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INTRODUCTION: Frontotemporal dementia (FTD) is characterized by phenotypic and genetic heterogeneities. However, reports on the large Chinese FTD cohort are lacking. METHODS: Two hundred forty‐eight patients with FTD were enrolled. All patients and 2010 healthy controls underwent next generation sequencing. Plasma samples were analyzed for glial fibrillary acidic protein (GFAP), α‐synuclein (α‐syn), neurofilament light chain (NfL), and phosphorylated tau protein 181 (p‐tau181). RESULTS: Gene sequencing identified 48 pathogenic or likely pathogenic mutations in a total of 19.4% of patients with FTD (48/248). The most common mutation was the C9orf72 dynamic mutation (5.2%, 13/248). Significantly increased levels of GFAP, α‐syn, NfL, and p‐tau181 were detected in patients compared to controls (all p < 0.05). GFAP and α‐syn presented better performance for diagnosing FTD. DISCUSSION: We investigated the characteristics of phenotypic and genetic spectrum in a large Chinese FTD cohort, and highlighted the utility of plasma biomarkers for diagnosing FTD. Highlights: This study used a frontotemporal dementia (FTD) cohort with a large sample size in Asia to update and reveal the clinical and genetic spectrum, and explore the relationship between multiple plasma biomarkers and FTD phenotypes as well as genotypes.We found for the first time that the C9orf72 dynamic mutation frequency ranks first among all mutations, which broke the previous impression that it was rare in Asian patients.Notably, it was the first time the C9orf72 G4C2 repeat expansion had been identified via whole‐genome sequencing data, and this was verified using triplet repeat primed polymerase chain reaction (TP‐PCR).We analyzed the diagnostic accuracy of four plasma biomarkers (glial fibrillary acidic protein [GFAP], α‐synuclein [α‐syn], neurofilament light chain [NfL], and phosphorylated tau protein 181 [p‐tau181]) at the same time, especially for α‐syn being included in the FTD cohort for the first time, and found GFAP and α‐syn had the highest diagnostic accuracy for FTD and its varied subtypes. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The cognitive impairment patterns and the association with Alzheimer's disease (AD) in mental disorders remain poorly understood. METHODS: We analyzed data from 486,297 UK Biobank participants, categorizing them by mental disorder history to identify the risk of AD and the cognitive impairment characteristics. Causation was further assessed using Mendelian randomization (MR). RESULTS: AD risk was higher in individuals with bipolar disorder (BD; hazard ratio [HR] = 2.37, P < 0.01) and major depressive disorder (MDD; HR = 1.63, P < 0.001). MR confirmed a causal link between BD and AD (ORIVW = 1.098), as well as obsessive‐compulsive disorder (OCD) and AD (ORIVW = 1.050). Cognitive impairments varied, with BD and schizophrenia showing widespread deficits, and OCD affecting complex task performance. DISCUSSION: Observational study and MR provide consistent evidence that mental disorders are independent risk factors for AD. Mental disorders exhibit distinct cognitive impairment prior to dementia, indicating the potential different mechanisms in AD pathogenesis. Early detection of these impairments in mental disorders is crucial for AD prevention. Highlights: This is the most comprehensive study that investigates the risk and causal relationships between a history of mental disorders and the development of Alzheimer's disease (AD), alongside exploring the cognitive impairment characteristics associated with different mental disorders.Individuals with bipolar disorder (BD) exhibited the highest risk of developing AD (hazard ratio [HR] = 2.37, P < 0.01), followed by those with major depressive disorder (MDD; HR = 1.63, P < 0.001). Individuals with schizophrenia (SCZ) showed a borderline higher risk of AD (HR = 2.36, P = 0.056).Two‐sample Mendelian randomization (MR) confirmed a causal association between BD and AD (ORIVW = 1.098, P < 0.05), as well as AD family history (proxy‐AD, ORIVW = 1.098, P < 0.001), and kept significant after false discovery rate correction. MR also identified a nominal significant causal relationship between the obsessive‐compulsive disorder (OCD) spectrum and AD (ORIVW = 1.050, P < 0.05).Individuals with SCZ, BD, and MDD exhibited impairments in multiple cognitive domains with distinct patterns, whereas those with OCD showed only slight declines in complex tasks. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Whether the integration of eye‐tracking, gait, and corresponding dual‐task analysis can distinguish cognitive impairment (CI) patients from controls remains unclear. METHODS: One thousand four hundred eighty‐one participants, including 724 CI and 757 controls, were enrolled in this study. Eye movement and gait, combined with dual‐task patterns, were measured. The LightGBM machine learning models were constructed. RESULTS: A total of 105 gait and eye‐tracking features were extracted. Forty‐six parameters, including 32 gait and 14 eye‐tracking features, showed significant differences between two groups (P < 0.05). Of these, the Gait_3Back‐TurnTime and Dual‐task cost‐TurnTime patterns were significantly correlated with plasma phosphorylated tau 181 (p‐tau181) level. A model based on dual‐task gait, dual‐task smooth pursuit, prosaccade, and anti‐saccade achieved the best area under the receiver operating characteristics curve (AUC) of 0.987 for CI detection, while combined with p‐tau181, the model discriminated mild cognitive impairment from controls with an AUC of 0.824. DISCUSSION: Combining dual‐task gait and dual‐task eye‐tracking analysis is feasible for the detection of CI. Highlights: This is the first study to report the efficiency of integrated parameters of dual‐task gait and eye‐tracking for cognitive impairment (CI) detection in a large cohort.We identified 46 gait and eye‐tracking features associated with CI, and two were correlated to plasma phosphorylated tau 181.We constructed the model based on dual‐task gait, smooth pursuit, prosaccade, and anti‐saccade, achieving the best area under the curve of 0.987 for CI detection. [ABSTRACT FROM AUTHOR]

