Review
Tursun Alkam, Andrew H Van Benschoten, Ebrahim Tarshizi
Large language models for Alzheimer’s disease drug discovery
Abstract: Alzheimer’s disease (AD) is a complex neurodegenerative disorder with significant global health and economic impacts. Despite decades of research, therapeutic progress has been hindered by the multifactorial nature of AD and limitations in traditional drug discovery approaches. This review explores the transformative potential of large language models (LLMs) in advancing medicinal chemistry for AD drug discovery. LLMs excel at processing and synthesizing vast biomedical datasets, enabling breakthroughs in hypothesis generation, target identification, and de novo drug design. By integrating multi-modal data, these models address key challenges, including patient heterogeneity, inefficiencies in preclinical models, and high failure rates in clinical trials. This paper highlights case studies and current implementations, including their roles in literature mining, protein structure prediction, and absorption, distribution, metabolism, excretion, and toxicity (ADME-Tox) property assessment, showcasing LLMs' capacity to enhance drug discovery efficiency and precision. Despite challenges related to data quality, interpretability, and ethical concerns, LLMs offer a promising paradigm shift in AD research, paving the way for innovative therapeutic solutions and interdisciplinary collaboration. This review serves as a resource for fostering artificial intelligence-biomedicine integration to combat AD and improve patient outcomes.
Review
Kamil Walczak, Weronika Kołodziejczyk, Magdalena Pszczołowska, Magdalena Kozłowska, Jan Aleksander Beszłej, Jerzy Leszek
Klotho protein in Alzheimer’s disease: Diet leading to immortality?
Abstract: Alzheimer’s disease (AD) is the most common cause of dementia, leading to progressive cognitive decline and premature death. Despite decades of research, the exact cause of AD remains unknown, and current treatments only slow disease progression without addressing its root cause. Recent studies suggest that endogenous factors such as the Klotho protein may have neuroprotective properties and influence AD progression. This review aims to explore the role of Klotho protein in AD, with a particular focus on its biological functions, expression, and potential therapeutic implications. Additionally, it examines the relationship between Klotho levels and dietary patterns. A literature review was conducted to analyze existing research on Klotho protein, its neuroprotective effects, and its correlation with different dietary factors in the context of AD. Evidence suggests that Klotho protein plays a crucial role in cellular metabolism and neuroprotection. Higher levels of Klotho have been linked to better cognitive function and reduced neurodegeneration. Emerging research also indicates that certain dietary patterns, particularly the Mediterranean diet, may positively influence Klotho expression. Klotho protein represents a promising therapeutic target in AD, potentially slowing disease progression through its neuroprotective effects. Further research is needed to better understand the mechanisms regulating Klotho levels, particularly the impact of diet, and how they can be leveraged for AD prevention and treatment.
Systematic Review
Jing Yu#, Sisi Zhang#, Lin Li#, Qin Shen #These authors contributed equally to this work.
Dyadic coping experience of persons with young-onset dementia and their spousal caregivers: A review of qualitative studies and meta-synthesis
Abstract: Background: Persons with young-onset dementia (PwYOD) often face issues with social role conflicts, financial crises, and family relationship breakdowns. Spousal caregivers (SCGs) balance numerous family responsibilities while facing a significant burden of care and emotional strain. Currently, an increasing number of qualitative studies focus on the experience of illness from the perspective of the YOD couple's dyadic experience. Objective: This study aims to synthesize the qualitative findings of the dyadic coping experiences of PwYODs and SCGs. Methods: We conducted a comprehensive search in 10 databases from their inception to 1 October 2024. Methodological quality assessment and extraction were performed using the Joanna Briggs Institute (JBI) Critical Appraisal Tool for Qualitative Research, and the research results were classified and synthesized. Results: A total of 19 studies were included, with 136 findings extracted and grouped into 14 categories, which were synthesized into six synthesized findings. These synthesized findings were: (1) Diagnosis brings mixed emotions; (2) Interrupt the previous trajectory of life; (3) Deeply troubled by the stigma of illness; (4) PwYODs and SCGs desire multiple support; (5) Positive coping and personal growth; (6) Social factors lead to differences in dyadic coping. Conclusions: The findings show that PwYODs and SCGs experience different emotional changes and personal needs in the face of the disease, and use multiple strategies to cope with life. Ultimately, this review elaborates on the arguments for helping PwYODs and SCGs access practical needs and support resources.
Systematic Review
Meire Ellen Pereira, Júlia Vicentin de Souza, Gabriella Giandotti Gomar, Isabeli Lopes Kruk, Cláudia Sirlene Oliveira
Glutathione peroxidase activity in Alzheimer’s disease patients: A systematic review and meta-analysis
Abstract: Background: Oxidative stress can trigger and even aggravate Alzheimer’s disease (AD). Glutathione peroxidase (GPX) can regulate oxidative stress by controlling the accumulation of hydrogen peroxide. Objective: This study aimed to evaluate the GPX activity in patients with AD through a systematic review and meta-analysis. Methods: Following the PRISMA guidelines, data were retrieved from four electronic databases, including those containing cohort and case-control studies, published up to December 2024. Statistical analyses were conducted using RevMan, and risk of bias was evaluated with the Newcastle-Ottawa Scale. Results: A total of 1999 scientific papers were collected, and 30 papers were included in this systematic review; 20 were included in the meta-analysis. GPX activity was measured in different tissues, such as erythrocytes, plasma, and postmortem brain. The analyses showed that erythrocytes and plasma GPX activity in most studies were inhibited in AD patients compared to healthy controls. Conclusions: The analyses showed that GPX activity was decreased in AD patients compared to healthy controls in most of the included studies. More detailed research is needed to better assess the effects of GPX activity on AD-associated cognitive impairment and oxidative stress.
Systematic Review
Bowen Zhang, Bei Wu, Jianlin Lou, Chen Zhang, Yaolin Pei, Xinhua Shen, Lina Wang (Handling Associate Editor: Birgit Teichmann)
Supportive care needs of individuals with young-onset dementia: A systematic review and qualitative meta-synthesis
Abstract: Background: Young-onset dementia (YOD) presents distinct health and care needs due to its earlier onset compared to late-onset dementia (LOD). Understanding these challenges is crucial for developing tailored interventions. Objective: This systematic review describes and analyzes the supportive care needs of individuals with YOD and identifies key areas for further research. Methods: A qualitative systematic review was conducted following PRISMA guidelines, with comprehensive searches of databases, including PubMed, Embase, and Web of Science, etc. Screening and data extraction were performed, followed by a “Best-fit” framework synthesis. Study quality was appraised using the JBI Critical Appraisal Tool, and confidence in the findings was assessed using the ConQual approach. Results: Seventeen articles yielded 42 findings categorized into 17 groups and synthesized into three themes: (1) needs for empowerment through knowledge, planning, and meaningful engagement, (2) needs for promoting physical health, mental support, and social engagement, and (3) needs for a comprehensive support network. Theme 1 encompassed six sub-themes: accurate and timely diagnosis, pre-determined care plan, desire for disease-related knowledge, autonomy in decision-making and dignity preservation, future planning, and a sense of self-worth. Theme 2 involved physical activity, symptom management, psychotherapy, social and recreational activities, employment, and public awareness. Theme 3 comprised financial and family responsibilities, caregiver support, professional support, information support, and caregiving institutions. Conclusions: Individuals with YOD remain an under-researched group with unique needs. This review highlights their specific needs and experiences, emphasizes the importance of tailored support, and informs the development of targeted future interventions.
