Early-onset Alzheimer's Disease Research Articles

Gut pathobiont enrichment observed in a population predisposed to dementia, type 2 diabetics of Mexican descent living in South Texas

Type 2 diabetes (T2D) is a common forerunner of neurodegeneration and accompanying dementia, including Alzheimer’s Disease (AD), yet the mechanisms underlying this comorbidity remain unresolved. Individuals of Mexican descent living in South Texas have increased prevalence of comorbid T2D and early onset AD, despite low incidence of the APOE-ε4 risk variant among the population and an absence of a similar predisposition among relatives residing in Mexico – suggesting a role for environmental factors in coincident T2D and AD susceptibility. We therefore sought to test if differences in gut community structure could be observed in this population prior to any AD diagnosis. Here, in a small clinical trial (ClinicalTrials.gov Identifier NCT04602650), we report evidence for altered gut microbial ecology among subjects of Mexican descent living in South Texas with T2D (sT2D) compared to healthy controls without T2D (HC), despite no differences in expressed dietary preferences. We performed metataxonomic 16S rRNA gene amplicon sequencing of study participant stool samples. Although no significant decrease in microbial alpha diversity was observed between sT2D gut communities versus those of HC, body mass index was identified as a driver of gut community structure. Intriguingly, we observed a significant negative association of Faecalibacterium and Lachnospiraceae with T2D and an increase in the abundance of pathobionts Escherichia-Shigella, Enterobacter, and the erysipelotrichial species Clostridia innocuum among sT2D gut microbiota, as well as differentially abundant gene and metabolic pathways. Future large-scale, longitudinal sequencing efforts of the gut microbiome of individuals with T2D who go on to develop AD might identify key actors among “disease state” microbiota that contribute to increased susceptibility to comorbid dementia. Finally, we identified candidate microbiome-targeted approaches for the treatment of T2D.

The effects of mosaicism on biological and clinical markers of Alzheimer's disease in adults with Down syndrome

Individuals with Down syndrome (DS) are at high risk of early-onset Alzheimer's disease (AD); yet, some 20 percent do not develop any signs of dementia until after 65 years or in their lifetime. Mosaicism could contribute to this phenotypic variation, where some disomic cells could lead to lower levels of gene products from chromosome21. We examined longitudinal neuropsychological and biomarker data from two large studies of DS: the Alzheimer Biomarker Consortium-Down syndrome study (ABC-DS) (n=357); and a legacy study (n=468). We assessed mosaicism using karyotyping or GWAS data. Participants had data on plasma AD biomarkers (Aβ40, Aβ42, tau, and NfL) and longitudinal cognitive measures. A subset had cerebrospinal fluid biomarkers (Aβ40, Aβ42, tau, ptau181, and NfL) and amyloid and tau PET data. For both cohorts, the prevalence of mosaicism was <10% (ABC-DS: 7.3%; Legacy: 9.6%), and those with mosaicism had lower plasma Aβ40 and Aβ42 concentrations. For the older legacy cohort, when compared to those with full trisomy, those with mosaicism had significantly smaller decline in total and annualized neurocognitive scores, and lower incidence and prevalence of dementia. Mosaicism in DS was associated with lower concentrations of plasma Aβ peptides, possibly leading to lower AD risk. However, its clinical impact was less clear in the younger ABC-DC cohort, and a follow-up study is warranted. National Institutes of Health (R01AG014673, P01HD035897, R56AG061837), NIA (U01AG051412, U19AG068054), NICHD, ADRC programs, the Eunice Kennedy Shriver Intellectual and Developmental Disabilities Research Centers Program, and NCATS (UL1TR001873).

CRISPR/Cas9 Gene Editing: A Novel Approach Towards Alzheimer's Disease Treatment.

In defiance of the vast amount of information regarding Alzheimer's disease (AD) that has been learned over the past thirty years, progress toward developing an effective therapy has been difficult. A neurological ailment that progresses and cannot be reversed is Alzheimer's disease, which shows neurofibrillary tangles, beta-amyloid plaque, and a lack of cognitive processes that is created by tau protein clumps with hyperphosphorylation that finally advances to neuronal damage without a recognized treatment, which has stimulated research into new therapeutic strategies. The protein CAS9 is linked to CRISPR, which is a clustered Regularly Interspaced Short Palindromic Repeat that inactivates or corrects a gene by recognizing a gene sequence that produces a doublestranded break has enchanted a whole amount of interest towards its potency to cure gene sequences in AD. The novel CRISPR-Cas9 applications for developing in vitro and in vivo models to the benefit of AD investigation and therapies are thoroughly analyzed in this work. The discussion will also touch on the creation of delivery methods, which is a significant obstacle to the therapeutic use of CRISPR/Cas9 technology. By concentrating on specific genes, such as those that are significant early- onset AD risk factors and late-onset AD risk factors, like the apolipoprotein E4 (APOE4) gene, this study aims to evaluate the potential application of CRISPR/Cas9 as a possible treatment for AD.

