Executive Summary of 2023 International Conference of the Korean Dementia Association (IC-KDA 2023): A Report From the Academic Committee of the Korean Dementia Association

Modern Koch’s Postulates Applied to Bacterial Pathogenesis of Alzheimer’s Disease (Jan Potempa, Jagiellonian University, University of Louisville School of Dentistry, Poland/USA)

Professor Potempa provided an overview of the pathogenesis of AD with respect to the microbiome. In the 19th century, Robert Koch established criteria for evaluating the causation of infectious diseases, which have been updated with modern methods.1 Applying these to Porphyromonas gingivalis, a bacterium linked to AD, revealed its potential role in AD pathogenesis. DNA and gingipain antigens from P. gingivalis were identified in the brains of AD patients, correlating with tau and ubiquitin pathology. Gingipains were found in age-matched controls, but at lower levels. Oral infection of mice with wild-type P. gingivalis led to brain colonization and increased Aβ1–42 plaques, with gingipains contributing to neurotoxicity.2 Targeting gingipains with inhibitors in a murine model reduced bacterial load, blocked Aβ1–42 production, and alleviated neuroinflammation, suggesting a causal link between chronic periodontitis and AD. The findings propose gingipain inhibitors as potential treatments for P. gingivalis-associated neurodegeneration in AD.

Fecal Microbiota Transplantation in Patients with Dementia (Seong Hye Choi, Inha University College of Medicine, Republic of Korea)

In her presentation, Professor Choi presented the clinical effects of fecal microbiota transplantation in patients with dementia. Fecal microbiota transplantation (FMT) for Clostridioides difficile infection (CDI) has shown cognitive improvements, suggesting a link between the gut microbiome and brain function.3 In a study with ten dementia patients and severe CDI who underwent FMT, cognitive function significantly improved, compared to a control group receiving antibiotics. Evaluations using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating scale–Sum of Boxes (CDR–SB) demonstrated notable enhancements in the FMT group. Analysis of fecal samples revealed changes in gut microbiota composition, including the enrichment of Proteobacteria and Bacteroidetes. Metabolic pathways related to alanine, aspartate, and glutamate also increased after FMT. These findings indicate the potential benefits of FMT in delaying cognitive decline in dementia patients, highlighting the significant interaction between the gut microbiome and cognitive function.

ApoE Isoform- and Microbiota-Dependent Progression of Neurodegeneration in a Mouse Model of Tauopathy (Dong-oh Seo, Washington University in St. Louis, USA)

Dr. Seo elucidated the connection between microbiota, neuroinflammation, and tau-mediated neurodegeneration, a key feature of AD. Notably, apolipoprotein E (ApoE)-mediated neuroinflammation plays a role in tau-mediated neurodegeneration,4 a hallmark of AD progression. While there is growing evidence of the gut microbiota influencing neuroinflammation in an ApoE genotype-dependent manner, a definitive causal link to tau-mediated neurodegeneration has been lacking. Dr. Seo addressed this gap by presenting experimental results involving tauopathy expressing human ApoE isoforms raised under germ-free conditions, or subjected to gut microbiota perturbation with antibiotics. Both manipulations demonstrated a sex- and ApoE isoform-dependent reduction in gliosis, tau pathology, and neurodegeneration.5 These findings uncover mechanistic insights and translational implications for the intricate relationships between microbiota, neuroinflammation, and tau-mediated neurodegeneration.

Implementation of High-Performance Blood Biomarkers in Routine Clinical Care for the Evaluation of Individuals with Cognitive Impairment (Joel Braunstein, C2N, USA)

The presentation by Dr. Braunstein was focused on blood biomarkers in individuals with cognitive impairment with AD. The PrecivityAD2™ blood test by C2N Diagnostics addresses this need, offering an analytically and clinically validated multianalyte assay with algorithmic assessment (MAAA). This high-throughput mass spectrometry-based test quantifies key AD biomarkers, including Aβ42/40 ratio and p-tau217/np-tau217 ratio, aiding in early AD diagnosis and identifying amyloid pathology. The discussion outlined the rationale behind the PrecivityAD2™ test, designed as a diagnostic aid for AD, and its predecessor, the PrecivityAD^® blood test. These tests showed the significant reliability of measuring brain amyloid plaques in individuals aged 55 and older with cognitive impairment.8, 9 His presentation also addressed the integration of blood biomarkers into routine clinical care, emphasizing diagnostic accuracy, clinical usefulness, and economic considerations in shaping the future role of blood biomarkers in cognitive care and management.