Systematic Review
Duo Yang, Na Hou, Mingyuan Jia (Handling Associate Editor: Terence Chong)
Multicomponent exercise interventions for older adults with Alzheimer’s disease: A systematic review and meta-analytical perspective
Abstract: Background: Exercise, as an adjunctive therapy for Alzheimer’s disease (AD) patients, is meaningful and common. However, it remains unclear whether the modality of exercise has a positive impact on elderly AD patients. Objective: The exploration of how multicomponent exercise can have positive effects on older adults with AD. Methods: A detailed search was conducted across six databases, followed by independent screening to identify the final studies included in the analysis. The study was conducted following the guidelines of the Cochrane Handbook. Results: Seventeen studies were included in the final analysis. The results showed that ME effectively improved activities of daily living (ADL) [SMD=0.46, 95% CI (0.13, 0.79)], depression [SMD=-0.32, 95% CI (-0.63, -0.01)], and balance [SMD=0.73, 95% CI (0.32, 1.14)]. In terms of ADL, an intervention period of 12 weeks, with 3-5 sessions per week and each session lasting 30-60 minutes, may be more effective. Conclusions: Multicomponent exercise demonstrates statistically significant effects in improving ADL, depression, and balance in AD patients aged 60 and above. Future studies with larger sample sizes are needed to provide higher-level evidence.
Hypothesis
James P Garrahy
Astrocytic lipidopathy and bioenergetic failure in ApoE4-associated late-onset Alzheimer’s disease: A unifying hypothesis
Abstract: Late-onset Alzheimer’s disease (LOAD) is traditionally attributed to amyloid-β (Aβ) accumulation and tau pathology as primary drivers of neurodegeneration. However, growing evidence suggests these may be secondary events arising from earlier disturbances in brain metabolism and lipid homeostasis. The ε4 allele of apolipoprotein E (ApoE4) remains the strongest genetic risk factor for LOAD, with carriers exhibiting both increased lifetime risk and earlier age of onset compared to ε2 or ε3 carriers. ApoE4 disrupts lipid metabolism and is associated with increased lipid droplet accumulation within astrocytes, implicating astrocytic lipidopathy in disease pathogenesis. Here, we propose a self-reinforcing pathogenic feedback loop—driven by dysregulated lipid homeostasis, chronic neuroinflammation, impaired glucose-handling, and cerebrovascular dysfunction—that culminates in astrocytic bioenergetic failure. This framework helps explain why ApoE4 carriers reach a critical bioenergetic threshold earlier in life, triggering the clinical onset of LOAD. Targeting astrocytic lipid homeostasis, through interventions such as blood-brain barrier-permeable statins, choline supplementation, or metabolic therapies, may offer novel strategies to delay disease progression or onset. Beyond AD, the framework proposed here, if validated, may have broader implications for unifying the cellular origins of age-related degenerative diseases and cancer through a shared vulnerability to progressive bioenergetic collapse.
Short Communication
Ian P Johnson, Tia M Peterson, Kathryn Gudsnuk, C Dirk Keene, Thomas D Bird, Suman Jayadev, Paul N Valdmanis, Meredith M Course
Presence of Alzheimer’s disease variants in circular RNA of PSEN1 and PSEN2
Abstract: Circular RNAs (circRNAs) are emerging as a promising object of study in Alzheimer’s disease (AD) pathogenesis. Expression differences in circRNAs have been correlated with disease; however, the presence of pathogenic variants has not been observed until now. Here, we examine circRNAs derived from two AD-related genes, presenilin 1 (PSEN1) and presenilin 2 (PSEN2), in the prefrontal cortex from individuals with familial AD, identifying four variants in circRNAs derived from PSEN1 (I143T, S212Y, M146L) and PSEN2 (N141I). The discovery of pathogenic variants in PSEN1 and PSEN2 circRNAs marks a first step in determining whether they play a role in AD etiology.
Commentary
Patrizia Vannini, Giovanna Zamboni
To know or to not know: The importance of assessing awareness of cognitive function in the early stages of Alzheimer’s disease
Abstract: Self-awareness has become an important research topic in Alzheimer’s disease, with both decreased and increased awareness of cognitive deficits observed in the early stages of the disease. Understanding the pathological underpinning and factors associated with altered self-awareness is crucial for diagnostic purposes and its implications in patient treatment. The study by Furuya et al., showed that decreased awareness was associated with an increased likelihood of harboring amyloid pathology in cognitively normal and mild cognitive impairment participants. Here, we discuss these findings as well as psychiatric and social determinants of awareness and the need to refine tools to understand altered self-awareness.
Commentary
Godpower C Michael
Knowledge and attitudes about Alzheimer’s disease in Nigerian geriatric outpatients: The role of primary care professionals
Abstract: The global population growth and aging have resulted in an increase in dementia/Alzheimer's disease. This suggests that both geriatric patients and those who care for them must be knowledgeable about the disease to inform appropriate health-seeking behavior on the part of the patient. and diagnosis and care provision by healthcare professionals. This commentary attempts to highlight the preponderance of insufficient knowledge of dementia/Alzheimer’s disease among geriatric patients as well as healthcare professionals. It advocates training and retraining primary care professionals (physicians and nurses) in geriatric care/dementia, which will have a ripple effect on patient education and care.
Commentary
Ifrah Zawar, Jaideep Kapur
Seizing the link: Exploring the potential association between anti-seizure medications and Alzheimer’s disease
Abstract: Ongoing seizures in Alzheimer’s disease (AD) are associated with worse cognitive and mortality outcomes. However, the relationship between anti-seizure medications (ASMs) and AD remains uncertain. This scoping review of 27 studies (1,241,796 participants) found ASM use to be associated with slightly increased AD risk, though findings were largely inconclusive. Associations between ASMs and AD-related symptoms, including mood, cognition, quality of life, function, and neuropsychiatric symptoms, were similarly mixed. The review establishes the scope of the problem, highlights the gaps, and maps available evidence. However, the included studies have methodological limitations, including inadequate control for the presence and severity of seizures, unclear ASM indications, lack of biomarker-based AD diagnosis, and limited ethnic and racial diversity, which limit conclusions and generalizability. Addressing these gaps in future studies will provide a more nuanced understanding of the relationship between seizures, ASMs, and AD.
Commentary
Joshua W Miller, Andrew McCaddon, Jin-tai Yu, Babak Hooshmand, Helga Refsum, A David Smith
Concerning the debate about homocysteine, B vitamins, and dementia
Abstract: It is important to identify modifiable risk factors for dementia and to introduce policies to implement their modification. The Lancet Commission on Dementia Prevention, Intervention and Care failed to identify raised plasma homocysteine as a risk factor, despite considerable evidence; hence there is a need for a debate on this matter.
Editorial
Poul F Høilund-Carlsen, Jorge R Barrio
History repeats itself: A new trivializing term for a potentially life-threatening side effect of antibody Alzheimer’s disease therapy
Abstract: The term “amyloid-removal-related pseudo-atrophy” has recently been proposed for the accelerated brain volume loss caused by anti-Alzheimer's antibody therapies, although most trials seem to neglect it. As with ‘amyloid-related imaging abnormalities’ (ARIAs), this is downplaying yet another side effect of passive antibody therapy that cannot be justified until its impact on brain function is fully understood. ARIAs and accelerated volume loss are likely due to antibody-induced brain tissue damage, making amyloid-PET imaging an unreliable indicator of amyloid removal. Therefore, approval of antibody therapy based on presumed amyloid removal should be suspended until this looming possibility has been fully investigated.