Introduction: We explored whether volatile organic compound (VOC) detection can serve as a screening tool to distinguish cognitive dysfunction (CD) from cognitively normal (CN) individuals. Methods: The cognitive function of 1467 participants was assessed and their VOCs were detected. Six machine learning algorithms were conducted and the performance was determined. The plasma neurofilament light chain (NfL) was measured. Results: Distinguished VOC patterns existed between CD and CN groups. The CD detection model showed good accuracy with an area under the receiver‐operating characteristic curve (AUC) of 0.876. In addition, we found that 10 VOC ions showed significant differences between CD and CN individuals (p < 0.05); three VOCs were significantly related to plasma NfL (p < 0.005). Moreover, a combination of VOCs with NfL showed the best discriminating power (AUC = 0.877). Discussion: Detection of VOCs from exhaled breath samples has the potential to provide a novel solution for the dilemma of CD screening. [ABSTRACT FROM AUTHOR]

Background: Various studies indicated that the immune system is a cardinal feature of Alzheimer's disease (AD), which can either ameliorate or exacerbate AD neuropathogenesis. Nevertheless, the associations between genes involved in the immune system and AD remain unclear. Method: To systematically evaluate the associations of these genes with AD, we investigated 370 genes implicated in the immune system based on previous studies selected using the PubMed database. Our study recruited 1511 AD patients and 2001 cognitively normal controls. 370 genes were sequenced using a targeted panel. Variants were classified into common or rare variants with the minor allele frequencies (MAF) cutoff of 0.01. Common variant (MAF≥0.01)‐based association test was performed by PLINK 1.9, and gene‐based (MAF <0.01) association analysis was conducted using Sequence Kernel Association Test‐Optimal (SKAT‐O test) by combining rare variants between AD patients and cognitively normal controls. Rare variants were further categorized as followings: rare damaging variants (MAF <0.01, LoF or ReVe >0.7), rare damaging missense variants (MAF <0.01, ReVe >0.7), rare LoF variants (MAF <0.01, LoF), and rare missense variants (MAF <0.01, missense). Age, sex, and APOE ε4 status were adjusted in our study. Result: After quality control, 73,885 common variants were left. A common variant, MGMT rs147073440, was suggestively associated with AD risk after adjusting for age, sex, and APOE ε4 status and performing the Bonferroni correction {adjusted P = 1.62 × 10‐6, odds ratio (OR) [95% confidence interval (CI)] = 2.726 (1.809‐4.106)}. 250 genes with rare damaging variants were analyzed in our study. The gene‐based association analysis revealed that the rare damaging variants in the RAB37 and EPCAM genes were nominally associated with AD (p <0.004). Conclusion: This study suggested that MGMT rs147073440 and rare damaging variants in RAB37 and EPCAM may be implicated in AD pathogenesis. [ABSTRACT FROM AUTHOR]

