INTRODUCTION:We evaluated lecanemab's safety and cognitive outcomes in Chinese patients with Alzheimer's disease (AD) and the utility of blood-based biomarkers (BBMs) for treatment guidance. METHODS:A multicenter, real-world cohort enrolled 1042 patients receiving lecanemab, with 453, 359, 97 patients followed up at 3, 6, 12 months, respectively. Safety outcomes included amyloid-related imaging abnormalities (ARIA) and infusion-related reactions (IRRs), and the main clinical outcome was Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) score change. RESULTS:Of 1,042 patients, ARIA occurred in 7.87%, and IRRs in 16.12%. Discontinuation was 16.51%, mainly due to financial burden. CDR-SB did not change at 12 months overall or in any subgroup. High-accuracy BBMs were the sole AD biomarker assay in 5.28%, with comparable outcomes. DISCUSSION:Lecanemab exhibited favorable 12-month safety, with no clear evidence of cognitive decline, and BBMs hold potential for treatment guidance. Further studies using a control group are now warranted.

The transglutaminase (TG) family comprises calcium-dependent enzymes that catalyze covalent ε-(γ-glutamyl)lysine isopeptide bond formation between glutamine and lysine residues, thereby promoting protein cross-linking, polymerization, and stabilization, while also exerting important non-enzymatic functions in the central nervous system (CNS) through conformation-dependent signaling and scaffolding. Among TG family members, transglutaminase 2 (TGM2) is the best-characterized CNS isoenzyme, whereas TGM6 is predominantly neuronal. Under physiological conditions, TGs contribute to neuronal structure, myelination-related processes, synaptic remodeling, and neural circuit homeostasis; however, increasing evidence indicates that TG dysregulation is involved in multiple CNS disorders and extends beyond passive bystander up-regulation. In this review, we propose that TG family members, particularly TGM2, form a TG–pathology axis linking proteostasis disruption and neuroimmune activation. In pathological contexts, TG-driven pathways may promote pathogenic protein aggregation, amplify inflammatory signaling, and facilitate cell death, thereby contributing to the progression from early, potentially reversible cellular stress to persistent and progressive pathology. Importantly, these effects are highly context-dependent, varying with coenzymes, cell type, subcellular localization, and disease stage, and different TG isoenzymes may exert distinct or even opposing roles despite sharing a common cross-linking chemistry. We summarize the structural basis, enzymatic and non-enzymatic functions, and disease-specific roles of TG family members in neurodegenerative, neuroinflammatory, cerebrovascular, and injury-related CNS disorders and further evaluate current genetic and pharmacological evidence, emerging therapeutic strategies, and key barriers to clinical translation to provide an updated framework for the development of more precise TG-targeted interventions in CNS disease.

INTRODUCTION:Obesity may increase Alzheimer's disease (AD) risk, yet the underlying mechanisms remain unclear. METHODS:We investigated this link through global epidemiology, Mendelian randomization (MR), transcriptomics, clinical cohort validation, and mechanistic exploration. RESULTS:High body mass index (BMI)-attributable AD disability-adjusted life years and deaths increased 4-fold from 1990-2021, with projections indicating a tripling by 2050. MR analyses found that elevated BMI was genetically related to increased AD risk. Haptoglobin (HP) was identified as a core mediator between them. HP expression was correlated with plasma AD biomarkers and cognitive scores. Mechanistically, HP localized to plaque-associated microglia and suppressed microglial amyloid beta (Aβ) phagocytosis and DNAX activating protein of 12 kDa (Dap12)/Spleen tyrosine kinase (Syk) pathway with modulating disease-associated microglial transcriptional programs. CONCLUSION:This study identified HP as a strong candidate mediator linking obesity to AD pathogenesis through inhibiting the phagocytosis of Aβ by microglia.

