The nervous system processes a vast amount of information, performing computations that underlie perception, cognition, and behavior. During development, neuronal guidance genes, which encode extracellular cues, their receptors, and downstream signal transducers, organize neural wiring to generate the complex architecture of the nervous system. It is now evident that many of these neuroguidance cues and their receptors are active during development and are also expressed in the adult nervous system. This suggests that neuronal guidance pathways are critical not only for neural wiring but also for ongoing function and maintenance of the mature nervous system. Supporting this view, these pathways continue to regulate synaptic connectivity, plasticity, and remodeling, and overall brain homeostasis throughout adulthood. Genetic and transcriptomic analyses have further revealed many neuronal guidance genes to be associated with a wide range of neurodegenerative and neuropsychiatric disorders. Although the precise mechanisms by which aberrant neuronal guidance signaling drives the pathogenesis of these diseases remain to be clarified, emerging evidence points to several common themes, including dysfunction in neurons, microglia, astrocytes, and endothelial cells, along with dysregulation of neuron-microglia-astrocyte, neuroimmune, and neurovascular interactions. In this review, we explore recent advances in understanding the molecular and cellular mechanisms by which aberrant neuronal guidance signaling contributes to disease pathogenesis through altered cell-cell interactions. For instance, recent studies have unveiled two distinct semaphorin-plexin signaling pathways that affect microglial activation and neuroinflammation. We discuss the challenges ahead, along with the therapeutic potentials of targeting neuronal guidance pathways for treating neurodegenerative diseases. Particular focus is placed on how neuronal guidance mechanisms control neuron-glia and neuroimmune interactions and modulate microglial function under physiological and pathological conditions. Specifically, we examine the crosstalk between neuronal guidance signaling and TREM2, a master regulator of microglial function, in the context of pathogenic protein aggregates. It is well-established that age is a major risk factor for neurodegeneration. Future research should address how aging and neuronal guidance signaling interact to influence an individual's susceptibility to various late-onset neurological diseases and how the progression of these diseases could be therapeutically blocked by targeting neuronal guidance pathways.

The function of microglia during progression of Alzheimer's disease (AD) can be investigated using mouse models that enable genetic manipulation of microglial subpopulations in a temporal manner. We developed mouse lines that express either Cre recombinase (Cre) for constitutive targeting, or destabilized-domain Cre recombinase (DD-Cre) for inducible targeting from the Cst7 locus (Cst7 DD-Cre) to specifically manipulate disease associated microglia (DAM) and crossed with Ai14 tdTomato cre-reporter line mice. Cst7Cre was found to target all brain resident myeloid cells, due to transient developmental expression of Cst7, but no expression was found in the inducible Cst7 DD-Cre mice. Further crossing of this line with 5xFAD mice combined with dietary administration of trimethoprim to induce DD-Cre activity produces long-term labeling in DAM without evidence of leakiness, with tdTomato-expression restricted to cells surrounding plaques. Using this model, we found that DAMs are a subset of plaque-associated microglia (PAMs) and their transition to DAM increases with age and disease stage. Spatial transcriptomic analysis revealed that tdTomato+ cells show higher expression of disease and inflammatory genes compared to other microglial populations, including non-labeled PAMs. These models allow either complete cre-loxP targeting of all brain myeloid cells (Cst7Cre), or inducible targeting of DAMs, without leakiness (Cst7 DD-Cre).

Reactive astrocytes are associated with Alzheimer's disease (AD), and several AD genetic risk variants are associated with genes highly expressed in astrocytes. However, the contribution of genetic risk within astrocytes to cellular processes relevant to the pathogenesis of AD remains ill-defined. Here, we present a resource for studying AD genetic risk in astrocytes using a large collection of induced pluripotent stem cell (iPSC) lines from deeply phenotyped individuals with a range of neuropathological and cognitive outcomes. IPSC lines from 44 individuals were differentiated into astrocytes followed by unbiased molecular profiling using RNA sequencing and tandem mass tag-mass spectrometry. We demonstrate the utility of this resource in examining gene- and pathway-level associations with clinical and neuropathological traits, as well as in analyzing genetic risk and resilience factors through parallel analyses of iPSC-astrocytes and brain tissue from the same individuals. Our analyses reveal that genes and pathways altered in iPSC-derived astrocytes from individuals with AD are concordantly dysregulated in AD brain tissue. This includes increased levels of prefoldin proteins, extracellular matrix factors, COPI-mediated trafficking components and reduced levels of proteins involved in cellular respiration and fatty acid oxidation. Additionally, iPSC-derived astrocytes from individuals resilient to high AD neuropathology show elevated basal levels of interferon response proteins and increased secretion of interferon gamma. Correspondingly, higher polygenic risk scores for AD are associated with lower levels of interferon response proteins in astrocytes. This study establishes an experimental system that integrates genetic information with a matched iPSC lines and brain tissue data from a large cohort of individuals to identify genetic contributions to molecular pathways affecting AD risk and resilience.

