The risk of Alzheimer's disease and cognitive impairment characteristics in eight mental disorders: A UK Biobank observational study and Mendelian randomization analysis.

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.

Genetic spectrum features and diagnostic accuracy of four plasma biomarkers in 248 Chinese patients with frontotemporal dementia.

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.

A detection model of cognitive impairment via the integrated gait and eye movement analysis from a large Chinese community cohort.

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.

A detection model for cognitive dysfunction based on volatile organic compounds from a large Chinese community cohort.

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.

Genetics of progressive supranuclear palsy in a Chinese population.

BACKGROUND: Genetics plays an important role in progressive supranuclear palsy (PSP) and remains poorly understood. A detailed literature search identified 19 PSP-associated genes: MAPT, LRRK2, LRP10, DCTN1, GRN, NPC1, PARK, TARDBP, TBK1, BSN, GBA, STX6, EIF2AK3, MOBP, DUSP10, SLCO1A2, RUNX2, CXCR4, and APOE. To date, genetic studies on PSP have focused on Caucasian population. The gaps in PSP genetic study on East Asian populations need to be filled. METHODS: Exon and flanking regions of the PSP-associated genes were sequenced in 104 patients with PSP and 488 healthy controls. Common variant-based association analysis and gene-based association tests of rare variants were performed using PLINK 1.9 and the sequence kernel association test-optimal, respectively. Additionally, the association of APOE and MAPT genotypes with PSP was evaluated. The above association analyses were repeated among probable PSP patients. Finally, PLINK 1.9 was used to test variants associated with the onset age of PSP. RESULTS: A rare non-pathogenic variant of MAPT (c.425C > T,p.A142V) was detected in a PSP patient. No common variants were significantly associated with PSP. In both the rare-variant and the rare-damaging-variant groups, the combined effect for GBA reached statistical significance (p = 1.43 × 10-3, p = 4.98 × 10-4). The result between APOE, MAPT genotypes and PSP risk were inconsistent across all PSP group and probably PSP group. CONCLUSIONS: The pathogenic variant in MAPT were uncommon in PSP patients. Moreover, GBA gene was likely to increase the risk of PSP, and GBA-associated diseases were beyond α-synucleinopathies. The association between APOE, MAPT and PSP is still unclear among the non-Caucasian population.

Lack of association between LGMN and Alzheimer's disease in the Southern Han Chinese population.

Recently, functional studies have demonstrated that legumain (LGMN) cleaves both amyloid ß-protein precursor and tau, promoting senile plaques and formation of neurofibrillary tangles, which may play a crucial role in the pathogenesis of Alzheimer's disease (AD). However, the genetic role of LGMN in AD has not been clearly elucidated. Here, we used Sanger sequencing to investigate the single independent (single-variant association test) and cumulative (gene-based association test) effects of variants in the LGMN gene as potential susceptibility factors for AD, in a cohort comprising 676 AD cases and 365 elderly controls from the Han population of South China. In single-variant association analysis, none of the common variants in LGMN were statistically significant. In gene-based analysis, the LGMN gene also showed no association with AD. The results of our replication study in the Alzheimer's Disease Neuroimaging Initiative cohort also showed no association between LGMN and AD. These findings suggest that the LGMN gene may not be a critical factor for AD development.

The prevalence and risk factors study of cognitive impairment: Analysis of the elderly population of Han nationality in Hunan province, China.

OBJECTIVE: A large number of studies have found that the prevalence of cognitive impairment varies in different regions. However, data on cognitive impairment in the Chinese population is still lacking. The goal of this study was to assess the prevalence of cognitive impairment among the elderly in a region of China and explore the associated risk factors. METHODS: We performed a population-based cross-sectional survey from April to June 2022. Residents come from three villages and six urban communities in the county-level city of Liuyang in southern China (N = 3233) and the coverage rate of our study population reached 73%. Participants were assessed with a series of clinical examinations and neuropsychological measures. A total of 2598 participants were selected after filtering out those under 60 years old or with incomplete data. Patients with cognitive impairment included those with mild cognitive impairment (MCI) or dementia who met standard diagnostic criteria. RESULTS: The prevalence of cognitive impairment, MCI, and dementia among participants aged 60 years and older were 21.48% (95% CI, 19.90-23.10), 15.70% (95% CI, 14.30-17.10), and 5.77 (95% CI, 4.90-6.70), respectively. And residents in villagers were more likely to have cognitive impairment than in urban communities (p < 0.001). Age growth and education level were independent influencing factors for cognitive impairment in all populations (p < 0.001). For lifestyles factors, both smoking and drinking reduced the risk of cognitive impairment (p < 0.05), but when further quantified, the link disappeared. Moreover, having cerebrovascular disease and severe vision impairment were risk factors (p < 0.05). CONCLUSION: A representative prevalence of cognitive impairment, MCI, and dementia was found in the elderly Han Chinese population in Southern China. And we further explored the role of known risk factors, particularly in physical activity, smoking, and alcohol consumption.