INTRODUCTION:Microglial activation can either support neuronal function or exacerbate damage, contributing to Alzheimer's disease (AD) progression. We investigated spatial relationships among microglial activation, neuronal health, and amyloid beta (Aβ) in the AD spectrum. METHODS:Forty healthy controls, 37 patients with mild cognitive impairment (MCI), and 62 patients with AD underwent whole-brain high-resolution 1H-magnetic resonance spectroscopic imaging (MRSI), [1 8F]DPA-714, and [1 8F]AV-45 positron emission tomography (PET). Regional and voxel-wise analyses assessed changes and associations of microglial activation with N-acetylaspartate (NAA) and Aβ. RESULTS:MCI and AD patients showed higher microglial activation and lower NAA, correlating with cognitive decline. In controls and MCI, microglial activation correlated positively with NAA and Aβ in early amyloid-accumulating regions. Conversely, negative correlations with NAA emerged in the hippocampus in MCI and extended to temporal and occipital regions in AD. DISCUSSION:For the first time, we identified two distinct spatial association patterns between [1 8F]DPA-714 PET and NAA, shedding light on the complex interplay between neuroinflammation and neuronal health in AD.

INTRODUCTION:Understanding the neurometabolic changes associated with amyloid-β (Aβ) deposition is important for early Alzheimer's disease (AD) diagnosis, but their spatial relationships remained unexplored due to technical limitations. METHODS:We investigated the relationship between Aβ deposition and neuronal and glial metabolites using high-resolution 3D magnetic resonance spectroscopic imaging (MRSI) (8-min scan, 2 × 3 × 3 mm3 resolution) and Aβ-positron emission tomography (Aβ-PET) imaging. N-acetylaspartate, myo-inositol, and creatine maps were obtained from 174 participants: 39 controls, 65 mild cognitive impairment (MCI), and 70 AD patients. RESULTS:N-Acetylaspartate levels were negatively correlated with Aβ, while myo-inositol levels were positively correlated globally. Regional associations with Aβ include N-acetylaspartate reductions in frontal cortex, anterior cingulate cortex, and precuneus, and myo-inositol increases in precuneus, lateral temporal, and lateral parietal cortices. Combined MRSI and PET biomarkers achieved the highest diagnostic accuracy for MCI and AD . DISCUSSION:Hybrid high-resolution 3D MRSI and Aβ-PET imaging provides valuable insights into Aβ's impact on neurometabolic changes, improving early AD diagnosis. HIGHLIGHTS:Hybrid 3D magnetic resonance spectroscopic imaging-positron emission tomography (MRSI-PET) imaging reveals Aβ deposition impact on neurometabolism in Alzheimer's disease (AD). N-acetylaspartate (NAA) as a neuronal metabolic marker is negatively associated with Aβ globally and locally. Myo-inositol (mI) as a glial metabolic marker is positively associated with Aβ globally and locally. Combining 3D magnetic resonance spectroscopic imaging (MRSI) and PET biomarkers improves diagnostic accuracy for mild cognitive impairment (MCI) and AD.

Anti-Amyloid β (Aβ) immunotherapy has been shown to clear Aβ and delay cognitive decline in Alzheimer’s disease (AD). Recent studies suggest that the efficacy of this treatment is linked to microglial activation. However, direct evidence from cohort studies is lacking. The 18-kDa translocator protein (TSPO)-positron emission tomography (PET) imaging allows for in vivo assessment of microglial activation. The study included 10 early AD patients ((i.e., mild cognitive impairment or mild AD) treated with Lecanemab monoclonal antibody (10 mg/kg, biweekly) for 12 months, and 7 untreated early AD patients as controls. All participants underwent Aβ (AV45) and TSPO (DPA714) PET scans and cognitive tests at baseline and after 12 months. No significant demographic differences were found between the Lecanemab and control groups. Both groups had similar proportions of APOE4-positive individuals, cognitive levels, Aβ load, and microglial activation. At 12 months, the Lecanemab group showed a -0.34 SUVR for AV45/PET and a +0.05 SUVR for DPA714/PET. Correlation analysis revealed a positive correlation between increased frontal (r=-0.59, p =0.023) and temporal (r=-0.59, p =0.023) DPA714 SUVR levels and decreased AV45 SUVR levels. Additionally, an increase in parietal DPA714 SUVR was negatively correlated with MMSE score reduction (r=-0.53, p =0.04). Microglial activation plays a crucial role in the efficacy of Anti-Aβ immunotherapy, promoting Aβ clearance and delaying cognitive decline.

