Background and Purpose:Gait dysfunctions have been frequently observed in patients with Alzheimer's disease (AD). Previous studies have used various methods to assess the gait impairment in AD. Here, we developed a wearable gait sensor, a Smart-insole, which is embedded in shoe insoles. We evaluated whether gait parameters measured using the Smart-insole were associated with cognitive performance in patients with AD. Methods:Participants aged 45-90 years, who were either cognitively unimpaired (CU) or had Alzheimer's disease dementia (ADD) were recruited from a hospital-based outpatient clinic, between January and December 2023. Participants performed three gait tasks (walk straight and turn test, timed up and go test, and ramp and stair test) while wearing the Smart-insole. The association of gait parameters with individual's cognitive status (CU vs. ADD) and cognitive test scores (Mini-Mental State Examination [MMSE] and various domain-specific cognitive tests from the Seoul Neuropsychological Screening Battery, 2nd Edition) was assessed. Results:Patients with ADD demonstrated decreased gait pace, rhythm, and stability as evidenced by longer task, cycle, and stance times, a higher number of steps, greater variability in swing time, and lower cadence during the gait task. Furthermore, gait parameters showed nominal associations with individual's MMSE score and each cognitive domain score (fronto-executive, memory, and language function). Conclusions:Smart-insole wearable sensors showed exploratory gait-related alterations in patients with ADD. These hypothesis-generating findings suggest that wearable insole-based gait assessment may provide complementary information for characterizing gait and cognitive dysfunction in ADD.
Alzheimer disease (AD) is no longer viewed only as a clinical syndrome of memory impairment but as a biological disease continuum driven by interacting amyloid-β, tau, glial, vascular, metabolic, and synaptic mechanisms. This shift has practical therapeutic consequences. Symptomatic agents such as cholinesterase inhibitors and memantine remain useful for selected patients, but they do not directly modify the core neurodegenerative process. In contrast, amyloid-β monoclonal antibodies have provided proof that biomarker-confirmed early AD can be slowed, although the magnitude of clinical benefit is modest, treatment is restricted to carefully selected patients, and amyloid-related imaging abnormalities require structured monitoring. Tau pathology, neuroinflammation, blood-brain barrier dysfunction, mitochondrial and oxidative stress, and impaired proteostasis are therefore increasingly important druggable axes rather than secondary background phenomena. A staged, biomarker-guided druggability framework can evaluate each target by biological proximity to clinical decline, biomarker measurability, therapeutic modifiability, implementation feasibility, and suitability for sequencing or combination therapy. Validated and emerging targets are summarized with emphasis on how biomarkers reshape patient selection and outcome assessment and how anti-amyloid therapy can be integrated with stage-specific interventions targeting tau propagation, glial activation, vascular injury, clearance failure, and metabolic vulnerability. The central conclusion is that AD drug development should move from a single-target rescue model toward biomarker-guided, mechanism-matched, and combination-ready strategies that can be tested earlier in the disease course while maintaining realistic safety and implementation standards.
Magnetic resonance imaging (MRI)-based artificial intelligence (AI) models are increasingly applied to brain MRI for diagnosing Alzheimer's disease (AD) and mild cognitive impairment (MCI), but their overall diagnostic performance remains unclear. We systematically searched PubMed/MEDLINE, Embase, Web of Science, Scopus, and IEEE Xplore until February 15, 2026, for diagnostic accuracy studies of machine-learning or deep-learning models using structural brain MRI to distinguish AD vs. cognitively normal (CN) controls and MCI or late mild cognitive impairment (LMCI) vs. CN controls. Seven studies met inclusion criteria, contributing five AD vs. CN and two MCI/LMCI vs. CN tasks, predominantly using deep-learning architectures applied to Alzheimer's Disease Neuroimaging Initiative cohorts. For AD vs. CN (five studies), pooled sensitivity was 0.96 (95% confidence interval [CI], 0.93-0.97) and pooled specificity was 0.95 (95% CI, 0.92-0.97), indicating excellent discrimination. For MCI/LMCI vs. CN (two studies), sensitivity was consistently high (0.91-0.93), whereas specificity varied widely (0.54-0.98), limiting the interpretability of pooled estimates. MRI-based AI models therefore show strong performance for established AD but heterogeneous specificity for MCI, underscoring the need for larger, externally validated studies in diverse populations.