Plasma Biomarkers of Neurodegenerative Diseases toward Clinical Practice (MagQu) (Charles Shieh-Yueh Yang, MagQu, Taiwan)

Professor Yang presented plasma biomarker assay for AD using immunomagnetic reduction (IMR), which is commercialized by MagQu. Clinical trials evaluating plasma amyloid β peptides and total tau proteins using the IMR assay have been successfully completed. The international multi-centered trials validated the IMR plasma biomarker assay against clinical diagnoses, brain atrophy, amyloid positron emission tomography (PET), and amyloid neuropathology at autopsy.10, 11 The results demonstrate that plasma Aβ1–42/Aβ1–40 or Aβ1–42×T–Tau levels align closely with clinical diagnoses, distinguishing normal controls from patients with amnesic mild cognitive impairment (MCI) or AD. Plasma T–Tau levels show a negatively moderated correlation with brain volumes, and that Aβ1–42/Aβ1–40 levels moderately correlate with amyloid PET standardized uptake values ratios (SUVRs). The IMR assay predicts amyloid neuropathology, and provides insights into the progression of cognitive decline. Since 2020, the IMR assay for AD biomarkers in plasma has been approved for clinical use in Taiwan, aiding in assistant diagnoses and treatment monitoring. The IMR assay is entering in vitro diagnostic markets in Taiwan, Korea, the Middle East, China, and the United States.

AlzOn: The Real-World Example of Blood-based Biomarker Test Utility in Clinical Practice (Sungmin Kang, PeopleBio, Republic of Korea)

The presentation of Sungmin Kang introduced blood-based diagnosis of protein misfolding diseases based on multimer detection system (MDS) and the first commercial blood biomarker test for AD in Korea, which received product approval from the Ministry of Food and Drug Safety (MFDS) in 2018, and successfully passed on new Health Technology Assessment (nHTA) in 2021. AlzOn, an enzyme-linked immunosorbent assay based on MDS, serves as a blood-based biomarker test for AD, detecting and measuring plasma β-amyloid (Aβ) oligomerization—the core and earliest pathological change in AD. Approved for aiding AD diagnosis, AlzOn boasts over 85% accuracy in detecting ongoing AD pathology, and has been validated in various clinical studies.12, 13 Widely accessible, it is employed in over 500 hospitals, including 35 tertiary hospitals and major medical checkup centers in Korea. In primary care, AlzOn is a first-line blood test, complementing neuropsychological tests for cognition assessment. In secondary and tertiary hospitals, it aids in enriching AD diagnosis. Due to the practical constraints of costly and invasive ‘golden-standard’ biomarkers, AlzOn offers a simple, inexpensive option for routine clinical use and differential diagnosis in dementia cases. Its ability to reflect peripheral amyloidosis enhances its clinical utility, making it valuable for proactive AD risk factor testing in medical check-up centers.

Advances in AD Experimental Therapeutics (Alireza Atri, Banner Sun Health Research Institute [AZ] & Harvard Medical School [MA], USA)

Professor Atri offered a comprehensive overview of the latest advancements in experimental therapeutics for AD. Currently, most treatments for AD primarily offer symptomatic relief, yielding initial benefits; however, patients will still experience a progressive decline.14 A disease-modifying treatment would slow the disease progression of the patient.15 It will cover the current AD drug development pipeline, emphasizing the most recent data on efficacy and safety.16 The focus will extend to crucial considerations, such as patient selection, risk assessment, and the detection, monitoring, and management of amyloid-related imaging abnormalities (ARIA).17 He pointed out in particular the process from clinical trials to the practical implementation of monoclonal antibodies targeting amyloid plaques, such as aducanumab, lecanemab, and donanemab, providing valuable insights for both researchers and practitioners in the field. He emphasized that we are now moving beyond the beginning of AD therapeutics and anti-amyloid treatment.

Gene Therapy for Neurodegenerative Diseases (Jae young Lee, ToolGen, Republic of Korea)

Gene therapy has the capacity to target both the symptoms and the fundamental pathologies of neurodegenerative diseases. Introduction of viral vectors into the central nervous system enables the delivery of genes that can either restore lost functions, or encode neurological growth factors and metabolic enzymes. Concurrently, the potential of genome editing techniques like CRISPR offers significant promise in directly addressing the mutations responsible for these pathologies.

In this presentation, Professor Lee reviewed recent developments in gene therapy for neurodegenerative diseases, delving into its potential as a crucial therapeutic modality.18, 19

The discussion encompassed both opportunities and challenges associated with gene therapy in the context of neurological diseases, emphasizing the need to address hurdles in its development.

