementia, including the role of cerebrovascular disease and other risk factors. We review the available screening tools for the diagnosis of dementia. We discuss how the diagnosis of dementia differs from the diagnosis of mild cognitive impairment and also detail how delirium and depression can mimic dementia. In terms of treatments for dementia, we highlight 4 components. First, we describe pharmacologic treatments for the management of dementia, including the cholinesterase inhibitors N-methyl-d-aspartate antagonists as well as the newer antiamyloid antibody drugs for Alzheimer dementia. Second, we discuss the importance of nonpharmacologic interventions for the management of dementia, especially exercise. Third, we review approaches for the behavioral and neuropsychiatric symptoms associated with dementia, including potential medication management. Fourth, we highlight the essential and valuable role of caregivers in both the diagnosis and management of dementia. We conclude with key considerations about the impact of dementia for persons receiving dialysis and the role of dementia in kidney transplant evaluation.

Brexpirazole was approved for the treatment of nonpsychotic agitation in Alzheimer's disease (AD) dementia by the United States Food and Drug Administration (FDA) in May 2023 after three phase 3 clinical trials found brexpiprazole 2 to 3 mg/day to be an effective and well-tolerated treatment for agitation in AD dementia, albeit with small effect sizes. It appeared to especially benefit dementia patients with severe agitation/aggression, but it took between 6 and 12 weeks across the three studies for the medication to separate from placebo. However, much remains unknown about its place in the psychopharmacological armamentarium for the treatment of AD dementia-related agitation, including the optimal duration of a brexpiprazole trial, bridging options during the time it takes for brexpiprazole to become effective, and whether it should be continued in the presence of or upon emergence of psychosis during treatment. This Research in Action article uses a case vignette to synthesize the findings of the brexpiprazole trials and apply them to clinical practice, highlight the current uncertainties associated with its use, and compare it with other psychopharmacological options for the treatment of agitation in AD dementia.

Dementia is associated with psychiatric symptoms but the effects of antidepressants on cognitive function in dementia are understudied. We aimed to investigate the association between antidepressants and cognitive decline in patients with dementia, and the risk of severe dementia, fractures and death, depending on antidepressant class, drug, and dose.

This is a national cohort study. Patients with dementia registered in the Swedish Registry for Cognitive/Dementia Disorders-SveDem from May 1, 2007, until October 16, 2018, with at least one follow-up after dementia diagnosis, and who were new users of antidepressants, were included. Antidepressant use as a time varying exposure defined during the 6 months leading up to dementia diagnosis or each subsequent follow-up. We used linear mixed models to examine the association between antidepressant use and cognitive trajectories assessed by Mini-Mental State Examination (MMSE) scores. We used Cox proportional hazards models to calculate the hazard ratios for severe dementia (MMSE score < 10), fracture, and death. We compared antidepressant classes and drugs, and analyzed dose-response.

We included 18740 patients (10 205 women [54.5%]; mean [SD] age, 78.2[7.4] years), of which 4271 (22.8%) received at least one prescription for an antidepressant. During follow-up, a total of 11912 prescriptions for antidepressants were issued, with selective serotonin reuptake inhibitors (SSRI) being the most common (64.8%). Antidepressant use was associated with faster cognitive decline (β (95% CI) = - 0.30(- 0.39, - 0.21) points/year), in particular sertraline (- 0.25(- 0.43, - 0.06) points/year), citalopram (- 0.41(- 0.55, - 0.27) points/year), escitalopram (- 0.76(- 1.09, - 0.44) points/year), and mirtazapine (- 0.19(- 0.34, - 0.04) points/year) compared with non-use. The association was stronger in patients with severe dementia (initial MMSE scores 0-9). Escitalopram showed a greater decline rate than sertraline. Compared with non-use, dose response of SSRIs on greater cognitive decline and higher risks of severe dementia, all-cause mortality, and fracture were observed.

In this cohort study, current antidepressant use was associated with faster cognitive decline; furthermore, higher dispensed doses of SSRIs were associated with higher risk for severe dementia, fractures, and all-cause mortality. These findings highlight the significance of careful and regular monitoring to assess the risks and benefits of different antidepressants use in patients with dementia.

Psychosis and agitation are among the most distressing neuropsychiatric symptoms (NPSs) of Alzheimer's disease (AD), linked to faster disease progression and earlier admission to nursing homes. While nonpharmacological treatments may alleviate mild behavioral symptoms, more severe syndromes often require pharmacological intervention. Brexpiprazole is the only medication approved for agitation in AD, although its limited clinical efficacy has raised criticism. No drugs have been approved for treating psychosis in AD, highlighting the critical need for new, effective, and safe treatments. Recent studies have elucidated part of the neurobiological basis of NPSs in the AD brain, offering insights for testing repurposed and novel drugs. We conducted a comprehensive nonsystematic literature review, aiming to provide a critical overview of both current treatments and emerging pharmacological interventions under clinical development for treating psychosis and agitation in AD. Additionally, we present strategies to optimize the clinical development of new drug candidates. We identify three promising compounds that are currently in phase 3 trials: xanomeline-trospium for AD psychosis, and dextromethorphan-bupropion and dexmedetomidine for agitation in AD. We propose that biomarkers linked to the neuropsychiatric traits of AD patients should be identified in dedicated studies and then included in phase 2 dose-range-finding studies with novel compounds to establish biological engagement. Furthermore, phase 3 placebo-controlled studies should be carried out in AD biomarker-confirmed subjects with narrower cognitive impairment ranges and precise NPS severity at screening. Alternative study designs, such as sequential phase approaches, may also be adopted.

