Research Papers from the AFA Research Department

Background

Alzheimer’s disease (AD) is one of the most significant and rapidly expanding public health challenges associated with global population aging. Advances in biomarker diagnostics and the development of disease-modifying therapies have increased the clinical importance of detecting cognitive impairment during the earliest stages of disease progression. Early recognition allows for timely care planning, improved management of comorbid conditions, access to emerging therapeutic interventions, and participation in clinical research. Despite these developments, substantial variability persists in Alzheimer’s detection within primary care.

Historically, limited physician knowledge has been considered a principal barrier to early dementia diagnosis. However, emerging research suggests that structural factors, including diagnostic confidence, clinical workflow integration, and healthcare system capacity may play a more influential role in determining whether cognitive screening and referral occur in routine practice.

Objective

This narrative review examines physician-level and system-level determinants that influence whether primary care physicians perform cognitive screening, initiate diagnostic evaluations, or refer patients for specialist assessment when Alzheimer’s disease is suspected.

Methods

A narrative literature review was conducted using PubMed, Embase, MEDLINE, CINAHL, Web of Science, Scopus, and PsycINFO. Peer-reviewed studies examining dementia detection practices in primary care were included, with emphasis on global research published between 2022 and 2026. Eligible studies evaluated physician knowledge, diagnostic confidence, workflow integration, healthcare system capacity, reimbursement structures, or referral access. Evidence from quantitative, qualitative, mixed-methods, and implementation studies was synthesized using thematic analysis.

Results

Findings indicate that most primary care physicians possess adequate conceptual knowledge of Alzheimer’s symptoms and commonly used cognitive screening tools. However, knowledge alone does not consistently predict screening behavior. Diagnostic confidence, integration of screening tools into routine workflows, electronic health record decision-support systems, and access to specialist referral networks were more consistent predictors of physician action. Time constraints and competing clinical demands remain significant barriers, although structured workflows and team-based care models substantially improve screening and referral rates.

Dementia caregiving represents a major public health challenge, with spousal caregivers assuming the greatest burden. Spouses, themselves typically older adults, provide high intensity, long-term, and largely unpaid care across all stages of cognitive decline.

Despite their central role in dementia care, the health consequences experienced by spousal caregivers remain insufficiently characterized in the literature and inadequately addressed in clinical and public health practice. This structured narrative review synthesizes current evidence on the multidimensional impact of dementia caregiving on the physical, psychological, cognitive, social, and financial health of spousal caregivers. It further contextualizes these consequences within the trajectory of dementia progression, and identifies interventions, support systems, and policy considerations necessary to mitigate caregiver burden.

Spousal caregivers experience disproportionate burden due to continuous, escalating responsibilities that often mirror the progressive deterioration of their partners. Emotional burdens, including uncertainty during pre-diagnostic stages, role strain, conflict, loss of intimacy, and anticipatory grief.

Physically, spouses endure musculoskeletal strain, sleep disruption, poor nutrition, and heightened frailty risk. Psychologically, spousal caregivers exhibit elevated rates of depression, anxiety, loneliness, and stress-related disorders. Socially, caregivers experience substantial isolation, stigma, and erosion of social networks. Financial hardship, including early retirement, reduced employment, and uncompensated care hours, further exacerbate stress.

Evidence suggests that chronic caregiving stress contributes to biological changes such as immune dysregulation, inflammation, acceleration, aging, and potential cognitive decline in caregivers themselves. Caregiver burden influences patient outcomes as evidenced by increased emergency department use, falls, and earlier institutionalization in persons with dementia whose caregiver is subjected to a high burden.

Current care models rarely include routine, caregiver assessment or structured guidance following diagnosis, resulting in substantial unmet needs. Effective mitigation requires integrated, stage-sensitive interventions, including psychosocial support, caregiver education, respite services, culturally tailored programs, and digital health tools, alongside broader policy reforms to reduce financial and structural barriers.

Primary care physicians play a vital role in the clinical care of their patients, early identification of dementia, and disease advocacy. It is essential to assess the knowledge and attitudes of physicians in the diagnosis of Alzheimer’s disease and other dementias. In primary care, the diagnosis of Alzheimer’s disease is often missed or delayed. With the increased prevalence of Alzheimer’s disease and the growing impact of dementia on health care resources, early detection by primary care physicians (PCP) is essential. Thus, their knowledge and attitudes about early detection and diagnosis are crucial.

To examine the knowledge and attitudes of primary care physicians regarding early detection and diagnosis of Alzheimer’s disease and how barriers may contribute to missed and delayed detection and diagnosis, an interpretive scope review was used to synthesize and analyze a body of literature published over the past decade. The study population are physicians in the United States.

The current health systems experience challenges in providing early, safe, accurate, and comprehensive Alzheimer’s diagnosis and care by a primary care physician trained or knowledgeable in diagnosing the various forms of dementia. This article identifies several interrelated obstacles to early detection and diagnosis in primary dementia care, including gaps in knowledge, attitudes, skills, and resources for person with dementia (PWD)/caregivers and their primary care providers and systematic and structural barriers that negatively impact dementia care. Research shows that Alzheimer’s disease has gone underdiagnosed and undertreated. Delays in detection, diagnosis, and resource utilization may have social and clinical implications for individuals affected by Alzheimer’s disease and their families, including challenges in obtaining an accurate diagnosis.

