Biomarker Changes during 20 Years Preceding Alzheimer's Disease.

BACKGROUND: Biomarker changes that occur in the period between normal cognition and the diagnosis of sporadic Alzheimer's disease have not been extensively investigated in longitudinal studies. METHODS: We conducted a multicenter, nested case-control study of Alzheimer's disease biomarkers in cognitively normal participants who were enrolled in the China Cognition and Aging Study from January 2000 through December 2020. A subgroup of these participants underwent testing of cerebrospinal fluid (CSF), cognitive assessments, and brain imaging at 2-year-to-3-year intervals. A total of 648 participants in whom Alzheimer's disease developed were matched with 648 participants who had normal cognition, and the temporal trajectories of CSF biochemical marker concentrations, cognitive testing, and imaging were analyzed in the two groups. RESULTS: The median follow-up was 19.9 years (interquartile range, 19.5 to 20.2). CSF and imaging biomarkers in the Alzheimer's disease group diverged from those in the cognitively normal group at the following estimated number of years before diagnosis: amyloid-beta (Aß)42, 18 years; the ratio of Aß42 to Aß40, 14 years; phosphorylated tau 181, 11 years; total tau, 10 years; neurofilament light chain, 9 years; hippocampal volume, 8 years; and cognitive decline, 6 years. As cognitive impairment progressed, the changes in CSF biomarker levels in the Alzheimer's disease group initially accelerated and then slowed. CONCLUSIONS: In this study involving Chinese participants during the 20 years preceding clinical diagnosis of sporadic Alzheimer's disease, we observed the time courses of CSF biomarkers, the times before diagnosis at which they diverged from the biomarkers from a matched group of participants who remained cognitively normal, and the temporal order in which the biomarkers became abnormal. (Funded by the Key Project of the National Natural Science Foundation of China and others; ClinicalTrials.gov number, NCT03653156.).

Gut inflammation triggers C/EBPß/δ-secretase-dependent gut-to-brain propagation of Aß and Tau fibrils in Alzheimer's disease.

Inflammation plays an important role in the pathogenesis of Alzheimer's disease (AD). Some evidence suggests that misfolded protein aggregates found in AD brains may have originated from the gut, but the mechanism underlying this phenomenon is not fully understood. C/EBPß/δ-secretase signaling in the colon was investigated in a 3xTg AD mouse model in an age-dependent manner. We applied chronic administration of 1% dextran sodium sulfate (DSS) to trigger gut leakage or colonic injection of Aß or Tau fibrils or AD patient brain lysates in 3xTg mice and combined it with excision/cutting of the gut-brain connecting vagus nerve (vagotomy), in order to explore the role of the gut-brain axis in the development of AD-like pathologies and to monitor C/EBPß/δ-secretase signaling under those conditions. We found that C/EBPß/δ-secretase signaling is temporally activated in the gut of AD patients and 3xTg mice, initiating formation of Aß and Tau fibrils that spread to the brain. DSS treatment promotes gut leakage and facilitates AD-like pathologies in both the gut and the brain of 3xTg mice in a C/EBPß/δ-secretase-dependent manner. Vagotomy selectively blunts this signaling, attenuates Aß and Tau pathologies, and restores learning and memory. Aß or Tau fibrils or AD patient brain lysates injected into the colon propagate from the gut into the brain via the vagus nerve, triggering AD pathology and cognitive dysfunction. The results indicate that inflammation activates C/EBPß/δ-secretase and initiates AD-associated pathologies in the gut, which are subsequently transmitted to the brain via the vagus nerve.

Exome sequencing revealed PDE11A as a novel candidate gene for early-onset Alzheimer's disease.