Neuromodulation for Gliopathy in Alzheimer’s Disease (Tae Kim, GIST, Republic of Korea)

Professor Kim’s presentation focused on neuromodulation for gliopathy in AD. Recognizing the increasing evidence of glial cells contribution in AD progression, novel therapeutic strategies, specifically non-invasive neuromodulation techniques, have emerged as promising interventions to address glial pathophysiology. Professor Kim presented groundbreaking research concentrating on astrocytic GABA in AD, unveiling the presence of astrocytic GABA in sleep-promoting areas of AD models. Acoustic stimulation at 40 Hz demonstrated a reduction in astrocytic GABA levels, correlating with observed sleep disturbances. Additionally, the research indicated that neuronal activity induces astrocytic volume expansion, leading to a secondary increase in calcium influx, potentially offering a protective effect on brain pathology.20, 21 These findings suggest that the benefits of gamma entrainment may originate from cascading secondary responses initiated by astrocytic changes. Overall, the research implicates the potential of 40 Hz acoustic neuromodulation in inducing glial alterations, providing a promising therapeutic pathway to ameliorate AD pathology.

Unsupervised Remote Memory Assessments in the Early Stages of Alzheimer’s Disease (David Berron, German Center for Neurodegenerative Diseases [DZNE], Germany)

Dr. Berron presented remote assessment for the early stage of AD. He explored the mobile application of a set of digital remote and unsupervised memory assessments to detect MCI in AD. He demonstrated that longitudinal digital remote memory assessments conducted over a year could capture changes in memory among individuals with MCI.22 Additionally, he showed that these cognitive changes corresponded to alterations observed in established in-clinic cognitive assessments.

Predictive Utility of Machine Learning Approach with Neuropsychological Test in AD Spectrum (Seyul Kwak, Pusan National University, Republic of Korea)

The presentation by Professor Kwak focused on how complex patterns of test performances could be harnessed for specific predictive purposes using machine learning. Based on the nonlinear modeling of a large-scale dataset, he demonstrated how multiple scores of detailed neuropsychological batteries (CERAD–K) can be utilized to predict the clinical outcomes of dementia in more than 2,600 older adults with varying cognitive statuses (no impairment, mild cognitive impairment, and dementia with AD). He presented the findings that linear models demonstrated superior performance with a relatively smaller sample size, whereas nonlinear models with low and high complexity exhibited improved accuracy with a larger dataset.23 Notably, the nonlinear models showed a gradual increase in predictive accuracy, in particular when the sample size exceeded 500, emphasizing their effectiveness in exploiting complex patterns within the dataset. He suggested that nonlinear models, particularly with sufficient data, can predict levels of functional impairment, offering a valuable augmentation to the summary index of neuropsychological batteries, especially in estimating dementia-related functional status.

Digital Neuropsychological Assessments for Frontotemporal Dementia (Adam Staffaroni, University of California San Francisco, USA)

In the presentation, Professor Staffaroni introduced digital neuropsychological assessments for FTD, a neurodegenerative condition characterized by cognitive, behavioral, language, or motor impairments. These digital assessments aimed to quantify deficits within the domains affected by FTD, offering a valuable tool for both clinical care improvement and remote evaluations. He showed that the use of digital tools enhanced clinical practices, while also addressing recruitment barriers for observational research and FTD clinical trials.24 The presentation highlighted various existing digital technologies for FTD assessment, encompassing tablet-based testing solutions, and smartphone applications.

North American FTD Registry (ALLFTD) (Howard Rosen, University of California San Francisco, USA)

Professor Rosen introduced the North American FTD registry (ALLFTD). The ARTFL–LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) consortium, established in 2014, has significantly advanced the development of such treatments for FTLD. With over 4,000 visits across 28 North American sites involving 2,500 participants, ALLFTD has highlighted the value of clinical rating scales, cognitive tests, MRI-based volumetrics, and Neurofilament Light Chain (NfL) as crucial markers for disease progression. Notable achievements include the creation of mutation-specific multimodal models, streamlining the efficiency of clinical trials. ALLFTD has also identified novel clinical and fluid-based measures potentially tracking disease evolution and individual vulnerability to neurodegeneration.31, 34 Furthermore, the consortium has piloted mobile-phone-based applications,33 aiming to enhance clinical trial efficiency and broaden research participation opportunities. This substantial progress signifies a crucial step toward developing effective treatments for this devastating disorder.

