Unique Properties of Synaptosomes and Prospects for Their Use for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a severe neurodegenerative condition affecting millions worldwide. Prevalence of AD correlates with increased life expectancy and aging population in the developed countries. Considering that AD is a multifactorial disease involving various pathological processes such as synaptic dysfunction, neuroinflammation, oxidative stress, and improper protein folding, a comprehensive approach targeting multiple pathways may prove effective in slowing the disease progression. Cellular therapy and its further development in the form of cell vesicle and particularly mitochondrial transplantation represent promising approaches for treating neurodegeneration. The use of synaptosomes, due to uniqueness of their contents, could mark a new stage in the development of comprehensive therapies for neurodegenerative diseases, particularly AD. Synaptosomes contain unique memory mitochondria, which differ not only in size but also in functionality compared to the mitochondria in the neuronal soma. These synaptosomal mitochondria actively participate in cellular communication and signal transmission within synapses. Synaptosomes also contain other elements such as their own protein synthesis machinery, synaptic vesicles with neurotransmitters, synaptic adhesion molecules, and microRNAs - all crucial for synaptic transmission and, consequently, cognitive processes. Complex molecular ensemble ensures maintenance of the synaptic autonomy of mitochondria. Additionally, synaptosomes, with their affinity for neurons, can serve as an optimal platform for targeted drug delivery to nerve cells. This review discusses unique composition of synaptosomes, their capabilities and advantages, as well as limitations of their suggested use as therapeutic agents for treating neurodegenerative pathologies, particularly AD.

Macro and micro structural preservation of grey matter integrity after 24 weeks of rTMS in Alzheimer's disease patients: a pilot study.

Alzheimer's Disease (AD) is characterized by structural and functional dysfunction involving the Default Mode Network (DMN), for which the Precuneus (PC) is a key node. We proposed a randomized double-blind pilot study to determine neurobiological changes after 24 weeks of PC-rTMS in patients with mild-to-moderate AD. Sixteen patients were randomly assigned to SHAM or PC-rTMS, and received an intensive 2-weeks course with daily rTMS sessions, followed by a maintenance phase in which rTMS has been applied once a week. Before and after the treatment structural and functional MRIs were collected. Our results showed macro- and micro-structural preservation in PC-rTMS compared to SHAM-rTMS group after 24 weeks of treatment, correlated to an increase of functional connectivity (FC) within the PC in the PC-rTMS group. Even if preliminary, these results trigger the possibility of using PC-rTMS to arrest atrophy progression by manipulating distributed network connectivity patterns.

Effectiveness of Resistance Exercise on Cognitive Function in Animal Models of Alzheimer Disease: A Systematic Review and Meta-Analysis.

AIM: Alzheimer's disease (AD) is among common cause of dementia. Complementary therapies, such as resistance exercise (RE), have been proposed as an alternative for the treatment of AD. We performed a systematic review and meta-analysis to investigate the effects of RE on the cognitive function of AD animal models and their physiological mechanisms. METHODS: This review was submitted to PROSPERO (CRD42019131266) and was done according to PRISMA checklist. Four databases were used in the search: MEDLINE/PUBMED, SCOPUS, Web of Science and Google Scholar. We used SYRCLE and CAMAREDES to assess the risk of bias and methodological quality. We calculated the standardized mean difference using 95% confidence intervals and considered the random effects model and p < 0.05 to determine significance. KEY FINDINGS: A total of 1,807 studies were founded, and after the selection process, only 11 studies were included in this review and 8 studies were included for meta-analysis. Four studies applied RE before AD induction, 7 studies applied RE after AD induction or in the AD condition. All studies included 550 adult and older animals weighing 25-280g. Our analysis revealed that RE had a positive effect on memory in AD animal models but did not show a significant impact on anxiety. CONCLUSION: RE performed four or six weeks, more than three days a week, had a significant protective effect on memory. The included studies had a high risk of bias and moderate methodological quality. Therefore, RE can be a potential strategy for preventing cognitive decline in animal models.

Progress in mitochondrial and omics studies in Alzheimer's disease research: from molecular mechanisms to therapeutic interventions.

