Assessing systemic, developmental, and reproductive toxicity and estrogenicity of Korean red ginseng extract G1899 in juvenile Sprague-Dawley Rats.

Background: Korean red ginseng (KRG) is a product from ginseng roots, which is enriched with ginsenosides and has been utilized for a long time as an adaptogen to alleviate various physiological or disease conditions. While KRG is generally considered safe, conducting a thorough toxicological assessment of the spray-dried powder G1899 during the juvenile period is essential to establish its safety profile. This study aimed to assess the safety of G1899 during the juvenile period using Sprague-Dawley rats. Methods: Two studies were conducted separately: a juvenile toxicity study and a uterotrophic bioassay. To assess the potential toxicity at systemic, postnatal developmental, and reproductive levels, G1899 was orally gavaged once a day in post-weaning juvenile Sprague-Dawley (SD) rats at 0, 1250, 2500, or 5000 mg/kg/day. Estrogenicity was assessed by orally gavaging G1899 in immature female SD rats at 0, 2500, or 5000 mg/kg/day on postnatal days (PND) 19-21, followed by a uterotrophic bioassay. These studies were conducted in accordance with the Good Laboratory Practice (GLP) regulations and regulatory test guidelines. Results: Regarding juvenile toxicity, no abnormalities related to the G1899 treatment were observed in any group during the experiment. Moreover, no uterotrophic responses were observed in the dosed female group. Based on these results, the no observed adverse effect level (NOAEL) of G1899 was determined to be at least 5000 mg/kg/day for general systemic function, developmental/reproductive function, and estrogenic activity. Conclusion: Our results suggest that G1899 is not toxic to juveniles at doses of up to 5000 mg/kg/day.

Ventral Anterior Cingulate Atrophy as a Predisposing Factor for Transient Global Amnesia.

Background and Purpose: This study aimed to evaluate the brain magnetic resonance imaging (MRI) of patients with acute transient global amnesia (TGA) using volumetric analysis to verify whether the brains of TGA patients have pre-existing structural abnormalities. Methods: We evaluated the brain MRI data from 87 TGA patients and 20 age- and sex-matched control subjects. We included brain MRIs obtained from TGA patients within 72 hours of symptom onset to verify the pre-existence of structural change. For voxel-based morphometric analyses, statistical parametric mapping was employed to analyze the structural differences between patients with TGA and control subjects. Results: TGA patients exhibited significant volume reductions in the bilateral ventral anterior cingulate cortices (corrected p<0.05). Conclusions: TGA patients might have pre-existing structural changes in bilateral ventral anterior cingulate cortices prior to TGA attacks.

Characteristics of discordance between amyloid positron emission tomography and plasma amyloid-ß 42/40 positivity.

Various plasma biomarkers for amyloid-ß (Aß) have shown high predictability of amyloid PET positivity. However, the characteristics of discordance between amyloid PET and plasma Aß42/40 positivity are poorly understood. Thorough interpretation of discordant cases is vital as Aß plasma biomarker is imminent to integrate into clinical guidelines. We aimed to determine the characteristics of discordant groups between amyloid PET and plasma Aß42/40 positivity, and inter-assays variability depending on plasma assays. We compared tau burden measured by PET, brain volume assessed by MRI, cross-sectional cognitive function, longitudinal cognitive decline and polygenic risk score (PRS) between PET/plasma groups (PET-/plasma-, PET-/plasma+, PET+/plasma-, PET+/plasma+) using Alzheimer's Disease Neuroimaging Initiative database. Additionally, we investigated inter-assays variability between immunoprecipitation followed by mass spectrometry method developed at Washington University (IP-MS-WashU) and Elecsys immunoassay from Roche (IA-Elc). PET+/plasma+ was significantly associated with higher tau burden assessed by PET in entorhinal, Braak III/IV, and Braak V/VI regions, and with decreased volume of hippocampal and precuneus regions compared to PET-/plasma-. PET+/plasma+ showed poor performances in global cognition, memory, executive and daily-life function, and rapid cognitive decline. PET+/plasma+ was related to high PRS. The PET-/plasma+ showed intermediate changes between PET-/plasma- and PET+/plasma+ in terms of tau burden, hippocampal and precuneus volume, cross-sectional and longitudinal cognition, and PRS. PET+/plasma- represented heterogeneous characteristics with most prominent variability depending on plasma assays. Moreover, IP-MS-WashU showed more linear association between amyloid PET standardized uptake value ratio and plasma Aß42/40 than IA-Elc. IA-Elc showed more plasma Aß42/40 positivity in the amyloid PET-negative stage than IP-MS-WashU. Characteristics of PET-/plasma+ support plasma biomarkers as early biomarker of amyloidopathy prior to amyloid PET. Various plasma biomarker assays might be applied distinctively to detect different target subjects or disease stages.