To identify novel risk genes and better understand the molecular pathway underlying Alzheimer's disease (AD), whole-exome sequencing was performed in 215 early-onset AD (EOAD) patients and 255 unrelated healthy controls of Han Chinese ethnicity. Subsequent validation, computational annotation and in vitro functional studies were performed to evaluate the role of candidate variants in EOAD. We identified two rare missense variants in the phosphodiesterase 11A (PDE11A) gene in individuals with EOAD. Both variants are located in evolutionarily highly conserved amino acids, are predicted to alter the protein conformation and are classified as pathogenic. Furthermore, we found significantly decreased protein levels of PDE11A in brain samples of AD patients. Expression of PDE11A variants and knockdown experiments with specific short hairpin RNA (shRNA) for PDE11A both resulted in an increase of AD-associated Tau hyperphosphorylation at multiple epitopes in vitro. PDE11A variants or PDE11A shRNA also caused increased cyclic adenosine monophosphate (cAMP) levels, protein kinase A (PKA) activation and cAMP response element-binding protein phosphorylation. In addition, pretreatment with a PKA inhibitor (H89) suppressed PDE11A variant-induced Tau phosphorylation formation. This study offers insight into the involvement of Tau phosphorylation via the cAMP/PKA pathway in EOAD pathogenesis and provides a potential new target for intervention.

Aberrant palmitoylation caused by a ZDHHC21 mutation contributes to pathophysiology of Alzheimer's disease.

BACKGROUND: The identification of pathogenic mutations in Alzheimer's disease (AD) causal genes led to a better understanding of the pathobiology of AD. Familial Alzheimer's disease (FAD) is known to be associated with mutations in the APP, PSEN1, and PSEN2 genes involved in Aß production; however, these genetic defects occur in only about 10-20% of FAD cases, and more genes and new mechanism causing FAD remain largely obscure. METHODS: We performed exome sequencing on family members with a FAD pedigree and identified gene variant ZDHHC21 p.T209S. A ZDHHC21T209S/T209S knock-in mouse model was then generated using CRISPR/Cas9. The Morris water navigation task was then used to examine spatial learning and memory. The involvement of aberrant palmitoylation of FYN tyrosine kinase and APP in AD pathology was evaluated using biochemical methods and immunostaining. Aß and tau pathophysiology was evaluated using ELISA, biochemical methods, and immunostaining. Field recordings of synaptic long-term potentiation were obtained to examine synaptic plasticity. The density of synapses and dendritic branches was quantified using electron microscopy and Golgi staining. RESULTS: We identified a variant (c.999A > T, p.T209S) of ZDHHC21 gene in a Han Chinese family. The proband presented marked cognitive impairment at 55 years of age (Mini-Mental State Examination score = 5, Clinical Dementia Rating = 3). Considerable Aß retention was observed in the bilateral frontal, parietal, and lateral temporal cortices. The novel heterozygous missense mutation (p.T209S) was detected in all family members with AD and was not present in those unaffected, indicating cosegregation. ZDHHC21T209S/T209S mice exhibited cognitive impairment and synaptic dysfunction, suggesting the strong pathogenicity of the mutation. The ZDHHC21 p.T209S mutation significantly enhanced FYN palmitoylation, causing overactivation of NMDAR2B, inducing increased neuronal sensitivity to excitotoxicity leading to further synaptic dysfunction and neuronal loss. The palmitoylation of APP was also increased in ZDHHC21T209S/T209S mice, possibly contributing to Aß production. Palmitoyltransferase inhibitors reversed synaptic function impairment. CONCLUSIONS: ZDHHC21 p.T209S is a novel, candidate causal gene mutation in a Chinese FAD pedigree. Our discoveries strongly suggest that aberrant protein palmitoylation mediated by ZDHHC21 mutations is a new pathogenic mechanism of AD, warranting further investigations for the development of therapeutic interventions.

Meloidogyne graminicola Population Structure in China Suggests a South-to-North Expansion.