Background: Genetics plays an important role in dementia with Lewy bodies (DLB) and remains poorly understood. Previous research has identified several genes associated with DLB, including APOE, GBA, SNCA, BIN1, TMEM175, PLCG2, and CNTN1. To date, genetic studies on DLB have focused on Caucasian population. The gaps in DLB genetic study on East Asian populations need to be filled. Therefore, we conducted a comprehensive genome‐wide association study (GWAS) to identify genetic risk factors for DLB in China. Method: We performed whole‐genome sequencing on a cohort of 143 patients with DLB and 2007 healthy controls. Common variant‐based association analysis was conducted using PLINK 1.9, while gene‐based association tests for rare variants were performed using the sequence kernel association test‐optimal. Adjustments were made for gender, age, and principal components. Additionally, PLINK 1.9 was used to test variants associated with the onset age of DLB. Result: Our results confirmed previously reported associations with common variants to a certain extent, particularly the APOE gene (rs429358, p = 1.71 × 10–10). No rare‐damaging variants were significantly associated with DLB in our cohort. In the rare‐missense‐variant groups, the combined effect for USP13 gene showed suggestive association with DLB at p‐value < 1 × 10−4 (p = 7.75 × 10‐5). The protein encoded by the USP13 gene has been considered a major contributing factor to the presence of Lewy bodies based on previous research. No variants were associated with the onset age of DLB. Conclusion: Despite the small sample size for a genome‐wide association study, we present the first comprehensive study in dementia with Lewy bodies in China so far. These data show that common genetic variability has a role in the disease. Further replication study of USP13 gene will be important. [ABSTRACT FROM AUTHOR]

Background: Single nucleotide polymorphism (SNP)‐based genetic studies have identified many risk genes for Alzheimer's disease (AD), but only explain part of the heritability. Structural variation (SVs) may account for some of this otherwise unexplained heritability. In this study, we sequenced 1,519 AD patients and 2,010 controls using 30X whole‐genome sequencing (WGS). Method: Using six complementary CNV callers, we generated a high‐confidence CNV set. We reviewed rare variants within the reported 117 causal genes for dementia in our cohort. We also assessed the linkage disequilibrium (LD) between single nucleotide variants (SNVs) and copy number variants (CNVs). Result: We identified 66990 deletions and 10906 duplications. On dementia genes, we observed the a total of 28 AD patients carried with rare CNVs in APP (duplication, 1 EOAD, Known pathogenicity), OPTN (deletion, 6 AD and 2 control), PRKAR1B (duplication, 1 EOAD), VPS13A (deletion, 1 EOAD), and et al. LD Analysis revealed that a 5.2 Kb deletion in NBEAL1 intron highly LD (R2 = 0.95) with rs139643391 (chr2:202878716) and a 291bp deletion in TMEM106B highly LD (R2 = 0.97) with rs5011436 (chr7: 12229132). Conclusion: Overall, our findings suggest that the occurrence of APP locus duplication appears to be less common in the Chinese population. Other rare CNV variants in dementia genes may have potentially pathogenic and further validation of their pathogenicity is needed. [ABSTRACT FROM AUTHOR]