Progesterone increases hepatic lipid content and plasma lipid levels through PR- B-mediated lipogenesis.

Progesterone (P4) is a crucial reproductive hormone that acts as a precursor for all other endogenous steroids. P4 modulates transcriptional activity during reproduction by binding to progesterone receptors (PR). However, the physiological role of P4 in the liver is understudied. P4-mediated lipid metabolism in the liver was investigated in this study, as P4 facilitates insulin resistance and influences energy metabolism. While exogenous lipids are mainly obtained from food, the liver synthesizes endogenous triglycerides and cholesterol from a carbohydrate diet. Hepatic de novo lipogenesis (DNL) is primarily determined by acetyl-CoA and its biosynthetic pathways, which involve fatty acid and cholesterol synthesis. While P4 increased the hepatic levels of sterol regulatory element-binding protein 1 C (SREBP-1 C), peroxisome proliferator-activated receptor-gamma (PPARγ), acetyl-CoA carboxylase (ACC), and CD36, co-treatment with the P4 receptor antagonist RU486 blocked these proteins and P4-mediated lipogenesis. RNA sequencing was used to assess the role of P4 in lipogenic events, such as fatty liver and fatty acid metabolism, lipoprotein signaling, and cholesterol metabolism. P4 induced hepatic DNL and lipid anabolism were confirmed in the liver of ovarian resection mice fed a high-fat diet or in pregnant mice. P4 increased lipogenesis directly in mice exposed to P4 and indirectly in fetuses exposed to maternal P4. The lipid balance between lipogenesis and lipolysis determines fat build-up and is linked to lipid metabolism dysfunction, which involves the breakdown and storage of fats for energy and the synthesis of structural and functional lipids. Therefore, P4 may impact the lipid metabolism and reproductive development during gestation.

Subsequent correlated changes in complement component 3 and amyloid beta oligomers in the blood of patients with Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) involves the complement cascade, with complement component 3 (C3) playing a key role. However, the relationship between C3 and amyloid beta (Aß) in blood is limited. METHODS: Plasma C3 and Aß oligomerization tendency (AßOt) were measured in 35 AD patients and 62 healthy controls. Correlations with cerebrospinal fluid (CSF) biomarkers, cognitive impairment, and amyloid positron emission tomography (PET) were analyzed. Differences between biomarkers were compared in groups classified by concordances of biomarkers. RESULTS: Plasma C3 and AßOt were elevated in AD patients and in CSF or amyloid PET-positive groups. Weak positive correlation was found between C3 and AßOt, while both had strong negative correlations with CSF Aß42 and cognitive performance. Abnormalities were observed for AßOt and CSF Aß42 followed by C3 changes. DISCUSSION: Increased plasma C3 in AD are associated with amyloid pathology, possibly reflecting a defense response for Aß clearance. Further studies on Aß-binding proteins will enhance understanding of Aß mechanisms in blood.

Harnessing the Power of Voice: A Deep Neural Network Model for Alzheimer's Disease Detection.

Background and Purpose: Voice, reflecting cerebral functions, holds potential for analyzing and understanding brain function, especially in the context of cognitive impairment (CI) and Alzheimer's disease (AD). This study used voice data to distinguish between normal cognition and CI or Alzheimer's disease dementia (ADD). Methods: This study enrolled 3 groups of subjects: 1) 52 subjects with subjective cognitive decline; 2) 110 subjects with mild CI; and 3) 59 subjects with ADD. Voice features were extracted using Mel-frequency cepstral coefficients and Chroma. Results: A deep neural network (DNN) model showed promising performance, with an accuracy of roughly 81% in 10 trials in predicting ADD, which increased to an average value of about 82.0%±1.6% when evaluated against unseen test dataset. Conclusions: Although results did not demonstrate the level of accuracy necessary for a definitive clinical tool, they provided a compelling proof-of-concept for the potential use of voice data in cognitive status assessment. DNN algorithms using voice offer a promising approach to early detection of AD. They could improve the accuracy and accessibility of diagnosis, ultimately leading to better outcomes for patients.