The distribution range of root-knot nematode Meloidogyne graminicola is rapidly expanding, posing a severe threat to rice production. In this study, the sequences of cytochrome oxidase subunit I (COI) genes of rice M. graminicola populations from all reported provinces in China were amplified and sequenced by PCR. The distribution pattern and phylogenetic tree showed that all 54 M. graminicola populations in China have distinct geographical distribution characteristics; specifically, cluster 1 (southern China), cluster 2 (central south and southwest China), and cluster 3 (central and eastern China). The high haplotype diversity (Hd = 0.646) and low nucleotide diversity (π = 0.00682), combined with the negative value of Tajima's D (-1.252) and Fu's Fs (-3.06764), suggested that all nematode populations were expanding. The existence of high genetic differentiation (Fst = 0.5933) and low gene flow (Nm = 0.3333) indicated that there was a block of gene exchange between most populations. Mutation accumulation with population expansion might be directly responsible for the high genetic differentiation; therefore, the tested nematode population showed high within-group genetic variation (96.30%). The haplotype Hap8 was located at the bottom of the network topology, with the widest distribution and the highest frequency (59.26%), indicating that it was the ancestral haplotype. The populations in cluster 3 were newly invasive according to the lowest frequency of occurrence of Hap8, the highest number of endemic haplotypes, and the highest total haplotype frequency (60%). In contrast, cluster 1 having the highest genetic diversity (Hd = 0.772, π = 0.01127) indicated that it was the most primitive. Interestingly, the highest gene flow (Nm > 1), lowest genetic differentiation (Fst ≤ 0.33), and closest genetic distance (0.000) only occurred between the Guangdong/Hainan population and others, which suggested that there might be channels for gene exchange between them and that long-distance dispersal occurred. This suggestion is further confirmed by the weak correlation between genetic distance and geographical distance. Based on these data, a hypothesis can be drawn that M. graminicola populations in China were spreading from south to north, specifically from Guangdong and Hainan Provinces to other regions. Natural selection (including anthropogenic) and genetic drift were the main drivers of their evolution. Coincidentally, this hypothesis was consistent with the gradual warming trend and the chronological order of reporting these populations. The main factors influencing current M. graminicola population expansion and distribution patterns might be geography, climate, long-distance seedling transport, interregional operations of agricultural machinery, and rotation mode. It reminds human beings of the necessity to be vigilant about preventing nematode disease according to local conditions all year round.

Unsupervised machine learning model to predict cognitive impairment in subcortical ischemic vascular disease.

INTRODUCTION: It is challenging to predict which patients who meet criteria for subcortical ischemic vascular disease (SIVD) will ultimately progress to subcortical vascular cognitive impairment (SVCI). METHODS: We collected clinical information, neuropsychological assessments, T1 imaging, diffusion tensor imaging, and resting-state functional magnetic resonance imaging from 83 patients with SVCI and 53 age-matched patients with SIVD without cognitive impairment. We built an unsupervised machine learning model to isolate patients with SVCI. The model was validated using multimodal data from an external cohort comprising 45 patients with SVCI and 32 patients with SIVD without cognitive impairment. RESULTS: The accuracy, sensitivity, and specificity of the unsupervised machine learning model were 86.03%, 79.52%, and 96.23% and 80.52%, 71.11%, and 93.75% for internal and external cohort, respectively. DISCUSSION: We developed an accurate and accessible clinical tool which requires only data from routine imaging to predict patients at risk of progressing from SIVD to SVCI. HIGHLIGHTS: Our unsupervised machine learning model provides an accurate and accessible clinical tool to predict patients at risk of progressing from subcortical ischemic vascular disease (SIVD) to subcortical vascular cognitive impairment (SVCI) and requires only data from imaging routinely used during the diagnosis of suspected SVCI. The model yields good accuracy, sensitivity, and specificity and is portable to other cohorts and to clinical practice to distinguish patients with SIVD at risk for progressing to SVCI. The model combines assessment of diffusion tensor imaging and functional magnetic resonance imaging measures in patients with SVCI to analyze whether the "disconnection hypothesis" contributes to functional and structural changes and to the clinical presentation of SVCI.

Ginsenoside compound K acts via LRP1 to alleviate Amyloid ß42-induced neuroinflammation in microglia by suppressing NF-κB.