Until the issues of missed and delayed Alzheimer’s screening become more compelling, efforts to promote early detection and diagnosis should focus on the education of physicians and removing the barriers to diagnosis.

Primary care professionals play a critical role in the care of their patients. In clinical practice, early detection and diagnosis of Mild Cognitive Impairment, Alzheimer’s disease and related dementia are often missed or delayed. Disclosure of diagnosis is not timely or not revealed. Though the methods that could improve early detection and diagnosis have remained the same over the decades with little change, they provide opportunities for early intervention, treatment and improvement in patient care.

Emerging research suggests that though the disease process begins years prior to the clinical diagnosis, the healthcare system and health care professionals remain distant and reluctant to provide the service of annual cognitive assessment, which has been recommended by the Medicare program for older adults aged 65 years and older. Findings support that Alzheimer’s disease and related cognitive impairments have gone under detected, underdiagnosed and undertreated.

This article seeks to provide valuable and equitable information in the form of a clinician’s guide for removing the barriers to early detection and diagnosis of cognitive impairments and offers an unprecedented opportunity to improve the clinical outcomes and care of older adults with various levels of cognitive decline, including mild cognitive impairment, Alzheimer’s disease, and related dementias. This article provides information on understanding and addressing the challenges faced by health care professionals, including primary care clinicians; removing the barriers to cognitive assessments; educating this professional group on the importance of brain health, early detection, and diagnosis for their older adult patients; and providing these professionals with the ability to transfer their knowledge into more defined care planning.

Until cognitive screening has been fully accepted and implemented for the optimal the care of older adults, health-related efforts should include the promotion and education of brain health, early detection, and diagnosis in the education of health care providers.

Background

Alzheimer’s disease (AD) and mild cognitive impairment (MCI) are widely recognized for their hallmark cognitive deficits, typically characterized by progressive cognitive deterioration. However, neuropsychiatric symptoms (NPS), including depression, apathy, anxiety, irritability, and sleep disturbances, are increasingly prevalent in the early stages of these conditions and significantly influence the disease trajectory and patient outcomes. Importantly, neuropsychiatric symptoms often precede overt memory loss by several years, with subtle mood and behavioral disturbances serving as early pre-diagnostic markers of an underlying Alzheimer’s pathology. Their presence complicates the diagnosis, accelerates the disease progression, and intensifies the caregiver burden. However, distinguishing NPS arising from neurodegeneration and primary psychiatric disorders remains a profound diagnostic challenge, thus delaying timely intervention and obscuring early disease recognition.

Objective

This structured narrative review examines the diagnostic complexities, clinical impact, and current management of NPS in early-stage Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI), alongside the biological underpinnings, clinical relevance, diagnostic challenges, and treatment perspectives. We argue that understanding and managing NPS is essential to improve the clinical outcomes, reduce the caregiver burden, and guide therapeutic innovation.

Methods

A structured narrative review of peer-reviewed studies published between 2012 and 2025 was conducted using PubMed, MEDLINE, Scopus, PsycINFO, Google Scholar, and CINAHL. The included studies investigated NPS prevalence, neurobiological correlations, and management strategies in individuals with AD or MCI.

Findings

NPS affects up to 80% of individuals with early AD or MCI, often preceding cognitive decline. The current management strategies heavily rely on non-pharmacological interventions such as caregiver support, behavioral activation, and structured routines, while pharmacological options remain limited by modest efficacy and safety concerns.

Discussion

Advancing knowledge of NPS and their association with cognitive decline is critical to establish more precise diagnostic criteria and to inform personalized therapeutic approaches. Future research should emphasize biomarker-driven diagnostics and the development of novel, targeted interventions that simultaneously address cognitive and neuropsychiatric domains to optimize outcomes for patients and caregivers. This study contributes to the field by reframing NPS as potential early biomarkers in the trajectory of MCI and dementia progression.

Major depressive disorder is one of the most burdensome mental health disorders. Probiotics have been shown to ameliorate depressive symptoms, though the mechanism remains unclear. This study was conducted to investigate whether extracellular vesicles (EVs) extracted from the probiotic beverage water kefir could influence gene and protein expression in human-derived neuroblastoma cells in vitro.

EVs were extracted from lab-cultured water kefir and a control solution without water kefir grains by ultracentrifugation. Water kefir vesicles were imaged via electron microscopy. Neuroblastoma, microglia, and neuroblastoma-microglia co-cultures were exposed to water kefir EVs or negative control medium. Uptake of water kefir EVs was identified by microscopy.

All conditions were quantified for brain derived neurotrophic factor, fractalkine, and synaptophysin RNA and protein. Data were analyzed using factorial ANOVAs with significance set at 0.05. Water kefir vesicles were taken up by neuroblastoma cells, and incubation in neuroblastoma-microglia co-culture resulted in significantly higher levels of fractalkine protein compared to media-only control (p = 0.029).

To our knowledge, this is the first study to identify potential interactions between EVs derived from the probiotic beverage water kefir and human neuronal cells. Further research is needed to fully elucidate the role played by probiotic-derived EVs in human health.