Alzheimer's disease (Alzheimer's disease, AD) is a progressive neurological disorder characterized by memory loss and cognitive impairment. It is characterized by the formation of tau protein neurofibrillary tangles and ß-amyloid plaques. Recent studies have found that mitochondria in neuronal cells of AD patients exhibit various dysfunctions, including reduced numbers, ultrastructural changes, reduced enzyme activity, and abnormal kinetics. These abnormal mitochondria not only lead to the loss of normal neuronal cell function, but are also a major driver of AD progression. In this review, we will focus on the advances of mitochondria and their multi-omics in AD research, with particular emphasis on how mitochondrial dysfunction in AD drives disease progression. At the same time, we will focus on summarizing how mitochondrial genomics technologies have revealed specific details of these dysfunctions and how therapeutic strategies targeting mitochondria may provide new directions for future AD treatments. By delving into the key mechanisms of mitochondria in AD related to energy metabolism, altered kinetics, regulation of cell death, and dysregulation of calcium-ion homeostasis, and how mitochondrial multi-omics technologies can be utilized to provide us with a better understanding of these processes. In the future, mitochondria-centered therapeutic strategies will be a key idea in the treatment of AD.

Exercise to Counteract Alzheimer's Disease: What Do Fluid Biomarkers Say?

Neurodegenerative diseases (NDs) represent an unsolved problem to date with an ever-increasing population incidence. Particularly, Alzheimer's disease (AD) is the most widespread ND characterized by an accumulation of amyloid aggregates of beta-amyloid (Aß) and Tau proteins that lead to neuronal death and subsequent cognitive decline. Although neuroimaging techniques are needed to diagnose AD, the investigation of biomarkers within body fluids could provide important information on neurodegeneration. Indeed, as there is no definitive solution for AD, the monitoring of these biomarkers is of strategic importance as they are useful for both diagnosing AD and assessing the progression of the neurodegenerative state. In this context, exercise is known to be an effective non-pharmacological management strategy for AD that can counteract cognitive decline and neurodegeneration. However, investigation of the concentration of fluid biomarkers in AD patients undergoing exercise protocols has led to unclear and often conflicting results, suggesting the need to clarify the role of exercise in modulating fluid biomarkers in AD. Therefore, this critical literature review aims to gather evidence on the main fluid biomarkers of AD and the modulatory effects of exercise to clarify the efficacy and usefulness of this non-pharmacological strategy in counteracting neurodegeneration in AD.

Moderate aerobic training enhances the effectiveness of insulin therapy through hypothalamic IGF1 signaling in rat model of Alzheimer's disease.

Alzheimer's disease (AD) is a neurological condition that is connected with a decline in a person's memory as well as their cognitive ability. One of the key topics of AD research has been the exploration of metabolic causes. We investigated the effects of treadmill exercise and intranasal insulin on learning and memory impairment and the expression of IGF1, BDNF, and GLUT4 in hypothalamus. The animals were put into 9 groups at random. In this study, we examined the impact of insulin on spatial memory in male Wistar rats and analyzed the effects of a 4-week pretreatment of moderate treadmill exercise and insulin on the mechanisms of improved hypothalamic glucose metabolism through changes in gene and protein expression of IGF1, BDNF, and GLUT4. We discovered that rat given Aß25-35 had impaired spatial learning and memory, which was accompanied by higher levels of Aß plaque burden in the hippocampus and lower levels of IGF1, BDNF, and GLUT4 mRNA and protein expression in the hypothalamus. Additionally, the administration of exercise training and intranasal insulin results in the enhancement of spatial learning and memory impairments, the reduction of plaque burden in the hippocampus, and the enhancement of the expression of IGF1, BDNF, and GLUT4 in the hypothalamus of rats that were treated with Aß25-35. Our results show that the improvement of learning and spatial memory due to the improvement of metabolism and upregulation of the IGF1, BDNF, and GLUT4 pathways can be affected by pretreatment exercise and intranasal insulin.

CeO2 In Situ Growth on Red Blood Cell Membranes: CQD Coating and Multipathway Alzheimer's Disease Therapy under NIR.