Background and Purpose:The Korean-Montreal Cognitive Assessment (K-MoCA) is widely used for cognitive screening, but its normative data require updating to reflect current demographic characteristics. Norms are also unavailable for the K-MoCA domain index scores and the K-MoCA-22. This study aimed to update norms for the K-MoCA total score and to establish norms for the six domain index scores and the K-MoCA-22. Methods:A nationwide normative sample of 1,177 cognitively healthy adults aged 19-90 years completed the K-MoCA and the Korean-Mini Mental State Examination, Second Edition: Standard Version (K-MMSE~2:SV). Six domain index scores and K-MoCA-22 scores were derived from the K-MoCA. Demographic effects and score distributions were examined. Ordinary least-squares regression modeled the K-MoCA and K-MoCA-22 scores, while quantile regression modeled the domain index scores. Results:K-MoCA and K-MoCA-22 performance was primarily influenced by age and education, with sex contributing little independent variance. Compared with the K-MMSE~2:SV, the K-MoCA showed a broader score distribution and a smaller ceiling effect. Among domain index scores, the Memory Index Score showed the broadest distribution and the smallest ceiling effect. The K-MoCA-22 showed improved distributional characteristics relative to the K-MoCA, with reduced negative skewness. Age- and education-specific norms were established for all measures. Conclusions:This study provides updated age- and education-adjusted norms for the K-MoCA, along with the first Korean norms for its domain index scores and the K-MoCA-22. These norms extend the K-MoCA's clinical utility by enabling age- and education-adjusted interpretation of global and domain-specific cognitive performance in clinical practice and research.
Background and Purpose:Given the irreversible nature of dementia, this study examined the effects of a 20-week exercise-based dementia prevention program in community-dwelling older adults, focusing on prior exercise experience and program adherence. Methods:In this exploratory, non-randomized trial, 55 older adults (65-79 years) were allocated to an intervention (n=26) or control (n=29) group, and blinding was not feasible. The intervention comprised supervised rhythmic aerobic exercise with cognitive-motor components performed three times per week. Cognition was the primary outcome, and secondary outcomes included physical fitness, blood pressure, and blood biomarkers. Subgroup analyses classified participants by prior exercise experience and intervention exposure: G1 and G2 comprised control subgroups with no intervention exposure, whereas G3 and G4 comprised intervention-exposed subgroups stratified by adherence. Results:No significant group-by-time interactions were observed for cognitive outcomes. Participants with prior exercise experience and low adherence (G2) showed significant improvement on the Korean Mini-Mental State Examination (β=1.66, p=0.024) despite declines in physical fitness, whereas higher adherence in G3-G4 was associated with stable or favorable physical performance, with G4 showing a positive trend in the 30-second sit-to-stand test. Systolic blood pressure decreased significantly in G2-G4. Conclusions:Although overall cognitive gains were modest and not group specific, prior exercise experience and sustained adherence were associated with favorable changes in physical fitness and vascular outcomes, suggesting that tailored multicomponent exercise programs and long-term engagement may help promote cognitive health in older adults.
Background and Purpose:Amyloid positron emission tomography (PET) is a crucial diagnostic tool for Alzheimer's disease (AD), but its application is constrained by cost and accessibility. This study aimed to create a practical composite index to predict cerebral amyloid positivity in patients with cognitive impairment. Methods:We included patients with mild cognitive impairment or early-stage AD who underwent amyloid PET. Various combinations of clinical and imaging variables were assessed through receiver operating characteristic analysis to identify the optimal model for predicting amyloid positivity. The Amyloid Beta Composite (ABC) index, a risk scoring model, was developed using logistic regression and a weighted scoring system. We evaluated the ABC index's performance based on accuracy, sensitivity, and specificity, and conducted internal validation using a chronological split-sample from the same cohort. Results:We analyzed a total of 223 patients. The best-performing model incorporated five variables: Mini-Mental State Examination (MMSE), secondary memory recall from the modified MMSE, Clinical Dementia Rating-Sum of Boxes, medial temporal lobe atrophy, and apolipoprotein E genotype. This model demonstrated excellent performance in the development group (area under the curve [AUC], 0.88; 95% confidence interval, 0.82-0.94). In the validation group, the ABC index achieved an AUC of 0.74, with an accuracy of 0.70, sensitivity of 0.63, and specificity of 0.78. Conclusions:The ABC index, utilizing commonly accessible clinical data, serves as a simple and practical screening tool for predicting cerebral amyloid deposition. It may aid in patient selection for amyloid PET, anti-amyloid therapies, and clinical trials, thereby reducing unnecessary imaging.