Hyunwoo Lee, Atri Chatterjee, Ian R A Mackenzie, Imogene Scott, Mirza Faisal Beg, Karteek Popuri, Dana Wittenberg, Rosa Rademakers, Ging-Yuek Robin Hsiung
Longitudinal behavioral and neuropsychiatric changes and their MRI correlates in predementia C9orf72 and GRN mutation carriers
Abstract: Background: Neuropsychiatric symptoms (NPS) progress differently among individuals with autosomal dominant familial frontotemporal dementia (FTD) caused by genetic mutations in granulin (GRN+) or chromosome 9 open reading frame 72 (C9orf72+). Objective: To determine whether these differences begin prior to the onset of dementia, we compared the longitudinal rates of change of NPS among C9orf72+, GRN+, and noncarrier controls in the predementia phase. Additionally, we assessed whether the NPS changes were correlated with grey matter (GM) volume loss or white matter signal abnormalities (WMSAs) on MRI. Methods: Eighty-two participants (N=10 GRN+, N=23 C9orf72+, N=49 noncarriers) were followed using various NPS rating scales for an average of 7.8 years. Group differences were compared using generalized linear mixed-effects models. GM volume and WMSA volumes were measured on 42 participants (N=8 GRN+, N=11 C9orf72+, N=23 noncarriers) who had two MRI visits. These measures were correlated with the rates of NPS score changes. Results: C9orf72+ showed higher rates of increase in the Beck Depression Inventory (BDI) total and the Iowa Scales of Personality Change (ISPC) dysexecutive disturbance scores versus noncarriers. GRN+ showed higher rates of increase in the BDI total, the ISPC total, and the emotional/social disturbance scores versus noncarriers; and higher rates of increase in the ISPC emotional/social personality and distressed disturbance scores versus C9orf72+. Across all groups, faster WMSA accumulation correlated with higher rates of increase in the Neuropsychiatric Inventory Questionnaire (NPI-Q) total score. Conclusions: Changes in NPS differ among C9orf72+, GRN+, and noncarrier controls prior to the onset of overt FTD.
Pei-Jung Lin, Abigail G Riley, Patricia G Synnott, Terry L Frangiosa, Amber Roniger, Peter J Neumann, Joshua T Cohen (Handling Associate Editor: Bernhard Michalowsky)
Health utilities in Alzheimer’s disease: A survey of patients and caregivers in the United States
Abstract: Background: The introduction of new Alzheimer’s disease (AD) treatments necessitates updated health utilities for economic evaluations. Objective: Measure health utilities of US adults with mild cognitive impairment (MCI) and AD and their caregivers. Methods: We conducted a web-based survey using the EuroQol EQ-5D-5L and Quality of Life in AD (QoL-AD), stratified by disease stage and care setting. Individuals with MCI or mild Alzheimer’s dementia self-reported their utilities. Caregivers randomly received either a proxy survey to complete on behalf of the person with moderate to severe AD they cared for, or a caregiver survey that asked them to self-report their own utilities. Results: We received 241 patient responses and 176 caregiver responses. Patient EQ-5D-5L scores decreased monotonically as disease severity increased, with a 0.55 utility difference between individuals with MCI and severe AD in the community setting. EQ-5D-5L values were generally lower for individuals residing in nursing homes (0.04 to 0.78) compared to those in community settings (0.22 to 0.77). Patients’ QoL-AD scores did not exhibit a consistent association with their disease severity. Similarly, caregivers’ EQ-5D-5L scores did not exhibit a monotonic trend with the patient’s disease severity, although caregiver utilities were generally higher for those caring for someone in a nursing home than for those caring for patients in the community. Conclusions: Our results contribute to improving AD economic evaluations by reflecting the lived experience of more contemporary populations and facilitating the value assessment of novel therapies that delay progression from MCI to more severe disease stages.
Kenichiro Sato, Yoshiki Niimi, Ryoko Ihara, Atsushi Iwata, Kazushi Suzuki, Takeshi Iwatsubo; for Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Carla Abdelnour)
Effect of corrections for renal function on plasma phosphorylated tau performance for Alzheimer’s disease
Abstract: Background: Blood-based biomarkers (BBMs), including plasma phosphorylated tau (pTau), have been considered as a promising, less-invasive tool for detecting Alzheimer’s disease (AD) pathology in real-world applications. Plasma pTau levels are known to be elevated in individuals with chronic kidney disease (CKD), which may require caution when corrected for renal function since it alters testing performance—decreased sensitivity and increased specificity. Objective: We aimed to quantify how correcting for renal function affects BBM test performance. Methods: We analyzed plasma pTau181 and pTau217 measured by multiple platforms, using data from our ongoing trial-ready cohort study in Japan and the ADNI study, in which approximately 30% of participants had mild or moderate renal impairment (eGFR < 60). We compared models with and without renal correction to predict amyloid PET positivity status. Results: Compared to no correction, adjusting for renal function reduced sensitivity by 0.06-0.07 and increased specificity by 0.04-0.10. It also slightly increased positive predictive value, negative predictive value, balanced accuracy, and area under the curve–each by less than 0.02. These shifts by correction were more pronounced when the participant prevalence of those with renal function was higher, though mainly for sensitivity and specificity. Conclusions: Our findings demonstrated that applying renal function correction decreases sensitivity and increases specificity of BBM test depending on the prevalence of renal impairment, without undermining overall prediction accuracy. They emphasize the need of considering the background characteristics of the target population when interpreting BBM performances in the real-world settings.
José A Luchsinger, Jeanne A Teresi, Lenfis Valdez, Dahiana Rosario, Maria de Miguel, Delphine Taylor, Jessica Singer, Nancy Chang, William S Fuller, Cyrus Boquín, Stephanie Silver, Joseph P Eimicke, Jian Kong, Terry E Goldberg, Davangere P Devanand
Performance of a smell identification test versus the Mini-Mental Status Exam for the detection of dementia and cognitive impairment among persons with cognitive concerns in primary care
Abstract: Background: Odor identification deficits predict Alzheimer’s disease (AD) in epidemiological studies. Objective: To compare the accuracy of a short odor identification test with a short cognitive screening test for the detection of dementia and cognitive impairment in elderly persons with cognitive concerns. Methods: This was a cross-sectional study of 600 participants 65 years and older, without known mild cognitive impairment (MCI) or dementia, with cognitive concerns, attending primary care practices in New York City. The odor identification test was the Brief Smell Identification Test (BSIT). The comparator test was the Mini Mental Status Exam II (MMSE). Cognitive diagnoses were made using the National Alzheimer’s Coordinating Center Uniform Data set (NACC-UDS) version 3 forms with slight modifications. Test performance was compared using Receiver Operating Characteristic analyses. Results: The mean age was 72.65± 6.31 years, 73.3% were female, 63.3% were Hispanic, 13.5% non-Hispanic Black, and 20.8% non-Hispanic White; 23.5% were classified as normal cognition, 27.7% as cognitive impairment-not mild cognitive impairment (MCI), 31.2% as amnestic MCI, 5.7% as non-amnestic MCI, and 12% as dementia. The MMSE was superior to the BSIT in detecting dementia and any cognitive impairment. Combining abnormal scores in the BSIT (≤8) to MMSE (≤24) improved the MMSE’s specificity and positive predictive value (PPV) in detecting cognitive impairment. Conclusions: The MMSE was superior to the BSIT in detecting dementia and cognitive impairment in primary care but using both tests improved specificity and PPV for identifying persons with subjective complaints needing further cognitive and biomarker evaluation.