Multiplexed detection is a challenging yet essential task in analytical chemistry, especially for complex systems. Surface-enhanced Raman spectroscopy (SERS) is a promising analytical tool due to its molecular fingerprinting capability, sensitivity, low cost, and tractability. Considering the molecular profusion and diversity, SERSome, namely, spectral set, facilitates robust detection but is still challenged by spectral overlapping-induced uncertainty of molecular assignment and multiplexed quantification. Herein, we introduce molecule-resolvable (MORE) SERSome, identifying specific analytes contributing to the complex SERS spectra, which are then used in spectral decomposition for multiplexed analysis. Taking metabolic profiling for Alzheimer's disease as a proof of concept, ten metabolites are screened in human serum. A deep-learning model enables accurate and rapid diagnosis, achieving an area under the receiver operating characteristic curve as high as 91.5%. Comparing with conventional methods, MORE SERSome presents a methodological advancement in multiplexed detection with strong potential for general applications and fundamental research in analytical chemistry.

Background: Alzheimer's disease (AD), the most prevalent type of dementia, still lacks disease-modifying treatment strategies. Recent evidence indicates that maintaining gut microbiota homeostasis plays a crucial role in AD. Targeted regulation of gut microbiota, including probiotics, is anticipated to emerge as a potential approach for AD treatment. However, the efficacy and mechanism of multi-strain probiotics treatment in AD remain unclear. Methods: In this study, 6-month-old senescence-accelerated-mouse-prone 8 (SAMP8) and senescence-acceleratedmouse-resistant 1 (SAMR1) were utilized. The SAMP8 mice were treated with probiotic-2 (P2, a probiotic mixture of Bifidobacterium lactis and Lactobacillus rhamnosus ) and probiotic-3 (P3, a probiotic mixture of Bifidobacterium lactis , Lactobacillus acidophilus , and Lactobacillus rhamnosus ) (1 x 10 9 colony-forming units) once daily for 8 weeks. Morris water maze (MWM) and novel object recognition (NOR) tests were employed to assess the memory ability. 16S sequencing was applied to determine the composition of gut microbiota, along with detecting serum short-chain fatty acids (SCFAs) concentrations. Neural injury, A beta and Tau pathology, and neuroinflammation level were assessed through western blot and immunofluorescence. Finally, potential molecular mechanisms was explored through transcriptomic analysis and western blotting. Results: The MWM and NOR test results indicated a significant improvement in the cognitive level of SAMP8 mice treated with P2 and P3 probiotics compared to the SAMP8 control group. Fecal 16S sequencing revealed an evident difference in the alpha diversity index between SAMP8 and SAMR1 mice, while the alpha diversity of SAMP8 mice remained unchanged after P2 and P3 treatment. At the genus level, the relative abundance of ten bacteria differed significantly among the four groups. Multi-strain probiotics treatment could modulate serum SCFAs (valeric acid, isovaleric acid, and hexanoic acid) concentration. Neuropathological results demonstrated a substantial decrease in neural injury, A beta and Tau pathology and neuroinflammation in the brain of SAMP8 mice treated with P3 and P2. Transcriptomic analysis identified the chemokine signaling pathway as the most significantly enriched signaling pathway between SAMP8 and SAMR1 mice. Western blot test indicated a significant change in the phosphorylation level of downstream AKT/GSK-3 beta between the SAMP8 and SAMR1 groups, which could be reversed through P2 and P3 treatment. Conclusions: Multi-strain probiotics treatment can ameliorate cognitive impairment and pathological change in SAMP8 mice, including neural damage, A beta and Tau pathology, and neuroinflammation. This effect is associated with the regulation of the phosphorylation of the AKT/GSK-3 beta pathway.

INTRODUCTION:Altered neurometabolism, detectable via proton magnetic resonance spectroscopic imaging (1H-MRSI), is spatially heterogeneous and underpins cognitive impairments in Alzheimer's disease (AD). However, the spatial relationships between neurometabolic topography and cognitive impairment in AD remain unexplored due to technical limitations. METHODS:We used a novel whole-brain high-resolution 1H-MRSI technique, with simultaneously acquired 18F-florbetapir positron emission tomography (PET) imaging, to investigate the relationship between neurometabolic topography and cognitive functions in 117 participants, including 22 prodromal AD, 51 AD dementia, and 44 controls. RESULTS:Prodromal AD and AD dementia patients exhibited spatially distinct reductions in N-acetylaspartate, and increases in myo-inositol. Reduced N-acetylaspartate and increased myo-inositol were associated with worse global cognitive performance, and N-acetylaspartate correlated with five specific cognitive scores. Neurometabolic topography provides biological insights into diverse cognitive dysfunctions. DISCUSSION:Whole-brain high-resolution 1H-MRSI revealed spatially distinct neurometabolic topographies associated with cognitive decline in AD, suggesting potential for noninvasive brain metabolic imaging to track AD progression. HIGHLIGHTS:Whole-brain high-resolution 1H-MRSI unveils neurometabolic topography in AD. Spatially distinct reductions in NAA, and increases in mI, are demonstrated. NAA and mI topography correlates with global cognitive performance. NAA topography correlates with specific cognitive performance.