BACKGROUND: Alzheimer's disease (AD), has caused a mass of disability and mortality in elder populations, which increases global health burden. There are still limited effective disease-modifying drugs. Alleviating microglia-evoked neuroinflammation has become a promising treatment strategy for AD. Ginsenoside Compound K has been demonstrated to exhibit anti-inflammatory and neuroprotective benefits. Here we measured the effects of Ginsenoside Compound K in inhibiting amyloid-induced microglia inflammation and the possible molecular mechanisms and target of action in vitro. METHODS: The cytotoxicity of all chemical reagents on BV2 cells were evaluated using the MTT assay. qRT-PCR and ELISA were carried out to detect the inflammatory cytokines levels. Western blot was utilized to determine the effect of Ginsenoside Compound K on the nuclear factor-κB (NF-κB) p65 nuclear translocation. Antagonist Receptor Associated Protein (RAP) was used to verify the engagement of low-density lipoprotein receptor-related protein 1(LRP1). RESULTS: Ginsenoside Compound K diminished inflammatory cytokine production and reversed NF-κB p65 nuclear translocation induced by Aß42 oligomers. LRP1 expression was up-regulated by Ginsenoside Compound K. When LRP1 was blocked by antagonist RAP, the protective effect of Ginsenoside Compound K was massively eliminated. CONCLUSION: These observations provide evidence for anti-inflammatory effect of Ginsenoside Compound K through NF-κB pathway via LRP1 activation, and support further evaluation of Ginsenoside Compound K as a potential effective modulator for AD.

Prediction of Alzheimer's disease using multi-variants from a Chinese genome-wide association study.

Previous genome-wide association studies have identified dozens of susceptibility loci for sporadic Alzheimer's disease, but few of these loci have been validated in longitudinal cohorts. Establishing predictive models of Alzheimer's disease based on these novel variants is clinically important for verifying whether they have pathological functions and provide a useful tool for screening of disease risk. In the current study, we performed a two-stage genome-wide association study of 3913 patients with Alzheimer's disease and 7593 controls and identified four novel variants (rs3777215, rs6859823, rs234434, and rs2255835; Pcombined = 3.07 × 10-19, 2.49 × 10-23, 1.35 × 10-67, and 4.81 × 10-9, respectively) as well as nine variants in the apolipoprotein E region with genome-wide significance (P < 5.0 × 10-8). Literature mining suggested that these novel single nucleotide polymorphisms are related to amyloid precursor protein transport and metabolism, antioxidation, and neurogenesis. Based on their possible roles in the development of Alzheimer's disease, we used different combinations of these variants and the apolipoprotein E status and successively built 11 predictive models. The predictive models include relatively few single nucleotide polymorphisms useful for clinical practice, in which the maximum number was 13 and the minimum was only four. These predictive models were all significant and their peak of area under the curve reached 0.73 both in the first and second stages. Finally, these models were validated using a separate longitudinal cohort of 5474 individuals. The results showed that individuals carrying risk variants included in the models had a shorter latency and higher incidence of Alzheimer's disease, suggesting that our models can predict Alzheimer's disease onset in a population with genetic susceptibility. The effectiveness of the models for predicting Alzheimer's disease onset confirmed the contributions of these identified variants to disease pathogenesis. In conclusion, this is the first study to validate genome-wide association study-based predictive models for evaluating the risk of Alzheimer's disease onset in a large Chinese population. The clinical application of these models will be beneficial for individuals harbouring these risk variants, and particularly for young individuals seeking genetic consultation.

The synaptic marker neurogranin as a disease state biomarker in Alzheimer's disease: a systematic review and meta-analysis.