Takahisa Ohta, Narumi Kojima, Sho Hatanaka, Takashi Shida, Yosuke Osuka, Hiroyuki Sasai
Value of muscle strength in improving the predictive capability for cognitive decline in older women by established risk factors: A prospective cohort study in the Otassha Study
Abstract: Background: With a growing aging global population, dementia has become an important public health concern. However, few predictive models of cognitive decline include muscle strength as a variable. Objective: This study aimed to assess whether handgrip and knee extensor muscle strengths could be associated with cognitive decline in older Japanese women and to examine the potential contribution of these measurements to established dementia onset prediction models. Methods: A prospective cohort study was conducted involving the data analyzed from 787 community-dwelling aged 65 years and older women, originally from the "Otassha Study." The baseline handgrip and knee extensor muscle strengths were measured. Cognitive decline was defined as a decrease of three or more points from the baseline score of the Japanese version of the Mini-Mental State Examination. Multivariate analyses were performed adjusting for various potential confounding factors, and interaction effects were explored. The discriminative performances of the extended models were evaluated using receiver operating characteristic (ROC) curve analysis. Results: Notably, lower handgrip and knee extensor muscle strengths were associated with cognitive decline in participants ≥ 75-year-old. Adding handgrip strength to the established models slightly improved the predictive performance, thereof; however, adding knee extensor muscle strength did not. Conclusions: Our study revealed the values of handgrip and knee extensor muscle strengths were associated with cognitive decline among women aged 75 years and older. Incorporating handgrip strength into predictive models enhanced their accuracy, which highlighted the importance of assessing muscle strength to predict cognitive decline in older women.
Ryan McGrath, Jeremy M Hamm, Bong-Jin Choi, Jagdish Singh, Donald A Jurivich, Sherri N Stastny, Chloe Carling, Jacob Kieser, Kyle J Hackney
Examining the directional associations of handgrip strength asymmetry and cognitive function in American males and females
Abstract: Background: While low handgrip strength (HGS) and cognitive impairment could be bidirectionally associated through shared neurological systems, the role of HGS asymmetry for this directional association is not well-understood in males and females. Objective: The purpose of this investigation was to determine the directional associations between HGS asymmetry and cognitive impairment in Americans by sex. Methods: The analytical sample included 5,298 male and 7,070 female participants aged at least 50-years from the 2006-2018 waves of the Health and Retirement Study. HGS was measured with a handgrip dynamometer. The highest recorded HGS on both hands were included in the quantification of HGS asymmetry. Cognitive function was assessed with the Telephone Interview of Cognitive Status. Individual generalized estimating equations evaluated the directional associations of HGS asymmetry and impaired cognitive function. Results: Categorical asymmetric HGS was associated with 1.25 (95% confidence interval (CI): 1.01-1.54) greater odds for future cognitive impairment in males. Every unit increase in continuous HGS asymmetry ratio was also associated with 1.37 (CI: 1.04-1.80) greater odds for future cognitive impairment in males. However, cognitive impairment, in males, was not significantly associated with future asymmetric HGS (odds ratio: 1.18; CI: 0.97-1.44). No significant directional associations between asymmetric HGS and impaired cognitive function were observed in females. Conclusions: Asymmetric HGS, as another marker of muscle dysfunction, may provide direction for the association between muscle and cognitive function, particularly in males. While more research is needed for examining the prognostic value of asymmetric HGS, including asymmetry is feasible in conventional HGS protocol guidelines.
Sze Kei Liu, Han Cao, Xin Yang, Xiaopu Zhou, Yu Chen, Wing-Yu Fu, San Yuen Chan, Fanny C F Ip, Kin Y Mok, Vincent C T Mok, Timothy C Y Kwok, John Hardy, Amy K Y Fu, Nancy Y Ip (Handling Associate Editor: Colin Masters)
An ABCA1 missense variant decreases cholesterol efflux and confers Alzheimer’s disease risk in the Chinese population
Abstract: Background: Genetic studies have revealed that single-nucleotide polymorphisms (SNPs) of ABCA1 are associated with Alzheimer’s disease (AD) risk. However, their AD-related effects in non-European populations are not well studied. Moreover, the functional implications of these AD-associated SNPs remain unclear. Objective: We examined the AD associations of ABCA1 SNPs in the Chinese population and investigated the underlying mechanisms whereby these SNPs modulate AD risk. Methods: We conducted a genetic analysis in a Hong Kong Chinese AD cohort (n = 332 patients with AD, n = 316 normal controls). Specifically, we analyzed 6 independent ABCA1 SNPs reported to be associated with AD risk in populations of European descent. To investigate the effects of these SNPs on ABCA1 protein function and brain molecular phenotypes, we analyzed cholesterol efflux in human glioblastoma cells as well as the associations between the AD risk SNPs and brain transcriptomic profiles, respectively. Results: The ABCA1 coding SNP, rs2230806 (p.R219K), was significantly associated with AD in the Chinese population, specifically in females (odds ratio [95% confidence interval] = 1.65 [1.16–2.33]). Notably, human glioblastoma cells expressing the ABCA1 R219K showed a 17% cholesterol efflux reduction (p < 0.001). Moreover, ABCA1 rs2230806 was associated with changes in the expression of oligodendrocyte genes involved in myelination in the brain in females. Conclusions: We identified a significant AD risk ABCA1 coding variant in the Chinese population and demonstrated its effects on cholesterol efflux and brain molecular phenotypes. These results shed light on the genetic basis whereby an ABCA1 genetic variant contributes to AD pathogenesis.
Sakura Sakakibara, Abigail Dove, Jie Guo, Giulia Grande, Ulrika Akenine, Britt-Marie Sjölund, Janne Agerholm, Erika J Laukka, Amaia Calderon-Larrañaga, Weili Xu
Formal and informal care use before, during, and after detection of cognitive impairment and dementia: A population-based matched study
Abstract: Background: Dementia is linked to increased care use, but formal and informal care use throughout the dementia journey remains unclear. Objective: To investigate care use before and after the detection of cognitive impairment, no dementia (CIND) and dementia and to identify care-related factors. Methods: Within a population-based study, we matched older adults (≥78 years) who developed CIND (n=244) and dementia (n=175) with cognitively intact participants to form CIND/intact (n=732) and dementia/intact (n=525) samples. Dementia was clinically diagnosed and CIND was determined through a neuropsychological battery. Formal (from public and private providers) and informal (provided by family and friends) care use was interviewed. Care-related factors included age, sex, education, living alone, chronic diseases, and social network. Data was analyzed using logistic regressions and linear mixed-effect models. Results: Compared to cognitively intact participants, those with CIND had increased care use 3 years after detection (odds ratio [OR] 2.30 and 2.63, 95% confidence interval [95%CI] 1.36-4.85 and 1.25-5.53) and those with dementia had greater care use over time (OR 2.01, 95% CI 1.20-3.38 to OR 13.58, 95% CI 4.46-41.34). People with CIND/dementia showed 6.3 to 32.3 hours rapid increase in informal care hours. Older age, female, living alone, and chronic diseases further increased care use. Conclusions: Formal and informal care use during the progression of cognitive impairment begins to increase at the CIND stage, but only informal care hours continue to increase. The findings highlight the complex care needs of people with cognitive impairment and the importance of coordination of care.