Introduction: Observational studies have reported inconsistent results on the relationship between age‐related macular degeneration (AMD) and Alzheimer's disease (AD). Therefore, we aimed to determine whether there is a causal association between AMD and AD. Methods: This two‐sample bidirectional Mendelian randomization (MR) study evaluated causal associations between advanced AMD and AD using summary data from large genome‐wide association studies. Results: Genetic liability for advanced AMD showed no statistical causal association with AD risk (odds ratio [OR] = 0.999, 95% confidence interval [CI]: 0.955–1.044, P =.948). Reverse MR analysis provided little support for a causal effect of AD on advanced AMD (OR = 0.973, 95%CI: 0.938–1.008, P =.133). Discussion: This MR study found no evidence to support a bidirectional causality between advanced AMD and AD. Highlights: We evaluated the bidirectional causal relationship between advanced AMD and AD.Advanced AMD showed no statistical causal association with risk of AD.We found no evidence to support a causal effect of AD on advanced AMD risk.The associations observed in epidemiological studies should not be considered causal. [ABSTRACT FROM AUTHOR]

Background: It has been shown that Aß is a normal component in urine (Ghiso et al, FEBS Lett, 1997) and may change with disease status (Takata et al, Neurosci Lett, 2008), however, research on amyloid in urine has been neglected for long time. Method: We examined β amyloid proteins in urine from cognitive normal and dementia patients including Alzheimer's disease (AD) and frontotemporal dementia (FTD) using Western blotting. Result: Several protein fragments were identified including the 12KD and 14KD bands recognized by the anti‐APP C‐termini antibody (Ab369), 14KD and 28KD bands by W0‐2 (Figure 1), and 28KD, 56KD and 68KD bands by Aducanumab (Figure 2) and anti‐APP N‐termini antibody (22C11). Further analysis with immunoprecipitation and mass spectrometry confirmed the presence of various APP fragments and Aß in urine. One type of peptide was found to have high affinity to Aß and APP fragments using microscale thermophoresis and circular dichroism spectroscopy. With the assistance from AIBL, we further invented a lateral flow immunoassay device with colloidal gold nanoparticles coated with anti‐APP/Aß antibodies. In the early clinical trials with aged people and children, 95% of dementia patients, 90% of MCI, 85% of SMC showed positivity while 90% of healthy children were negative. The second quality examination was performed in Oriental (Dongfeng) Hospital (Pudong, Shanghai) in Mar‐June 2022. The examination of detection limit, critical threshold, repeatability, tolerance to interferences (creatinine, protein, glucose, nitrites, pH) was performed and all passed. Furthermore, 43 of 49 cases showed positive (87.7%) while only 1 out of 30 controls was positive (3.3%). Since then, the device has been tested in a dozen of large hospitals and pathology laboratories in China, all provided positive feedback. The preliminary results from 175 AIBL participants showed overall 83.8% positivity to clinically diagnosed MCI (n = 37), while for those Aβ PET scan negative MCI (n = 17), positivity was 94.1% (Figure 3). Conclusion: Our results indicates the high accuracy of this device, which has high potential to be used as an early screening tool for MCI and dementia. The longitudinal studies are currently undergoing in China (Xiangya Hospital) and in Australia (AIBL). [ABSTRACT FROM AUTHOR]

Introduction: The genetic risk effects of apolipoprotein E (APOE) on familial Alzheimer's disease (FAD) with or without gene mutations, sporadic AD (SAD), and normal controls (NC) remain unclear in the Chinese population. Methods: In total, 15 119 subjects, including 311 FAD patients without PSEN1, PSEN2, APP, TREM2, and SORL1 pathogenic mutations (FAD [unknown]); 126 FAD patients with PSENs/APP mutations (FAD [PSENs/APP]); 7234 SAD patients; and 7448 NC were enrolled. The risk effects of APOE ε4 were analyzed across groups. Results: The prevalence of the APOE ε4 genotype in FAD (unknown), FAD (PSENs/APP), SAD, and NC groups was 56.27%, 26.19%, 36.23%, and 19.54%, respectively. Further, the APOE ε4 positive genotype had predictive power for FAD (unknown) risk (odds ratio: 4.51, 95% confidence interval: 3.57–5.45, P <.001). Discussion: APOE ε4 positive genotype may cause familial aggregation, and the investigation of multiple interventions targeting APOE pathological function to reduce the risk for this disease warrants attention. [ABSTRACT FROM AUTHOR]