Correlation between retinal structure and brain multimodal magnetic resonance imaging in patients with Alzheimer's disease.

Background: The retina imaging and brain magnetic resonance imaging (MRI) can both reflect early changes in Alzheimer's disease (AD) and may serve as potential biomarker for early diagnosis, but their correlation and the internal mechanism of retinal structural changes remain unclear. This study aimed to explore the possible correlation between retinal structure and visual pathway, brain structure, intrinsic activity changes in AD patients, as well as to build a classification model to identify AD patients. Methods: In the study, 49 AD patients and 48 healthy controls (HCs) were enrolled. Retinal images were obtained by optical coherence tomography (OCT). Multimodal MRI sequences of all subjects were collected. Spearman correlation analysis and multiple linear regression models were used to assess the correlation between OCT parameters and multimodal MRI findings. The diagnostic value of combination of retinal imaging and brain multimodal MRI was assessed by performing a receiver operating characteristic (ROC) curve. Results: Compared with HCs, retinal thickness and multimodal MRI findings of AD patients were significantly altered (p < 0.05). Significant correlations were presented between the fractional anisotropy (FA) value of optic tract and mean retinal thickness, macular volume, macular ganglion cell layer (GCL) thickness, inner plexiform layer (IPL) thickness in AD patients (p < 0.01). The fractional amplitude of low frequency fluctuations (fALFF) value of primary visual cortex (V1) was correlated with temporal quadrant peripapillary retinal nerve fiber layer (pRNFL) thickness (p < 0.05). The model combining thickness of GCL and temporal quadrant pRNFL, volume of hippocampus and lateral geniculate nucleus, and age showed the best performance to identify AD patients [area under the curve (AUC) = 0.936, sensitivity = 89.1%, specificity = 87.0%]. Conclusion: Our study demonstrated that retinal structure change was related to the loss of integrity of white matter fiber tracts in the visual pathway and the decreased LGN volume and functional metabolism of V1 in AD patients. Trans-synaptic axonal retrograde lesions may be the underlying mechanism. Combining retinal imaging and multimodal MRI may provide new insight into the mechanism of retinal structural changes in AD and may serve as new target for early auxiliary diagnosis of AD.

Clinical features of progressive supranuclear palsy.

Background: Progressive supranuclear palsy (PSP) is a clinically heterogenous atypical parkinsonian syndrome. Therefore, early recognition and correct diagnosis of PSP is challenging but essential. This study aims to characterize the clinical manifestations, magnetic resonance imaging (MRI), and longitudinal MRI changes of PSP in China. Method: Clinical and MRI presentations were compared among 150 cases with PSP. Then the longitudinal MRI changes among 20 patients with PSP were further explored. Additionally, a series of midbrain-based MRI parameters was compared between PSP-P and PD. Results: Throughout the course of the disease, there were differences in the symptoms of the fall and hand tremor between the PSP-RS and PSP-P. There were significant differences in the six midbrain-based MRI parameters between the PSP-RS and the PSP-P, including hummingbird sign, midbrain diameter, midbrain to pons ratio (MTPR), midbrain area, midbrain area to pons area ratio (Ma/Pa), and midbrain tegmental length (MBTegm). Longitudinal MRI studies revealed that the annual rel.ΔMTPR and rel.Δ (Ma/Pa) for PSP were 5.55 and 6.52%, respectively; additionally, PSP-RS presented a higher decline rate than PSP-P. Moreover, MTPR ≤0.56, midbrain diameter ≤ 0.92, midbrain area ≤ 1.00, and third ventricle width ≤ 0.75 could identify PSP-P from PD. Conclusion: PSP-P differs from PSP-RS regarding clinical manifestations, MRI, and longitudinal MRI changes. MRI parameters could be potential imaging markers to identify PSP-P from PD.