Humans present sex-driven biological differences. Consequently, the prevalence of analyzing specific diseases and comorbidities differs between the sexes, directly impacting patients' management and treatment. Despite its relevance and the growing evidence of said differences across numerous diseases (with 4,370 PubMed results published within the past year), knowledge at the comorbidity level remains limited. In fact, to date, no study has attempted to identify the biological processes altered differently in women and men, promoting differences in comorbidities. To shed light on this problem, we analyze expression data for more than 100 diseases from public repositories, analyzing each sex independently. We calculate similarities between differential expression profiles by disease pairs and find that 13-16% of transcriptomically similar disease pairs are sex-specific. By comparing these results with epidemiological evidence, we recapitulate 53-60% of known comorbidities distinctly described for men and women, finding sex-specific transcriptomic similarities between sex-specific comorbid diseases. The analysis of shared underlying pathways shows that diseases can co-occur in men and women by altering alternative biological processes. Finally, we identify different drugs differentially associated with comorbid diseases depending on patients' sex, highlighting the need to consider this relevant variable in the administration of drugs due to their possible influence on comorbidities.

Agitation is a common and disruptive syndrome in dementia due to Alzheimer's disease (AD). Brexpiprazole was recently approved for this agitation of AD dementia and is the only therapy approved for this indication.

The authors review the chemistry, pharmacokinetics, mechanism of action, and pharmacodynamics of brexpiprazole. Phase 2/3 and Phase 3 studies of brexpiprazole for the treatment of agitation in dementia due to AD are described. These studies demonstrated efficacy and safety for the 2 mg/d and 3 mg/d doses. Agitation reduction from baseline was significantly greater in the active treatment groups compared to the participants on placebo as measured by the Cohen-Mansfield Agitation Inventory, the primary outcome. Treatment benefit was demonstrated on the Clinician Global Impression - Severity, the key secondary outcome. Safety and tolerability were comparable in drug and placebo arms of the studies.

Approval by the Food and Drug Administration (FDA) of brexpiprazole for the treatment of agitation in dementia due to AD is an important milestone and regulatory precedent. This is the first approval for the treatment of any neuropsychiatric syndrome of AD. Brexpiprazole has a 'black box' warning for its use in psychosis caused by dementia due to an observed increase in mortality when using this class of antipsychotic agents in patients with dementia. Post-marketing surveillance will be key to understanding the safety profile of brexpiprazole. Brexpiprazole may be prioritized over the 'off label' use of other potential treatments for agitation.

Behavioral and psychological symptoms of dementia (BPSD) are common and difficult to manage. Although experimental data suggest that antidepressants may reduce BPSD, the results are inconclusive. To evaluate the efficacy and tolerability of antidepressants monotherapy for treating BPSD. We searched 10 cross-disciplinary electronic databases from inception to October 2023.Randomized controlled trials (RCTs) comparing antidepressants versus placebo for treating BPSD were included. The primary outcome was change in total neuropsychiatric symptom scale scores. Secondary outcomes included changes on agitation and psychosis subscale scores, change in total score of Mini-mental State Examination (MMSE). Tolerability outcomes included incidences and discontinuations due to adverse events. Finally, 8 RCTs including 676 patients were identified. We found a small beneficial effect of antidepressants on overall BPSD However, when trials with potential high-dose citalopram were excluded, no improvement was observed. No significant effects were detected on agitation and cognition. Currently there is no clear evidence of a beneficial effect of currently available antidepressants on overall BPSD and in particular agitation. Notably, clinician should be cautious of the potential risk of arrhythmias, dizziness and diarrhea when prescribing an antidepressant.

This chapter describes how the clinical efficacy of orally administered cholinesterase inhibitors has been demonstrated through placebo-controlled randomized clinical trials leading to regulatory approval worldwide for the symptomatic treatment of Alzheimer disease. Over time, other clinical indications have been found, such as Dementia with Lewy Bodies and Parkinson disease Dementia. The route of administration includes transdermal patches. Side effects predominantly arise from peripheral parasympathetic stimulation. There is hope that drugs acting on acetylcholine release or on muscarinic receptors can exert additional symptomatic benefits.

Behavioral and psychological symptoms of dementia (BPSD), such as agitation, apathy, and psychosis, are highly prevalent and have a significant impact on patients and their care partners. The neurobiology of BPSD involves a complex interplay of structural brain changes and alterations in the neurotransmitter system. Various genetic and plasma biomarkers have also been studied. Research in BPSD has been limited by heterogeneity in the diagnostic criteria and assessment tools. As such, there have been ongoing efforts to develop a gold-standard assessment tool and diagnostic criteria. Current practice guidelines recommend nonpharmacological therapies as first-line treatments. Pharmacological options are often used when there is an insufficient response to nonpharmacological strategies, but there can be serious adverse effects with existing pharmacological agents. This has resulted in growing efforts to develop novel therapeutics with more favorable tolerability profiles, with some showing promising results. Other biological therapies, such as neurostimulation, have also demonstrated positive results. As our understanding of BPSD evolves, ongoing research efforts in treatment of BPSD are warranted in order to enhance the quality of life for patients and their care partners.

This article discusses the prevalence, pathophysiology, assessment, and management of neuropsychiatric symptoms in patients with dementia.

There is a growing body of evidence localizing neuropsychiatric symptoms in dementia to frontal circuits in the brain, as well as relating them to pathologic changes seen in different dementias. Although very few medications have been approved by the US Food and Drug Administration (FDA) for the treatment of neuropsychiatric symptoms in dementia, there are more clinical trials showing the benefit of antidepressants, stimulants, and antipsychotics. In line with that trend, in 2023, the FDA approved the use of brexpiprazole, an atypical antipsychotic, for the treatment of agitation in Alzheimer disease dementia.