Background: The genetic risk effects of apolipoprotein E (APOE) on familial Alzheimer's disease (FAD) with or without gene mutations, sporadic AD (SAD), and normal controls (NC) remain unclear in the Chinese population. Previous genome‐wide association studies (GWAS) have identified dozens of susceptibility loci for sporadic Alzheimer's disease, but few of these loci have been validated in longitudinal cohorts. Method: More than 15 thousand Chinese subjects, including FAD patients with or without pathogenic mutations (PSENs/APP), SAD patients, and normal controls (NC) were included from our large multi‐center FAD and SAD cohorts. We analyzed the risk effects of APOE ε4 and performed a two‐stage GWAS and built predictive models. Result: The prevalence of the APOE ε4 genotype in FAD (unknown), FAD (PSENs/APP), SAD, and NC groups was 56.27%, 26.19%, 36.23%, and 19.54%, respectively. The APOE ε4 positive genotype had predictive power for FAD (unknown) risk (fig. 1, odds ratio: 4.51, 95% confidence interval: 3.57–5.45, P<.001). Four novel variants (rs3777215, rs6859823, rs234434, and rs2255835) as well as nine variants in the APOE region were identified with genome‐wide significance. They are related to APP transport and metabolism, antioxidation, and neurogenesis. Using these variants, we built 11 predictive models that were all significant in predicting AD onset in both stages (fig. 2, peak of area under the curve reached 0.73). These models were validated using a separate longitudinal cohort, and results showed that individuals carrying risk variants included in the models had a shorter latency and higher incidence of AD. Conclusion: APOE ε4 positive genotype may cause familial aggregation, and the investigation of multiple interventions targeting APOE pathological function to reduce the risk for this disease warrants attention. This is the first study to validate GWAS‐based predictive models for evaluating the risk of AD onset in a large Chinese population. The clinical application of these models will be beneficial for individuals harbouring these risk variants. [ABSTRACT FROM AUTHOR]

Background: Electroencephalogram (EEG) has emerged as a non‐invasive tool to detect the aberrant neuronal activity related to different stages of Alzheimer's disease (AD). However, the effectiveness of EEG in the precise diagnosis and prediction of AD and its preclinical stage, mild cognitive impairment (MCI), has yet to be fully elucidated. In this study, we aimed to identify key EEG biomarkers that are effective in distinguishing patients at the early stage of AD and monitoring the progression of AD. Method: A total of 890 participants, including 189 patients with MCI, 330 patients with AD, 125 patients with other dementias (frontotemporal dementia, dementia with Lewy bodies, and vascular cognitive impairment), and 246 healthy controls (HC) were enrolled. Biomarkers were extracted from resting‐state EEG recordings for a three‐level classification of HC, MCI, and AD. The optimal EEG biomarkers were then identified based on the classification performance. Random forest regression was used to train a series of predictive models by combining participants' EEG biomarkers, demographic information (i.e., sex, age), CSF biomarkers, and APOE phenotype for predicting the disease progression and individual's cognitive function. Result: The identified EEG biomarkers achieved over 70% accuracy in the three‐level classification of HC, MCI, and AD. Among all six groups, the most prominent effects of AD‐linked neurodegeneration on EEG metrics were localized at parieto‐occipital regions. Noteworthy, the absolute theta power of channel O2 was negatively correlated with Aβ42 (r = ‐0.358, p < 0.001) and positively correlated with p‐tau (r = 0.442, p < 0.001). In terms of cognitive assessment, the Hjorth mobility of channel O1, O2 and P4 were found to be positively associated with MMSE and MoCA scores (r = 0.416‐0.464, all p < 0.001). In the predictive analyses, the optimal EEG features were more effective than the CSF + APOE biomarkers in predicting the age of onset and disease course, whereas the combination of EEG + CSF + APOE measures achieved the best performance for all targets of prediction. Conclusion: Our study indicates that EEG can be used as a useful screening tool for the diagnosis and disease progression evaluation of MCI and AD. [ABSTRACT FROM AUTHOR]