The associations of APP, PSEN1, and PSEN2 genes with Alzheimer's disease: A large case-control study in Chinese population.

AIM: The associations of non-pathogenic variants of APP, PSEN1, and PSEN2 with Alzheimer's disease (AD) remain unclear. This study is aimed at determining the role of these variants in AD. METHODS: Our study recruited 1154 AD patients and 2403 controls. APP, PSEN1, PSEN2, and APOE 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). Additionally, using PLINK 1.9, we performed AD endophenotypes association studies. RESULTS: A common variant, PSEN2 rs11405, was suggestively associated with AD risk (p = 1.08 × 10-2 ). The gene-based association analysis revealed that the APP gene exhibited a significant association with AD (p = 1.43 × 10-2 ). In the AD endophenotypes association studies, APP rs459543 was nominally correlated with CSF Aß42 level (p = 7.91 × 10-3 ). CONCLUSION: Our study indicated that non-pathogenic variants in PSEN2 and APP may be involved in AD pathogenesis in the Chinese population.

Mendelian randomization analyses of smoking and Alzheimer's disease in Chinese and Japanese populations.

Background: Previous epidemiological studies have reported controversial results on the relationship between smoking and Alzheimer's disease (AD). Therefore, we sought to assess the association using Mendelian randomization (MR) analysis. Methods: We used single nucleotide polymorphisms (SNPs) associated with smoking quantity (cigarettes per day, CPD) from genome-wide association studies (GWAS) of Japanese population as instrumental variables, then we performed two-sample MR analysis to investigate the association between smoking and AD in a Chinese cohort (1,000 AD cases and 500 controls) and a Japanese cohort (3,962 AD cases and 4,074 controls), respectively. Results: Genetically higher smoking quantity showed no statistical causal association with AD risk (the inverse variance weighted (IVW) estimate in the Chinese cohort: odds ratio (OR) = 0.510, 95% confidence interval (CI) = 0.149-1.744, p = 0.284; IVW estimate in the Japanese cohort: OR = 1.170, 95% confidence interval CI = 0.790-1.734, p = 0.434). Conclusion: This MR study, for the first time in Chinese and Japanese populations, found no significant association between smoking and AD.

Brain-derived extracellular vesicles promote bone-fat imbalance in Alzheimer's disease.

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. Here, we show that brain-derived extracellular vesicles (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. This study identifies the role of B-EVs as a promoter of osteoporosis in AD by transferring miR-483-5p.

Neural biomarker diagnosis and prediction to mild cognitive impairment and Alzheimer's disease using EEG technology.

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 assessment of AD and its preclinical stage, amnestic 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. METHODS: 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 models by combining participants' EEG biomarkers, demographic information (i.e., sex, age), CSF biomarkers, and APOE phenotype for assessing the disease progression and individual's cognitive function. RESULTS: 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. In the cross-validation 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. CONCLUSIONS: Our study indicates that EEG can be used as a useful screening tool for the diagnosis and disease progression evaluation of MCI and AD.

Primary familial brain calcification in a patient with a novel compound heterozygous mutation in MYORG presenting with an acute ischemic stroke: a case report.