Neuropsychiatric symptoms are a core feature of all dementias and often emerge before cognitive symptoms manifest. They are highly clinically significant symptoms that disrupt the lives of patients and care partners and greatly influence the decision to place patients in long-term care facilities. The first line of treatment for neuropsychiatric symptoms in dementia is nonpharmacologic behavioral modification, but clinicians often must supplement this intervention with medications using an empiric approach.

Agitation is a common complication of Alzheimer's dementia (Agit-AD) associated with substantial morbidity, high healthcare service utilization, and adverse emotional and physical impact on care partners. There are currently no FDA-approved pharmacological treatments for Agit-AD. We present the study design and baseline data for an ongoing multisite, three-week, double-blind, placebo-controlled, randomized clinical trial of dronabinol (synthetic tetrahydrocannabinol [THC]), titrated to a dose of 10 mg daily, in 80 participants to examine the safety and efficacy of dronabinol as an adjunctive treatment for Agit-AD. Preliminary findings for 44 participants enrolled thus far show a predominately female, white sample with advanced cognitive impairment (Mini Mental Status Examination mean 7.8) and agitation (Neuropsychiatric Inventory-Clinician Agitation subscale mean 14.1). Adjustments to study design in light of the COVID-19 pandemic are described. Findings from this study will provide guidance for the clinical utility of dronabinol for Agit-AD. ClinicalTrials.gov Identifier: NCT02792257.

During the COVID-19 pandemic, the provision of quality care for behavioral and psychological symptoms in older adults with dementia may have been impeded due to physical distancing and infection control measures. Of particular concern is whether psychotropic medication use has increased despite its limited efficacy and adverse effects. This systematic review described the trajectory of psychotropic use for older adults with dementia across various settings, from community living to healthcare settings during the pandemic. Also, psychotropic use was explored in relation to patients, caregivers, and environment-related factors along with the occurrence of the pandemic.

We conducted a comprehensive search across five databases: Embase, PubMed, PsycINFO, CINAHL, and Cochrane Library. Methodological quality was assessed using Joanna Briggs Institute Critical Appraisal tools. A random-effects model was used to estimate the pooled risk ratios (RRs) of psychotropic use in older adults with dementia, comparing the pandemic period to the pre-pandemic period. Subgroup analyses based on the class of psychotropics and sensitivity analyses also were conducted. A funnel plot and Egger's regression test were used to detect potential publication bias.

Of the 3,123 screened articles, 15 studies were included in this systematic review, with 10 of them being part of the meta-analysis. Our meta-analysis yielded an RR of 1.16 (95% CI = 1.05-1.26) for overall psychotropic medication use. Further subgroup analysis based on the type of psychotropic medication revealed a significantly greater prevalence in the use of antipsychotics (RR = 1.19, 95% CI = 1.08-1.30). However, no significant differences were observed in the use of anxiolytics and/or hypnotics (including benzodiazepines), antidepressants, and mood stabilizers. Among psychotropics, some studies on antipsychotic use additionally explored patients, caregivers, and environmental-related factors during the pandemic.

The review indicates a higher risk of psychotropic use, especially antipsychotics, during the pandemic. Nonetheless, underlying reasons for the increased psychotropic use are not fully available from the reviewed studies. Therefore, further research is needed to identify the factors driving psychotropic use during the pandemic and facilitate the development of quality improvement interventions that can be implemented to minimize inappropriate psychotropic prescribing in future pandemics.

Alzheimer's Disease (AD) is an irreversible, progressive syndrome characterized by neurocognitive impairment. Two neuropathological features seen in AD are extracellular amyloid plaques consisting of amyloid beta1-40 and 1-42, and intracellular neurofibrillary tangles (NFTs). For decades, neuroscience research has heavily focused on seeking to understand the primary mechanism of AD and searching for pharmacological approaches for the treatment of dementia. Three monoclonal antibodies that act against amyloid beta-aducanumab, lecanemab, and donanemab-have been approved by the Food and Drug Administration (FDA) for the treatment of mild cognitive impairment and mild AD, in addition to medications for cognitive symptom management such as acetylcholinesterase inhibitors and the N-methyl-D-aspartate (NMDA) antagonist. Further trials should focus on the combination of therapies targeting amyloid plaques and tau pathology.

Alzheimer's disease (AD) is the most common cause of dementia, and the gradual deterioration of brain function eventually leads to death. Almost all AD patients suffer from neuropsychiatric symptoms (NPS), the emergence of which correlates with dysfunctional serotonergic systems. Our aim is to generate hindbrain organoids containing serotonergic neurons using human induced Pluripotent Stem Cells (iPSCs). Work presented here is laying the groundwork for the application of hindbrain organoids to evaluate individual differences in disease progression, NPS development, and pharmacological treatment response. Human peripheral blood mononuclear cells (PBMCs) from healthy volunteers (n = 3), an AD patient without NPS (n = 1), and AD patients with NPS (n = 2) were reprogrammed into iPSCs and subsequently differentiated into hindbrain organoids. The presence of serotonergic neurons was confirmed by quantitative reverse transcription PCR, flow cytometry, immunocytochemistry, and detection of released serotonin (5-HT). We successfully reprogrammed PBMCs into 6 iPSC lines, and subsequently generated hindbrain organoids from 6 individuals to study inter-patient variability using a precision medicine approach. To assess patient-specific treatment effects, organoids were treated with different concentrations of escitalopram oxalate, commonly prescribed for NPS. Changes in 5-HT levels before and after treatment with escitalopram were dose-dependent and variable across patients. Organoids from different people responded differently to the application of escitalopram in vitro. We propose that this 3D platform might be effectively used for drug screening purposes to predict patients with NPS most likely to respond to treatment in vivo and to understand the heterogeneity of treatment responses.