Although many studies have investigated the influence of HLA on the risk of Alzheimer's Disease (AD), there have been inconsistent results. Part of this problem has been attributed to limitations of a clinical assessment in the absence of histopathological confirmation or other quantitative assessments. This study employed a subset of the AD Sequencing Project, representing 2663 cases with histopathological confirmation of AD and confirmation of 881 cognitively normal cases. Two HLA allelic subtypes, DQB1*02:01 and DQB1*02:02, were associated with lower Braak staging, a measure of tauopathy in the brain. These HLA subtypes were also associated with a later age of onset. There was a lower occurrence of HLA-DQB1*02:01 and HLA-DQB1*02:02 in AD cases compared to cognitively normal cases. For all of the above results, replicative sets were confirmatory. The above results were also maintained for both HLA-DQB1*02:01 and HLA-DQB1*02:02 when removing the effect of APOE4 or APOE2. Interestingly, the HLA-DQB1*02 allele binds tau better than all other HLA-DQB1 alleles tested, per an in silico assessment, raising the question of whether deletion of tau binding, auto-reactive T-cells in the thymus could reduce the likelihood of the onset of AD?

Alzheimer's disease (AD) is a multifaceted neurodegenerative condition distinguished by the occurrence of memory impairment, cognitive deterioration, and neuronal impairment. Despite extensive research efforts, conventional treatment strategies primarily focus on symptom management, highlighting the need for innovative therapeutic approaches. This review explores the challenges of AD treatment and the integration of computational methodologies to advance therapeutic interventions. A comprehensive analysis of recent literature was conducted to elucidate the broad scope of Alzheimer's etiology and the limitations of conventional drug discovery approaches. Our findings underscore the critical role of computational models in elucidating disease mechanisms, identifying therapeutic targets, and expediting drug discovery. Through computational simulations, researchers can predict drug efficacy, optimize lead compounds, and facilitate personalized medicine approaches. Moreover, machine learning algorithms enhance early diagnosis and enable precision medicine strategies by analyzing multi-modal datasets. Case studies highlight the application of computational techniques in AD therapeutics, including the suppression of crucial proteins implicated in disease progression and the repurposing of existing drugs for AD management. Computational models elucidate the interplay between oxidative stress and neurodegeneration, offering insights into potential therapeutic interventions. Collaborative efforts between computational biologists, pharmacologists, and clinicians are essential to translate computational insights into clinically actionable interventions, ultimately improving patient outcomes and addressing the unmet medical needs of individuals affected by AD. Overall, integrating computational methodologies represents a promising paradigm shift in AD therapeutics, offering innovative solutions to overcome existing challenges and transform the landscape of AD treatment.

Alzheimer's disease (AD) remains a formidable challenge in neurodegeneration research, with limited therapeutic options despite decades of study. While Drosophila melanogaster has been instrumental in in modeling AD related Tau and amyloid beta toxicity, inflammation, a key driver of AD pathology, remains unexplored in fly models. Given the evolutionary conservation of innate immune pathways between flies and mammals, drosophila presents a powerful yet underutilized tool for inflammation led drug discovery in AD.

This perspective highlights the relevance of Drosophila in studying neuroinflammatory processes, including microglial-like glial activation, systemic inflammation and gut-brain axis interactions. It further explores how fly models can be leveraged to screen anti-inflammatory compounds and dissect immune related genetic factors implicated in AD.

By integrating immune modulation in Drosophila-based drug discovery pipeline we can accelerate the identification of novel therapeutic strategies. Fully exploiting the potential of Drosophila in inflammation led drug screening may usher in a new era of AD therapeutics, bridging gaps between fundamental research and translational medicine.

The escalating prevalence of dementia worldwide necessitates preventive strategies to mitigate its extensive health, psychological, and social impacts. As the prevalence of dementia continues to rise, gaining insights into its risk factors and causes becomes paramount, given the absence of a definitive cure. Cardiovascular disease has emerged as a prominent player in the complex landscape of dementia. Preventing dyslipidaemia, unhealthy western-type diets, hypertension, diabetes, being overweight, physical inactivity, smoking, and high alcohol intake have the potential to diminish not only cardiovascular disease but also dementia. The purpose of this review is to present our current understanding of cardiovascular risk factors for Alzheimer's disease and vascular dementia (VaD) by using clinical human data from observational, genetic studies and clinical trials, while elaborating on potential mechanisms. Hypertension and Type 2 diabetes surface as significant causal risk factors for both Alzheimer's disease and VaD, as consistently illustrated in observational and Mendelian randomization studies. Anti-hypertensive drugs and physical activity have been shown to improve cognitive function in clinical trials. Important to note is that robust genome-wide association studies are lacking for VaD, and indeed more and prolonged clinical trials are needed to establish these findings and investigate other risk factors. Trials should strategically target individuals at the highest dementia risk, identified using risk charts incorporating genetic markers, biomarkers, and cardiovascular risk factors. Understanding causal risk factors for dementia will optimize preventive measures, and the implementation of well-known therapeutics can halt or alleviate dementia symptoms if started early. Needless to mention is that future health policies should prioritize primordial prevention from early childhood to prevent risk factors from even occurring in the first place. Together, understanding the role of cardiovascular risk factors in dementia, improving genome-wide association studies for VaD, and advancing clinical trials are crucial steps in addressing this significant public health challenge.