Background: Autoimmunity plays a key role in the pathogenesis of Alzheimer's disease (AD); however, whether autoantibodies in peripheral blood can be used as biomarkers has not been reported. Method: Serum samples were obtained from 767, 146, and 255 patients with AD, mild cognitive impairment (MCI), and other neurodegenerative diseases, respectively, and 518 healthy controls. Specific autoantibodies were measured using a custom‐made immunoassay. Multivariate support vector machine models were employed to investigate the correlation between serum autoantibody levels and disease states. Result: Seven candidate AD‐specific autoantibodies were identified, and a classification model with high accuracy (area under the curve (AUC) = 0.94) was established. Importantly, these autoantibodies could distinguish AD from other neurodegenerative diseases and out‐performed amyloid and tau protein concentrations in cerebrospinal fluid in predicting cognitive decline (P < 0.001). Conclusion: AD onset and progression are associated with an unappreciated serum autoantibody response. Therefore, future studies could optimize its application as a convenient biomarker for the early detection of AD. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is a neurodegenerative disease, characterized by glial cell dysfunction and progressive neuron loss, leading to varying degrees of neuropathology and cognition impairment. Aging and epigenetic alterations accompany the progression of AD and disrupt cellular functions; therefore, whether reprogramming could restore epigenetic information while maintaining cellular identity remains unclear. Method: The polycistronic expression cassette contained multiple transcription factors of the Oct4, Sox2, and Klf4 genes (OSK) that were cloned into a coexpression vector (Ad‐OSK). The effects of OSK on cognitive function and neuropathology were explored in 4‐month‐old and 6‐month‐old APP/PS1 transgenic AD model mice via stereotaxic injection into the bilateral hippocampus. Result: Ad‐OSK maintained microglial and neuronal cellular identities while attenuating microglia‐induced neuroinflammation and neuronal apoptosis. Ectopic expression of OSK in mouse brain tissue alleviates and restores cognitive function, youthful neuronal pathogenesis, Aβ plaque deposition, microglial activation, and myelin damage in early stage and later stage AD mice, respectively. The DNA demethylation process is required for the beneficial effects of OSK induced reprogramming in brain health. Conclusion: These results suggest that brain tissues preserve youthful epigenetic information, which is primarily stored by DNA demethylation during OSK reprogramming and can be accessed to improve brain health in AD mice. Our findings provide the foundation for the future use of OSK adenovirus or mRNA medicine to treat AD. [ABSTRACT FROM AUTHOR]

Background: Inadequate osteogenesis and excessive adipogenesis of bone marrow mesenchymal stem cells (BMSCs) are key factors in the pathogenesis of osteoporosis. Patients with Alzheimer's disease (AD) have a higher incidence of osteoporosis than healthy adults, but the underlying mechanism is not clear. The aim of this study was to investigate the role of brain‐derived extracellular vesicles (EVs) from AD mice on the regulation of bone metabolism. Method: Brain‐derived EVs from AD or wide‐type mice was injected into C57BL/6 mice intravenously once a week for two months. Result: Here, we show that brain‐derived EVs from adult AD or wild‐type mice can cross the blood‐brain barrier to reach the distal bone tissue, while only AD brain‐derived EVs (AD‐B‐EVs) significantly promote the shift of the BMSC differentiation fate from osteogenesis to adipogenesis and induce a bone‐fat imbalance. MiR‐483‐5p is highly enriched in AD‐B‐EVs, brain tissues from AD mice, and plasma‐derived EVs from AD patients. This miRNA mediates the anti‐osteogenic, pro‐adipogenic, and pro‐osteoporotic effects of AD‐B‐EVs by inhibiting Igf2. Conclusion: This study identifies the role of B‐EVs as a promoter of osteoporosis in AD by transferring miR‐483‐5p. [ABSTRACT FROM AUTHOR]