Yinghua Fu, Li Jiang, John A Detre, Ze Wang, for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Peiyu Huang)
Alzheimer’s disease classification using mutual information generated graph convolutional network for functional MRI
Abstract: Background: High-order cognitive functions depend on collaborative actions and information exchange between multiple brain regions. These inter-regional interactions can be characterized by mutual information (MI). Alzheimer's disease (AD) is known to affect many high-order cognitive functions, suggesting an alteration to inter-regional MI, which remains unstudied. Objective: To examine whether inter-regional MI can effectively distinguish different stages of AD from normal control (NC) through a connectome-based graph convolutional network (GCN). Methods: MI was calculated between the mean time series of each pair of brain regions, forming the connectome which was input to a multi-level connectome based GCN (MLC-GCN) to predict the different stages of AD and NC. The spatio-temporal feature extraction (STFE) in MLC-GCN was used to capture multi-level functional connectivity patterns generating connectomes. The GCN predictor learns and optimizes graph representations at each level, concatenating the representations for final classification. We validated our model on 552 subjects from ADNI and OASIS3. The MI-based model was compared to models with several different connectomes defined by Kullback-Leibler divergence, cross-entropy, cross-sample entropy, and correlation coefficient. Model performance was evaluated using 5-fold cross-validation. Results: The MI-based connectome achieved the highest prediction performance for both ADNI2 and OASIS3 where it’s accuracy/AUC/F1 were 87.72%/0.96/0.88 and 84.11%/0.96/0.91 respectively. Model visualization revealed that prominent MI features located in temporal, prefrontal, and parietal cortices. Conclusions: MI-based connectomes can reliably differentiate NC, mild cognitive impairment and AD. Compared to other four measures, MI demonstrated the best performance. The model should be further tested with other independent datasets.
Rebecca Grønning, Anna Jeppsson, Per Hellström, Kerstin Andrén, Katarina Laurell, Dan Farahmand, Henrik Zetterberg, Kaj Blennow, Carsten Wikkelsø, Mats Tullberg (Handling Associate Editor: Robert Rissman)
Postoperative changes in ventricular cerebrospinal fluid biomarkers with correlation to clinical outcome in idiopathic normal pressure hydrocephalus
Abstract: Background: Ventricular cerebrospinal fluid (CSF) was analysed peri- and postoperatively to elucidate the pathophysiology of Idiopathic normal pressure hydrocephalus (iNPH). Objective: To capture the dynamics of biomarkers and their relation to clinical symptoms. Methods: In 113 consecutively diagnosed patients, the Hellström iNPH scale was used to quantify symptom burden pre- and postoperatively. CSF was collected at shunt insertion and postoperatively by shunt reservoir puncture, and analyzed for concentrations of GFAP, YKL40, MCP-1, NfL, Aβ40, sAβPPα, sAβPPβ, GAP43, Alzheimer’s disease biomarkers Aβ42, Aβ42/40, total tau (T-tau), phosphorylated tau (P-tau), and neurogranin. Results: Concentrations increased postoperatively for Aβ40 (134%), Aβ42 (106%), sAβPPα (112%), sAβPPβ (83%), NfL (128%), YKL40 (86%), GAP43 (124%), and MCP-1 (5%) (p<0.001, MCP-1 (p=0.03)), while mean concentration reductions were seen in T-tau (32%), GFAP (31%), neurogranin (49%), and Aβ42/40 (10%) (p<0.001). A higher perioperative concentration of AβPPβ correlated with less pronounced gait disturbance (Rp 0.20 (0.01-0.38) (95% CI)), whereas higher levels of NfL (-0.23 (-0.41-(-)0.04) and MCP-1 (-0.21 (-0.37-(-)0.01)) correlated with impaired cognition. Higher MCP-1 correlated with a lower balance domain score (-0.20 (-0.37-(-)0.01)). Postoperative increases in levels of Aβ40 (Rs 0.27 (0.05-0.46)), Aβ42 (Rs 0.24 (0.02-0.44)) and YKL40 (Rs 0.22 (-0.00-0.43)) correlated with gait improvement, and a postoperative increase in Aβ40 (Rs 0.36 (0.05-0.60)) was associated with improvement in urinary continence (p 0.01 - 0.05). Conclusions: CSF biomarker concentrations change after shunt insertion. These changes, seen as increased concentrations for some biomarkers and decreased concentrations for others, are associated with improvement in core clinical symptoms and may illustrate reversibility of pathophysiological mechanisms in iNPH.
Aleksandra Ochneva, Valeriya Zakurazhnaya, Yana Zorkina, Olga Abramova, Valeriya Ushakova, Anna Tsurina, Elizaveta Golubeva, Olga Gurina, Aleksandr Berdalin, Timur Sunyakov, Alisa Andryushchenko, Marat Kurmyshev, Anna Kagramanova, Mikhail Shinkin, Nina Fadeeva, Natalia Bodunova, Georgiy Kostyuk, Anna Morozova
The increase in TDP-43 and neurogranin blood levels at different stages of cognitive impairment in elderly people: A cross-sectional study
Abstract: Background: Alzheimer's disease (AD), a neurodegenerative condition and major subtype of dementia, is often preceded by mild cognitive impairment (MCI), a transitional stage before dementia. While cerebrospinal fluid (CSF) biomarkers are widely used for diagnosing AD and MCI, blood-based biomarkers offer the advantage of easier accessibility. This study aimed to compare blood levels of nine biomarkers among healthy controls, patients with MCI, and those with dementia, and to evaluate their potential for predicting AD progression. Objective: The aim of our study was to study biomarkers in three groups of elderly people with varying degrees of cognitive decline. Methods: The study included 234 participants aged 65 and older with dementia, MCI, or no cognitive impairment. Cognitive function was assessed using the Mini-Mental State Examination scale. Plasma levels of nine biomarkers, including amyloid-β40 (Aβ40), amyloid-β42 (Aβ42), KLK-6, NCAM-1, FGF-21, neurogranin, Tau, pTau181, and TDP-43, were measured by multiplex analysis. Results: Aβ42 levels were higher in the MCI group compared to controls (p=0.002) and in dementia patients compared to those with MCI (p=0.018). TDP-43 and neurogranin levels were elevated in dementia patients compared to both the MCI group (p < 0.05 and p < 0.01, respectively) and controls (p < 0.05 and p < 0.001, respectively). Neurogranin levels were also higher in the MCI group compared to controls (p < 0.001) and significantly differed between MCI and dementia (p=0.003). Conclusions: Aβ42, TDP-43, and neurogranin show potential as blood-based biomarkers for cognitive decline and may provide insight into the pathogenesis of neurodegeneration.