Background and Objectives: Over the past few years, there has been a significant shift in focus from developing better diagnostic tools to detecting Alzheimer’s disease (AD) earlier and initiating treatment interventions.

This review will explore four main objectives: (a) the role of biomarkers in enhancing the diagnostic accuracy of AD, highlighting the major strides that have been made in recent years; (b) the role of neuropsychological testing in identifying biomarkers of AD, including the relationship between cognitive performance and neuroimaging biomarkers; (c) the amyloid hypothesis and possible molecular mechanisms of AD; and (d) the innovative AD therapeutics and the challenges and limitations of AD research.

Materials and Methods: We have searched PubMed and Scopus databases for peer-reviewed research articles published in English (preclinical and clinical studies as well as relevant reviews and meta-analyses) investigating the molecular mechanisms, biomarkers, and treatments of AD.

Results: Genome-wide association studies (GWASs) discovered 37 loci associated with AD risk. Core 1 biomarkers (α-amyloid Aβ42, phosphorylated tau, and amyloid PET) detect early AD phases, identifying both symptomatic and asymptomatic individuals, while core 2 biomarkers inform the short-term progression risk in individuals without symptoms. The recurrent failures of Aβ-targeted clinical studies undermine the amyloid cascade hypothesis and the objectives of AD medication development. The molecular mechanisms of AD include the accumulation of amyloid plaques and tau protein, vascular dysfunction, neuroinflammation, oxidative stress, and lipid metabolism dysregulation. Significant advancements in drug delivery technologies, such as focused Low-Ultrasound Stem, T cells, exosomes, nanoparticles, transferin, nicotinic and acetylcholine receptors, and glutathione transporters, are aimed at overcoming the BBB to enhance treatment efficacy for AD. Aducanumab and Lecanemab are IgG1 monoclonal antibodies that retard the progression of AD. BACE inhibitors have been explored as a therapeutic strategy for AD. Gene therapies targeting APOE using the CRISPR/Cas9 genome-editing system are another therapeutic avenue.

Conclusions: Classic neurodegenerative biomarkers have emerged as powerful tools for enhancing the diagnostic accuracy of AD. Despite the supporting evidence, the amyloid hypothesis has several unresolved issues. Novel monoclonal antibodies may halt the AD course. Advances in delivery systems across the BBB are promising for the efficacy of AD treatments.

Background/Objectives: Impaired cognition is a key trait of the diseases of aging and is an important quality of life factor for older adults and their families. Over the past decade, there has been an increasing appreciation for the role of the microbiome in cognition, as well as emerging evidence that probiotics, such as those in yogurt and other dairy products, can have a positive impact on cognitive function. However, it is unclear to what extent the consumption of yogurt is associated with improved cognitive function in older adults.

Methods: Therefore, we compared the scores for the Wechsler Adult Intelligence Scale, Digit–Symbol Substitution Test between respondents who self-reported daily yogurt/dairy consumption with those who claimed they did not in an NHANES.

Results: We found that cognitive scores were significantly higher (40.03 ± 0.64 vs. 36.28 ± 1.26, p = 0.017) in respondents reporting daily yogurt/dairy consumption, though only a trend remained after adjusting for sociodemographic covariates (p = 0.074). Conclusions: Further studies are required to confirm that this is a cause–effect relationship and whether changing diets is a low-cost means of protecting aging populations from cognitive decline and improving their quality of life.

Alzheimer’s disease (AD) is an incurable and progressive neurodegenerative disease with increasing prevalence worldwide. Previous trials of anti-amyloid and anti-tau immunotherapy indicate that additional research needs to be conducted on other mechanisms to find curative or disease-modifying therapy.

This review focuses on apolipoprotein E (ApoE), a critical protein in brain lipid metabolism that acts specifically in the clearance and transport of lipids and cholesterol. The ApoE4 allele confers substantial gene dose-dependent risk of developing AD and lowers the age of onset of AD, although the mechanisms of influence remain incompletely understood. The other isoforms bring different levels of AD risk. ApoE2 is protective while ApoE3 is the most common isoform and is considered neutral.

An overview is presented of the latest information on the role of ApoE in AD pathogenesis with an emphasis on pathways that are involved in AD development and interactions with crucial processes in different cell types in the brain.

Elucidating the key interactions of ApoE with multiple aspects of brain function can be useful for designing novel ApoE-targeted therapeutic approaches.

Nilotinib, a tyrosine kinase inhibitor that targets the Abelson tyrosine kinase (c-Abl) signaling pathway, is FDA-approved to treat chronic myeloid leukemia. Nilotinib has properties indicative of a possible utility in neuroprotection that have prompted exploration of repurposing the drug for the treatment of Alzheimer’s disease (AD) and Parkinson’s disease (PD).

AD is a progressive age-related neurodegenerative disorder characterized by the deposition of extracellular amyloid-β plaques and intracellular neurofibrillary tangles. It is incurable and affects approximately 50 million patients worldwide. Nilotinib reduces c-Abl phosphorylation, amyloid-β levels, and dopaminergic neuron degeneration in preclinical AD models.