Assessing the Benefit of Dietary Choline Supplementation Throughout Adulthood in the Ts65Dn Mouse Model of Down Syndrome

Background/Objectives: Down syndrome (DS) is the most common cause of early-onset Alzheimer’s disease (AD). Dietary choline has been proposed as a modifiable factor to improve the cognitive and pathological outcomes of AD and DS, especially as many do not reach adequate daily intake levels of choline. While lower circulating choline levels correlate with worse pathological measures in AD patients, choline status and intake in DS is widely understudied. Perinatal choline supplementation (Ch+) in the Ts65Dn mouse model of DS protects offspring against AD-relevant pathology and improves cognition. Further, dietary Ch+ in adult AD models also ameliorates pathology and improves cognition. However, dietary Ch+ in adult Ts65Dn mice has not yet been explored; thus, this study aimed to supply Ch+ throughout adulthood to determine the effects on cognition and DS co-morbidities. Methods: We fed trisomic Ts65Dn mice and disomic littermate controls either a choline normal (ChN; 1.1 g/kg) or a Ch+ (5 g/kg) diet from 4.5 to 14 months of age. Results: We found that Ch+ in adulthood failed to improve genotype-specific deficits in spatial learning. However, in both genotypes of female mice, Ch+ significantly improved cognitive flexibility in a reverse place preference task in the IntelliCage behavioral phenotyping system. Further, Ch+ significantly reduced weight gain and peripheral inflammation in female mice of both genotypes, and significantly improved glucose metabolism in male mice of both genotypes. Conclusions: Our findings suggest that adulthood choline supplementation benefits behavioral and biological factors important for general well-being in DS and related to AD risk.

Functional network disruption in cognitively unimpaired autosomal dominant Alzheimer’s disease: a magnetoencephalography study

Functional network disruption in cognitively unimpaired autosomal dominant Alzheimer’s disease: a magnetoencephalography study

Etiology of Late-Onset Alzheimer’s Disease, Biomarker Efficacy, and the Role of Machine Learning in Stage Diagnosis

Late-onset Alzheimer’s disease (LOAD) is a subtype of dementia that manifests after the age of 65. It is characterized by progressive impairments in cognitive functions, behavioral changes, and learning difficulties. Given the progressive nature of the disease, early diagnosis is crucial. Early-onset Alzheimer’s disease (EOAD) is solely attributable to genetic factors, whereas LOAD has multiple contributing factors. A complex pathway mechanism involving multiple factors contributes to LOAD progression. Employing a systems biology approach, our analysis encompassed the genetic, epigenetic, metabolic, and environmental factors that modulate the molecular networks and pathways. These factors affect the brain’s structural integrity, functional capacity, and connectivity, ultimately leading to the manifestation of the disease. This study has aggregated diverse biomarkers associated with factors capable of altering the molecular networks and pathways that influence brain structure, functionality, and connectivity. These biomarkers serve as potential early indicators for AD diagnosis and are designated as early biomarkers. The other biomarker datasets associated with the brain structure, functionality, connectivity, and related parameters of an individual are broadly categorized as clinical-stage biomarkers. This study has compiled research papers on Alzheimer’s disease (AD) diagnosis utilizing machine learning (ML) methodologies from both categories of biomarker data, including the applications of ML techniques for AD diagnosis. The broad objectives of our study are research gap identification, assessment of biomarker efficacy, and the most effective or prevalent ML technology used in AD diagnosis. This paper examines the predominant use of deep learning (DL) and convolutional neural networks (CNNs) in Alzheimer’s disease (AD) diagnosis utilizing various types of biomarker data. Furthermore, this study has addressed the potential scope of using generative AI and the Synthetic Minority Oversampling Technique (SMOTE) for data augmentation.

Distinct tau pathologies in the nucleus basalis of Meynert between early-onset and late-onset Alzheimer's disease patients revealed by positron emission tomography.