Alzheimer's disease (AD) has a complex etiology and diverse pathological processes. The therapeutic effect of single-target drugs is limited, so simultaneous intervention of multiple targets is gradually becoming a new research trend. Critical stages in AD progression involve amyloid-ß (Aß) self-aggregation, metal-ion-triggered fibril formation, and elevated reactive oxygen species (ROS). Herein, red blood cell membranes (RBC) are used as templates for the in situ growth of cerium oxide (CeO2) nanocrystals. Then, carbon quantum dots (CQDs) are encapsulated to form nanocomposites (CQD-Ce-RBC). This strategy is combined with photothermal therapy (PTT) for AD therapy. The application of RBC enhances the materials' biocompatibility and improves immune evasion. RBC-grown CeO2, the first application in the field of AD, demonstrates outstanding antioxidant properties. CQD acts as a chelating agent for copper ions, which prevents the aggregation of Aß. In addition, the thermal effect induced by near-infrared laser-induced CQD can break down Aß fibers and improve the permeability of the blood-brain barrier. In vivo experiments on APP/PS1 mice demonstrate that CQD-Ce-RBC combined with PTT effectively clears cerebral amyloid deposits and significantly enhances learning and cognitive abilities, thereby retarding disease progression. This innovative multipathway approach under light-induced conditions holds promise for AD treatment.

True or false? Alzheimer's disease is type 3 diabetes: Evidences from bench to bedside.

Globally, Alzheimer's disease (AD) is the most widespread chronic neurodegenerative disorder, leading to cognitive impairment, such as aphasia and agnosia, as well as mental symptoms, like behavioral abnormalities, that place a heavy psychological and financial burden on the families of the afflicted. Unfortunately, no particular medications exist to treat AD, as the current treatments only impede its progression.The link between AD and type 2 diabetes (T2D) has been increasingly revealed by research; the danger of developing both AD and T2D rises exponentially with age, with T2D being especially prone to AD. This has propelled researchers to investigate the mechanism(s) underlying this connection. A critical review of the relationship between insulin resistance, Aß, oxidative stress, mitochondrial hypothesis, abnormal phosphorylation of Tau protein, inflammatory response, high blood glucose levels, neurotransmitters and signaling pathways, vascular issues in AD and diabetes, and the similarities between the two diseases, is presented in this review. Grasping the essential mechanisms behind this detrimental interaction may offer chances to devise successful therapeutic strategies.

Rotating magnetic field inhibits Aß protein aggregation and alleviates cognitive impairment in Alzheimer's disease mice.

Amyloid beta (Aß) monomers aggregate to form fibrils and amyloid plaques, which are critical mechanisms in the pathogenesis of Alzheimer's disease (AD). Given the important role of Aß1-42 aggregation in plaque formation, leading to brain lesions and cognitive impairment, numerous studies have aimed to reduce Aß aggregation and slow AD progression. The diphenylalanine (FF) sequence is critical for amyloid aggregation, and magnetic fields can affect peptide alignment due to the diamagnetic anisotropy of aromatic rings. In this study, we examined the effects of a moderate-intensity rotating magnetic field (RMF) on Aß aggregation and AD pathogenesis. Results indicated that the RMF directly inhibited Aß amyloid fibril formation and reduced Aß-induced cytotoxicity in neural cells in vitro. Using the AD mouse model APP/PS1, RMF restored motor abilities to healthy control levels and significantly alleviated cognitive impairments, including exploration and spatial and non-spatial memory abilities. Tissue examinations demonstrated that RMF reduced amyloid plaque accumulation, attenuated microglial activation, and reduced oxidative stress in the APP/PS1 mouse brain. These findings suggest that RMF holds considerable potential as a non-invasive, high-penetration physical approach for AD treatment.

Scalp acupuncture targets for neurological disorders：evidence from neuroimaging studies (part 2). / åŸºäºŽç¥žç»å½±åƒå­¦çš„å¸¸è§ç¥žç»ç³»ç»Ÿç–¾ç— å¤´é’ˆåˆºæ¿€é¶ç‚¹ç ”ç©¶ï¼ˆä¸‹ï¼‰.