Relationship Between Amyloid Positivity and Sleep Characteristics in the Elderly With Subjective Cognitive Decline.

Background and Purpose: Alzheimer's disease (AD) is a neurodegenerative disease characterized by a progressive decline in cognition and performance of daily activities. Recent studies have attempted to establish the relationship between AD and sleep. It is believed that patients with AD pathology show altered sleep characteristics years before clinical symptoms appear. This study evaluated the differences in sleep characteristics between cognitively asymptomatic patients with and without some amyloid burden. Methods: Sleep characteristics of 76 subjects aged 60 years or older who were diagnosed with subjective cognitive decline (SCD) but not mild cognitive impairment (MCI) or AD were measured using Fitbit® Alta HR, a wristwatch-shaped wearable device. Amyloid deposition was evaluated using brain amyloid plaque load (BAPL) and global standardized uptake value ratio (SUVR) from fluorine-18 florbetaben positron emission tomography. Each component of measured sleep characteristics was analyzed for statistically significant differences between the amyloid-positive group and the amyloid-negative group. Results: Of the 76 subjects included in this study, 49 (64.5%) were female. The average age of the subjects was 70.72±6.09 years when the study started. 15 subjects were classified as amyloid-positive based on BAPL. The average global SUVR was 1.598±0.263 in the amyloid-positive group and 1.187±0.100 in the amyloid-negative group. Time spent in slow-wave sleep (SWS) was significantly lower in the amyloid-positive group (39.4±13.1 minutes) than in the amyloid-negative group (49.5±13.1 minutes) (p=0.009). Conclusions: This study showed that SWS is different between the elderly SCD population with and without amyloid positivity. How SWS affects AD pathology requires further research.

Artificial Intelligence-Enhanced Quantitative Ultrasound for Breast Cancer: Pilot Study on Quantitative Parameters and Biopsy Outcomes.

Traditional B-mode ultrasound has difficulties distinguishing benign from malignant breast lesions. It appears that Quantitative Ultrasound (QUS) may offer advantages. We examined the QUS imaging system's potential, utilizing parameters like Attenuation Coefficient (AC), Speed of Sound (SoS), Effective Scatterer Diameter (ESD), and Effective Scatterer Concentration (ESC) to enhance diagnostic accuracy. B-mode images and radiofrequency signals were gathered from breast lesions. These parameters were processed and analyzed by a QUS system trained on a simulated acoustic dataset and equipped with an encoder-decoder structure. Fifty-seven patients were enrolled over six months. Biopsies served as the diagnostic ground truth. AC, SoS, and ESD showed significant differences between benign and malignant lesions (p < 0.05), but ESC did not. A logistic regression model was developed, demonstrating an area under the receiver operating characteristic curve of 0.90 (95% CI: 0.78, 0.96) for distinguishing between benign and malignant lesions. In conclusion, the QUS system shows promise in enhancing diagnostic accuracy by leveraging AC, SoS, and ESD. Further studies are needed to validate these findings and optimize the system for clinical use.

Transcriptional risk scores in Alzheimer's disease: From pathology to cognition.

INTRODUCTION: Our previously developed blood-based transcriptional risk scores (TRS) showed associations with diagnosis and neuroimaging biomarkers for Alzheimer's disease (AD). Here, we developed brain-based TRS. METHODS: We integrated AD genome-wide association study summary and expression quantitative trait locus data to prioritize target genes using Mendelian randomization. We calculated TRS using brain transcriptome data of two independent cohorts (N = 878) and performed association analysis of TRS with diagnosis, amyloidopathy, tauopathy, and cognition. We compared AD classification performance of TRS with polygenic risk scores (PRS). RESULTS: Higher TRS values were significantly associated with AD, amyloidopathy, tauopathy, worse cognition, and faster cognitive decline, which were replicated in an independent cohort. The AD classification performance of PRS was increased with the inclusion of TRS up to 16% with the area under the curve value of 0.850. DISCUSSION: Our results suggest brain-based TRS improves the AD classification of PRS and may be a potential AD biomarker. HIGHLIGHTS: Transcriptional risk score (TRS) is developed using brain RNA-Seq data. Higher TRS values are shown in Alzheimer's disease (AD). TRS improves the AD classification power of PRS up to 16%. TRS is associated with AD pathology presence. TRS is associated with worse cognitive performance and faster cognitive decline.