Tau accumulation in the nucleus basalis of Meynert (nbM) has been documented in Alzheimer's disease (AD), but its relationship to neuropathological changes in other brain regions and cognitive deficits remains unclear, particularly between early-onset AD (EOAD) and late-onset AD (LOAD). To evaluate tau accumulation patterns in the nbM and other brain regions in EOAD and LOAD using 18F-florzolotau PET and examine correlations with cognitive function. Thirty-eight amyloid-positive AD patients (15 EOAD, 23 LOAD) and 46 healthy controls underwent 18F-florzolotau PET. Tau levels were quantified in the nbM and Braak-staging regions. Postmortem brain samples were examined to assess 18F-florzolotau binding to tau deposits. EOAD showed a higher overall tau burden, including in the nbM, compared with LOAD. However, nbM tau levels correlated more strongly with cognitive decline in LOAD than EOAD. The relationship between nbM tau and neocortical tau differed between EOAD and LOAD. Histopathology revealed abundant 18F-florzolotau labeling of neurofibrillary tangles (NFTs) and ghost tangles in AD nbM samples. This study provides the first in vivo PET evidence of differential nbM tau pathology between EOAD and LOAD, with higher accumulation but weaker correlation to cognition in EOAD. The distinct relationships between nbM and cortical tau in EOAD and LOAD suggest divergent pathological trajectories. 18F-florzolotau PET successfully visualized NFTs and extracellular ghost tangles in the nbM across AD stages. These findings highlight the importance of considering age of onset when evaluating tau pathology and its clinical correlates in AD.

Targeting the cholinergic anti-inflammatory pathway for type 2 diabetes prevention: A retrospective cohort study.

Chronic inflammation is a key factor in type 2 diabetes mellitus (T2DM) development. The cholinergic anti-inflammatory pathway (CAP) reduces inflammation by activating α7 nicotinic acetylcholine receptors (α7nAChRs) on macrophages, suppressing proinflammatory cytokines. Acetylcholinesterase inhibitors (AChEis), primarily used for Alzheimer's disease (AD), may exert anti-inflammatory effects through the CAP. One AChEi, galantamine, also directly agonizes α7nAChRs, potentially enhancing its anti-inflammatory properties. This study aimed to investigate the association between AChEi use, particularly galantamine, and T2DM risk in AD patients. We conducted a retrospective analysis of Veterans Health Administration (VA) data, examining early- and late-onset AD patients receiving galantamine or other AD medications. Propensity score matching was used to balance groups and minimize confounding. Cox proportional hazard models assessed T2DM risk for galantamine, other AChEis and memantine. A total of 40 065 AD patients were included in the study. Among early-onset AD patients, galantamine use significantly reduced T2DM risk (hazard ratio [HR] = 0.80, 95% confidence interval [CI]: 0.66-0.98). Memantine also showed a protective effect (HR = 0.82, 95% CI: 0.69-1) in this group. Neither galantamine nor memantine influenced T2DM risk in late-onset AD. Other AD medications showed no association with T2DM risk. Galantamine use was associated with a lower risk of T2DM in early-onset AD patients, potentially due to enhanced anti-inflammatory effects through both AChE inhibition and direct α7nAChR agonism. Memantine also demonstrated a protective effect. These findings suggest potential new applications for existing AD medications in T2DM prevention, particularly in early-onset AD patients. Further research, including randomized controlled trials with diverse populations, is needed to confirm these results and the underlying mechanisms.

Amyloid beta-induced signalling in leptomeningeal cells and its impact on astrocyte response.

The pathological signature of Alzheimer's disease (AD) includes the accumulation of toxic protein aggregates, mainly consisting of amyloid beta (Aβ). Recent strides in fundamental research underscore the pivotal role of waste clearance mechanisms in the brain suggesting it may be an early indication of early onset AD. This study delves into the involvement of leptomeningeal cells (LMCs), crucial components forming integral barriers within the clearance system, in the context of AD. We examined the inflammatory cytokine responses of LMCs in the presence of Aβ, alongside assessments of LMC growth response, viability, oxidative stress, and changes in vimentin expression. The LMCs showed no changes in growth, viability, oxidative stress, or vimentin expression in the presence of Aβ, indicating that LMCs are less susceptible to Aβ damage compared to other CNS cells. However, LMCs exhibited a unique pro-inflammatory response to Aβ when compared to an LPS inflammatory control, showing an mRNA expression of pro-inflammatory cytokines such IL-6, IL-10 and IL-33 but no changes in IL-1α and IL-1β. Furthermore, LMCs influenced the astrocyte response to Aβ, as conditioned media from Aβ-treated LMCs was observed to downregulate somatic S100β in astrocytes. We also investigated whether the JAK/STAT3 pathway was involved in the Aβ response of the LMCs, as this pathway has been shown to be activated in astrocytes and neurons in the presence of Aβ. JAK/STAT3 activation was assessed through phosphorylated STAT3, revealing that JAK/STAT3 was not active in the cells when in the presence of Aβ. However, when JAK1 and JAK2 were inhibited, cytokine protein levels of IL7, IL10, IL15 and IL33 levels, which had shown alteration when LMCs were treated with Aβ, returned to base levels. This indicates that although JAK1/STAT3 and JAK2/STAT3 are not the direct pathway for Aβ response in LMCs, JAK1 and JAK2 may still play a role in regulating cytokine levels, potentially through indirect means or crosstalk. Overall, our findings reveal that LMCs are resilient to Aβ toxicity and suggest that JAK1/STAT3 and JAK2/STAT3 does not play a central role in the inflammatory response, providing new insights into the cellular mechanisms underlying AD.