OBJECTIVES: Scalp acupuncture is a method of treating diseases by dividing and stimulating the corresponding function-oriented cortical scalp areas. It is a commonly used therapy for neurological disorders. However, the specific target selection for scalp acupuncture remains to be explored. This manuscript aims to initiate an attempt to develop/identify scalp acupuncture targets based on neuroimaging findings and noninvasive brain stimulation. METHODS: Neurosynth-based meta-analysis of neuroimaging studies was conducted to identify brain stimulation targets of neurological disorders. The identified target regions were further projected to the scalp. The traditional acupoints and 10-20 EEG system were referenced for the localization of these targets. In this study, the "mild cognitive impairment" (MCI), "Alzheimer's disease" (AD) and "dementia" were used as the retrieval terms respectively, and a unity detection method was used to generate brain maps, with the default FDR (false discovery rate, P<0.01) threshold of Neurosynth set for subsequent exploration of various disease-related brain regions. The literature search was conducted on July 30, 2022. RESULTS: The localization and manipulation suggestions of neuroimage-based scalp acupuncture targets for MCI, AD, and dementia were introduced in the present paper (part 2). Here are 3 target examples for each of these 3 diseases due to word limitation. 1) MCI：Based on the 81 papers retrieved, we identified 6 potential scalp acupuncture points for MCI, their corresponding brain regions, brain functions and the possible resultant effects of the scalp target acupoint stimulation respectively are as below. MCI1：the orbital part of the left inferior frontal gyrus (left Brodmann area ［BA］47), related to semantic coding, working memory and episodic memory, improving semantic coding and memory function；MCI2：the anterior motor area/left anterior central gyrus (left BA6), the motor center area, improving MCI motor function；MCI3：the left medial temporal gyrus (left BA21), related to the processing of speech, visual space, language and word understanding, improving language and memory. 2) AD：Based on the 196 papers retrieved, we found 6 potential scalp acupuncture targets for AD, their corresponding brain regions and brain functions of the 3 example targets respectively are as below. AD1：the left medial temporal gyrus (left BA21), participating in language and semantic processing, sentence and word generation, intent expression, deductive reasoning；AD2：the left angular gyrus (left BA39), related to semantic processing, word reading and comprehension, memory retrieval, attention and spatial cognition, reasoning, etc.；AD3：the left fusiform/suboccipital gyrus (left BA37), related to semantic classification, text generation, sign language, phonology processing, etc. 3) Dementia：Based on the 142 papers retrieved, we found 4 potential scalp acupuncture targets for dementia, their corresponding brain regions, brain functions and the possible targets of the proposed scalp stimulation respectively are as below. D1 and D2：the left inferior frontal gyrus (i.e., left BA46, and left BA47, respectively), being closely related to working memory, emotional response regulation, melody and other processing processes, may be suitable for treating memory decline and advanced executive dysfunction in patients with dementia；D3：the left medial temporal gyrus (left BA21), an important brain region for various sensory integration, cognitive processing and memory functions, and emotional processing, may be suitable for temporal dementia. CONCLUSIONS: We identified scalp acupuncture targets for several common neurological disorders based on neuroimaging findings and noninvasive brain stimulation. The proposed targets may also be used for treating these disorders using nerve/brain stimulation methods.

Clinician's perspectives on gene therapy for Alzheimer's disease: A qualitative study.

INTRODUCTION: We aimed to understand clinician views regarding gene therapy as a future treatment for Alzheimer's disease (AD) and potential barriers and facilitators to its use. METHODS: We interviewed ten clinicians who treat patients with AD. Clinicians helped design a semi-structured interview including the following domains: establishing understanding, cost/access, quality of life, and religion/spirituality. Transcripts were analyzed by a coding team using descriptive content analysis with inductive approach. RESULTS: Clinicians identified three main areas of concern: 1) potential clinician and patient understanding of gene therapy and Alzheimer's disease 2) consideration of inequity (i.e., care access, disease awareness along with education level, family support, trust in care systems); and 3) considerations in decision-making (i.e., religious/spiritual beliefs and method of treatment delivery as a decision-making tools). DISCUSSION AND CONCLUSION: Findings highlight areas for knowledge-building for patients and clinicians alike. Clinicians must be aware of patient/family educational needs and gaps in their own clinical knowledge before engaging patients/families with new technology. Allowing time for questions is crucial to building rapport and trust.

mHealth Apps for Dementia, Alzheimer Disease, and Other Neurocognitive Disorders: Systematic Search and Environmental Scan.