Joseph Asante, Jr, Corey L Nagel, Steven W Barger
Prescription-based association of P-glycoprotein substrates with Alzheimer’s disease risk: A nested case-control study
Abstract: Background: P-glycoprotein (P-gp) is linked to Alzheimer's disease (AD), as P-gp contributes to clearance of amyloid-ꞵ (Aꞵ) from the CNS. Thus, other P-gp substrates (Pgp-S) could affect Aꞵ clearance, either negatively through competitive inhibition or positively via cooperative transport, impacting risk for AD. Objective: We probed impacts of Pgp-S on AD risk by querying AD rates among individuals prescribed medications that are considered Pgp-S. Methods: A retrospective cohort study was performed using the PharMetrics Plus database (IQVIA), encompassing 70,340 users of prescription drugs identified as Pgp-S and 352,382 Pgp-S non-users. Users and non-users were matched by age, sex, and geographical region. Cox regression models afforded adjustments for covariates and comorbidities. Results: Pgp-S use was generally associated with a significant reduction in the hazard ratio of AD in both crude (HR=0.89, 95% CI=0.79-0.99) and matched (HR=0.87; 95% CI=0.78–0.98) analyses. AD risk was higher among the subsets diagnosed with comorbidities: depression (HR=4.44; 95% CI, 3.99–4.94), stroke (HR=1.98, 95% CI=1.63–2.41), and hypertension (HR=1.24, 95% CI=1.13–1.36). In an analysis of individual drugs, digoxin (OR=0.52, 95% CI, 0.34–0.77), atorvastatin (OR=0.80, 95% CI, 0.73–0.87), omeprazole (OR=0.83, 95% CI, 0.73–0.94), and prednisone (OR=0.64, 95% CI, 0.46–0.86) were associated with significantly decreased odds of incident AD; rivaroxaban (OR=1.29, 95% CI=0.97–1.68) and mirabegron (OR=1.45, 95% CI=0.86–2.28) trended toward increased risk. Conclusions: The findings suggest an association between Pgp-S use and AD, but limitations of the study design impel additional work to confirm the direction of impact for individual drugs.
Kosei Nakamura, Kenji Tagai, Hitoshi Shinotoh, Shigeki Hirano, Soichiro Kitamura, Hironobu Endo, Keisuke Takahata, Yuhei Takado, Ming-Rong Zhang, Kazunori Kawamura, Osamu Onodera, Makoto Higuchi, Hitoshi Shimada (Handling Associate Editor: Kenjiro Ono)
Concurrent Alzheimer’s disease pathologies in Lewy body diseases affect cognition and glucose metabolism in the posterior cingulate gyrus: A multimodal PET study
Abstract: Background: Lewy body disease (LBD) is a neurodegenerative disease characterized by Lewy bodies, and it clinically presents dementia with Lewy bodies (DLB) and Parkinson’s disease (PD). Alzheimer's disease (AD) pathologies frequently coexist with LBD, complicating the clinical manifestation. Objective: We evaluated the impact of AD pathologies, including amyloid-β and tau depositions, on cognitive dysfunction and glucose metabolism in LBD using multiple positron emission tomography (PET) scans. Methods: Our study cohort consisted of 14 patients diagnosed with LBD, including five from the PD spectrum and nine from the DLB spectrum. In addition, 12 amyloid-negative cognitively healthy controls (HCs) and 13 amyloid-positive AD-spectrum patients were included. We subsequently explored the influence of amyloid and tau deposition on cognitive dysfunction and glucose metabolism among the LBD patients. Results: In the LBD group, 44.4% of the DLB patients were amyloid-positive, and all PD patients were amyloid-negative. While tau accumulation was lower than in AD and similar to HCs at the group level, tau accumulation in the AD signature region was correlated with cognitive dysfunction. Among the changes in glucose metabolism, the cingulate island sign (CIS) index was elevated compared to AD. However, as cognitive impairment progressed, the CIS index decreased, reflecting reduced metabolism in the posterior cingulate gyrus, which was closely associated with tau accumulation in the same region. Conclusions: Our findings indicate that AD pathologies, and particularly tau accumulation, significantly impact both cognitive dysfunction and glucose metabolism in LBD. This underscores the importance of addressing AD-related changes in the clinical management of LBD patients.
Leah Holm-Mercer, Tze How Mok, Danielle Sequeira, Thomas Coysh, Peter Rudge, Hawraman Ramadan, Lee Darwent, Tracy Campbell, Thomas Murphy, Colin Smith, Diane Ritchie, Sebastian Brandner, Zane Jaunmuktane, John Collinge, Simon Mead
Inherited prion disease caused by a novel frameshift mutation of PRNP resulting in protein truncation at codon 157
Abstract: Background: PrP systemic amyloidosis is increasingly recognized as a novel inherited prion disease (IPD) syndrome caused by PRNP C-terminal truncating mutations. As well as systemic manifestations they cause gradually progressive cognitive impairment with neurofibrillary tangle pathology which can be mistaken for Alzheimer’s disease (AD). Objective: We describe the clinical, biomarker and neuropathological features of a novel frameshift mutation of PRNP resulting in protein truncation at codon 157. Methods: The clinical phenotype and biomarker findings, including plasma biomarkers measured using Single Molecule Array (SiMOA) technology are reported for affected living individuals, with neuropathological examination available for the index case. Results: The Y157X PRNP mutation has resulted in a phenotype of gradually progressive cognitive decline, peripheral sensory and autonomic polyneuropathy, and gastrointestinal symptoms, with one case presenting with recurrent episodes of nausea, vomiting and electrolyte derangement requiring intensive care unit admission. Plasma biomarkers revealed an AD-like pattern with raised neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP) and phospho-tau 181 (P-tau 181) in affected individuals. On neuropathological examination there was PrP-cerebral amyloid angiopathy (CAA) and neurofibrillary tau pathology. Conclusions: We present the clinical, biomarker and pathological findings on investigation of this family and provide further evidence for the association of truncation mutations with PrP systemic amyloidosis.
Jiyeon Park, Erin L Abner, Pei Wang, Changrui Liu, Gregory Jicha, Jordan P Harp, Frederick A Schmitt, Richard J Kryscio
Estimation of events in cohort studies based on probability of cognitive impairment
Abstract: Background: Dementia and Alzheimer’s disease-causing pathologies progress slowly over decades, and participants are recruited cognitively intact, so designing studies to observe enough cases within a feasible timeframe is important. Objective: In this study, we used readily available basic predictors, age, family history, sex, and apolipoprotein E (APOE) 4 allele carriership, to generate cumulative incidence functions for serious cognitive impairments over years of follow-up. Methods: The data were taken from the University of Kentucky Alzheimer’s Disease Research Center longitudinal cohort established in 1989. The participants were recruited cognitively unimpaired and aged 60+. The probability of serious cognitive impairment was assessed using a multinomial logistic model, with age, the number of risk factors (family history and APOE4 allele) and sex as predictors. Results: We estimated that when two or more risk factors are present, the long-term incidence of clinical mild cognitive impairment and dementia is 2.3 to 2.7 times higher than that of the 0-risk group for both sexes, whereas the 0-risk group experienced approximately 7.9% to 11.6% longer observation times for female and 0.9% to 4.8% for male compared to the two or more risks group. Conclusions: This study presents the expected cumulative incidence functions over varying follow-up times, and the expected observation time of serious cognitive impairment for given family history, carriership of APOE4, age and sex.