Objective: Synaptic degeneration is the pathologic foundation of cognitive decline in the Alzheimer's disease (AD) continuum. We aimed to determine whether cerebrospinal fluid (CSF) synaptic marker neurogranin (Ng) is a disease state or a disease stage biomarker in the AD continuum.Methods: Studies comparing CSF Ng levels among AD, mild cognitive impairment (MCI) and healthy participants were included. Studies were eligible if the correlation between CSF Ng levels and Mini-Mental Status Examination (MMSE) scores was investigated.Results: Twenty-one studies met our inclusion criteria (n = 4515). The magnitude of effect sizes was more apparent in AD (standardized mean difference [SMD] = 1.72; 95% confidence interval [CI] = 1.23-2.22), than in MCI (SMD = 0.82; 95% CI = 0.29-1.34) compared to control populations. These results suggest that CSF Ng can discriminate AD and MCI from control populations, implying that synaptic degeneration worsens as patients progress from MCI to AD. However, there was a very weak correlation between CSF Ng levels and MMSE scores (r = -0.15; 95% CI = -0.21--0.08) among the whole populations, suggesting that an increment of CSF Ng is best considered a biological evidence of disease state in the AD continuum.Conclusion: Our study provides evidence that the synaptic marker CSF Ng can be used as a disease state biomarker for the AD continuum. Because synaptic degeneration is a distinct pathologic event from amyloid deposition and neurofibrillary tangle formation, CSF Ng may provide an important supplementation to the AT(N) biomarker system to reveal the sequence of neuropathology.

Binaural processing deficit and cognitive impairment in Alzheimer's disease.

Speech comprehension in noisy environments depends on central auditory functions, which are vulnerable in Alzheimer's disease (AD). Binaural processing exploits two ear sounds to optimally process degraded sound information; its characteristics are poorly understood in AD. We studied behavioral and electrophysiological alterations in binaural processing among 121 participants (AD = 27; amnestic mild cognitive impairment [aMCI] = 33; subjective cognitive decline [SCD] = 30; cognitively normal [CN] = 31). We observed impairment of binaural processing in AD and aMCI, and detected a U-shaped curve change in phase synchrony (declining from CN to SCD and to aMCI, but increasing from aMCI to AD). This improvement in phase synchrony accompanying more severe cognitive stages could reflect neural adaptation for binaural processing. Moreover, increased phase synchrony is associated with worse memory during the stages when neural adaptation apparently occurs. These findings support a hypothesis that neural adaptation for binaural processing deficit may exacerbate cognitive impairment, which could help identify biomarkers and therapeutic targets in AD.

State-of-the-art of lumbar puncture and its place in the journey of patients with Alzheimer's disease.

Recent advances in developing disease-modifying therapies (DMT) for Alzheimer's disease (AD), and the recognition that AD pathophysiology emerges decades before clinical symptoms, necessitate a paradigm shift of health-care systems toward biomarker-guided early detection, diagnosis, and therapeutic decision-making. Appropriate incorporation of cerebrospinal fluid biomarker analysis in clinical practice is an essential step toward system readiness for accommodating the demand of AD diagnosis and proper use of DMTs-once they become available. However, the use of lumbar puncture (LP) in individuals with suspected neurodegenerative diseases such as AD is inconsistent, and the perception of its utility and safety differs considerably among medical specialties as well as among regions and countries. This review describes the state-of-the-art evidence concerning the safety profile of LP in older adults, discusses the risk factors for LP-associated adverse events, and provides recommendations and an outlook for optimized use and global implementation of LP in individuals with suspected AD.

Silicon Mediated Plant Immunity against Nematodes: Summarizing the Underline Defence Mechanisms in Plant Nematodes Interaction.

Silicon (Si) is known to stimulate plant resistance against different phytopathogens, i.e., bacteria, fungi, and nematodes. It is an efficient plant growth regulator under various biotic and abiotic stresses. Silicon-containing compounds, including silicon dioxide, SiO2 nanoparticles (NPs), nano-chelated silicon fertilizer (NCSF), sodium siliconate, and sodium metasilicate, are effective in damaging various nematodes that reduce their reproduction, galling, and disease severity. The defence mechanisms in plant-nematodes interaction may involve a physical barrier, plant defence-associated enzyme activity, synthesis of antimicrobial compounds, and transcriptional regulation of defence-related genes. In the current review, we focused on silicon and its compounds in controlling plant nematodes and regulating different defence mechanisms involved in plant-nematodes interaction. Furthermore, the review aims to evaluate the potential role of Si application in improving plant resistance against nematodes and highlight its need for efficient plant-nematodes disease management.

Cognitive profiles in adult-onset neuronal intranuclear inclusion disease: a case series from the memory clinic.