A Longitudinal Study on Memory Enhancement in Subjective Cognitive Decline Patients: Clinical and Neuroimaging Perspectives.

BACKGROUND: Subjective cognitive decline (SCD) refers to the self-reported persistent cognitive decline despite normal objective testing, increasing the risk of dementia compared to cognitively normal individuals. OBJECTIVE: This study aims to investigate the attributes of SCD patients who demonstrated memory function improvement. METHODS: In this prospective study of SCD, a total of 120 subjects were enrolled as part of a multicenter cohort study aimed at identifying predictors for the clinical progression to mild cognitive impairment or dementia (CoSCo study). All subjects underwent 18F-florbetaben PET and brain MRI scans at baseline and annual neuropsychological tests. At the 24-month follow-up, we classified SCD patients based on changes in memory function, the z-score of the Seoul verbal learning test delayed recall. RESULTS: Of the 120 enrolled patients, 107 successfully completed the 24-month follow-up assessment. Among these, 80 patients (74.8%) with SCD exhibited memory function improvements. SCD patients with improved memory function had a lower prevalence of coronary artery disease at baseline and performed better in the trail-making test part B compared to those without improvement. Anatomical and biomarker analysis showed a lower frequency of amyloid PET positivity and larger volumes in the left and right superior parietal lobes in subjects with improved memory function. CONCLUSIONS: Our prospective study indicates that SCD patients experiencing memory improvement over a 24-month period had a lower amyloid burden, fewer cardiovascular risk factors, and superior executive cognitive function. Identifying these key factors associated with cognitive improvement may assist clinicians in predicting future memory function improvements in SCD patients.

A Novel Mutation in Sacsin, p.Val1335IIe, May Cause Late-Onset Sacsinopathy Due to Haploinsufficiency.

Autosomal recessive spastic ataxia in Charlevoix-Saguenay (ARSACS) is a neurodegenerative disorder caused by mutations in the sacsin molecular chaperone protein (SACS) gene. Since the first report from Quebec in 1978, many pathogenic ARSACS variants with significantly reduced chaperone activities have been reported worldwide in adolescents, with presumably altered protein folding. In this study, a novel SACS mutation (p.Val1335IIe, Heterozygous) was identified in a Korean patient in their 50s with late-onset ARSACS characterized by cerebellar ataxia and spasticity without peripheral neuropathy. The mutation was confirmed via whole exome sequencing and Sanger sequencing and was predicted to likely cause disease using prediction software. RT-PCR and ELISA showed decreased SACS mRNA expression and sacsin protein concentrations in the proband, supporting its implications in diseases with pathogenicity and reduced chaperone function from haploinsufficiency. Our results revealed the pathogenicity of the SACS Val1335IIe mutation in the proband patient's disease manifestation, even though the symptoms had a limited correlation with the typical ARSACS clinical triad, which could be due to the reduced chaperon function from haploinsufficiency. Furthermore, our study suggests that variants of SACS heterozygosity may have diverse symptoms, with a wide range of disease onsets for late-onset sacsinopathy.

miR-129-5p as a biomarker for pathology and cognitive decline in Alzheimer's disease.

Background: Alzheimer's dementia (AD) pathogenesis involves complex mechanisms, including microRNA (miRNA) dysregulation. Integrative network and machine learning analysis of miRNA can provide insights into AD pathology and prognostic/diagnostic biomarkers. Methods: We performed co-expression network analysis to identify network modules associated with AD, its neuropathology markers, and cognition using brain tissue miRNA profiles from the Religious Orders Study and Rush Memory and Aging Project (ROS/MAP) (N = 702) as a discovery dataset. We performed association analysis of hub miRNAs with AD, its neuropathology markers, and cognition. After selecting target genes of the hub miRNAs, we performed association analysis of the hub miRNAs with their target genes and then performed pathway-based enrichment analysis. For replication, we performed a consensus miRNA co-expression network analysis using the ROS/MAP dataset and an independent dataset (N = 16) from the Gene Expression Omnibus (GEO). Furthermore, we performed a machine learning approach to assess the performance of hub miRNAs for AD classification. Results: Network analysis identified a glucose metabolism pathway-enriched module (M3) as significantly associated with AD and cognition. Five hub miRNAs (miR-129-5p, miR-433, miR-1260, miR-200a, and miR-221) of M3 had significant associations with AD clinical and/or pathologic traits, with miR129-5p by far the strongest across all phenotypes. Gene-set enrichment analysis of target genes associated with their corresponding hub miRNAs identified significantly enriched biological pathways including ErbB, AMPK, MAPK, and mTOR signaling pathways. Consensus network analysis identified two AD-associated consensus network modules, and two hub miRNAs (miR-129-5p and miR-221). Machine learning analysis showed that the AD classification performance (area under the curve (AUC) = 0.807) of age, sex, and apoE ε4 carrier status was significantly improved by 6.3% with inclusion of five AD-associated hub miRNAs. Conclusions: Integrative network and machine learning analysis identified miRNA signatures, especially miR-129-5p, as associated with AD, its neuropathology markers, and cognition, enhancing our understanding of AD pathogenesis and leading to better performance of AD classification as potential diagnostic/prognostic biomarkers.