Korean FTD Registry (LEAF-FTD) (Eun Joo Kim, Pusan National University Hospital, Republic of Korea)

Professor Kim introduced the Longitudinal study of early onset dementia and family members (LEAF), a Korean cohort focusing on early onset dementia, initiated in April 2021, with participation from 31 centers across Korea. Within LEAF, LEAF–FTD constitutes one of the sub-studies alongside LEAF–AD and LEAF–Other early onset dementia. LEAF–FTD is specifically aimed at enrolling patients diagnosed with bvFTD, svPPA, non-fluent variant agrammatic primary progressive aphasia, FTD–MND (FTD with motor neuron disease), corticobasal syndrome, and progressive supranuclear palsy syndrome. Currently, LEAF-FTD has enrolled nearly 80 patients, encompassing both sporadic and familial cases of FTD. The cohort is collecting neuropsychological tests, various behavior scales, brain MRI, amyloid PET, blood samples, and whole exome sequencing data. These data will further enhance our understanding of the characteristics of FTD patients in Korea.

Familial FTD in China: Progress and Prospects (Qin Chen, West China Hospital of Sichuan University, China)

Professor Chen presented cross-sectional reports of Chinese FTD patients with gene mutations and updated status of the longitudinal study by the Chinese Familial Frontotemporal Lobar Degeneration Consortium (CFFC). The CFFC was initiated in October 2022 with seven top teaching hospitals, and has expanded to over 20 centers. Comprehensive electronic searches to review the current status of Chinese FTD patients revealed genetic mutations in 5.13%–27.9% of Chinese FTD patients, predominantly MAPT, GRN, TBK1, CHCHD10, C9orf72, VCP, and SQSTM1. To date, the CFFC has enrolled 26 pedigrees with MAPT mutations, 11 with GRN mutations, and 9 with C9orf72 repeat expansions. The CFFC has also endeavored to create a behavioral assessment scale for Chinese bvFTD patients, to develop voice-based digital biomarkers for various PPA types, and to participate in international phase III clinical trials for familial FTD. The high prevalence of MAPT mutations in Chinese FTD patients has suggested genetic heterogeneity, emphasizing the need for longitudinal studies with larger sample sizes to model biomarker trajectories for early diagnosis and intervention.

Molecular Neuropathology of Chronic Traumatic Encephalopathy (CTE) Reveals Alzheimer’s Disease-like Signatures (Hoon Ryu, KIST, Republic of Korea)

Professor Ryu introduced CTE, which is a progressive neurodegenerative disorder linked to repetitive head injuries, featuring distinct neuropathological characteristics.35 Although intraneuronal tau aggregates are key diagnostic features of CTE, the underlying tauopathy mechanism remains unclear. He presented the results of recent research employing multiomic analyses on post-mortem brain tissues from CTE patients, which revealed significant downregulation of gene signatures associated with MAP Kinase and calcium signaling pathways. The altered expression of protein phosphatases (PP) suggests shared pathological mechanisms with AD. Experimental validation using cell lines and animal models has confirmed a direct link between reduced PPP3CA/PP2B phosphatase activity and an increase in phosphorylated tau. This finding suggests that PP-dependent neurodegeneration might offer a potential biomarker and therapeutic target for modulating CTE-associated tauopathy.

Molecular Mechanism of α-Synuclein in Non-AD Dementia (Seung-Jae Lee, Seoul National University, Republic of Korea)

Professor Lee presented the interconnection of compound proteinopathies in dementia. His study showed that intracerebral transplantation of Aβ-activated microglia induced cognitive and motor deficits, along with compound proteinopathies like tauopathy and synucleinopathy, gliosis, and neuroinflammation. Notably, these features extended beyond the injection site, mirroring the progressive spread observed in neurodegenerative diseases.36, 37 This protocol offered a model for neurodegenerative diseases, particularly the post-Aβ phase of AD. Unlike cross-seeding mechanisms requiring physical interactions between different aggregate proteins, he proposed a new mechanism that involves Aβ oligomers activating microglia, creating an inflammatory microenvironment that fosters the aggregation of downstream proteins like tau and α-synuclein. This alternative perspective emphasized environmental changes promoting protein aggregation, providing valuable insights into the complex interplay of neuropathological features in AD.

Identifying the Early Events in ALS Pathogenesis (Jeehye Park, University of Toronto, Canada)

Professor Park elucidated early molecular pathways in amyotrophic lateral sclerosis (ALS), a condition marked by severe motor impairment, muscle atrophy, and paralysis, highlighting the pressing need to unravel the disease’s early stages for effective interventions.38, 39 Despite insights gained from ALS studies, understanding the initiation and development of the disease, particularly its mechanisms in the early phases, has remained elusive. Leveraging a MATR3 S85C knock-in (KI) mouse model that closely mirrors the human ALS genotype, Professor Park discerned early events in the disease, and explained how the ALS-linked mutation in MATR3 alters RNA splicing. This study, unraveling features of early-stage ALS development, holds promise for advancing prevention and intervention strategies, presenting a transformative approach to mitigate ALS’s devastating impact.