Background: Optical coherence tomography (OCT), is an advanced, noninvasive technology that can provide the images of retinal structure, including peripapillary retinal nerve fiber layer (pRNFL), macular retinal thickness (MRT), as well as macular volume (MV). However, whether the retinal structure varied in Alzheimer's disease (AD) patients was still unclear. This study aims to detect the retinal changes of AD patients and explore their correction with severity of disease and classic biomarker. Method: 78 AD patients and 188 HC matched with age and sex were enrolled in this study. The pRNFL thickness, MRT and MV were assessed using OCT. In addition, Aβ42, Aβ40 and tau protein in plasma were detected using Simoa technology. Result: The results showed that the pRNFL thickness of AD patients was significantly thinner than HC (96.76±10.44 vs 101.4±17.74, p=0.023). Compared with HC, MRT and MV were reduced in AD patients, but the differences were not significant(p>0.05). Furthermore, the pRNFL thickness was significantly negatively correlated with MMSE (r=‐0.362, p=0.005) and disease duration (r=‐0.295, p=0.002); In addition, the pRNFL thickness was positively correlated with t‐tau protein in plasma(r=0.409, p=0.002); while negatively correlated with Aβ42/40 in plasma(r=‐0.277, p=0.041). However, there was no significant correction between neither MRT nor MV and MMSE, disease duration, Aβ42, Aβ40 and tau protein in plasma (p>0.05). Conclusion: These results supported that pRNFL thickness measured using OCT may serve as a useful predictor of AD. [ABSTRACT FROM AUTHOR]

Background: Amyloid protein deposition is a common mechanism of hereditary amyloidosis (HA) and Alzheimer's disease (AD). Mutations in gelsolin (GSN), cystatin C (CST3), transthyretin (TTR) and integral membrane protein 2B (ITM2B) genes can lead to HA. But the relationship is unclear between these genes and AD. Method: Genes targeted sequencing (GTS), including GSN, CST3, TTR and ITM2B, was performed in a total of 636 patients with clinical AD and 365 normal controls from China. Result: According to American College of Medical Genetics and Genomics (ACMG) guidelines, two novel likely pathogenic frame‐shift mutations (GSN: p.K346fs and GSN: p.P3fs) were detected in five patients with AD, whose initial symptom was memory decline, accompanied with psychological and behavioral abnormalities later. Interestingly, the patient with K346fs mutation, presented cerebral β‐amyloid protein deposition, had an early onset (48 years) and experienced rapid progression, while other four patients with P3fs mutation had a late onset ((Mean ± SD): 69.50 ± 5.20 years) and a long course of illness ((Mean ± SD): 9.24 ± 4.86 years). Conclusion: To our knowledge, we firstly report AD phenotype with GSN mutations in patients with AD in Chinese cohort. Although mutations in GSN gene are rare, it may explain a small portion of clinically diagnosed AD. [ABSTRACT FROM AUTHOR]

Background: Genome‐wide association studies (GWAS) and whole‐exome sequencing have identified a number of risk genes playing a significant role in the pathogenesis of Alzheimer's disease (AD). However, most of the genetic studies are from Caucasian populations and relatively rare in Chinese population. Method: We sequenced 33 AD risk genes using Targeted panel sequencing in 721 AD patients and 365 normal controls in Han population of Southern China. A series of bioinformatic methods including common‐variant (0.01≤MAF≤0.5) based association analysis and gene‐based association analysis on rare variants (MAF<0.01) were performed between AD patients and normal controls. Result: We identified nine common variants with significant differences, three of them had been reported, including rs429358 in APOE, rs4147929 in ABCA7 and rs3752246 in ABCA7, while other six variants were novel, including rs3752229 in ABCA7, rs4147935 in ABCA7, rs17125497 in SORL1, rs2282647 in SORL1, rs11218355 in SORL1, and rs11682128 in BIN1. The area under the ROC (AUC) of the nine significant loci model was 0.670. Gene‐based association analysis on rare variants showed that the p value of RIN3 was less than 0.05 both in the Sequence Kernel Association Test‐Optimal (SKAT‐O) test and logistic regression analysis (age, gender and APOE ε4 as covariates) between AD patients and normal controls (p = 0.0399, corrected P = 0.0346). Conclusion: We conclude that APOE, ABCA7, SORL1, BIN1 and RIN3 are risk factors for AD in Chinese population. [ABSTRACT FROM AUTHOR]