Impacts of baseline biomarkers on cognitive trajectories in subjective cognitive decline: the CoSCo prospective cohort study.

BACKGROUND: Subjective cognitive decline (SCD) is a risk factor for Alzheimer's disease (AD); however, the rates of cognitive decline are variable according to underlying pathologies and biomarker status. We conducted an observational study and aimed to investigate baseline characteristics and biomarkers related with cognitive declines in SCD. Our study also assessed whether SCD participants showed different cognitive and biomarker trajectories according to baseline amyloid deposition. METHODS: This study is a part of a longitudinal cohort study conducted in multi-centers in South Korea between 2018 and 2021. Individuals (≥ 60 years old) with persistent cognitive complaint despite of normal cognitive functions were eligible for the study. All participants underwent neuropsychological tests, florbetaben PET scans, plasma amyloid markers, and brain MRI scans. Annual follow-up evaluations included neuropsychological tests and assessments for clinical progressions. Regional brain volumetry and amyloid burden represented by PET-based standardized uptake value ratio (SUVR) were measured. We compared cognitive and brain atrophic changes over 24 months between amyloid positive-SCD (Aß + SCD) and amyloid negative-SCD (Aß-SCD) groups. Baseline factors associated with cognitive outcomes were investigated. RESULTS: A total of 120 participants with SCD were enrolled and 107 completed follow-up evaluations. Aß + SCD participants (n = 20, 18.5%) were older and more frequently APOE4 carriers compared with Aß-SCD participants (n = 87). Baseline cognitive scores were not different between the two groups, except the Seoul Verbal Learning Test (SVLT) scores showing lower scores in the Aß + SCD group. After 24 months, plasma amyloid markers were higher, and regional volumes (entorhinal, hippocampal, and pallidum) were smaller in the Aß + SCD participants compared with Aß-SCD participants adjusted by age, sex, and baseline volumes. SVLT delayed recall and controlled oral word association test (COWAT) scores indicated more declines in Aß + SCD participants. Baseline left entorhinal volumes were related to verbal memory decline, while baseline frontal volumes and global SUVR values were related to frontal functional decline. CONCLUSION: Aß + SCD participants showed more cognitive decline and medial temporal atrophic changes during 24 months. Baseline neurodegeneration and amyloid burden were related with future cognitive trajectories in SCD. TRIAL REGISTRATION: This study was registered at CRIS (KCT0003397).

Increased oligomeric TDP-43 in the plasma of Korean frontotemporal dementia patients with semantic dementia.

INTRODUCTION: Semantic dementia (SD) is a progressive neurodegenerative disease associated with impaired vocabulary that progresses to memory impairment. Post-mortem immunohistochemical analysis is the current reliable method of differentiating TDP-43 deposits in cortical tissue; no means of antemortem diagnosis exists in biofluids, let alone in plasma. METHODS: Here the multimer detection system (MDS) was used to quantify the oligomeric TDP-43 (o-TDP-43) concentrations in plasma of Korean SD patients (n = 16, 6 male, 10 female, ages 59-87). The o-TDP-43 concentrations were compared with the total TDP-43 (t-TDP-43) concentrations quantified through conventional enzyme-linked immunosorbent assay (ELISA). RESULTS AND DISCUSSION: Only MDS showed a significant increase in o-TDP-43 concentrations in the plasma of patients with SD compared to other neurodegenerative disorders and normal controls (p < 0.05). Based on these results, o-TDP-43 concentrations through the application of MDS may be a useful plasma biomarker in SD-FTD (frontotemporal dementia) diagnosis.