This study explores the effects of nilotinib on amyloid processing and mitochondrial functioning in the SH-SY5Y human neuroblastoma cell line. SH-SY5Y cells were exposed to nilotinib (1, 5, and 10 µM). Real-time PCR and immunoblot analysis were performed to quantify the expression of genes pertaining to amyloid-β processing and neuronal health.

Nilotinib did not significantly change APP, BACE1, or ADAM10 mRNA levels. However, BACE1 protein was significantly increased at 1 µM, and ADAM10 was increased at 10 µM nilotinib without affecting APP protein expression. Further, nilotinib treatment did not affect the expression of genes associated with neuronal health and mitochondrial functioning.

Taken together, our findings do not support the efficacy of nilotinib treatment for neuroprotection.

Alzheimer’s disease (AD) is the most common form of dementia in older persons. It is a relentless, progressive neurodegenerative disorder, leading to cognitive impairment, deterioration of functional capacity and, ultimately, death [1,2]. The underlying causes of AD remain incompletely understood and, despite the allocation of huge resources towards finding a cure, progress has been slow. Pathologically, the AD brain is characterized by the accumulation of extracellular amyloid plaques and intraneuronal neurofibrillary tangles of phosphorylated tau protein [3]. Mitochondrial abnormalities, neuroinflammation, and synaptic dysfunction are also observed [4]. The economic burden and stress on caregivers and loved ones continues to grow as the population ages [5]. This compelling collection of articles provides a unique update on many practical aspects of navigating the care and treatment of persons with AD with a forward-looking perspective on promising therapeutic approaches.

In this Special Issue, we showcase several studies addressing the caregivers who take on the responsibilities of tending to the needs of a person with AD. This can take a heavy toll [6,7]. In their article, Sánchez-Alcón et al. present a descriptive correlational cross-sectional study of family caregivers studying dementia grief, which is the feeling of loss experienced by the caregiver prior to the physical death of the person with dementia [8]. Based on self-administered questionnaires, they found that dementia grief intensity was correlated to depressive symptoms and caregiver strain. Cohen and his team used a cross-sectional design in an exploratory analysis of the relationships among caregiver burden, physical frailty, race, and behavioral and psychological symptoms (BPSD) [9]. They found that frailty affected caregiver burden and BPSD functioned as a mediator between various predictor variables and caregiver burden. Hellis and Mukaetova-Ladinska present a review article covering the mental and physical demands placed on informal caregivers, with an emphasis on the need for support from within and outside the network of friends and relatives to mitigate some of the stress, anxiety and depression that can accompany caregiving [10].

Three articles draw attention to key aspects of making the diagnosis of AD. De Levante Raphael discusses the role of the primary care physician in recognizing dementia and the obstacles and difficulties involved. The author points out the need to educate primary care physicians so that they can perform cognitive assessment in older adults, detect impairment, and manage care [11]. Cummings and Kinney undertake a review of the rapidly evolving field of AD biomarkers [12]. They summarize the categories of biomarkers and their role in diagnosis, prediction, prognosis and monitoring of AD. Attention is given to the regulatory process in biomarker development, clinical validation, and the transition from use in clinical trials to application in clinical care. Dastgheib et al. report on their pilot study, applying electrovestibulography to 16 patients with AD, 13 with a mixed pathology of AD-cerebrovascular disease (AD-CVD), and 24 healthy age-matched controls [13]. They incorporated a cutoff Montreal Cognitive Assessment score, and then used their pilot electrovestibulography data to develop a hierarchy diagnostic algorithm to classify subjects as AD, AD-CVD, or control, and tested the robustness of the most informative features of the results against a blind testing dataset. They hope to use this algorithm to bring better accuracy to the challenge of distinguishing AD from AD-CVD.

The treatment of AD is the focus of three papers. Stecker gives a perspective on the broad issues in AD and the potential for implementing a new model encompassing large-scale collaborations and big data to achieve desperately needed innovations in treatment [14]. Angelopoulou et al. consider the value of telemedicine as a tool for bringing care to persons with dementia [15]. They point out the advantages of telemedicine in providing broad access to patient-centered, integrated care, especially for those living in remote areas and those with mobility issues. The convenience, reliability and reasonable costs associated with virtual visits are considered, and the limitations, such as need for digital proficiency and internet connectivity, are outlined. Reiss et al. investigate the current status of developments in AD therapy based on our escalating knowledge of brain biology at the molecular and genetic level [16]. They give a synopsis of novel approaches using small molecules, stem cells, repurposed drugs, deep brain stimulation, and dietary measures. New delivery systems and the shifting of resources away from anti-amyloid therapy brings optimism for future progress toward disease-modifying original therapeutics. Ding et al. examine the value of a plant-based diet in maintaining cognitive health and mental sharpness [17]. In an organized fashion, they lay out the dietary guidelines and recommendations for nutrients and fiber that have been found to benefit brain health. Consideration is also given to the gut–brain axis and microbiome.

Together, the studies in this Special Issue highlight the importance of caregiving, diagnosis, treatment, and lifestyle in AD. We hope that the reader will find this collection to be a useful reference with tools and information dealing with both pragmatic and theoretical aspects of AD management.

As Guest Editors, we thank the distinguished authors who contributed to this Special Issue. We also extend our gratitude to the superb team at Medicina for their care in the handling of each manuscript, and for their support of this project.