Alzheimer’s disease (AD), the main type of dementia, involves in complex pathophysiological processes, including abnormal lysosomes function. Cathepsins are the predominant proteases responsible for the degradation of diverse substrates in the endo-lysosomal system. However, there was still a lack of systematic study on the causal association between cathepsins and AD. This study utilized Mendelian randomization (MR) to investigate the association between blood cathepsins and the risk of AD, as well as the level of amyloid-β (Aβ) and p-Tau in cerebrospinal fluid. Furthermore, an independent dataset was employed to corroborate the above result. Importantly, this study incorporated the Alzheimer’s disease Immunization and Microbiota Initiative study Cohort to further validate the alteration of blood cathepsins expression level and examine its correlation with cognitive level and plasma AD-related pathological markers. Using MR method, we observed that high level of cathepsin L (CTSL) was associated with a lower risk of AD in both training and validation data. In observational cohort, we found there was decreased blood CTSL expression level in Aβ+ cognitive impaired (CI) group, compared with Aβ− cognitive unimpaired (CU) group. Correlation analysis revealed that blood CTSL expression level was negatively correlated with Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) score, plasma Aβ42 and Aβ42/40 level in Aβ+ CI group. Mediation analysis showed that plasma Aβ42/40 level was the key mediator in the association between blood CTSL and MMSE score in Aβ+ CI participants. This study revealed that blood CTSL was an important factor affecting the risk of AD, and it affected the cognitive level of AD patients through plasma Aβ42/40 level.

ABSTRACTNumerous studies have described the notable impact of gut microbiota on the brain in Alzheimer’s disease (AD) via the gut – brain axis. However, the molecular mechanisms underlying the involvement of gut microbiota in the development of AD are limited. This study aimed to explore the potential mechanisms of gut microbiota in AD by integrating multi-omics data. In this study, APP/PS1 and WT mice at nine months of age were used as study mouse model. Cognitive function was assessed using the Morris water maze test. The levels of Aβ plaque and neuroinflammation in the brain were detected using immunofluorescence and PET/CT. In addition, we not only used 16S rRNA gene sequencing and metabolomics to explore the variation characteristics of gut microbiota and serum metabolism abundance, but also combined spatial metabolomics and transcriptomics to explore the change in the brain and identify their potential correlation. APP/PS1 mice showed significant cognitive impairment and amyloid-β deposits in the brain. The abundance of gut microbiota was significantly changed in APP/PS1 mice, including decreased Desulfoviobrio, Enterococcus, Turicibacter, and Ruminococcus and increased Pseudomonas. The integration of serum untargeted metabolomics and brain spatial metabolomics showed that glycerophospholipid metabolism was a common alteration pathway in APP/PS1 mice. Significant proliferation and activation of astrocyte and microglia were observed in APP/PS1 mice, accompanied by alterations in immune pathways. Integration analysis and fecal microbiota transplantation (FMT) intervention revealed potential association of gut microbiota, host glycerophospholipid metabolism, and neuroinflammation levels in APP/PS1 mice.

Alzheimer’s disease (AD) is the most common type of neurodegenerative disease and its pathogenesis is still unclear. Genetic factors are thought to account for a large proportion of the overall AD phenotypes. ATP-binding cassette transporter A7 ( ABCA7 ) is one of the most important risk gene for AD. Multiple forms of ABCA7 variants significantly increase the risk of AD, such as single-nucleotide polymorphisms, premature termination codon variants, missense variants, variable number tandem repeat, mutations, and alternative splicing. AD patients with ABCA7 variants usually exhibit typical clinical and pathological features of traditional AD with a wide age of onset range. ABCA7 variants can alter ABCA7 protein expression levels and protein structure to affect protein functions such as abnormal lipid metabolism, amyloid precursor protein (APP) processing, and immune cell function. Specifically, ABCA7 deficiency can cause neuronal apoptosis by inducing endoplasmic reticulum stress through the PERK/eIF2α pathway. Second, ABCA7 deficiency can increase Aβ production by upregulating the SREBP2/BACE1 pathway and promoting APP endocytosis. In addition, the ability of microglia to phagocytose and degrade Aβ is destroyed by ABCA7 deficiency, leading to reduced clearance of Aβ. Finally, disturbance of lipid metabolism may also be an important method by which ABCA7 variants influence the incidence rate of AD. In the future, more attention should be given to different ABCA7 variants and ABCA7 targeted therapies for AD.

