Variants in the APOE gene region may explain ethnic differences in the association of Alzheimer’s disease (AD) with ε4. Ethnic differences in allele frequencies for three APOE region SNPs (single nucleotide polymorphisms) were identified and tested for association in 19,398 East Asians (EastA), including Koreans and Japanese, 15,836 European ancestry (EuroA) individuals, and 4985 African Americans, and with brain imaging measures of cortical atrophy in sub-samples of Koreans and EuroAs. Among ε4/ε4 individuals, AD risk increased substantially in a dose-dependent manner with the number of APOE promoter SNP rs405509 T alleles in EastAs (TT: OR (odds ratio) = 27.02, p = 8.80 × 10⁻⁹⁴; GT: OR = 15.87, p = 2.62 × 10⁻⁹) and EuroAs (TT: OR = 18.13, p = 2.69 × 10⁻¹⁰⁸; GT: OR = 12.63, p = 3.44 × 10⁻⁶⁴), and rs405509-T homozygotes had a younger onset and more severe cortical atrophy than those with G-allele. Functional experiments using APOE promoter fragments demonstrated that TT lowered APOE expression in human brain and serum. The modifying effect of rs405509 genotype explained much of the ethnic variability in the AD/ε4 association, and increasing APOE expression might lower AD risk among ε4 homozygotes.

Background: Recently, several studies suggested potential involvements of α-synuclein in Alzheimer’s disease (AD) pathophysiology. Higher concentrations of α-synuclein were reported in cerebrospinal fluid (CSF) of AD patients with a positive correlation towards CSF tau, indicating its possible role in AD. We analyzed the CSF biomarkers to verify whether α-synuclein could be an additional supported biomarker in AD diagnosis.Methods: In this cross-sectional study, CSF samples of 71 early-onset AD, 34 late-onset AD, 11 mild cognitive impairment, 17 subjective cognitive decline, 45 Parkinson’s disease, and 32 healthy control (HC) were collected. CSF amyloid-β1-42 (A), total tau (N), and phosphorylated tau181 (T) were measured by commercial ELISA kits, and in-house ELISA kit was developed to quantify α-synuclein. The cognitive assessments and amyloid-PET imaging were also performed.Results: CSF α-synuclein manifested a tendency to increase in AD and to decreased in Parkinson’s disease compared to HC. The equilibrium states of total tau and α-synuclein concentrations were changed significantly in AD, and the ratio of total tau/α-synuclein (N/αS) was dramatically increased in AD than HC. Remarkably, N/αS revealed a strong positive correlation with tau phosphorylation rate. Also, the combination of N/αS with amyloid-β1-42/phosphorylated tau181 ratio had the best diagnosis performance (AUC = 0.956, sensitivity = 96%, specificity = 87%). In concordance analysis, N/αS showed the higher diagnostic agreement with amyloid-β1-42 and amyloid-PET. Analysis of biomarker profiling with N/αS had distinctive characteristics and clustering of each group. Especially, among the group of suspected non-Alzheimer’s disease pathophysiology, all A−T+N+ patients with N/αS+ were reintegrated into AD.Conclusions: The high correlation of α-synuclein with tau and the elevated N/αS in AD supported the involvement of α-synuclein in AD pathophysiology. Importantly, N/αS improved the diagnostic performance, confirming the needs of incorporating α-synuclein as a biomarker for neurodegenerative disorders. The incorporation of a biomarker group [N/αS] could contribute to provide better understanding and diagnosis of neurodegenerative disorders.

Mesenchymal stem cell (MSC) therapy is a promising alternative approach for the treatment of neurodegenerative diseases, according to its neuroprotective and immunomodulatory potential. Despite numerous clinical trials involving autologous MSCs, their outcomes have often been unsuccessful. Several reports have indicated that MSCs from patients have low capacities in terms of the secretion of neurotrophic or anti-inflammatory factors, which might be associated with cell senescence or disease severity. Therefore, a new strategy to improve their capacities is required for optimal efficacy of autologous MSC therapy. In this study, we compared the secretory potential of MSCs among cerebellar ataxia patients (CA-MSCs) and healthy individuals (H-MSCs). Our results, including secretome analysis findings, revealed that CA-MSCs have lower capacities in terms of proliferation, oxidative stress response, motility, and immunomodulatory functions when compared with H-MSCs. The functional differences were validated in a scratch wound healing assay and neuron-glia co-cultures. In addition, the neuroprotective and immunoregulatory protein follistatin-like 1 (FSTL1) was identified as one of the downregulated proteins in the CA-MSC secretome, with suppressive effects on proinflammatory microglial activation. Our study findings suggest that targeting aspects of the downregulated anti-inflammatory secretome, such as FSTL1, might improve the efficacy of autologous MSC therapy for CA.

To date, there is no curable treatment option for non-hereditary degenerative cerebellar ataxia. Here we report the case of a patient with sporadic adult-onset ataxia (SAOA) who underwent allogeneic bone marrow-derived mesenchymal stem cell (MSC) therapy via the intrathecal route. A 60-year-old male patient visited our clinic complaining of progressive gait disturbance that commenced two years ago. Upon neurologic examination, the patient exhibited limb dysmetria and gait ataxia. Brain magnetic resonance imaging (MRI) revealed cerebellar atrophy whereas the autonomic function test was normal. The patient was diagnosed with SAOA. The medications that were initially prescribed had no significant effects on the course of this disease and the symptoms deteriorated progressively. At the age of 64, the patient was treated with allogeneic bone marrow-derived MSC therapy. The subsequent K-SARA (Korean version of the Scale for the Assessment and Rating of Ataxia) scores demonstrated a distinct improvement up until 10 months post-administration. No adverse events were reported. The improved post-treatment K-SARA scores may suggest that the MSC therapy can have a neuroprotective effect and that stem cell therapy may serve as a potential therapeutic option for degenerative cerebellar ataxia.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with numerous causes that include genetic factors. Efforts to reveal the genetics of ALS have identified several candidate genes that are associated with familial and sporadic ALS. Here we report a Korean ALS patient who showed prominent upper motor-neuron-related symptoms with marked brain atrophy and neuropsychological deficits. The findings were highly suggestive of ALS in a patient with a likely pathogenic FIG4 variant.

In this study, we report two new possible susceptible genes for late-onset Alzheimer’s disease identified through an APOE-stratified genome-wide association analysis (GWAS) using East Asian samples. In the discovery phase, we performed a GWAS of Alzheimer’s disease in 2,291 Korean seniors from the Gwangju Alzheimer’s and Related Dementias (GARD) cohort study. A successive replication analysis with a Japanese sample of size 1,956 suggested three novel susceptible SNPs in two genes: LRIG1 and CACNA1A . This study demonstrates that the discovery of AD-associated variants can be accomplished in non-European ethnic groups with a more homogeneous genetic background using samples comprising fewer subjects.