Alzheimer’s disease (AD) is a progressive and incurable neurodegenerative disorder that primarily affects persons aged 65 years and above. It causes dementia with memory loss and deterioration in thinking and language skills. AD is characterized by specific pathology resulting from the accumulation in the brain of extracellular plaques of amyloid-β and intracellular tangles of phosphorylated tau.

The importance of mitochondrial dysfunction in AD pathogenesis, while previously underrecognized, is now more and more appreciated. Mitochondria are an essential organelle involved in cellular bioenergetics and signaling pathways. Mitochondrial processes crucial for synaptic activity such as mitophagy, mitochondrial trafficking, mitochondrial fission, and mitochondrial fusion are dysregulated in the AD brain.

Excess fission and fragmentation yield mitochondria with low energy production. Reduced glucose metabolism is also observed in the AD brain with a hypometabolic state, particularly in the temporo-parietal brain regions.

This review addresses the multiple ways in which abnormal mitochondrial structure and function contribute to AD. Disruption of the electron transport chain and ATP production are particularly neurotoxic because brain cells have disproportionately high energy demands. In addition, oxidative stress, which is extremely damaging to nerve cells, rises dramatically with mitochondrial dyshomeostasis.

Restoring mitochondrial health may be a viable approach to AD treatment.

Prostate cancer is the second leading cause of cancer death in men in the United States. Androgen deprivation therapy (ADT) is currently the primary treatment for metastatic prostate cancer, and some studies have shown that the use of anti-androgen drugs is related to a reduction in cognitive function, mood changes, diminished quality of life, dementia, and possibly Alzheimer’s disease.

ADT has potential physiological effects such as a reduction in white matter integrity and a negative impact on hypothalamic functions due to the lowering of testosterone levels or the blockade of downstream androgen receptor signaling by first- and second-generation anti-androgen drugs.

A comparative analysis of prostate cancer patients undergoing ADT and Alzheimer patients identified over 30 shared genes, illustrating common ground for the mechanistic underpinning of the symptomatology.

The purpose of this review was to investigate the effects of ADT on cognitive function, mood, and quality of life, as well as to analyze the relationship between ADT and Alzheimer’s disease. The evaluation of prostate cancer patient cognitive ability via neurocognitive testing is described. Future studies should further explore the connection among cognitive deficits, mood disturbances, and the physiological changes that occur when hormonal balance is altered.

Mitochondrial degeneration in various neurodegenerative diseases, specifically in Alzheimer’s disease, involves excessive mitochondrial fission and reduced fusion, leading to cell damage.

P110 is a seven-amino acid peptide that restores mitochondrial dynamics by acting as an inhibitor of mitochondrial fission. However, the role of P110 as a neuroprotective agent in AD remains unclear. Therefore, we performed cell culture studies to evaluate the neuroprotective effect of P110 on amyloid-β accumulation and mitochondrial functioning.

Human SH-SY5Y neuronal cells were incubated with 1 µM and 10 µM of P110, and Real-Time PCR and Western blot analysis were done to quantify the expression of genes pertaining to AD and neuronal health. Exposure of SH-SY5Y cells to P110 significantly increased APP mRNA levels at 1 µM, while BACE1 mRNA levels were increased at both 1 µM and 10 µM. However, protein levels of both APP and BACE1 were significantly reduced at 10 µM of P110. Further, P110 treatment significantly increased ADAM10 and Klotho protein levels at 10 µM. In addition, P110 exposure significantly increased active mitochondria and reduced ROS in live SH-SY5Y cells at both 1 µM and 10 µM concentrations.

Taken together, our results indicate that P110 might be useful in attenuating amyloid-β generation and improving neuronal health by maintaining mitochondrial function in neurons.

Dysregulated cholesterol metabolism represents an increasingly recognized feature of autism spectrum disorder (ASD). Children with fetal valproate syndrome caused by prenatal exposure to valproic acid (VPA), an anti-epileptic and mood-stabilizing drug, have a higher incidence of developing ASD. However, the role of VPA in cholesterol homeostasis in neurons and microglial cells remains unclear.

Therefore, we examined the effect of VPA exposure on regulation of cholesterol homeostasis in the human microglial clone 3 (HMC3) cell line and the human neuroblastoma cell line SH-SY5Y. HMC3 and SH-SY5Y cells were each incubated in increasing concentrations of VPA, followed by quantification of mRNA and protein expression of cholesterol transporters and cholesterol metabolizing enzymes. Cholesterol efflux was evaluated using colorimetric assays.

We found that VPA treatment in HMC3 cells significantly reduced ABCA1 mRNA, but increased ABCG1 and CD36 mRNA levels in a dose-dependent manner. However, ABCA1 and ABCG1 protein levels were reduced by VPA in HMC3. Furthermore, similar experiments in SH-SY5Y cells showed increased mRNA levels for ABCA1, ABCG1, CD36, and 27-hydroxylase with VPA treatment.