AIMS:To compare the fecal levels of short-chain fatty acids (SCFAs) in patients with mild cognitive impairment (MCI) and normal controls (NCs) and to examine whether fecal SCFAs could be used as the biomarker for the identification of patients with MCI. To examine the relationship between fecal SCFAs and amyloid-β (Aβ) deposition in the brain.METHODS:A cohort of 32 MCI patients, 23 Parkinson's disease (PD) patients, and 27 NC were recruited in our study. Fecal levels of SCFAs were measured using chromatography and mass spectrometry. Disease duration, ApoE genotype, body mass index, constipation, and diabetes were evaluated. To assess cognitive impairment, we used the Mini-Mental Status Examination (MMSE). To assess brain atrophy, the degree of medial temporal atrophy (MTA score, Grade 0-4) was measured by structural MRI. Aβ positron emission tomography with 18 F-florbetapir (FBP) was performed in seven MCI patients at the time of stool sampling and in 28 MCI patients at an average of 12.3 ± 0.4 months from the time of stool sampling to detect and quantify Aβ deposition in the brain.RESULTS:Compared with NC, MCI patients had significantly lower fecal levels of acetic acid, butyric acid, and caproic acid. Among fecal SCFAs, acetic acid performed the best in discriminating MCI from NC, achieved an AUC of 0.752 (p = 0.001, 95% CI: 0.628-0.876), specificity of 66.7%, and sensitivity of 75%. By combining fecal levels of acetic acid, butyric acid, and caproic acid, the diagnostic specificity was significantly improved, reaching 88.9%. To better verify the diagnostic performance of SCFAs, we randomly assigned 60% of participants into training dataset and 40% into testing dataset. Only acetic acid showed significantly difference between these two groups in the training dataset. Based on the fecal levels of acetic acid, we achieved the ROC curve. Next, the ROC curve was evaluated in the independent test data and 61.5% (8 in 13) of patients with MCI, and 72.7% (8 in 11) of NC could be identified correctly. Subgroup analysis showed that reduced fecal SCFAs in MCI group were negatively associated with Aβ deposition in cognition-related brain regions.CONCLUSION:Reductions in fecal SCFAs were observed in patients with MCI compared with NC. Reduced fecal SCFAs were negatively associated with Aβ deposition in cognition-related brain regions in MCI group. Our findings suggest that gut metabolite SCFAs have the potential to serve as early diagnostic biomarkers for distinguishing patients with MCI from NC and could serve as potential targets for preventing AD.

Purpose Despite the revealed role of immunological dysfunctions in the development and progression of Alzheimer’s disease (AD) through animal and postmortem investigations, direct evidence regarding the impact of genetic factors on microglia response and amyloid-β (Aβ) deposition in AD individuals is lacking. This study aims to elucidate this mechanism by integrating transcriptomics and TSPO, Aβ PET imaging in clinical AD cohort. Methods We analyzed 85 patients with PET/MR imaging for microglial activation (TSPO, [ 18 F]DPA-714) and Aβ ([ 18 F]AV-45) within the prospective Alzheimer’s Disease Immunization and Microbiota Initiative Study Cohort (ADIMIC). Immune-related differentially expressed genes (IREDGs), identified based on AlzData, were screened and verified using blood samples from ADIMIC. Correlation and mediation analyses were applied to investigate the relationships between immune-related genes expression, TSPO and Aβ PET imaging. Results TSPO uptake increased significantly both in aMCI ( P < 0.05) and AD participants ( P < 0.01) and showed a positive correlation with Aβ deposition (r = 0.42, P < 0.001). Decreased expression of TGFBR3, FABP3, CXCR4 and CD200 was observed in AD group. CD200 expression was significantly negatively associated with TSPO PET uptake (r =—0.33, P = 0.013). Mediation analysis indicated that CD200 acted as a significant mediator between TSPO uptake and Aβ deposition (total effect B = 1.92, P = 0.004) and MMSE score (total effect B =—54.01, P = 0.003). Conclusion By integrating transcriptomics and TSPO PET imaging in the same clinical AD cohort, this study revealed CD200 played an important role in regulating neuroinflammation, Aβ deposition and cognitive dysfunction.