Erratum: Plasma Oligomeric Beta Amyloid in Alzheimer's Disease with History of Agent Orange Exposure.

[This corrects the article on p. 41 in vol. 17, PMID: 30906391.].

Ensemble graph neural network model for classification of major depressive disorder using whole-brain functional connectivity.

Major depressive disorder (MDD) is characterized by impairments in mood and cognitive functioning, and it is a prominent source of global disability and stress. A functional magnetic resonance imaging (fMRI) can aid clinicians in their assessments of individuals for the identification of MDD. Herein, we employ a deep learning approach to the issue of MDD classification. Resting-state fMRI data from 821 individuals with MDD and 765 healthy controls (HCs) is employed for investigation. An ensemble model based on graph neural network (GNN) has been created with the goal of identifying patients with MDD among HCs as well as differentiation between first-episode and recurrent MDDs. The graph convolutional network (GCN), graph attention network (GAT), and GraphSAGE models serve as a base models for the ensemble model that was developed with individual whole-brain functional networks. The ensemble's performance is evaluated using upsampling and downsampling, along with 10-fold cross-validation. The ensemble model achieved an upsampling accuracy of 71.18% and a downsampling accuracy of 70.24% for MDD and HC classification. While comparing first-episode patients with recurrent patients, the upsampling accuracy is 77.78% and the downsampling accuracy is 71.96%. According to the findings of this study, the proposed GNN-based ensemble model achieves a higher level of accuracy and suggests that our model produces can assist healthcare professionals in identifying MDD.

Dietary supplementation with nicotinamide riboside improves fetal growth under hypoglycemia.

Nicotinamide riboside (NR) is considered a super-supplement that prevents obesity and diabetes. While NR has been investigated for various effects depending on nutritional conditions, metabolic research on women and pregnant women has rarely been discussed. In this study, we focused on the glycemic control of NR in females and found the protective role of NR in pregnant animals under hypoglycemic conditions. Metabolic-tolerance tests were performed in vivo under progesterone (P4) exposure after ovariectomy (OVX). NR enhanced resistance to energy deprivation and showed a slight increase in gluconeogenesis in naïve control mice. However, NR reduced hyperglycemia and significantly induced gluconeogenesis in OVX mice. While NR reduced hyperglycemia in the P4-treated OVX mice, it reduced insulin response and substantially increased gluconeogenesis. Similar to animal experiments, NR increased gluconeogenesis and mitochondrial respiration in Hep3B cells. The gluconeogenic function of NR is mediated by tricarboxylic acid cycle (TCA) cycle enrichment, as residual pyruvate could induce gluconeogenesis. NR recovered fetal growth by increasing blood glucose levels when hypoglycemia was induced by diet-restriction during pregnancy. Our study revealed the glucose-metabolic function of NR in hypoglycemic pregnant animals, suggesting NR as a dietary supplement to improve fetal growth. Because diabetic women suffer from hypoglycemia due to insulin therapy, NR has therapeutic potential for use as a glycemic control pill.

Blood pressure and dementia risk by physical frailty in the elderly: a nationwide cohort study.

BACKGROUND: Midlife hypertension has been recognized as a modifiable risk factor for dementia, but association between blood pressure (BP) in late life and dementia has been inconclusive. In addition, few studies have investigated effects of BP control on dementia incidence in the frail elderly. Thus, this study aimed to investigate the association of BP and dementia incidence with concomitant consideration of physical frailty in the young elderly population. METHODS: Using the Korean National Health Information Database, we identified 804,024 subjects without history of dementia at age 66. Dementia diagnosis was defined with prescription records of anti-dementia drugs and dementia-related diagnostic codes. Physical frailty was measured using the Timed Up and Go test. Association of BP and dementia incidence with concomitant consideration of physical frailty was investigated using Cox hazards analyses. RESULTS: The risks of Alzheimer's and vascular dementia increased from systolic BP ≥ 160 and 130-139 mmHg, respectively; a significant association of dementia incidence with low BP was not observed. In the analyses stratified by the physical frailty status, low BP was not associated with increased risks of dementia within the groups both with and without physical frailty. CONCLUSIONS: High BP was associated with increased risks of dementia, especially for vascular dementia, while low BP was not associated with increased risks of any type of dementia in young elderly people, even in those with physical frailty. This study suggests the need for tight BP control in young elderly people, irrespective of frailty status, to prevent dementia and supports the current clinical guidelines of hypertension treatment.