Dementia, or major neurocognitive disorder, is defined as a decline in 1 or more cognitive domains that causes impairment in everyday function. Alzheimer disease is the most common type of dementia in the United States, with an estimated 6.9 million adults who have Alzheimer disease and are 65 years or older. This article discusses the latest findings in preventing cognitive decline. It also discusses dementia screening, diagnosis, treatment, and the quality of life for persons with dementia and their caregivers.

Alzheimer's dementia (AD) is a progressive, neurodegenerative disease often accompanied by neuropsychiatric symptoms that profoundly impact both patients and caregivers. Agitation is among the most prevalent and distressing of these symptoms and often requires treatment. Appropriate therapeutic interventions depend on understanding the biological basis of agitation and how it may be affected by treatment. This narrative review discusses a proposed pathophysiology of agitation in Alzheimer's dementia based on convergent evidence across research approaches. Available data indicate that agitation in Alzheimer's dementia is associated with an imbalance of activity between key prefrontal and subcortical brain regions. The monoamine neurotransmitter systems serve as key modulators of activity within these brain regions and circuits and are rendered abnormal in AD. Patients with AD who exhibited agitation symptoms during life have alterations in neurotransmitter nuclei and related systems when the brain is examined at autopsy. The authors present a model of agitation in Alzheimer's dementia in which noradrenergic hyperactivity along with serotonergic deficits and dysregulated striatal dopamine release contribute to agitated and aggressive behaviors.

Aggression exacts a significant toll on human societies and is highly prevalent among neuropsychiatric patients. The neural mechanisms of aggression are unclear and treatment options are limited.

Using a recently validated lesion network mapping technique, we derived an aggression-associated network by analyzing data from 182 patients who had experienced penetrating head injuries during their service in the Vietnam War. To test whether damage to this lesion-derived network would increase the risk of aggression-related neuropsychiatric symptoms, we used the Harvard Lesion Repository (N = 852). To explore potential therapeutic relevance of this network, we used an independent deep brain stimulation dataset of 25 patients with epilepsy, in which irritability and aggression are known potential side effects.

We found that lesions associated with aggression occurred in many different brain locations but were characterized by a specific brain network defined by functional connectivity to a hub region in the right prefrontal cortex. This network involves positive connectivity to the ventromedial prefrontal cortex, dorsolateral prefrontal cortex, frontal pole, posterior cingulate cortex, anterior cingulate cortex, temporal-parietal junction, and lateral temporal lobe and negative connectivity to the amygdala, hippocampus, insula, and visual cortex. Among all 24 neuropsychiatric symptoms included in the Harvard Lesion Repository, criminality demonstrated the most alignment with our aggression-associated network. Deep brain stimulation site connectivity to this same network was associated with increased irritability.

We conclude that brain lesions associated with aggression map to a specific human brain circuit, and the functionally connected regions in this circuit provide testable targets for therapeutic neuromodulation.

Alzheimer's disease (AD) is a prevalent neurodegenerative disease characterized by progressive cognitive and functional decline. Nearly all patients with AD develop neuropsychiatric symptoms (NPSs). Agitation is one of the most distressing and challenging NPS. Brexpiprazole is an oral antipsychotic and is the first approved pharmacologic agent in the United States for the treatment of agitation associated with dementia due to AD. Its effect is thought to be from its partial serotonin 5-HT1A and dopamine D2 receptor agonist activity and serotonin 5-HT2A receptor antagonism. Brexpiprazole is a maintenance medication, and it should not be used "as needed" or as a "PRN" treatment for breakthrough agitation. Brexpiprazole is a major substrate of CYP2D6 and CYP3A4. Dose adjustments may be required for drug interactions or impaired renal or hepatic function. Clinical trials found brexpiprazole 2 to 3 mg/d demonstrated significant improvements in agitation, with brexpiprazole showing an approximate 5-point greater reduction on change in the Cohen-Mansfield Agitation Inventory total score at week 12 from baseline compared with placebo. Brexpiprazole is generally well tolerated and safe, and common adverse reactions when used for this indication include dizziness, headaches, insomnia, nasopharyngitis, somnolence, and urinary tract infections. Like other antipsychotics used for agitation in AD, brexpiprazole is associated with higher mortality rates compared with placebo. In a long-term care setting, there are several considerations for its use. Benefits include an oral agent that is well tolerated and clinical data showing statistically significant effects on agitation. However, brexpiprazole has not been studied in head-to-head clinical trials against other antipsychotics, and there are differing opinions if the agitation score reductions translate to a clinically meaningful difference. The approval of brexpiprazole signals favorably for upcoming agents for this indication, including escitalopram and dextromethorphan-bupropion. Both escitalopram and dextromethorphan-bupropion are currently undergoing clinical trials.

Behavioral and psychological symptoms of dementia (BPSD) are common and impart a significant burden to patients, caregivers, and the health system. However, there are few pharmacological options for treating BPSD. We conducted a systematic review of clinical trials examining the efficacy of anticonvulsants in BPSD.

We searched five electronic databases through January 2023, for randomized controlled trials and systematic reviews evaluating the efficacy of non-benzodiazepine anticonvulsants for the treatment of BPSD. We used the Cochrane risk of bias tool to ascertain the risk of bias in included trials. Because statistical pooling of results using meta-analysis was not feasible, we synthesized findings using the Cochrane Synthesis Without Meta-analysis reporting guidelines.