OBJECTIVE: This study aimed to analyze the characteristics of cognitive impairment in adult-onset neuronal intranuclear inclusion disease (NIID). METHODS: Seven patients with adult-onset NIID were collected consecutively from the memory clinic of Xuanwu hospital from February to December 2019. These cases were diagnosed with skin biopsy triggered by DWI high-intensity signals in corticomedullary junction on brain MRI. We used a battery of neuropsychological scales to detect the patient's performance in each cognitive domain, and made a detailed analysis on the characteristics of cognitive impairment. RESULTS: All seven cases had cognitive impairment, and four of them had met the criteria for dementia. The scores of Montreal Cognitive Assessment and Frontal Assessment Battery were abnormal in all patients. The executive dysfunction was confirmed by the abnormal scores of Trail Making Test (5/7, 71%) and Clock Drawing Test (4/7, 57%). Bad performance in Auditory Verbal Learning Test (6/7, 86%) demonstrated that the memory was also a very commonly impaired cognitive domain. The low score on the animal fluency (4/7, 57%), Boston Naming Test (3/7, 43%), and Pentagon and Cube Copying Test (4/7, 57%) indicated that the language and visuospatial skills were also impaired. Fazekas scores were significantly correlated to the global cognition, executive and language functions (r = 0.788-0.906, P < 0.05). CONCLUSIONS: There is obvious impairment in multiple cognitive domains in adult-onset NIID, and both the executive dysfunction and memory deficit are very common. Leukoencephalopathy may be the main course of cognitive impairment in adult-onset NIID.

Blood neuro-exosomal synaptic proteins predict Alzheimer's disease at the asymptomatic stage.

INTRODUCTION: Exosomes are an emerging candidate for biomarkers of Alzheimer's disease (AD). This study investigated whether exosomal synaptic proteins can predict AD at the asymptomatic stage. METHODS: We conducted a two-stage-sectional study (discovery stage: AD, 28; amnestic mild cognitive impairment [aMCI], 25; controls, 29; validation stage: AD, 73; aMCI, 71; controls, 72), a study including preclinical AD (160) and controls (160), and a confirmation study in familial AD (mutation carriers: 59; non-mutation carriers: 62). RESULTS: The concentrations of growth associated protein 43 (GAP43), neurogranin, synaptosome associated protein 25 (SNAP25), and synaptotagmin 1 were lower in AD than in controls (P < .001). Exosomal biomarker levels were correlated with those in cerebrospinal fluid (R2  = 0.54-0.70). The combination of exosomal biomarkers detected AD 5 to 7 years before cognitive impairment (area under the curve = 0.87-0.89). DISCUSSION: This study revealed that exosomal GAP43, neurogranin, SNAP25, and synaptotagmin 1 act as effective biomarkers for prediction of AD 5 to 7 years before cognitive impairment.

Evidence-based prevention of Alzheimer's disease: systematic review and meta-analysis of 243 observational prospective studies and 153 randomised controlled trials.

BACKGROUND: Evidence on preventing Alzheimer's disease (AD) is challenging to interpret due to varying study designs with heterogeneous endpoints and credibility. We completed a systematic review and meta-analysis of current evidence with prospective designs to propose evidence-based suggestions on AD prevention. METHODS: Electronic databases and relevant websites were searched from inception to 1 March 2019. Both observational prospective studies (OPSs) and randomised controlled trials (RCTs) were included. The multivariable-adjusted effect estimates were pooled by random-effects models, with credibility assessment according to its risk of bias, inconsistency and imprecision. Levels of evidence and classes of suggestions were summarised. RESULTS: A total of 44 676 reports were identified, and 243 OPSs and 153 RCTs were eligible for analysis after exclusion based on pre-decided criteria, from which 104 modifiable factors and 11 interventions were included in the meta-analyses. Twenty-one suggestions are proposed based on the consolidated evidence, with Class I suggestions targeting 19 factors: 10 with Level A strong evidence (education, cognitive activity, high body mass index in latelife, hyperhomocysteinaemia, depression, stress, diabetes, head trauma, hypertension in midlife and orthostatic hypotension) and 9 with Level B weaker evidence (obesity in midlife, weight loss in late life, physical exercise, smoking, sleep, cerebrovascular disease, frailty, atrial fibrillation and vitamin C). In contrast, two interventions are not recommended: oestrogen replacement therapy (Level A2) and acetylcholinesterase inhibitors (Level B). INTERPRETATION: Evidence-based suggestions are proposed, offering clinicians and stakeholders current guidance for the prevention of AD.