Chronic stress mediates cerebral blood flow alterations via Xanthine Oxidase in an early-onset Alzheimer's Disease model

Chronic stress mediates cerebral blood flow alterations via Xanthine Oxidase in an early-onset Alzheimer's Disease model

Comprehensive mapping of synaptic vesicle protein 2A (SV2A) in health and neurodegenerative diseases: a comparative analysis with synaptophysin and ground truth for PET-imaging interpretation.

Synaptic dysfunction and loss are central to neurodegenerative diseases and correlate with cognitive decline. Synaptic Vesicle Protein 2A (SV2A) is a promising PET-imaging target for assessing synaptic density in vivo, but comprehensive mapping in the human brain is needed to validate its biomarker potential. This study used quantitative immunohistochemistry and Western blotting to map SV2A and synaptophysin (SYP) densities across six cortical regions in healthy controls and patients with early-onset Alzheimer's disease (EOAD), late-onset Alzheimer's disease (LOAD), progressive supranuclear palsy (PSP), and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-GRN). We identified region in SV2A density among controls and observed disease- and region-specific reductions, with the most severe in FTLD-GRN (up to 59.5%) and EOAD. EOAD showed a 49% reduction in the middle frontal gyrus (MFG), while LOAD had over 30% declines in the inferior frontal gyrus (IFG) and hippocampus (CA1). In PSP, smaller but significant reductions were noted in the hippocampal formation, with the inferior temporal gyrus (ITG) relatively unaffected. A strong positive correlation between SV2A and SYP densities confirmed SV2A's reliability as a synaptic integrity marker. This study supports the use of SV2A PET imaging for early diagnosis and monitoring of neurodegenerative diseases, providing essential data for interpreting in vivo PET results. Further research should explore SV2A as a therapeutic target and validate these findings in larger, longitudinal studies.

On the Therapeutic Use of Monoclonal Antibodies Against Amyloid Plaques in Older Adults with Down Syndrome: A Narrative Review and Perspective.

Down syndrome (DS) is a genetic disorder caused by an extra copy of chromosome 21 (trisomy 21 or T21) and is associated with an increased risk of early-onset Alzheimer's disease (AD), also known as DS-associated AD (DSAD). Individuals with DS typically develop amyloid neuropathology in their late-thirties to early-forties and the mean age of onset of clinical dementia is approximately 55 years. Recent advances in AD clinical research have focused on monoclonal antibodies (mAbs) targeting amyloid-β (Aβ) plaques as a potential therapeutic approach. Therefore, there has been guarded enthusiasm about using anti-amyloid mAbs in the prevention/treatment of DSAD. This narrative review and perspective explores the current understanding of amyloid pathology in AD and DSAD, the rationale for using anti-amyloid mAbs in the treatment of DSAD, and the challenges and opportunities for research toward the application of this therapeutic strategy to older adults with DS.