Background and Purpose:To assess the long-term effectiveness, safety, and economic viability of recently approved Alzheimer's disease (AD) therapies, as well as to evaluate the real-world application of novel diagnostics among AD patients with diverse comorbidities, comprehensive real-world data (RWD) analysis is essential. The Korean JOint RegistrY for ALZheimer's Treatment and Diagnostics (JOY-ALZ) endeavors to create a registry of RWD derived from clinical practice on new diagnostic methods and therapeutic agents for AD introduced in Korea since 2021. Methods:Participants must fulfill all the following: 1) be at least 19 years old; 2) be actively receiving, scheduled to initiate, or undergoing evaluation for any AD disease-modifying treatment; 3) have completed amyloid positron emission tomography or cerebrospinal fluid AD immunoassay (a positive result is not essential for participation); 4) have a clinical classification of cognitively unimpaired, mild cognitive impairment, or probable AD dementia. Data generated during routine care is segmented into a minimum dataset, extended dataset, and research-only dataset requiring extra consent. Assessments encompass clinical, cognitive, functional, neurobehavioral, neuroimaging, and biomarker evaluations, in addition to systematic monitoring of new AD treatments and their safety. Data are collected and monitored at baseline, at semiannual intervals during the initial 2 years, and then annually up to 2034. To date, 46 medical centers will participate in JOY-ALZ. Conclusions:JOY-ALZ is expected to promote understanding of the long-term clinical outcomes, safety, and cost-effectiveness of recently introduced diagnostics and treatments for AD, thereby supporting the progress of precision medicine in AD care and diagnosis. Trial Registration:ClinicalTrials.gov Identifier: NCT06889818.
Alzheimer's disease (AD), the primary cause of dementia accounting for 60% to 70% of cases globally, results in a gradual decline in cognitive abilities, affecting memory, executive function, and daily activities. Recent research highlights the essential involvement of the microbiota-gut-brain axis in AD pathogenesis, characterized by complex bidirectional signaling that modulates neuroinflammation, neurogenesis, neurotransmission, and immune functions. This manuscript extends the discussion beyond the gut alone by emphasizing the significance of the oral-gut microbiota axis as a dynamic and relatively under-investigated factor in AD progression. Microbial populations in both the oral cavity and gastrointestinal tract produce key neurotransmitters, such as gamma-aminobutyric acid, noradrenaline, and dopamine, as well as neuroactive metabolites like short-chain fatty acids, which together impact brain physiology. Disturbances in gut and oral microbial balance can compromise barrier integrity, promoting systemic inflammation and neuroinflammation, and facilitating amyloid-β plaque formation and tau-related changes typical of AD. This review introduces a novel probiotic, prebiotics, synbiotics, and postbiotics (PPSP) therapeutic model designed to modulate both oral and gut microbiota, aiming to restore homeostasis, regulate neuroimmune interactions, and counteract cognitive impairment. We comprehensively assess emerging clinical and translational findings supporting the effectiveness of microbiota-targeted therapies in the scope of this dual-axis framework, addressing both their potential to alter disease course and recognized limitations. By underscoring the importance of the integrated oral-gut microbiota axis alongside targeted PPSP interventions, this manuscript puts forth a paradigm-shifting conceptual strategy that may redefine approaches to AD management and improve cognitive outcomes.