Primary familial brain calcification (PFBC) is known as Fahr's disease (FD) or familial idiopathic basal ganglia calcification (FIBGC). PFBC is a genetically heterogeneous disease characterized by extensive intracranial calcium deposition. Currently, pathogenic variants in six genes (SLC20A2, PDGFB, PDGFRB, XPR1, MYORG and JAM2) have been associated with PFBC. MYORG was the first autosomal-recessive causal gene discovered in PFBC patients. PFBC is also a clinically heterogeneous disorder. Patients mostly present with movement disorders, cognitive impairment and psychiatric symptoms, and acute cerebrovascular attacks are rare. Here, we report the case of a PFBC patient with a novel compound heterozygous mutation in MYORG presenting with an acute ischemic stroke. A 52-year-old man had recurrent and progressively exacerbated transient-ischemic-attack-like episodes and finally had an acute ischemic stroke. Brain computed tomography (CT) showed extensive and symmetric calcifications. Brain magnetic resonance imaging (MRI) revealed an acute ischemic infarction. A novel compound heterozygous mutation in MYORG (p.R116_S117insLAFR and p.Q445*) was found in this patient by whole-exome sequencing (WES). Therefore, this patient was diagnosed with PFBC-MYORG and an acute ischemic stroke. He was treated with antiplatelet drugs (aspirin and clopidogrel) and received rehabilitation training. There was no physical disability at discharge. More efforts should be made to explore the association between acute ischemic strokes and PFBC.

Cerebrospinal Fluid Synaptosomal-Associated Protein 25 Levels in Patients with Alzheimer's Disease: A Meta-Analysis.

BACKGROUND: Several studies have shown increased levels of cerebrospinal fluid (CSF) synaptosomal-associated protein 25 (SNAP-25) in patients with Alzheimer's disease (AD). However, results have been inconsistent thus far. OBJECTIVE: We conducted meta-analyses summarizing the associations of CSF SNAP-25 levels with AD to assess the utility of SNAP-25 as a novel biomarker for AD. METHODS: We conducted a meta-analysis of differences in CSF SNAP-25 levels in patients with AD or mild cognitive impairment (MCI) and in cognitively healthy controls (HC). We calculated pooled correlation coefficients comparing SNAP-25 levels and total tau (T-tau) or hyperphosphorylated tau (P-tau) in CSF. RESULTS: Eight studies enrolling 1,162 individuals (423 AD, 275 MCI, 464 HC) were included for quantitative analysis. Patients with AD (ratio of means [RoM] = 1.50, 95% confidence interval [CI]: 1.30,1.74) and MCI (RoM = 1.45, 95% CI: 1.12,1.87) had increased levels of CSF SNAP-25 as compared to HC. The difference in CSF SNAP-25 levels when comparing AD and MCI (RoM = 1.05, 95% CI: 0.96,1.14) was not statistically significant but showed a trend toward significance. Statistically significant correlations were found when comparing CSF SNAP-25 with CSF T-tau (Spearman correlation coefficient, ρ=0.78; ρ=0.66; ρ=0.69, respectively) and P-tau (ρ=0.77; ρ=0.70; ρ=0.62, respectively) levels in patients with AD, MCI, and HC. CONCLUSION: Increased CSF SNAP-25 levels differentiated patients with AD or MCI from controls, suggesting the utility of this biomarker in the early diagnosis of AD.

Association Between Serum Vitamins and the Risk of Alzheimer's Disease in Chinese Population.

BACKGROUND: Alzheimer's disease (AD) is a chronic and fatal neurodegenerative disease; accumulating evidence suggests that vitamin deficiency is associated with the risk of AD. However, studies attempting to elucidate the relationship between vitamins and AD varied widely. OBJECTIVE: This study aimed to investigate the relationship between serum vitamin levels and AD in a cohort of the Chinese population. METHODS: A total of 368 AD patients and 574 healthy controls were recruited in this study; serum vitamin A, B1, B6, B9, B12, C, D, and E were measured in all participants. RESULTS: Compared with the controls, vitamin B2, B9, B12, D, and E were significantly reduced in AD patients. Lower levels of vitamin B2, B9, B12, D, and E were associated with the risk of AD. After adjusting for age and gender, low levels of vitamin B2, B9, and B12 were still related to the risk of AD. In addition, a negative correlation was determined between vitamin E concentration and Activity of Daily Living Scale score while no significant association was found between serum vitamins and age at onset, disease duration, Mini-Mental State Examination, and Neuropsychiatric Inventory Questionnaire score. CONCLUSION: We conclude that lower vitamin B2, B9, B12, D, and E might be associated with the risk of AD, especially vitamin B2, B9, and B12. And lower vitamin E might be related to severe ability impairment of daily activities.

Associations of risk genes with onset age and plasma biomarkers of Alzheimer's disease: a large case-control study in mainland China.