Identification of nitric oxide-mediated necroptosis as the predominant death route in Parkinson’s disease

Parkinson's disease (PD) involves multiple forms of neuronal cell death, but the dominant pathway involved in disease progression remains unclear. This study employed RNA sequencing (RNA-seq) of brain tissue to explore gene expression patterns across different stages of PD. Using the Scaden deep learning algorithm, we predicted neurocyte subtypes and modelled dynamic interactions for five classic cell death pathways to identify the predominant routes of neuronal death during PD progression. Our cell type-specific analysis revealed an increasing shift towards necroptosis, which was strongly correlated with nitric oxide synthase (NOS) expression across most neuronal subtypes. In vitro experiments confirmed that nitric oxide (NO) is a key mediator of necroptosis, leading to nuclear shrinkage and decreased mitochondrial membrane potential via phosphorylation of the PIP1/PIP3/MLKL signalling cascade. Importantly, specific necroptosis inhibitors significantly mitigated neuronal damage in both in vitro and in vivo PD models. Further analysis revealed that NO-mediated necroptosis is prevalent in early-onset Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS) and across multiple brain regions but not in brain tumours. Our findings suggest that NO-mediated necroptosis is a critical pathway in PD and other neurodegenerative disorders, providing potential targets for therapeutic intervention.

Early detection of dementia through retinal imaging and trustworthy AI

Alzheimer’s disease (AD) is a global healthcare challenge lacking a simple and affordable detection method. We propose a novel deep learning framework, Eye-AD, to detect Early-onset Alzheimer’s Disease (EOAD) and Mild Cognitive Impairment (MCI) using OCTA images of retinal microvasculature and choriocapillaris. Eye-AD employs a multilevel graph representation to analyze intra- and inter-instance relationships in retinal layers. Using 5751 OCTA images from 1671 participants in a multi-center study, our model demonstrated superior performance in EOAD (internal data: AUC = 0.9355, external data: AUC = 0.9007) and MCI detection (internal data: AUC = 0.8630, external data: AUC = 0.8037). Furthermore, we explored the associations between retinal structural biomarkers in OCTA images and EOAD/MCI, and the results align well with the conclusions drawn from our deep learning interpretability analysis. Our findings provide further evidence that retinal OCTA imaging, coupled with artificial intelligence, will serve as a rapid, noninvasive, and affordable dementia detection.

Systematic evaluation of multifactorial causal associations for Alzheimer's disease and an interactive platform MRAD developed based on Mendelian randomization analysis.

Alzheimer's disease (AD) is a complex degenerative disease of the central nervous system, and elucidating its pathogenesis remains challenging. In this study, we used the inverse-variance weighted (IVW) model as the major analysis method to perform hypothesis-free Mendelian randomization (MR) analysis on the data from MRC IEU OpenGWAS (18,097 exposure traits and 16 AD outcome traits), and conducted sensitivity analysis with six models, to assess the robustness of the IVW results, to identify various classes of risk or protective factors for AD, early-onset AD, and late-onset AD. We generated 400,274 data entries in total, among which the major analysis method of the IVW model consists of 73,129 records with 4840 exposure traits, which fall into 10 categories: Disease, Medical laboratory science, Imaging, Anthropometric, Treatment, Molecular trait, Gut microbiota, Past history, Family history, and Lifestyle trait. More importantly, a freely accessed online platform called MRAD (https://gwasmrad.com/mrad/) has been developed using the Shiny package with MR analysis results. Additionally, novel potential AD therapeutic targets (CD33, TBCA, VPS29, GNAI3, PSME1) are identified, among which CD33 was positively associated with the main outcome traits of AD, as well as with both EOAD and LOAD. TBCA and VPS29 were negatively associated with the main outcome traits of AD, as well as with both EOAD and LOAD. GNAI3 and PSME1 were negatively associated with the main outcome traits of AD, as well as with LOAD, but had no significant causal association with EOAD. The findings of our research advance our understanding of the etiology of AD.

Systematic evaluation of multifactorial causal associations for Alzheimer’s disease and an interactive platform MRAD developed based on Mendelian randomization analysis

Alzheimer’s disease (AD) is a complex degenerative disease of the central nervous system, and elucidating its pathogenesis remains challenging. In this study, we used the inverse-variance weighted (IVW) model as the major analysis method to perform hypothesis-free Mendelian randomization (MR) analysis on the data from MRC IEU OpenGWAS (18,097 exposure traits and 16 AD outcome traits), and conducted sensitivity analysis with six models, to assess the robustness of the IVW results, to identify various classes of risk or protective factors for AD, early-onset AD, and late-onset AD. We generated 400,274 data entries in total, among which the major analysis method of the IVW model consists of 73,129 records with 4840 exposure traits, which fall into 10 categories: Disease, Medical laboratory science, Imaging, Anthropometric, Treatment, Molecular trait, Gut microbiota, Past history, Family history, and Lifestyle trait. More importantly, a freely accessed online platform called MRAD (https://gwasmrad.com/mrad/) has been developed using the Shiny package with MR analysis results. Additionally, novel potential AD therapeutic targets (CD33, TBCA, VPS29, GNAI3, PSME1) are identified, among which CD33 was positively associated with the main outcome traits of AD, as well as with both EOAD and LOAD. TBCA and VPS29 were negatively associated with the main outcome traits of AD, as well as with both EOAD and LOAD. GNAI3 and PSME1 were negatively associated with the main outcome traits of AD, as well as with LOAD, but had no significant causal association with EOAD. The findings of our research advance our understanding of the etiology of AD.