We identified 12 studies, including randomized controlled trials (RCTs) and 1 systematic review. Five RCTs evaluating valproic acid were synthesized by a recent Cochrane review which concluded that this drug is likely ineffective for BPSD. We extracted data from 6 trials involving 248 individuals comparing non-benzodiazepine anticonvulsants to either placebo or risperidone. Four trials (n = 97 participants) evaluated carbamazepine, only one of which demonstrated an improvement in the Brief Psychiatric Rating Scale measuring agitation, hostility, psychosis, and withdrawal/depression (effect size: 1.13; 95% confidence interval [CI]: 0.54-1.73) relative to placebo. Adverse effects were more common in patients receiving carbamazepine (20/27; 74%) relative to placebo (5/24; 21%). There is low quality evidence that oxcarbazepine is likely ineffective and that topiramate may be comparable to risperidone.

Anticonvulsants are unlikely to be effective in BPSD, although the quality of existing evidence is low.

According to scientific literature, some 99% of patients affected by Alzheimer's disease (AD) suffer from behavioral and psychological symptoms of dementia (BPSD), also known as neuropsychiatric symptoms (NPSs). In particular, agitation is one of the most difficult disorders to treat. States of agitation represent a very serious problem as they make these subjects dangerous for themselves and others and worsen as the disease advances. To date, there are no specific solutions for treating agitation. The only authorized drug is risperidone (as well as brexpiprazole, approved by the FDA on 11 May 2023), which can be used for no longer than 6-12 weeks because it increases the risk of death-owing to cardiocerebrovascular accidents-by 1.6-1.7 times.

In order to address the latter noteworthy unmet medical need, NanoBEO was produced. The aim of the present work is to generate the health technology assessment (HTA) of this nanotechnological device. The latter consists of a controlled release system, based on solid lipid nanoparticles loaded with bergamot essential oil (BEO).

The results of the present research assessed the current evidence in the field of non-pharmacological treatments for this condition, including relevant primary preclinical and clinical data studies supporting the use of this device and the production of the operative plan for its launch on the market. The findings offer recommendations for decision-making on its implementation in dementia.

NanoBEO represents a public-worth innovation in this neglected area, marking a significant advancement in the history of dementia, moving from academic research to product development.

Alzheimer's disease (AD), characterized by cognitive impairment, brain plaques, and tangles, is a global health concern affecting millions. It involves the build-up of amyloid-β (Aβ) and tau proteins, the formation of neuritic plaques and neurofibrillary tangles, cholinergic system dysfunction, genetic variations, and mitochondrial dysfunction. Various signaling pathways and metabolic processes are implicated in AD, along with numerous biomarkers used for diagnosis, risk assessment, and research. Despite these, there is no cure or effective treatment for AD. It is critically important to address this immediately to develop novel drug delivery systems (NDDS) capable of targeting the brain and delivering therapeutic agents to modulate the pathological processes of AD. This review summarizes AD, its pathogenesis, related signaling pathways, biomarkers, conventional treatments, the need for NDDS, and their application in AD treatment. It also covers preclinical, clinical, and ongoing trials, patents, and marketed AD formulations.

Agitation, psychosis, and apathy are prevalent and highly distressing neuropsychiatric symptoms (NPS) of Alzheimer's disease (AD) that have been linked to numerous negative outcomes, including increased mortality, worsened cognitive decline, and caregiver burden. Current treatments for AD-associated agitation, namely atypical antipsychotics, provide some benefits but may increase the risk of serious adverse events and death. Meanwhile, no pharmacotherapies have been approved by regulatory agencies for the treatment of psychosis or apathy in AD. Over the past decade, many new and repurposed drugs have emerged as potential therapeutic options for managing these challenging NPS.

This review aims to provide a comprehensive summary of pharmacotherapies that have recently been investigated in phase 2 and 3 clinical trials for the treatment of agitation, psychosis, or apathy in AD.

Novel atypical antipsychotics, serotonergic antidepressants, cannabinoids, and dextromethorphan combination drugs have shown promising results for alleviating agitation. Pimavanserin appears to be the most effective emerging therapy for psychosis, while methylphenidate has demonstrated good efficacy for apathy. Further research on biomarkers of NPS severity and treatment response, as well as continued improvements in methodological approaches are needed to advance the field.

To study the effects of selective serotonin reuptake inhibitors (SSRIs) on cognitive functions, mental improvements, and adverse effects in patients with Alzheimer's disease (AD).

Registered in INPLASY (INPLASY202450004), five drugs (citalopram, s-citalopram, quetiapine, olanzapine, and sertraline) were selected as representatives. A comprehensive search was conducted in PubMed, EMBASE, Web of Science, and the Cochrane Library up to May 15, 2024. Search terms were combined using Boolean operators, specifically 'AND' between different categories (e.g., 'Alzheimer's Disease' AND 'SSRIs') and 'OR' within the same category (e.g., 'citalopram OR s-citalopram OR quetiapine OR olanzapine OR sertraline'), to ensure a thorough retrieval of relevant studies. The selection followed rigorous inclusion and exclusion criteria for meta-analysis.

Fourteen articles from 1118 were selected for meta-analysis. The indicators, including Neuropsychiatric Inventory (NPI), Mini-Mental State Examination (MMSE), Brief Psychiatric Rating Scale (BPRS), and Cornell Scale for Depression in Dementia (CSDD), were used to assess the effects of the drugs on AD treatment. According to the results of NPI, CSDD, BPRS, MMSE, and security assessments, the five antidepressants have significant advantages in AD treatment compared with placebo, while the MMSE of the patient treated with the antidepressants did not show notable changes compared with patients treated only with placebo. Statistical analyses were conducted using Review Manager 5.3, employing random-effects models to account for study heterogeneity and sensitivity analyses to test the robustness of our findings.

This study suggests that SSRI-related antidepressants have great potential values in AD treatment, and further research on the application of SSRI-related antidepressants in AD treatment is necessary.

People with multiple sclerosis (pwMS) are at risk of concurrently using multiple central nervous system (CNS)-active drugs, yet the prevalence of CNS-active polypharmacy remains unmeasured in pwMS.