Background and Purpose:The Cognitive Impairment Screening Test (CIST) was developed for use at the Community Dementia Reassurance Center in South Korea. This study evaluated convergent and discriminant validity of CIST, as well as its clinical utility in identifying cognitive impairment and differentiating amyloid deposition. Methods:We enrolled 252 participants from a hospital memory clinic (47 cognitively unimpaired [CU], 116 amnestic mild cognitive impairment, and 89 dementia). Participants completed CIST, K-MMSE-2, the Seoul Neuropsychological Screening Battery, 2nd edition (SNSB-II), and underwent amyloid positron emission tomography. To evaluate the convergent and discriminant validity of CIST, we conducted correlation analyses with SNSB-II. Receiver operating characteristic analyses were used to evaluate the ability to discriminate cognitive impairment and to distinguish amyloid positivity. Areas under the curve (AUCs) for CIST and K-MMSE-2 were compared using DeLong's test. Results:The total score of CIST correlated significantly with all SNSB-II subtests, and the domain scores of CIST showed stronger associations with corresponding SNSB-II subtests than with unrelated ones. Both CIST and K-MMSE-2 effectively distinguished cognitively impaired individuals from CU, with CIST demonstrating superior discrimination (AUC=0.926 vs. 0.887, p=0.042). In the non-demented group, both CIST and K-MMSE-2 showed acceptable discrimination for amyloid positivity (AUC≈0.73), with high specificity but low sensitivity; however, there were no significant differences between the two tests. Conclusions:The CIST demonstrated strong validity and discriminatory ability for detecting cognitive impairment. It also showed acceptable discrimination for amyloid positivity in non-demented participants, supporting its utility as a screening tool in both clinical and community settings.
Background and Purpose:Clinicians typically use 2 methods to determine impairment in a specific cognitive domain based on the Seoul Neuropsychological Screening Battery, 2nd Edition: (1) identifying impairment when one or more subtests fall below the normal range (< mean -1.5 standard deviation), and (2) using the cognitive domain score. Because agreement between these methods may differ by the severity of cognitive impairment, this study examined their concordance in the overall sample and across Clinical Dementia Rating (CDR) levels. Methods:A total of 1,086 patients (age 74.27±9.62 years; education 9.07±4.77 years) were included. Concordance between subtest-based and domain score-based classifications was assessed for each cognitive domain using cross-tabulation analyses and Cohen's kappa statistics. To assess the influence of the severity of cognitive impairment, analyses were conducted across CDR levels. Results:When impairment was defined as having at least one abnormal subtest, concordance rates were 90.8% for Attention, 88.8% for Language, 84.6% for Visuospatial Function, 74.3% for Memory, and 73.6% for Frontal/Executive Function. In the Frontal/Executive Function domain, requiring 2 or more abnormal subtests increased concordance to 90.9%. CDR subgroup analyses showed that Memory concordance was particularly low in the CDR 0.5 group (65.8%) compared with the CDR 1 (85.5%) and CDR 2 (98.5%) groups. Conclusions:Concordance between the 2 classification methods was moderately high for Attention, Language, and Visuospatial Function but substantially lower for Memory and Frontal/Executive Function, especially in individuals with mild cognitive impairment. These findings highlight the need to consider both subtest-level performance and domain scores when determining impairment in memory or frontal/executive function.
Background and Purpose:Tailored physical exercise interventions have the potential to promote cognitive health in older adults and offer significant advantages for those more vulnerable to decline. The specific relationship between physical fitness and cognition among the elderly has not been clearly established. The purpose of this investigation was to assess the relationship between physical fitness and cognitive function in older Korean adults. Methods:Eighty-four community-dwelling older adults (mean age: 70.7±5.3 years; 81.0% female) completed a standardized physical fitness battery assessing handgrip strength, sit-and-reach, 30-second sit-to-stand, 2-minute stationary march, 3-m sit-walk-and-return, figure-8-walk, and T-wall response time. Cognitive function was evaluated using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Descriptive statistics, partial correlation analyses, and stepwise multiple linear regression were conducted. Results:Slower T-wall response time was significantly correlated with lower RBANS total index, immediate memory, and delayed memory scores. In regression models, slower T-wall response time was independently associated with lower RBANS total index (β=-0.234, p=0.026) and delayed memory scores (β=-0.295, p=0.029). The regression model for immediate memory was not statistically significant overall; therefore, no predictive conclusion was drawn for this domain. Higher education showed a significant positive association with cognitive performance. Conclusions:Coordination, as measured by T-wall response time, emerged as the only physical fitness component consistently associated with cognitive performance in older adults. Coordination-related fitness may be an important correlate of cognitive function in older adults and a promising target for future exercise interventions.