BACKGROUND: Lifestyle behaviors including exercise, sleep, diet, stress, mental stimulation, and social interaction significantly impact the likelihood of developing dementia. Mobile health (mHealth) apps have been valuable tools in addressing these lifestyle behaviors for general health and well-being, and there is growing recognition of their potential use for brain health and dementia prevention. Effective apps must be evidence-based and safeguard user data, addressing gaps in the current state of dementia-related mHealth apps. OBJECTIVE: This study aims to describe the scope of available apps for dementia prevention and risk factors, highlighting gaps and suggesting a path forward for future development. METHODS: A systematic search of mobile app stores, peer-reviewed literature, dementia and Alzheimer association websites, and browser searches was conducted from October 19, 2022, to November 2, 2022. A total of 1044 mHealth apps were retrieved. After screening, 152 apps met the inclusion criteria and were coded by paired, independent reviewers using an extraction framework. The framework was adapted from the Silberg scale, other scoping reviews of mHealth apps for similar populations, and background research on modifiable dementia risk factors. Coded elements included evidence-based and expert credibility, app features, lifestyle elements of focus, and privacy and security. RESULTS: Of the 152 apps that met the final selection criteria, 88 (57.9%) addressed modifiable lifestyle behaviors associated with reducing dementia risk. However, many of these apps (59/152, 38.8%) only addressed one lifestyle behavior, with mental stimulation being the most frequently addressed. More than half (84/152, 55.2%) scored 2 points out of 9 on the Silberg scale, with a mean score of 2.4 (SD 1.0) points. Most of the 152 apps did not disclose essential information: 120 (78.9%) did not disclose expert consultation, 125 (82.2%) did not disclose evidence-based information, 146 (96.1%) did not disclose author credentials, and 134 (88.2%) did not disclose their information sources. In addition, 105 (69.2%) apps did not disclose adherence to data privacy and security practices. CONCLUSIONS: There is an opportunity for mHealth apps to support individuals in engaging in behaviors linked to reducing dementia risk. While there is a market for these products, there is a lack of dementia-related apps focused on multiple lifestyle behaviors. Gaps in the rigor of app development regarding evidence base, credibility, and adherence to data privacy and security standards must be addressed. Following established and validated guidelines will be necessary for dementia-related apps to be effective and advance successfully.

Resistance Exercise Training as a New Trend in Alzheimer's Disease Research: From Molecular Mechanisms to Prevention.

Alzheimer's disease is a pathology characterized by the progressive loss of neuronal connections, which leads to gray matter atrophy in the brain. Alzheimer's disease is the most prevalent type of dementia and has been classified into two types, early onset, which has been associated with genetic factors, and late onset, which has been associated with environmental factors. One of the greatest challenges regarding Alzheimer's disease is the high economic cost involved, which is why the number of studies aimed at prevention and treatment have increased. One possible approach is the use of resistance exercise training, given that it has been shown to have neuroprotective effects associated with Alzheimer's disease, such as increasing cortical and hippocampal volume, improving neuroplasticity, and promoting cognitive function throughout the life cycle. However, how resistance exercise training specifically prevents or ameliorates Alzheimer's disease has not been fully characterized. Therefore, the aim of this review was to identify the molecular basis by which resistance exercise training could prevent or treat Alzheimer's disease.

Possible Role of Tauroursodeoxycholic Acid (TUDCA) and Antibiotic Administration in Modulating Human Gut Microbiota in Home Enteral Nutrition Therapy for the Elderly: A Case Report.

Tauroursodeoxycholic acid (TUDCA) increases the influx of primary bile acids into the gut. Results obtained on animal models suggested that Firmicutes and Proteobacteria phyla are more resistant to bile acids in rats. As part of a pilot study investigating the role of probiotics supplementation in elderly people with home enteral nutrition (HEN), a case of a 92-year-old woman with HEN is reported in the present study. She lives in a nursing home and suffers from Alzheimer's disease (AD); the patient had been prescribed TUDCA for lithiasis cholangitis. The aim of this case report is therefore to investigate whether long-term TUDCA administration may play a role in altering the patient's gut microbiota (GM) and the impact of an antibiotic therapy on the diversity of microbial species. Using next generation sequencing (NGS) analysis of the bacterial 16S ribosomal RNA (rRNA) gene a dominant shift toward Firmicutes and a remodeling in Proteobacteria abundance was observed in the woman's gut microbiota. Considering the patient's age, health status and type of diet, we would have expected to find a GM with a prevalence of Bacteroidetes phylum. This represents the first study investigating the possible TUDCA's effect on human GM.

The interactive effects of different exercises and hawthorn consumption on the pain threshold of TMT-induced Alzheimer male rats.

Exercise increases the pain threshold in healthy people. However, the pain threshold modulation effect of exercise and hawthorn is unclear because of its potential benefits in people with persistent pain, including those with Alzheimer's disease. Accordingly, after the induction of Alzheimer's disease by trimethyl chloride, male rats with Alzheimer's disease were subjected to a 12-week training regimen consisting of resistance training, swimming endurance exercises, and combined exercises. In addition, hawthorn extract was orally administered to the rats. Then, their pain threshold was evaluated using three Tail-flick, Hot-plate, and Formalin tests. Our results showed that Alzheimer's decreased the pain threshold in all three behavioral tests. Combined exercise with hawthorn consumption had the most statistically significant effect on Alzheimer's male rats' pain threshold in all three experiments. A combination of swimming endurance and resistance exercises with hawthorn consumption may modulate hyperalgesia in Alzheimer's rats. Future studies need to determine the effects of these factors on the treatment and/or management of painful conditions.