PSEN1, PSEN2, and APP mutations in 404 Chinese pedigrees with familial Alzheimer's disease.

INTRODUCTION: The PSENs/APP mutation distribution in Chinese patients with familial Alzheimer's disease (FAD) remains unclear. We aimed to analyze the genetic features of Chinese FAD pedigrees with and without PSENs/APP mutations. METHODS: In total, 1330 patients with Alzheimer's disease (AD) or mild cognitive impairment in 404 pedigrees were enrolled from the Chinese Familial Alzheimer's Disease Network. PSENs/APP mutations and APOE frequencies were determined. RESULTS: In total, 13.12% of pedigrees carried PSENs/APP missense mutations, 3.71% carried PSENs/APP synonymous/untranslated region variants, and 83.17% did not carry PSENs/APP mutations. Eleven missense mutations were first identified. In patients without PSENs/APP mutations, 44.31% carried one APOEε4 allele, and 14.85% two APOEε4 alleles. DISCUSSION: The new PSENs/APP mutations indicate heterogeneity in AD pathogenesis between Chinese and other ethnic groups. The low mutation rate suggests the involvement of other genes/factors in Chinese FAD. APOEε4 might be a major gene for some FAD without PSENs/APP mutations.

The APOE ε4 exerts differential effects on familial and other subtypes of Alzheimer's disease.

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.

Tackling challenges in care of Alzheimer's disease and other dementias amid the COVID-19 pandemic, now and in the future.

We have provided an overview on the profound impact of COVID-19 upon older people with Alzheimer's disease and other dementias and the challenges encountered in our management of dementia in different health-care settings, including hospital, out-patient, care homes, and the community during the COVID-19 pandemic. We have also proposed a conceptual framework and practical suggestions for health-care providers in tackling these challenges, which can also apply to the care of older people in general, with or without other neurological diseases, such as stroke or parkinsonism. We believe this review will provide strategic directions and set standards for health-care leaders in dementia, including governmental bodies around the world in coordinating emergency response plans for protecting and caring for older people with dementia amid the COIVD-19 outbreak, which is likely to continue at varying severity in different regions around the world in the medium term.

Two novel presenilin-1 mutations (I249L and P433S) in early onset Chinese Alzheimer's pedigrees and their functional characterization.

Clinical case study and functional characterization of the disease-associated presenilin-1 (PSEN1) mutations may help reveal the roles of PSEN1 in the pathogenesis of Alzheimer's disease (AD). By mutation screening of PSEN1, presenilin-2, and amyloid precursor protein genes in two Chinese Alzheimer's pedigrees, we identified two novel PSEN1 mutations, I249L and P433S. The two probands presented with progressive memory decline and subsequent psychiatric symptoms, with the age of onset at 54 and 34 years old, respectively. The effects of these two mutations on presenilin-1 endoproteolysis and ß-amyloid (Aß) production were examined in SH-SY5Y neuroblastoma cells infected with lentiviruses expressing presenilin-1 wild type (WT), I249L and P433S mutants. Both mutants showed increased Aß42 levels and Aß42/Aß40 ratios. However, the I249L did not affect presenilin-1 endoproteolysis or Aß43 production, whereas the P433S mutant inhibited presenilin-1 endoproteolysis and enhanced Aß43 production. Our findings suggest that both I249L and P433S are pathogenic for early onset of AD by increasing Aß42 production and Aß42/Aß40 ratios. Furthermore, P433S may contribute to the very early onset of AD by inhibiting PS1 endoproteolysis and enhancing the production of longer Aß peptide Aß43.