The objective is to measure the prevalence of CNS-active polypharmacy in pwMS.

This serial, cross-sectional study measured CNS-active polypharmacy in people with MS in the United States from 2008 to 2021 using insurance claims data. CNS-active polypharmacy was defined as the concurrent prescription of ⩾3 CNS-active drugs for >30 continuous days. CNS-active drugs included antidepressants, antiepileptics, antipsychotics, benzodiazepines, nonbenzodiazepine benzodiazepine receptor agonist hypnotics, opioids, and skeletal muscle relaxants.

The number of subjects included at each time point ranged from 23,917 subjects in 2008 to 55,797 subjects in 2021. In 2021, subjects with CNS-active polypharmacy were more likely to be 46-65 years of age and have CNS-related comorbidities compared to those without CNS-active polypharmacy. From 2008 to 2021, the age-adjusted prevalence of CNS-active polypharmacy among female subjects increased from 19.8% (95% confidence interval (CI) = 19.1-20.4) to 26.4% (95% CI = 25.9-26.8) versus 15.9% (95% CI = 14.8-17.0) to 18.6% (95% CI = 17.9-19.2) in male subjects.

The prevalence of CNS-active polypharmacy has increased among people with MS with a growing disparity by sex.

Behavioural and psychological symptoms of dementia (BPSD) are highly prevalent in people living with dementia. Second-generation antipsychotics (SGAs) are commonly used to treat BPSD, but their comparative efficacy and acceptability are unknown.

The standard mean difference (SMD) was used to pool the fixed effects of continuous outcomes. We calculated ORs with corresponding 95% credible intervals (CI) for the categorical variable. Efficacy was defined as the scores improved on the standardised scales. Acceptability was defined as the all-cause dropout rate. Tolerability was defined as the discontinuation rate due to adverse effects (AEs). The relative treatment rankings were reported with the surface under the cumulative curve. The AE outcomes included mortality, cerebrovascular adverse events (CVAEs), falls, sedation, extrapyramidal symptoms and urinary symptoms.

Twenty randomised controlled trials with a total of 6374 individuals containing 5 types of SGAs (quetiapine, olanzapine, risperidone, brexpiprazole and aripiprazole) with intervention lengths ranging from 6 weeks to 36 weeks were included in this network meta-analysis. For the efficacy outcome, compared with the placebo, brexpiprazole (SMD=-1.77, 95% CI -2.80 to -0.74) was more efficacious, and brexpiprazole was better than quetiapine, olanzapine and aripiprazole. Regarding acceptability, only aripiprazole (OR=0.72, 95% CI 0.54 to 0.96) was better than the placebo, and aripiprazole was also better than brexpiprazole (OR=0.61, 95% CI 0.37 to 0.99). In terms of tolerability, olanzapine was worse than placebo (OR=6.02, 95% CI 2.87 to 12.66), risperidone (OR=3.67, 95% CI 1.66 to 8.11) and quetiapine (OR=3.71, 95% CI 1.46 to 9.42), while aripiprazole was better than olanzapine (OR=0.25, 95% CI 0.08 to 0.78). Quetiapine presented good safety in CVAE. Brexpiprazole has better safety in terms of falls and showed related safety in sedation among included SGAs.

Brexpiprazole showing great efficacy in the treatment of BPSD, with aripiprazole showing the highest acceptability and olanzapine showing the worst tolerability. The results of this study may be used to guide decision-making.

This study began as a single-blind randomized controlled trial (RCT) to investigate the efficacy and safety of electroconvulsive therapy (ECT) for severe treatment-refractory agitation in advanced dementia. The aims are to assess agitation reduction using the Cohen-Mansfield Agitation Inventory (CMAI), evaluate tolerability and safety outcomes, and explore the long-term stability of agitation reduction and global functioning. Due to challenges encountered during implementation, including recruitment obstacles and operational difficulties, the study design was modified to an open-label format and other protocol amendments were implemented.

Initially, the RCT randomized participants 1:1 to either ECT plus usual care or simulated ECT plus usual care (S-ECT) groups. As patients were enrolled, data were collected from both ECT and simulated ECT (S-ECT) patients. The study now continues in an open-label study design where all patients receive actual ECT, reducing the targeted sample size from 200 to 50 participants.

Study is ongoing and open to enrollment.

The transition of the ECT-AD study design from an RCT to open-label design exemplifies adaptive research methodologies in response to real-world challenges. Data from both the RCT and open-label phases of the study will provide a unique perspective on the role of ECT in managing severe treatment-refractory agitation in dementia, potentially influencing future clinical practices and research approaches.

Neuropsychiatric syndromes (NPSs) are common in neurodegenerative disorders (NDDs); compromise the quality of life of patients and their care partners; and are associated with faster disease progression, earlier need for nursing home care, and poorer quality of life. Advances in translational pharmacology, clinical trial design and conduct, and understanding of the pathobiology of NDDs are bringing new therapies to clinical care.

Consensus definitions have evolved for psychosis, agitation, apathy, depression, and disinhibition in NDDs. Psychosocial interventions may reduce mild behavioral symptoms in patients with NDD, and pharmacotherapy is available for NPSs in NDDs. Brexpiprazole is approved for treatment of agitation associated with Alzheimer disease dementia, and pimavanserin is approved for treatment of delusions and hallucinations associated with psychosis of Parkinson disease. Trials are being conducted across several of the NDDs, and a variety of mechanisms of action are being assessed for their effect on NPSs.

Detection and characterization of NPSs in patients with NDDs is the foundation for excellent care. New definitions for NPSs in NDDs may inform choices regarding clinical trial populations and translate into clinical practice. Psychosocial and pharmacologic therapies may reduce behavioral symptoms and improve quality of life for patients and caregivers. Approved agents may establish regulatory precedents, demonstrate successful trial strategies, and provide the foundation for further advances in treatment development.