VPA exposure significantly reduced protein levels of ABCA1 in a dose-dependent manner, but increased the ABCG1 protein level at the highest dose in SH-SY5Y cells. In addition, VPA treatment significantly increased cholesterol efflux in SH-SY5Y, but had no impact on efflux in HMC3. VPA differentially controls the expression of ABCA1 and ABCG1, but regulation at the transcriptional and translational levels are not consistent and changes in the expression of these genes do not correlate with cholesterol efflux in vitro.

Although there are many biochemical methods to measure amyloid-β (Aβ)42 concentration, one of the critical issues in the study of the effects of Aβ42 on the nervous system is a simple physiological measurement. The in vitro rat sciatic nerve model is employed and the nerve action potential (NAP) is quantified with different stimuli while exposed to different concentrations of Aβ42.

Aβ42 predominantly reduces the NAP amplitude with minimal effects on other parameters except at low stimulus currents and short inter-stimulus intervals.

The effects of Aβ42 are significantly concentration-dependent, with a maximum reduction in NAP amplitude at a concentration of 70 nM and smaller effects on the NAP amplitude at higher and lower concentrations. However, even physiologic concentrations in the range of 70 pM did reduce the NAP amplitude. The effects of Aβ42 became maximal 5–8 h after exposure and did not reverse during a 30 min washout period. The in vitro rat sciatic nerve model is sensitive to the effects of physiologic concentrations of Aβ42.

These experiments suggest that the effect of Aβ42 is a very complex function of concentration that may be the result of amyloid-related changes in membrane properties or sodium channels.

Dementia impacts over 55 million individuals globally, creating a pressing public health concern characterized by cognitive and functional decline beyond typical aging. As highlighted by the World Alzheimer Report (Alzheimer’s Disease International, 2022) and the World Health Organization (2022), Alzheimer’s disease (AD) and related dementia (ADRD) are the principal cause of disability, dependence, and death among the elderly. Its repercussions, both personally and socially, vary in magnitude, often reflecting the inequality gradients of the respective nations. Today’s research in aging, dementia, and other brain diseases is moving away from one-size-fits-all models to embrace multifaceted, heterogeneity-aware, and diversity-driven paradigms (Alladi and Hachinski, 2018; Parra et al., 2018, 2021, 2022; Dehghani et al., 2021; Deco et al., 2022; Frisoni et al., 2022; Ibanez, 2022; Moguilner et al., 2022; Ibanez and Zimmer, 2023; Ibanez et al., 2023; Maito et al., 2023; Santamaria-Garcia et al., 2023). This dynamic evolution in dementia studies is pioneering new interdisciplinary connections, spanning various methods, scales, populations, and regions. It dives into genetic diversity, protein aggregation patterns, synaptic activities, disparities across multiple fronts, advanced biomarkers, and the interplay of environmental triggers with physiological stress mechanisms. Moreover, a trend toward non-generalized samples and unique research designs in neuroscience has become evident. Years of research have enhanced our understanding of AD’s underlying mechanisms. Technological and diagnostic advancements have paved the way for therapeutic innovations, as evidenced by the recent FDA approval of drugs such as Aduhelm and Lecanemab, marking progress in the field. While research in ADRD has significantly broadened over the years, these advancements have led to improved patient outcomes. However, challenges persist, such as complexities related to heterogeneity in disease presentation, the lack of early detection biomarkers, and the absence of massive development of disease-modifying therapies.

As we journey into the third decade of the twenty first Century, remarkable strides have been made in Alzheimer’s disease and related dementia. Frontiers has curated a series of Research Topics to spotlight these advancements in Aging Neuroscience. This special edition, titled “Insights in Alzheimer’s disease and related dementias,” offers a concise overview of selected studies to enlighten and guide the research community.

There has been a growing interest in different factors impacting cognitive function, dementia, and Alzheimer’s disease (AD). Costa-Laparra et al. delved into the relationship between specific genetic factors, such as the APOE ε4 allele and G206D-PSEN1 mutation, and mitochondrial abnormalities in AD. Their study demonstrated that these genetic variations could lead to mitochondrial fragmentation and an increased propensity for oxidative stress-induced cell death, potentially contributing to AD and neurodegeneration. Yang et al. explored the impact of hearing aids on cognitive function in middle-aged and older adults with hearing loss, including those with AD, dementia, and depressive symptoms. Their meta-analysis revealed that for those with AD or dementia, hearing aids did not significantly enhance cognitive function. Thus, the efficacy of these aids in non-demented subjects remains uncertain.

In a diverse population, Chen et al. devised a predictive model for cognitive impairment in elderly illiterate Chinese women (n = 1864), determining that age, daily living activities, and waist-to-height ratio were critical predictors. Meanwhile, Hwangbo et al. drawing longitudinal data from South Korea (n = 794,448), identified physical inactivity, diabetes, and hypertension as the top modifiable risk factors for dementia, emphasizing the importance of lifestyle modifications for prevention. Lastly, Balzamino et al. used a Reeler murine model, deficient in the Reelin protein, to show parallels between pathological hallmarks of AD and ocular degeneration, suggesting potential shared pathways in neurodegenerative diseases and age-related macular degeneration.

Collectively, these studies underscore the multifaceted nature of cognitive decline and dementia, hinting at diverse intervention points for prevention and treatment. This Research Topic showcases handpicked studies from Alzheimer’s disease and related dementia research. Our aspiration is that these insights not only spotlight past advancements but also illuminate the upcoming challenges in the domain.