Most genetic studies concerning risk genes in Alzheimer's disease (AD) are from Caucasian populations, whereas the data remain limited in the Chinese population. In this study, we systematically explored the relationship between AD and risk genes in mainland China. We sequenced 33 risk genes previously reported to be associated with AD in a total of 3604 individuals in the mainland Chinese population. Common variant (MAF ≥ 0.01) based association analysis and gene-based (MAF < 0.01) association test were performed by PLINK 1.9 and Sequence Kernel Association Test-Optimal, respectively. Polygenic risk score (PRS) was calculated, and receiver operating characteristic curve (AUC) was computed. Plasma Aß42, Aß40, total tau (T-tau), and neurofilament light chain (NFL) were tested in a subgroup, and their associations with PRS were conducted using the Spearman correlation test. Six common variants varied significantly between AD patients and cognitively normal controls after the adjustment of age, gender, and APOE ε4 status, including variants in ABCA7 (n = 5) and APOE (n = 1). Among them, four variants were novel and two were reported previously. The AUC of PRS was 0.71. The high PRS was significantly associated with an earlier age at onset (P = 4.30 × 10-4). PRS was correlated with plasma Aß42, Aß42/Aß40 ratio, T-tau, and NFL levels. Gene-based association test revealed that ABCA7 and UNC5C reached statistical significance. The common variants in APOE and ABCA7, as well as rare variants in ABCA7 and UNC5C, may contribute to the etiology of AD. Moreover, the PRS, to some extent, could predict the risk, onset age, and biological changes of AD.

Variants in the Niemann-pick type C genes are not associated with Alzheimer's disease: a large case-control study in the Chinese population.

Despite the similar clinical and pathological features between Niemann-Pick type C (NPC) disease and Alzheimer's disease (AD), few studies have investigated the role of NPC genes in AD. To elucidate the role of NPC genes in AD, we sequenced NPC1 and NPC2 in 1192 AD patients and 2412 controls. Variants were divided into common variants and rare variants according to minor allele frequency (MAF). Common variant (MAF≥0.01) based association analysis was conducted by PLINK 1.9. Gene-based aggregation testing of rare variants was performed by Sequence Kernel Association Test-Optimal (SKAT-O test), respectively. Age at onset (AAO) and mini-mental state examination (MMSE) association studies were also performed with PLINK 1.9. Six common variants were identified and exhibited no association with AD. Gene-based aggregation testing revealed that both NPC1 and NPC2 were not associated with AD risk. Additionally, AAO and MMSE association studies revealed that no common variants were linked with AD endophenotypes. Taken together, our study indicated that NPC1 and NPC2 may not be implicated in AD pathogenesis in the Chinese population.

CYLD variants identified in Alzheimer's disease and frontotemporal dementia patients.

OBJECTIVES: CYLD was a novel causative gene for frontotemporal dementia (FTD) and amyotrophic lateral sclerosis. Given the clinical and pathological overlap of FTD and Alzheimer's disease (AD), it is necessary to screen CYLD in AD patients and FTD patients in the Chinese population. METHODS: In our study, using a targeted sequencing panel, we sequenced the CYLD gene in a large cohort of 2485 participants in the Chinese population, including 1008 AD patients, 105 FTD patients, and 1372 controls. RESULTS: In the present study, the average onset age of AD and FTD patients was 66.84 ± 30.42 years old and 60 ± 10.00 years old, respectively. Our study reported three novel CYLD variants: p.Phe288Leu (patient No. 1, AD), p.Tyr485Phe (patients No. 6-9, all AD) and p.Thr951Ala (patient No. 10, AD), plus a previously reported variant: p.Arg397Ser (patient No. 2-5, AD and No. 11, FTD). These variants were absent in our in-house controls and predicted to be deleterious according to the MutationTaster. The variant carriers were composed of 10 AD patients and one FTD patient, and the average onset age was 61.2 ± 10.9 years. The frequency of CYLD variants in AD was similar to that in FTD, which was 0.99% (10/1008) and 0.95% (1/105), respectively. INTERPRETATION: Our finding extended the genotype and phenotype of the CYLD gene and demonstrated that CYLD rare damaging variants may be implicated in AD and FTD pathogenesis.