Background There are many metabolic pathway abnormalities in Alzheimer's disease (AD). Several studies have linked branched-chain amino acid (BCAA) metabolism disorders with AD but have not obtained consistent results. The purpose of this study is to explore the causal association between BCAA concentration and the risk of AD. Methods A bidirectional Mendelian randomized (MR) study was applied to explore the causal effect between BCAA level and the risk of AD. Genetic instrumental variables from the genome-wide association study (GWAS) of serum BCAA levels [total BCAAs (115,047 participants), valine (115,048 participants), leucine (115,074 participants), and isoleucine (115,075 participants)] from the UK Biobank and AD (21,982 AD cases and 41,944 controls) from the International Genomics of Alzheimer's Project were applied to explore the causal effect through the inverse variance-weighted (IVW) method, MR-Egger, and weighted median, accompanied by multiple pluripotency and heterogeneity tests. Results The forward MR analysis showed that there was no causal effect of total BCAAs (OR: 1.067, 95% CI: 0.838–1.358; p = 0.838), valine (OR: 1.106, 95% CI: 0.917–1.333; p = 0.292), leucine (OR: 1.096, 95% CI: 0.861–1.396; p = 0.659), and isoleucine (OR: 1.457, 95% CI: 1.024–2.742; p = 0.037) levels on the risk of AD. The reverse analysis showed that AD was related to reduced levels of total BCAAs (OR: 0.979, 95% CI: 0.989–0.990; p < 0.001), valine (OR: 0.977, 95% CI: 0.963–0.991; p = 0.001), leucine (OR: 0.983, 95% CI: 0.973–0.994; p = 0.002), and isoleucine (OR: 0.982, 95% CI: 0.971–0.992; p = 0.001). Conclusion We provide robust evidence that AD was associated with a decreased level of BCAAs, which can serve as a marker for early diagnosis of AD.

INTRODUCTION:Cognitive training and physical exercise have shown positive effects on delaying progression of mild cognitive impairment (MCI) to dementia.METHODS:We explored the enhancing effect from Tai Chi when it was provided with cognitive training for MCI. In the first 12 months, the cognitive training group (CT) had cognitive training, and the mixed group (MixT) had additional Tai Chi training. In the second 12 months, training was only provided for a subgroup of MixT.RESULTS:In the first 12 months, MixT and CT groups were benefited from training. Compared to the CT group, MixT had additional positive effects with reference to baseline. In addition, Compared to short-time training, prolonged mixed training further delayed decline in global cognition and memory. Functional magnetic resonance imaging showed more increased regional activity in both CT and MixT.DISCUSSION:Tai Chi enhanced cognitive training effects in MCI. Moreover, Tai Chi and cognitive mixed training showed effects on delaying cognitive decline.

Short-chain fatty acids (SCFAs) are important metabolites derived from the gut microbiota through fermentation of dietary fiber. SCFAs participate a number of physiological and pathological processes in the human body, such as host metabolism, immune regulation, appetite regulation. Recent studies on gut-brain interaction have shown that SCFAs are important mediators of gut-brain interactions and are involved in the occurrence and development of many neurodegenerative diseases, including Alzheimer's disease. This review summarizes the current research on the potential roles and mechanisms of SCFAs in AD. First, we introduce the metabolic distribution, specific receptors and signaling pathways of SCFAs in human body. The concentration levels of SCFAs in AD patient/animal models are then summarized. In addition, we illustrate the effects and mechanisms of SCFAs on the cognitive level, pathological features (Aβ and tau) and neuroinflammation in AD. Finally, we analyze the translational value of SCFAs as potential therapeutic targets for the treatment of AD.