As the search for modalities to cure Alzheimer’s disease (AD) has made slow progress, research has now turned to innovative pathways involving neural and peripheral inflammation and neuro-regeneration.

Widely used AD treatments provide only symptomatic relief without changing the disease course. The recently FDA-approved anti-amyloid drugs, aducanumab and lecanemab, have demonstrated unclear real-world efficacy with a substantial side effect profile.

Interest is growing in targeting the early stages of AD before irreversible pathologic changes so that cognitive function and neuronal viability can be preserved. Neuroinflammation is a fundamental feature of AD that involves complex relationships among cerebral immune cells and pro-inflammatory cytokines, which could be altered pharmacologically by AD therapy.

Here, we provide an overview of the manipulations attempted in pre-clinical experiments. These include inhibition of microglial receptors, attenuation of inflammation and enhancement of toxin-clearing autophagy. In addition, modulation of the microbiome-brain-gut axis, dietary changes, and increased mental and physical exercise are under evaluation as ways to optimize brain health.

As the scientific and medical communities work together, new solutions may be on the horizon to slow or halt AD progression.

According to the World Alzheimer’s Report (Alzheimer’s Disease International, 2022) and the Global status report on the public health response to dementia (WHO, 2022), 55+ million people live with dementia, a condition characterized by deterioration in cognition and functionality beyond the expected effects of normal aging. WHO has recognized dementia as a public health priority.

Alzheimer’s disease and related dementias (ADRD) may result from a disparate combination of processes, including genetic and environmental factors (fiscal, social, economic), pathological processes, and injuries that primarily or secondarily affect the brain. Dementia is a leading cause of disability, dependence and death among older people globally. The impact of dementia at personal and societal levels is unequally distributed, usually following a distribution similar to that of the inequality index of the corresponding country.

Current dementia research is transitioning from more simplistic and universal models toward complex, multilevel, heterogeneity-sensitive, and diversity-oriented frameworks. These landscapes of dementia science are changing rapidly, creating novel bridges across disciplines, diverse populations, regions, scales, methods and approaches. Some of these reconfigurations are driven by animal and human research focused in multiple emerging areas such as diversity contributions to genetic traits (Dehghani et al., 2021); heterogeneity and variation in protein misfolding and aggregation (Frisoni et al., 2022); explanatory models based on excitation/inhibition synaptic activity (Babiloni et al., 2020); impact of multiple sources of disparities (gender, admixtures, cultural, socioeconomic) (Alladi and Hachinski, 2018; Parra et al., 2018, 2021); development of multimodal and region-specific biomarkers (Moguilner et al., 2022; Parra et al., 2022; Maito et al., 2023) and initiatives (Ibanez et al., 2021; Parra et al., 2021; Duran-Aniotz et al., 2022); interactions between environmental stressors and physiopathological mechanisms of allostatic overload (Birba et al., 2022; De Felice et al., 2022; Migeot et al., 2022); and going beyond universal models toward non-stereotypical samples (Greene et al., 2022) and designs (Ibanez, 2022) in neuroscience and dementia (Alladi and Hachinski, 2018).

Notably, many of these key matters are being covered in this special issue.

Despite intensive research, effective treatments for many common and devastating diseases are lacking. For example, huge efforts and billions of dollars have been invested in Alzheimer’s disease (AD), which affects over 50 million people worldwide.

However, there is still no effective drug that can slow or cure AD. This relates, in part, to the absence of an animal model or cellular system that incorporates all the relevant features of the disease.

Therefore, large scale studies on human populations and tissues will be key to better understanding dementia and developing methods to prevent or treat it. This is especially difficult because the dementia phenotype can result from many different processes and is likely to be affected by multiple personal and environmental variables.

We hypothesize that analyzing massive volumes of demographic data that are currently available and combining this with genomic, proteomic, and metabolomic profiles of AD patients and their families, new insights into pathophysiology and treatment of AD may arise. While this requires much coordination and cooperation among large institutions, the potential for advancement would be life-changing for millions of people.

In many ways this represents the next step in the information revolution started by the Human Genome Project.

Background and Objectives: Alzheimer’s disease (AD) is the most common form of dementia, with the risk of developing it attributed to non-modifiable and modifiable factors. Currently, there is no cure for AD. A plant-based diet may protect against cognitive decline, due to the effects of plant-based nutrients such as vitamins, antioxidants, and fiber. The aim of the review is to summarize current literature on plant-based nutrients and their impact on cognition.

Materials and Methods: A search was conducted on PubMed for clinical and murine studies, using combinations of the following words: “Alzheimer’s disease”, “dementia”, “cognition”, “plant-based diet”, “mild cognitive impairment”, “vitamin B”, “vitamin C”, “vitamin E, “beta carotene”, “antioxidants”, “fiber”, “vitamin K”, “Mediterranean diet”, “vitamin D”, and “mushrooms”.

Results and Conclusions: A diet rich in vitamin B and antioxidants can benefit the cognitive functions of individuals as shown in randomized clinical trials. Vitamin K is associated with improved cognition, although large randomized controlled trials need to be done. Fiber has been shown to prevent cognitive decline in animal studies. Vitamin D may contribute to cognitive health via anti-inflammatory processes. Several medical organizations have recommended a plant-based diet for optimizing cognitive health and potentially helping to prevent dementia.