Dementia affects 10% of those 65 years or older and 35% of those 90 years or older, often with profound cognitive, behavioral, and functional consequences. As the baby boomers and subsequent generations age, effective preventive and treatment strategies will assume increasing importance.

Preventive measures are aimed at modifiable risk factors, many of which have been identified. To date, no randomized clinical trial data conclusively confirm that interventions of any kind can prevent dementia. Nevertheless, addressing risk factors may have other health benefits and should be considered. Alzheimer disease can be treated with cholinesterase inhibitors, memantine, and antiamyloid immunomodulators, with the last modestly slowing cognitive and functional decline in people with mild cognitive impairment or mild dementia due to Alzheimer disease. Cholinesterase inhibitors and memantine may benefit persons with other types of dementia, including dementia with Lewy bodies, Parkinson disease dementia, vascular dementia, and dementia due to traumatic brain injury. Behavioral and psychological symptoms of dementia are best treated with nonpharmacologic management, including identifying and mitigating the underlying causes and individually tailored behavioral approaches. Psychotropic medications have minimal evidence of efficacy for treating these symptoms and are associated with increased mortality and clinically meaningful risks of falls and cognitive decline. Several emerging prevention and treatment strategies hold promise to improve dementia care in the future.

Although current prevention and treatment approaches to dementia have been less than optimally successful, substantial investments in dementia research will undoubtedly provide new answers to reducing the burden of dementia worldwide.

Alzheimer's disease (AD) is a neurodegenerative condition characterized by progressive cognitive deterioration, functional impairments, and neuropsychiatric symptoms. Valiltramiprosate is a tramiprosate prodrug being investigated as a novel treatment for AD.

The online databases PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov were searched using the terms 'ALZ-801' or 'valiltramiprosate.' Alzheon press releases were reviewed for emerging clinical information. Valiltramiprosate is an oral, well-tolerated synthetic valine-conjugate prodrug of tramiprosate. Valiltramiprosate's active metabolite include tramiprosate and 3-sulfopropanoic acid. Proposed mechanism of action is multiligand binding to Aβ42 which stabilizes amyloid monomers to prevent peptide aggregation and oligomerization. Pharmacokinetic studies show 52% oral bioavailability, rapid absorption, approximately 40% brain-drug exposure, and near complete renal clearance. Compared to tramiprosate, valiltramiprosate extends plasma tramiprosate half-life and improves interindividual pharmacokinetic variability. Interim analyses from valiltramiprosate's phase II biomarker trial show: (1) significant reductions in plasma p-tau181 and related AD fluid biomarkers; (2) brain structure preservation and reduced hippocampal atrophy by MRI; and (3) improvements on cognitive assessments at multiple timepoints. Its phase III clinical trial in ApoE ε4 homozygotes is near completion.

Valiltramiprosate's clinical trial data show early indications of efficacy with potential disease modifying effect in AD.

To develop an agitation reduction and prevention algorithm is intended to guide implementation of the definition of agitation developed by the International Psychogeriatric Association (IPA).

Review of literature on treatment guidelines and recommended algorithms; algorithm development through reiterative integration of research information and expert opinion.

IPA Agitation Workgroup.

IPA panel of international experts on agitation.

Integration of available information into a comprehensive algorithm.

None.

The IPA Agitation Work Group recommends the Investigate, Plan, and Act (IPA) approach to agitation reduction and prevention. A thorough investigation of the behavior is followed by planning and acting with an emphasis on shared decision-making; the success of the plan is evaluated and adjusted as needed. The process is repeated until agitation is reduced to an acceptable level and prevention of recurrence is optimized. Psychosocial interventions are part of every plan and are continued throughout the process. Pharmacologic interventions are organized into panels of choices for nocturnal/circadian agitation; mild-moderate agitation or agitation with prominent mood features; moderate-severe agitation; and severe agitation with threatened harm to the patient or others. Therapeutic alternatives are presented for each panel. The occurrence of agitation in a variety of venues-home, nursing home, emergency department, hospice-and adjustments to the therapeutic approach are presented.

The IPA definition of agitation is operationalized into an agitation management algorithm that emphasizes the integration of psychosocial and pharmacologic interventions, reiterative assessment of response to treatment, adjustment of therapeutic approaches to reflect the clinical situation, and shared decision-making.

Depression, a highly prevalent disorder affecting over 280 million people worldwide, is comorbid with many neurological disorders, particularly Alzheimer's disease (AD). Depression and AD share overlapping pathophysiology, and the search for accountable biological substrates made it an essential and intriguing field of research. The paper outlines the neurobiological pathways coinciding with depression and AD, including neurotrophin signalling, the hypothalamic-pituitary-adrenal axis (HPA), cellular apoptosis, neuroinflammation, and other aetiological factors. Understanding overlapping pathways is crucial in identifying common pathophysiological substrates that can be targeted for effective management of disease state. Antidepressants, particularly monoaminergic drugs (first-line therapy), are shown to have modest or no clinical benefits. Regardless of the ineffectiveness of conventional antidepressants, these drugs remain the mainstay for treating depressive symptoms in AD. To overcome the ineffectiveness of traditional pharmacological agents in treating comorbid conditions, a novel therapeutic class has been discussed in the paper. This includes neurotransmitter modulators, glutamatergic system modulators, mitochondrial modulators, antioxidant agents, HPA axis targeted therapy, inflammatory system targeted therapy, neurogenesis targeted therapy, repurposed anti-diabetic agents, and others. The primary clinical challenge is the development of therapeutic agents and the effective diagnosis of the comorbid condition for which no specific diagnosable scale is present. Hence, introducing Artificial Intelligence (AI) into the healthcare system is revolutionary. AI implemented with interdisciplinary strategies (neuroimaging, EEG, molecular biomarkers) bound to have accurate clinical interpretation of symptoms. Moreover, AI has the potential to forecast neurodegenerative and psychiatric illness much in advance before visible/observable clinical symptoms get precipitated.