Microcurrent Therapy Mitigates Neuronal Damage and Cognitive Decline in an Alzheimer's Disease Mouse Model: Insights into Mechanisms and Therapeutic Potential.

Alzheimer's disease (AD) presents a significant challenge due to its multifaceted nature, characterized by cognitive decline, memory loss, and neuroinflammation. Though AD is an extensively researched topic, effective pharmacological interventions remain elusive, prompting explorations into non-pharmacological approaches. Microcurrent (MC) therapy, which utilizes imperceptible currents, has emerged as a potent clinical protocol. While previous studies have focused on its therapeutic effects, this study investigates the impact of MC on neuronal damage and neuroinflammation in an AD mouse model, specifically addressing potential side effects. Utilizing 5xFAD transgenic mice, we examined the effects of MC therapy on neuronal integrity and inflammation. Our findings suggest that MC therapy attenuates memory impairment and reduces neurodegeneration, as evidenced by improved performance in memory tests and the preservation of the neuronal structure. Additionally, MC therapy significantly decreases amyloid-beta (Aß) plaque deposition and inhibits apoptosis, indicating its potential to mitigate AD pathology. This study determined that glial activation is effectively reduced by using MC therapy to suppress the TLR4-MyD88-NFκB pathway, which consequently causes the levels of inflammatory factors TNF-α, IL-1ß, and IL-6 to decrease, thus implicating TLR4 in neurodegenerative disease-related neuroinflammation. Furthermore, while our study did not observe significant adverse effects, a further clinical trial into potential side effects and neuroinflammatory responses associated with MC therapy is warranted.

Special Issue "Pathophysiology and Treatment of Alzheimer's Disease".

The majority of clinical trials, whose primary aims were to moderate Alzheimer's dementia (AD), have been based upon the prevailing paradigm, i [...].

Transcranial alternating current stimulation (tACS) at gamma frequency: an up-and-coming tool to modify the progression of Alzheimer's Disease.

The last decades have witnessed huge efforts devoted to deciphering the pathological mechanisms underlying Alzheimer's Disease (AD) and to testing new drugs, with the recent FDA approval of two anti-amyloid monoclonal antibodies for AD treatment. Beyond these drug-based experimentations, a number of pre-clinical and clinical trials are exploring the benefits of alternative treatments, such as non-invasive stimulation techniques on AD neuropathology and symptoms. Among the different non-invasive brain stimulation approaches, transcranial alternating current stimulation (tACS) is gaining particular attention due to its ability to externally control gamma oscillations. Here, we outline the current knowledge concerning the clinical efficacy, safety, ease-of-use and cost-effectiveness of tACS on early and advanced AD, applied specifically at 40 Hz frequency, and also summarise pre-clinical results on validated models of AD and ongoing patient-centred trials.

The path to next-generation disease-modifying immunomodulatory combination therapies in Alzheimer's disease.

The cautious optimism following recent anti-amyloid therapeutic trials for Alzheimer's disease (AD) provides a glimmer of hope after years of disappointment. Although these encouraging results represent discernible progress, they also highlight the need to enhance further the still modest clinical efficacy of current disease-modifying immunotherapies. Here, we highlight crucial milestones essential for advancing precision medicine in AD. These include reevaluating the choice of therapeutic targets by considering the key role of both central neuroinflammation and peripheral immunity in disease pathogenesis, refining patient stratification by further defining the inflammatory component within the forthcoming ATN(I) (amyloid, tau and neurodegeneration (and inflammation)) classification of AD biomarkers and defining more accurate clinical outcomes and prognostic biomarkers that better reflect disease heterogeneity. Next-generation immunotherapies will need to go beyond the current antibody-only approach by simultaneously targeting pathological proteins together with innate neuroinflammation and/or peripheral-central immune crosstalk. Such innovative immunomodulatory combination therapy approaches should be evaluated in appropriately redesigned clinical therapeutic trials, which must carefully integrate the neuroimmune component.