There is conflicting information on the relationship between diet and dementia. The purposes of this pilot study were twofold. First, to use publicly available data regarding food consumption (United Kingdom Family Food), dementia, risk and demographic factors to find relationships between the consumption of various foods to dementia prevalence. The second purpose was to identify elements of study design that had important effects on the results. Multiple analyses were performed on different data sets derived from the existing data.

Statistical testing began with univariate correlation analyses corrected for multiple testing followed by global tests for significance. Subsequently, a number of multivariate techniques were applied including stepwise linear regression, cluster regression, regularized regression, and principal components analysis. Permutation tests and simulations highlighted the strength and weakness of each technique.

The univariate analyses demonstrated that the consumption of certain foods was highly associated with the prevalence of dementia. However, because of the complexity of the data set and the high degree of correlation between variables, different multivariate analyses yielded different results, explainable by the correlations. Some factors identified as having potential associations were the consumption of rice, sugar, fruit, potatoes, meat products and fish. However, within a given dietary category there were often a number of different elements with different relations to dementia.

This pilot study demonstrates some critical elements for a future study: (1) dietary factors must be very narrowly defined, (2) large numbers of cases are needed to support multivariable analyses. (3) Multiple statistical methods along with simulations must be used to confirm results.

Background

Alzheimer’s disease (AD) is the most prevalent form of dementia worldwide and is characterized by progressive memory loss and cognitive impairment. Our understanding of AD pathogenesis is limited and no effective disease-modifying treatment is available. Mitochondria are cytoplasmic organelles critical to the homeostatic regulation of glucose and energy in the cell.

Methods

Mitochondrial abnormalities are found early in the course of AD and dysfunctional mitochondria are involved in AD progression. The resulting respiratory chain impairment, neuronal apoptosis, and generation of reactive oxygen species are highly damaging to neurons. Restoration of mitochondrial function may provide a novel therapeutic strategy for AD.

Results

This review discusses the specifics of mitochondrial fragmentation, imbalances in fission and fusion, and DNA damage seen in AD and the contribution of compromised mitochondrial activity to AD etiopathogenesis. It explores how an understanding of the processes underlying mitochondrial failure may lead to urgently needed treatment innovations. It considers individual mitochondrial proteins that have emerged as promising drug targets and evaluates neuroprotective agents that could improve the functional state of mitochondria in the setting of AD.

Conclusions

There is great promise in exploring original approaches to preserving mitochondrial viability as a means to achieve breakthroughs in treating AD.

Prostate cancer is the second most common form of cancer in men. For advanced, high risk prostate cancer, androgen deprivation therapy (ADT) is the preferred treatment and can induce remission, but resistance to ADT brings biochemical recurrence and progression of cancer. ADT brings adverse effects such as erectile dysfunction, decreased libido, and diminished physical strength. It is estimated that between 25 and 50% of men on ADT manifest some form of cognitive dysfunction that may be self-reported or reported by a family member.

There is concern that impaired cognitive function with ADT is due to loss of testosterone support. Testosterone and its metabolites are known to possess neuroprotective properties. While a direct causal relationship between ADT and cognitive decline in prostate cancer patients has not been established, this review describes the controversy surrounding the possible connection between ADT and neurocognitive deterioration.

The cellular and molecular mechanisms believed to underlie the protection of neuronal integrity by androgens are discussed. Results from animal models and human clinical studies are presented. Finally, we call attention to lifestyle modifications that may minimize cognitive issues in prostate cancer patients.

Alzheimer’s disease (AD) is a neurodegenerative brain disorder associated with relentlessly progressive loss of of memory and cognitive impairment. AD pathology proceed for decades before cognitive deficits become clinically apparent, opening a window for preventative therapy.

Imbalance of clearance and buildup of amyloid β and phosphorylated-Tau proteins in the central nervous system are believed to contribute to AD pathogenesis. However, multiple clinical trials of treatments aimed at averting accumulation of these proteins have yielded little success and there is still no disease-modifying intervention.

Here, we discuss current knowledge of AD pathology and treatment with an emphasis on emerging biomarkers and treatment strategies.

A major feature of Alzheimer’s disease (AD) pathology is the plaque composed of aggregated amyloid-β (Aβ) peptide. Although these plaques may have harmful properties, there is much evidence to implicate soluble oligomeric Aβ as the primary noxious form.

Aβ oligomers can be generated both extracellularly and intracellularly. Aβ is toxic to neurons in a myriad of ways. It can cause pore formation resulting in the leakage of ions, disruption of cellular calcium balance, and loss of membrane potential. It can promote apoptosis, cause synaptic loss, and disrupt the cytoskeleton.

Current treatments for AD are limited and palliative. Much research and effort is being devoted to reducing Aβ production as an approach to slowing or preventing the development of AD. Aβ formation results from the amyloidogenic cleavage of human amyloid precursor protein (APP).

Reconfiguring this process to disfavor amyloid generation might be possible through the reduction of APP or inhibition of enzymes that convert the precursor protein to amyloid.