Background and Purpose:The Seoul Cognitive Status Test (SCST) is a brief (~30 minutes), tablet-based battery that yields domain-specific and composite scores and uses automated scoring for rapid result generation, reduced examiner burden, and scalability for large or longitudinal assessments. We evaluated the SCST's psychometric and diagnostic performance against multidisciplinary final clinical diagnoses derived from a multidimensional workup. Methods:We conducted a cross-sectional diagnostic study of 777 outpatients (SCST-Seoul Neuropsychological Screening Battery [SNSB] n=639; SCST-Consortium to Establish a Registry for Alzheimer's Disease [CERAD] n=138) who underwent standardized diagnostic evaluation; multidisciplinary final diagnoses served as the reference. Participants completed the SCST and either the Korean version of CERAD (CERAD-K) or SNSB-second edition (SNSB-II). We assessed convergent validity of SCST subtests with traditional measures and compared SCST composite scores and classifications with reference diagnoses. Results:Pearson correlations between SCST subtests and corresponding CERAD-K/SNSB-II measures were all significant (p<0.001), with key domain correlations ≥0.7 (language, memory, executive). In the pooled sample, covariate-adjusted receiver operating characteristic area under the curves (AUCs) for the SCST composite ranged from 0.854 (cognitively unimpaired [CU] vs. mild cognitive impairment [MCI]) to 0.980 (CU vs. dementia); AUC for CU vs. cognitively impaired [CI] was 0.903. SCST-based classification sensitivity was 0.859 (CU vs. CI), 0.984 (CU vs. dementia), 0.758 (CU vs. MCI), 0.896 (MCI vs. dementia), and 0.882 (no dementia vs. dementia). Conclusions:These findings support the SCST's clinical utility; further studies in broader community-based cohorts are warranted to confirm generalizability.
Background and Purpose:The quality of life (QoL) of individuals with dementia is influenced by their ability to perform activities of daily living (ADLs), social engagement, and emotional well-being. Instrumental ADLs (IADLs) decline even in early stages, while basic ADLs (BADLs) are significantly affected in advanced stages. This study examined whether a home-based occupational therapy intervention improves QoL in people with dementia, reduces caregiver burden, depression, and anxiety, and enhances BADL performance. Methods:Forty-nine participants with moderate to severe dementia were assigned to an intervention group (n=26, mean age 83.5±5.0 years, t=2.63, p=0.011) or a control group (n=23, mean age 80.0±4.2 years). QoL was assessed using the QoL in Alzheimer's disease (QoL-AD) and QoL in late-stage dementia (QUALID) scales. The intervention group received a 3-month standardized home-based occupational therapy program (12 individualized sessions) focused on BADL training, in addition to ongoing support from the Greek Alzheimer's Disease Association. The control group received only standard support. Caregivers in both groups participated in counseling or standard support sessions, respectively. Results:Significant improvements were observed in patients' QoL (QoL-AD, p=0.008; QUALID, p=0.009) and in caregivers' anxiety and depression (p<0.001). No significant effects were found for BADL performance (p=0.857) or caregiver burden (p=0.773). Conclusions:Home-based standardized occupational therapy interventions enhance the quality of life and emotional well-being of individuals with moderate to severe dementia and improve caregiver mental health, highlighting their crucial role in community dementia care.