Grant L Iverson, Pouya Jamshidi, Amy Deep-Soboslay, Thomas M Hyde, Joel E Kleinman, Lili-Naz Hazrati, Rudolph J Castellani (Handling Editor: Paula Moreira)
Postmortem tau in the CA2 region of the hippocampus in older adult men who participated in youth amateur American-style football
Abstract: Background: Researchers have reported that hyperphosphorylated tau (p-tau) accumulates in the Cornu Ammonis 2 subfield (CA2) of the hippocampus with age, preferentially in primary age-related tau astrogliopathy, in association with early Alzheimer’s disease, and preferentially in chronic traumatic encephalopathy neuropathologic change. Objective: Examine the possible association between preferential p-tau in the CA2 region of the hippocampus and history of playing high school American-style football. Methods: Postmortem brain tissue samples were obtained from the Lieber Institute for Brain Development for 174 men (median age at death=65 years; range=50-96). There were 126 with no known history of participation in contact or collision sports and 48 (27.6%) who participated in football. Results: Approximately half were rated modified Braak stage I (47.1%) and modified CERAD stage 0 (52.0%). Preferential CA2 p-tau was present in 29.9%. The average age for those with versus without preferential CA2 p-tau was 75 and 63, respectively (Cohen’s d=-1.27, large effect). The sport history groups did not differ in age (p=0.607). In both univariate and multivariate logistic regressions, older age groups (odds ratio [OR]=3.42 and 3.23) and those with greater modified CERAD scores (OR=1.78 and 1.48) were significantly more likely to have preferential CA2 p-tau. There was not a significant association between football participation and preferential CA2 p-tau. Conclusions: There was not a significant association between participation in high school football and preferential CA2 p-tau identified after death. These results support other theories in the literature—that preferential CA2 p-tau is associated with aging and with Alzheimer’s disease neuropathologic change.
Shaun Eslick, Grace Austin, Jessica J A Ferguson, Manohar L Garg, Christopher Oldmeadow, Ralph N Martins
Blood biomarkers of Alzheimer’s disease in Australians habitually consuming various plant-based diets
Abstract: Background: Evidence suggests that plant-based diets (PBDs) may be protective against neurodegenerative diseases such as Alzheimer’s disease (AD). Objective: This study examined associations between blood-based AD biomarkers in individuals 30-75 years without current or diagnosed CVD following different PBDs versus regular meat-eating diets (RMEs). Methods: This secondary analysis of the Plant-based Diets study measured Aβ1-42/Aβ1-40, p-tau181, NFL, and GFAP in 237 plasma samples using SIMOA from individuals following vegan, pesco-vegetarian (PVs), lacto-ovo vegetarian (LOVs), semi-vegetarian (SVs), or RME diets. Multivariable regression adjusted for age and sex. Results: Following adjustments for age and sex, plasma Aβ1-42/Aβ1-40 ratio was significantly higher in PVs 0.011 (CI: 0.006, 0.016, p < 0.01), LOVs 0.011 (CI: 0.007, 0.016, p < 0.01) and SVs 0.015 (0.009-0.020, p < 0.01) groups compared to RMEs. Plasma p-tau181 was significantly higher in PVs 3.4 (CI: 0.4-6.4, p < 0.05) and LOVs 7.1 (CI: 2.5, 11.8, p < 0.01), NFL higher in PVs 5.2 (CI: 1.6, 8.7, p < 0.01) and LOVs 4.0 (CI: 1.6, 6.5, p = 0.01), and GFAP higher in PVs 26 (CI: 6, 47, p < 0.05) and LOVs 21 (5, 367, p = 0.01), all compared to RMEs. Conclusions: This analysis suggests that PBDs may be associated with blood-based AD biomarkers. Higher Aβ1-42/Aβ1-40 levels in PV, LOV and SV dietary patterns compared to RMEs could indicate lesser amyloid burden, but elevated levels of other AD biomarkers in some PBDs warrant further investigation into nutrient-specific roles in AD pathology.
Virginia G Wadley, Yue Zhang, Tyler Bull, Cheyanne Barba, Yvonne Bolaji, R Nick Bryan, Michael Crowe, Lisa Desiderio, Guray Erus, David S Geldmacher, Rodney Go, Caroline L Lassen-Greene, Olga A Mamaeva, Daniel C Marson, Marianne McLaughlin, Ilya M Nasrallah, Cynthia Owsley, Jesse Passler, Rodney T Perry, Giovanna Pilonieta, Kayla A Steward, Andrea Wood, Richard E Kennedy (Handling Associate Editor: Ozioma Okonkwo)
Daily function outcomes in adults with mild cognitive impairment due to Alzheimer’s disease after two years of processing speed training versus a control training protocol
Abstract: Background: Cognitive processing speed is integral to everyday activities and can be improved with training in persons with mild cognitive impairment (MCI). However, whether this training maintains everyday abilities is not known. Objective: We aimed to determine whether everyday functions key to independence could be preserved with two years of processing speed training. Methods: In a randomized controlled trial, we objectively evaluated a processing speed training protocol compared to a control training protocol, in 103 persons with MCI (n = 90) or very mild dementia (n = 13) due to Alzheimer’s disease (AD). Each protocol involved serial assessments, laboratory training, and home training over a two-year period. We accounted for APOE ε4 carrier status and MRI-based neurodegeneration conducted at baseline. Outcomes were longitudinal changes in performance-based Instrumental Activities of Daily Living (IADLs), community mobility, and on-road driving. We used linear mixed models to evaluate changes in these outcomes over time. Results: Changes in IADL function, driving, and community mobility did not differ by training assignment. Greater baseline neurodegeneration predicted larger declines in all functional outcomes (p values < 0.001). Conclusions: In persons with MCI or very mild dementia, processing speed training was no more effective for maintaining everyday functions than training involving common computer activities and games that do not target processing speed. Greater baseline neurodegeneration predicted worse performance over time on all measures of function.
T Rune Nielsen, Kasper Jørgensen, Alfonso Delgado-Álvarez, Sanne Franzen, Alvaro Lozano-Ruiz, Maria Özden, Juliette Palisson, Naaheed Mukadam, Gunhild Waldemar
Comparison of the diagnostic accuracy of five cross-cultural cognitive screening instruments for dementia and mild cognitive impairment in a multicultural memory clinic sample
Abstract: Background: With the changing demographic landscape in most countries worldwide, early identification of cognitive impairment in multicultural populations is increasingly relevant. Objective: To compare the diagnostic accuracy of the Brief Assessment of Impaired Cognition (BASIC), BASIC Questionnaire (BASIC-Q), Category Cued Memory Test (CCMT), Multicultural Cognitive Examination (MCE), and Rowland Universal Dementia Assessment Scale (RUDAS) for dementia and mild cognitive impairment (MCI) in a multicultural memory clinic sample. Methods: The study was a cross-sectional multi-center study across six sites in five European countries. All cognitive screening instruments were available in the majority languages of the collaborating countries. Participants with immigrant status were generally assessed in their first language by multilingual researchers or through interpreter-mediated assessment. Correlation analysis was used to explore associations between scores on the cognitive screening instruments. Receiver operating characteristic curve (ROC) analysis was used to examine diagnostic accuracy for dementia and MCI as compared to specialist diagnosis. Results: The study included 187 participants (94 cognitively intact, 36 MCI, 57 dementia), of which 105 (56%) had immigrant background. All cognitive screening instruments were strongly correlated and had high diagnostic accuracy for dementia (areas under the ROC curve (AUCs) in the range 0.86 - 0.97) and moderate to high diagnostic accuracy for MCI (AUCs in the range 0.72 - 0.86), with the MCE, BASIC, and BASIC-Q showing the best diagnostic properties. Overall, diagnostic accuracy for cognitive impairment (dementia or MCI) did not significantly differ between European native-born and immigrant participants, or between participants with < 7 compared to ≥ 7 years of formal schooling. Conclusions: In the present study, the MCE, BASIC, and BASIC-Q showed better diagnostic properties than the RUDAS and CCMT for the diagnosis of dementia and MCI in a multicultural memory clinic sample.