The history of antipsychotics in nursing homes is one piece of a much larger, more complex puzzle. In many ways, it reflects the virtues and limitations of the entire health care system and those who provide care. None of the issues related to the use of antipsychotics are specific to these medications or to nursing homes. After decades of effort to reduce unwarranted antipsychotics use, the current situation is still a work in progress. Many widely held assumptions and standard narratives, such as those about behavior, the place of medications in person-centered care, and the causes of inappropriate medication use are only partially correct. This second of 3 articles is not intended to discuss how to diagnose and manage behavior disorders or choose medications. Instead, it addresses the diverse perspectives and key players that have been involved and the results of their efforts. Ultimately, this will set the stage for specific recommendations (part 3) about learning from past efforts surrounding antipsychotics to identify more definitive and lasting improvements in the future.

Alzheimer's disease (AD) is characterized by neuropsychiatric symptoms (NPS), which cause great misery to those with dementia and those who care for them and may lead to early institutionalization.

The present systematic review aims to discuss the various aspects of Alzheimer's, including treatment options.

The databases Embase, PubMed, and Web of Science were searched to collect data.

Incipient cognitive deterioration is commonly accompanied by these early warning signals of neurocognitive diseases. The neurobiology of NPSs in Alzheimer's disease, as well as particular symptoms, including psychosis, agitation, apathy, sadness, and sleep disorders, will be examined in this review. For NPSs in Alzheimer's disease, clinical trial designs, as well as regulatory issues, were also addressed. A fresh wave of research, however, is helping to push the discipline ahead. For medication development and repurposing, we highlight the most recent results in genetics, neuroimaging, and neurobiology. Even though identifying and treating psychosis in adults with dementia is still a challenging endeavor, new options are coming up that give the field fresh focus and hope. Conclsuion: It can be concluded from the complete literature survey that Alzheimer's-related psychosis as well as other symptoms that are not psychotic, have made significant progress in the last decade. These milestones in the development of safer, more effective treatments have been achieved as a consequence of great focus on non-pharmacological interventions like DICE or WHELD; the investigation into ways to improve existing drugs like aripiprazole, risperidone, amisulpride, and Escitalopram for safer precision-based treatment; and the development of a clinical trial program for pimavanserin.

Several reviews on behavioral and psychological symptoms (BPSDs) in patients with Alzheimer's disease (AD) have summarized the current state of this field, but global trends are unclear.

This study utilized CiteSpace to provide a global overview of the current state of research on AD and its BPSDs and to predict future research trends in the field.

Data were retrieved from the Web of Science Core Collection. Bibliometric and cooccurrence analyses were performed using CiteSpace software. In total, 787 valid publications were included in the analysis.

Publications on AD and BPSD have shown an increasing trend since 2002. The United States and the University of Toronto were the countries and institutions with the highest total number of publications, respectively. Japan and China were the second and third most influential in the field. Clive Ballard was the top author in terms of the number of publications. Journal of Alzheimer's Disease had the highest number of publications on this topic. Co-occurrence analysis showed that AD, behavioral symptoms, cognitive impairment, and early markers are hot topics in this area. Non-drug management of BPSDs, pharmacological treatment, and physiotherapy will be a hot topic in this field in the future.

Our study visualized the relevant articles over the past 21 years to detect global hotspots and trends. Our findings may help researchers to identify research hotspots in this field and will help in the selection of appropriate research topics, while possibly leading to cross-regional cooperation.

Neuropsychiatric or behavioral symptoms of dementia encompass a series of disorders, such as anxiety, depression, apathy, psychosis, and agitation, all commonly present in individuals living with dementia. While they are not required for the diagnosis of Alzheimer's disease (AD), they are ubiquitously present in all stages of the disease, contributing to negative clinical outcomes, including cognitive decline, functional disability, and caregiver burden. Neuropsychiatric symptoms have been conceptualized not only as risk factors but as clinical markers of decline along the AD spectrum. The concept of "mild behavioral impairment", the behavioral correlate of mild cognitive impairment, has been proposed within this framework. The first steps in the management of behavioral symptoms in AD involve defining the target and investigating potential causes and/or aggravating factors. Once these factors are addressed, non-pharmacological approaches are preferred as first-line interventions. Following the optimization of anticholinesterase treatments, specific pharmacological approaches (e.g., antidepressants, antipsychotics) can be considered weighing potential side effects.

Alzheimer's disease (AD) is the most common cause of dementia worldwide that has an increasing impact on aging societies. Besides its critical role in the control of various physiological functions and behavior, brain serotonin (5-HT) system is involved in the regulation of migration, proliferation, differentiation, maturation, and programmed death of neurons. At the same time, a growing body of evidence indicates the involvement of 5-HT neurotransmission in the formation of insoluble aggregates of β-amyloid and tau protein, the main histopathological signs of AD. The review describes the role of various 5-HT receptors and intracellular signaling cascades induced by them in the pathological processes leading to the development of AD, first of all, in protein aggregation. Changes in the functioning of certain types of 5-HT receptors or associated intracellular signaling mediators prevent accumulation of β-amyloid plaques and tau protein neurofibrillary tangles. Based on the experimental data, it can be suggested that the use of 5-HT receptors as new drug targets will not only improve cognitive performance in AD, but will be also important in treating the causes of AD-related dementia.