The International Conference of the Korean Dementia Association (IC-KDA) 2025 was held jointly with the 19th International Congress of the Asian Society Against Dementia (ASAD) in Seoul, South Korea (May 8-10, 2025), under the theme "Breaking Barriers of Dementia: From Research to Real-world Practice." The program opened with a Pre-Conference Symposium on "Dementia Treatment Update: Lecanemab and NPH" featuring 14 speakers, followed by the main meeting comprising 3 plenary sessions (5 speakers), 7 luncheon-symposium presentations, 16 parallel symposia (48 speakers), a special symposium (2 speakers), and 4 oral-presentation sessions (20 presenters). The congress was attended by 1,052 participants from 27 countries and included 213 poster presentations. Scientific highlights spanned the continuum from discovery to implementation: plasma and imaging biomarkers, retinal and electroencephalogram/voice-based digital biomarkers, and multimodal neuroimaging for risk stratification and outcome prediction; updates on anti-amyloid monoclonal antibodies (MABs) (lecanemab, donanemab), safety/amyloid-related imaging abnormalities management, and real-world data frameworks; mechanistic and multi-omics insights (genetics, metabolomics, epigenomics, transcriptomics); neuroinflammation and glia-mediated pathways; young-onset dementia cohorts across Asia-Pacific; vascular cognitive impairment trials and pathophysiology; neuropsychiatric symptoms and evidence-based behavioral and psychological symptoms of dementia care; lifestyle and multidomain prevention (Mediterranean-Dietary Approaches to Stop Hypertension (DASH) Intervention for Neurodegenerative Delay-based interventions); dementia-friendly communities and caregiver support; and emerging neuromodulation modalities (low-intensity ultrasound, photobiomodulation, vagus nerve stimulation). Together, the joint IC-KDA & ASAD 2025 meeting emphasized precision medicine and implementation science, bridging laboratory advances with clinical practice and health-system delivery to improve outcomes for people living with dementia and their caregivers.
Background and Purpose:Prior research has indicated that changes in the amyloid-beta (Aβ) biomarker precede tau biomarker alterations in Alzheimer's disease (AD). However, establishing causality through temporal correlations remains contentious. This study aimed to explore the causal relationship between Aβ and tau using Mendelian randomization (MR) analysis. Methods:We conducted two-sample MR analyses employing genome-wide association studies (GWASs) summary statistics for Aβ positron emission tomography (PET) and cerebrospinal fluid phosphorylated tau (CSF pTau). Additionally, to reinforce and validate the results of the two-sample MR, we performed two-sample MR using tau PET GWAS summary statistics and one-sample MR analysis using autopsy data. In the one-sample MR analysis, the exposure and outcome variables were neuritic plaque burden and neurofibrillary tangle burden, respectively, determined through neuropathological examination. Results:The two-sample MR analysis unveiled a causal association between Aβ accumulation and CSF pTau level (BETA [standard error]=0.30 [0.10], p=0.004). The absence of heterogeneity and horizontal pleiotropy was confirmed. In contrast, there was no evidence causally relating CSF pTau level to Aβ accumulation (p=0.56). Our results were reinforced by consistently directional effects observed in the two-sample MR using tau PET GWAS and one-sample MR analysis, indicating a causal direction from Aβ burdens (measured by neuritic plaques) to tau burdens (measured by neurofibrillary tangles) (p=1.24×10-13). Conclusions:Our findings suggest a causal relationship between Aβ burdens and tau burdens in AD, reinforcing the notion of Aβ as a pivotal upstream factor in AD pathogenesis.
Background and Purpose:Accurate and early diagnosis of Parkinson's disease (PD) remains challenging, as clinical assessments have notable limitations. Gait impairment, a hallmark motor symptom, appears in the early stages and is indicative of disease evolution. This study aimed to examine gait parameters and their associations with established clinical measures to assess their potential as diagnostic and monitoring biomarkers in a Korean PD cohort. Methods:PD patients (n=18) and healthy controls (HCs, n=15) underwent gait assessments with MotionCore (JEIOS Inc.). Gait parameters were measured during both the 10-m walk (locomotion) and Timed Up and Go (TUG) tests, including stride length, cadence, single and double support time, toe-off time, and turning performance. Clinical assessments comprised the Hoehn & Yahr (H&Y) scale, Unified Parkinson's Disease Rating Scale Part III, Freezing of Gait Questionnaire, Korean version of the Mini-Mental State Examination, Geriatric Depression Scale, and Berg Balance Scale. Results:Patients with PD demonstrated significantly shortened stride length and higher cadence. Reduced single support time, extended double support time, and delayed toe-off time were observed in the PD group. Integrating gait metrics from both the 10-m locomotion and TUG tests improved discrimination between PD patients and healthy controls, as well as among different H&Y stages. Turning-related measures were significantly higher in PD patients. Gait measures showed robust correlations with clinical indices, including motor severity, cognitive status, and balance scores. Conclusions:Gait analysis identified prominent motor and balance deficits in PD patients that were strongly associated with clinical severity. Gait parameters hold considerable potential as objective digital biomarkers for the diagnosis and monitoring of PD progression.