BACKGROUND AND PURPOSE:Penetrance estimates of the leucine-rich repeat kinase 2 (LRRK2) variants for Parkinson disease (PD) vary widely. G2385R is one of the most common LRRK2 variants in Asian populations, and its penetrance is currently unknown. We aimed to estimate the penetrance of G2385R in the Chinese population. METHODS:The G2385R variant was tested by Sanger sequencing in 6386 participants older than 50 years, all from the community cohort established by Shanghai Ruijin Hospital in 2009-2011. G2385R carriers and matched noncarriers underwent a brief questionnaire survey (including sex, current age, PD diagnosis, and age at onset) and face-to-face PD assessment during 2020-2021. The penetrance of PD was estimated by the Kaplan-Meier method. RESULTS:A total of 396 G2385R carriers and 415 noncarriers were included, after excluding those with a baseline diagnosis of PD or unwilling to participate. In G2385R carriers, the penetrance of PD was 1.64% at 70 years, 10.26% at 80 years, and 18.49% at 90 years, and reached 25.90% at 95 years. The penetrance of PD in G2385R carriers was higher than in noncarriers (p = 0.0071). In noncarriers, only 0%, 3.72%, and 9.66% developed parkinsonism by 70, 80, and 90 years of age. Among carriers and noncarriers, there were no statistically significant differences in penetrance comparisons between males and females, or between urban and rural. CONCLUSIONS:The lifetime penetrance of LRRK2 G2385R in the Chinese population was 25.9%. The penetrance modifier of G2385R in our study was age-related. Further investigation of genetic and environmental modifiers affecting G2385R penetrance is warranted.

ABSTRACT Background The G2385R variant of leucine‐rich repeat kinase 2 (LRRK2) is mainly associated with Parkinson's disease(PD) in Asian populations. Objective The aim of this study was to investigate the PD conversion rate and clinical characteristics of LRRK2 G2385R nonmanifesting carriers. Methods All participants were from the community‐based longitudinal cohort of Shanghai Ruijin Hospital. The G2385R carriers and noncarriers were screened by Sanger sequencing and received face‐to‐face interviews at baseline and follow‐up assessments. The Kaplan–Meier method was used to compare the conversion rate of PD. Cox regression models were used to estimate the risk of G2385R variant for PD. Results In the combined cohort, 26 (7.9%) people developed PD in 329 carriers versus 9 (2.6%) in 345 noncarriers ( P = 0.0016). Cox regression model confirmed that the G2385R variant was a strong risk factor for PD in a Chinese population older than 50 years (hazard ratio, 3.314; 95% confidence interval, 1.551–7.078; P = 0.002). No difference was found in clinical symptoms between carriers and noncarriers. Conclusions We confirmed an increased conversion of PD in leucine‐rich repeat kinase 2 G2385R carriers during a 10‐year follow‐up. © 2022 International Parkinson and Movement Disorder Society.

Abstract Background Alzheimer's disease (AD) is the most common neurodegenerative disease and its pathogenesis is still unclear. There is dysbiosis of gut microbiota in AD patients. More importantly, dysbiosis of the gut microbiota has been observed not only in AD patients, but also in patients with mild cognitive impairment (MCI). However, the mechanism of gut microbiota dysbiosis in AD is poorly understood. Cholinergic anti-inflammatory pathway is an important pathway for the central nervous system (CNS) regulation of peripheral immune homeostasis, especially in the gut. Therefore, we speculated that dysfunction of cholinergic anti-inflammatory pathway is a potential pathway for dysbiosis of the gut microbiota in AD. Methods In this study, we constructed AD model mice by injecting Aβ1–42 into the lateral ventricle, and detected the cognitive level of mice by the Morris water maze test. In addition, 16S rDNA high-throughput analysis was used to detect the gut microbiota abundance of each group at baseline, 2 weeks and 4 weeks after surgery. Furthermore, immunofluorescence and western blot were used to detect alteration of intestinal structure of mice, cholinergic anti-inflammatory pathway, and APP process of brain and colon in each group. Results Aβ1–42 i.c.v induced cognitive impairment and neuron damage in the brain of mice. At the same time, Aβ1–42 i.c.v induced alteration of gut microbiota at 4 weeks after surgery, while there was no difference at the baseline and 2 weeks after surgery. In addition, changes in colon structure and increased levels of pro-inflammatory factors were detected in Aβ1–42 treatment group, accompanied by inhibition of cholinergic anti-inflammatory pathways. Amyloidogenic pathways in both the brain and colon were accelerated in Aβ1–42 treatment group. Conclusions The present findings suggested that Aβ in the CNS can induce gut microbiota dysbiosis, alter intestinal structure and accelerate the amyloidogenic pathways, which were related to inhibiting cholinergic anti-inflammatory pathways.