Francisco Lopera obituary: neurologist who traced genetic origin of early-onset Alzheimer's.

Francisco Lopera obituary: neurologist who traced genetic origin of early-onset Alzheimer's.

Understanding Down Syndrome: A Systematic Review of Genetic, Clinical, and Cognitive Implications

Down syndrome (DS) is the most common chromosomal disorder, primarily caused by trisomy 21, and is associated with a range of genetic, clinical, and cognitive challenges. This systematic review aims to provide a comprehensive understanding of these aspects by synthesizing recent research on the genetic mechanisms underlying DS, its common clinical manifestations, and the cognitive impairments often observed in affected individuals. Genetic studies highlight the complexity of trisomy 21 and its impact on phenotypic variability. Clinically, DS is associated with distinct physical features, congenital heart defects, and a predisposition to conditions such as thyroid disorders and leukemia. Cognitive impairments, including intellectual disability and early-onset Alzheimer's disease, present significant challenges for individuals with DS, often requiring early intervention and lifelong support. Recent advancements in medical care, therapeutic interventions, and educational strategies have improved quality of life and life expectancy for individuals with DS. This review identifies gaps in the current literature, such as the need for more personalized therapeutic approaches based on genetic variability, and highlights areas for future research to further improve outcomes for individuals with Down syndrome.

Identification of key proteins in early-onset Alzheimer's disease based on WGCNA.

Early-onset Alzheimer's disease (EOAD) is sporadic, highly heterogeneous, and its underlying pathogenic mechanisms remain largely elusive. Proteomics research aims to uncover the biological processes and key proteins involved in disease progression. However, no proteomic studies to date have specifically focused on EOAD brain tissue. We integrated proteomic data from brain tissues of two Alzheimer's disease (AD) cohorts and constructed a protein co-expression network using weighted gene co-expression network analysis (WGCNA). We identified modules associated with EOAD, conducted functional enrichment analysis to understand the biological processes involved in EOAD, and pinpointed potential key proteins within the core modules most closely linked to AD pathology. In this study, we identified a total of 2,749 proteins associated with EOAD. Through protein co-expression network analysis, we discovered 41 distinct co-expression modules. Notably, the proteins within the core module most closely linked to AD pathology were significantly enriched in neutrophil degranulation. Additionally, we identified two potential key proteins within this core module that have not been previously reported in AD and validated their expression levels in 5xFAD mice. In summary, through a protein co-expression network analysis, we identified EOAD-related biological processes and molecular pathways, and screened and validated two key proteins, ERBB2IP and LSP1. These proteins may play an important role in the progression of EOAD, suggesting they could serve as potential therapeutic targets for the disease.

Alzheimer's disease induced neurons bearing PSEN1 mutations exhibit reduced excitability.

Alzheimer's disease (AD) is a devastating neurodegenerative condition that affects memory and cognition, characterized by neuronal loss and currently lacking a cure. Mutations in PSEN1 (Presenilin 1) are among the most common causes of early-onset familial AD (fAD). While changes in neuronal excitability are believed to be early indicators of AD progression, the link between PSEN1 mutations and neuronal excitability remains to be fully elucidated. This study examined iPSC-derived neurons (iNs) from fAD patients with PSEN1 mutations S290C or A246E, alongside CRISPR-corrected isogenic cell lines, to investigate early changes in excitability. Electrophysiological profiling revealed reduced excitability in both PSEN1 mutant iNs compared to their isogenic controls. Neurons bearing S290C and A246E mutations exhibited divergent passive membrane properties compared to isogenic controls, suggesting distinct effects of PSEN1 mutations on neuronal excitability. Additionally, both PSEN1 backgrounds exhibited higher current density of voltage-gated potassium (Kv) channels relative to their isogenic iNs, while displaying comparable voltage-gated sodium (Nav) channel current density. This suggests that the Nav/Kv imbalance contributes to impaired neuronal firing in fAD iNs. Deciphering these early cellular and molecular changes in AD is crucial for understanding disease pathogenesis.