Ming Cheng#, Ya-Dong Wei#, Xin Zheng, Xin-Ran Gao, Huai-Zhi Sun, Jin-Fang Ge #These authors contributed equally to this work.
Bibliometric analysis of the interplay between Alzheimer’s disease and type 2 diabetes mellitus: Trends, hotspots, and emerging research areas
Abstract: Background: Type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD) are major global health concerns, characterized by rising prevalence, high healthcare costs, and significant reductions in patients’ quality of life. Emerging evidence suggests that individuals with T2DM have nearly double the risk of developing AD, potentially due to overlapping mechanisms such as insulin resistance, oxidative stress, and neuroinflammation. Objective: This study aims to systematically explore the evolving research landscape at the intersection of T2DM and AD over the past two decades, identifying major contributors, shifting research focuses, and emerging trends to inform future investigations and therapeutic development. Methods: A comprehensive bibliometric analysis was conducted using data retrieved from the Web of Science Core Collection (WoSCC) spanning 2000 to 2024. A total of 3087 publications were analyzed using CiteSpace and the R package bibliometrix to assess publication trends, collaborative networks, and thematic evolution. Results: The number of publications has steadily increased, with the United States and China emerging as dominant contributors. Institutions such as the University of California and Harvard University led in productivity and influence. Early research emphasized broad risk factors and cardiovascular comorbidities, while recent studies have shifted toward molecular mechanisms, particularly insulin resistance, neurodegeneration, and oxidative stress. Conclusions: This 24-year bibliometric overview reveals a dynamic and expanding research field linking T2DM and AD. The findings highlight key geographic and institutional contributors, evolving thematic foci, and knowledge gaps, offering a valuable foundation for future research and potential therapeutic innovations.
Chathura Siriwardhana, Enrique Carrazana, Kore Liow
Racial and socioeconomic influences on the interplay between Alzheimer’s disease-related dementia and cardio-cerebrovascular disease in an aging population
Abstract: Background: Cardio and cerebrovascular disease (CVD) and Alzheimer’s Disease-Related Dementia (ADRD) significantly impact older adult populations, with interlinked pathways influencing risk and progression. In Hawaii, where over 20% of the population is 65 or older and ethnic diversity is among the highest in the U.S., the relationship between ADRD and CVD requires closer examination, especially concerning racial and socioeconomic factors. Objective: This study aims to assess the effects of race, ethnicity, and socioeconomic status on the bidirectional risk pathways between ADRD and CVD among older populations in Hawaii. Methods: Utilizing a multistate modeling framework, we analyzed nine years of longitudinal Medicare data to track transitions between ADRD, CVD, and mortality outcomes. We investigated associations among racial and ethnic groups, including Native Hawaiian and other Pacific Islander (NHPI), Asian Americans (AA) and white populations, accounting for socioeconomic status to identify disparities in risk progression and outcomes. Results: The analysis revealed notable racial and socioeconomic disparities in the transitions between ADRD, heart disease (HD), Stroke, and mortality among Hawaii's older population. Overall, lower socioeconomic status indicates increased risks for transitioning to more severe clinical states and mortality. However, such effects were found to be varied among races: AA, NHPI, and whites. Our findings suggest that socioeconomic status modifies the ADRD, HD, Stroke progression dynamics across different ethnicities. Conclusions: This study highlights the significant role of race/ethnicity and socioeconomic status in the complex progression of ADRD and CVD.
Logan S Richards, Stephanie Kim, Hannah K Cho, Catherine M Cahill, Jack T Rogers, HyunDae D Cho
Targeting α-synuclein translation: Novel PROTEIMERs as 5’-UTR directed inhibitors
Abstract: Background: Amyloid aggregation of α-Synuclein is a defining feature of several neurodegenerative disorders, including Parkinson’s disease (PD), Lewy body dementia (LBD), and Alzheimer’s disease (AD). While there have been many attempts to reduce the α-Synuclein burden of neuronal cells through direct targeting of the protein, the conformationally dynamic nature of α-Synuclein make it a particularly difficult target to drug. Given the correlation between α-Synuclein levels and both familial and environmentally induced synucleinopathies, targeting the α-Synuclein mRNA transcript offers an alternative therapeutic avenue. Objective: To develop and evaluate protein-based RNA-binding therapeutics (PROTEIMERs) that selectively bind the 5′ untranslated region (UTR) of α-Synuclein mRNA and inhibit its translation to reduce α-Synuclein levels. Methods: We employed high-throughput phage display to identify novel RNA-binding PROTEIMER candidates targeting the 5′UTR of α-Synuclein mRNA. Binding affinities were assessed via surface plasmon resonance (SPR). Computational structural predictions were used to evaluate PROTEIMER-RNA interactions relative to known regulatory proteins IRP1 and IRP2. RNase domains were fused to the lead PROTEIMERs, and their RNA degradation activity was tested in vitro. Results: Three PROTEIMERs were identified that bind the α-Synuclein 5′UTR with high affinity. Structural predictions supported specific interactions with the structured RNA region. RNase-fused PROTEIMERs demonstrated targeted RNA degradation and induced decay of α-Synuclein mRNA in vitro, indicating translational suppression capability. Conclusions: Our findings demonstrate the feasibility of using engineered protein therapeutics to target α-Synuclein mRNA via the 5′UTR. These PROTEIMERs represent a promising new strategy for reducing α-Synuclein levels and mitigating neurodegenerative progression in LBD, PD, and AD.
Yong-Jin Park, Sang Won Seo, Seong Hye Choi, So Young Moon, Sang Joon Son, Chang Hyung Hong, Young-Sil An
Machine learning-based prediction of amyloid positivity using early-phase F-18 flutemetamol PET
Abstract: Background: Previous studies have suggested that early-phase imaging of amyloid positron emission tomography (PET) may offer information for predicting amyloid positivity. Objective: This study aimed to evaluate whether early-phase fluorine-18 flutemetamol (eFMM) PET images provide valuable information for predicting amyloid positivity using machine learning (ML) models and whether incorporating clinical and neuropsychological features improves predictive performance. Methods: In total, 454 patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD) were enrolled and randomly divided into training (n = 354) and test (n = 100) groups. We developed ML models using logistic regression (LR) and linear discriminant analyses (LDA) for predicting amyloid positivity: eFMM features alone (eFMM model), eFMM features combined with clinical features (eFMM + C model), eFMM features combined with neuropsychological features (eFMM + N model), eFMM features combined with both clinical and neuropsychological features (eFMM + C + N model), clinical and neuropsychological features combined (C + N model), and dFMM features alone (dFMM model). Results: In the test group, the eFMM models achieved areas under the receiver operating characteristic curves (AUROCs) of 0.791 (LR) and 0.779 (LDA). The eFMM + C + N models significantly improved predictive performance, with AUROCs of 0.902 for both LR and LDA, outperforming the eFMM models. Conclusions: ML predictive models using eFMM PET data demonstrated fair performance in predicting amyloid positivity in patients with MCI and AD. The addition of relevant clinical and neuropsychological features further enhanced the predictive performance of the eFMM models, achieving excellent performance.
Book Review
Living the Examined Life. A review of Ninety- Nine Lessons in Critical Thinking by Robert P. Friedland, 2025, Oxford University Press, 2025, 285 pp. Reviewed by Adhishree Chidambaram and George Perry