Genome-wide association studies (GWAS) of Alzheimer's disease (AD) have identified a plethora of risk loci. However, the disease variants/genes and the underlying mechanisms have not been extensively studied.

Bulk ATAC-seq was performed in induced pluripotent stem cells (iPSCs) differentiated various brain cell types to identify allele-specific open chromatin (ASoC) SNPs. CRISPR-Cas9 editing generated isogenic pairs, which were then differentiated into glutamatergic neurons (iGlut). Transcriptomic analysis and functional studies of iGlut co-cultured with mouse astrocytes assessed neuronal excitability and lipid droplet formation.

We identified a putative causal SNP of CLU that impacted neuronal chromatin accessibility to transcription-factor(s), with the AD protective allele upregulating neuronal CLU and promoting neuron excitability. And, neuronal CLU facilitated neuron-to-glia lipid transfer and astrocytic lipid droplet formation coupled with reactive oxygen species (ROS) accumulation. These changes caused astrocytes to uptake less glutamate thereby altering neuron excitability.

For a strong AD-associated locus near Clusterin (CLU), we connected an AD protective allele to a role of neuronal CLU in promoting neuron excitability through lipid-mediated neuron-glia communication. Our study provides insights into how CLU confers resilience to AD through neuron-glia interactions.

Alzheimer's disease (AD), an escalating global public health concern, demonstrates complex pathogenesis involving both genetic predisposition and vascular components. Blood pressure variability (BPV) has been implicated in neurodegenerative diseases, but its causal relationship with AD remains unclear. This study aims to explore the causal relationship between BPV and AD by applying Mendelian randomization (MR) to genome-wide association study (GWAS) summary data. Genetic instruments were selected from BPV GWAS based on UK Biobank data, ensuring relevance and significance(p < 5 × 10⁻⁶). Genetic estimates on exposure were obtained from three databases: The The International Genomic of Alzheimer's Project (IGAP); Maternal family history of AD from UK Biobank (MFH-UKBB), and Paternal family history of AD from UK Biobank (PFH-UKBB). Proxy SNPs were manually selected if SNPs were not available in the exposure GWAS. Data harmonization was performed to ensure consistency in effect and reference alleles. Three MR statistical methods were employed to assess causal effects, including inverse variance weighting (IVW) with random or fixed effect, MR-Egger regression, and the Weighted Median Method. Sensitivity analyses to evaluate robustness were also employed. Six SNPs associated with systolic BPV and six SNPs associated with diastolic BPV were included. Significant causal effects of SBPV on AD were found on the PFH-UKBB dataset in all four methods. The odds ratios for AD per 10-unit increment in SBPV were 1.028, 1.015, and 1.015 for MR-Egger, IVW-MR, and weighted median, respectively. In contrast, only IVW methods found significant results for DBPV in the MFH-UKBB dataset. SBPV is a possible causal risk factor for AD, while the evidence for DBPV needs further study. BPV control should be an important treatment target in preventing dementia.

BackgroundAlzheimer's disease (AD) and age-related macular degeneration (AMD) place considerable health burden on affected individuals and significant economic burden on society.ObjectiveThis study aims to explore the shared cellular and molecular mechanisms underlying the pathogenesis of AD and AMD.MethodsThe investigation in this study is conducted via single-cell and bulk tissue transcriptomic analysis. Transcriptomic datasets of AD and AMD were obtained from the GEO database. The shared differentially expressed genes (DEGs) in control and AD- and AMD-affected samples were identified. Functional enrichment analysis for DEGs was subsequently performed. Then, the protein-protein interaction (PPI) network of these DEGs was established via the STRING database and hub genes of this network were identified by Cytoscape software. Single-cell transcriptomic analysis was performed using Seurat R package to explore their expression in different cell types.ResultsDifferential analysis identified 127 shared DEGs of the two diseases, including 71 upregulated and 56 downregulated genes. Upregulated DEGs were enriched in inflammation, gliogenesis, cell apoptosis, and response to bacterial and viral infection and downregulated DEGs were enriched in mitochondrial function and energy production. PPI network and Cytoscape determined 10 hub genes, of which the NFKBIA gene was associated with the severity of both AD and AMD. Moreover, single-cell transcriptomic analysis showed that NFKBIA was highly expressed in microglia from disease-affected tissues.ConclusionsThe findings indicated that microglia with high NFKBIA expression were important contributors to the progression of both AD and AMD. Microglia-derived NFKBIA might serve as a potential therapeutic target for AD and AMD.

Autophagy disruption is important in Alzheimer's disease (AD) as it prevents misfolded proteins from being removed, which leads to the accumulation of amyloid plaques and neurofibrillary tangles (NFTs). Restoring autophagy improves neuronal survival and cognitive function, according to experimental models. In AD models, mTOR inhibition and AMPK activation enhance synaptic plasticity and lessen learning deficits. Inhibitors of phosphodiesterase-4 (PDE4) improve cognition and reduce neuroinflammation via altering cyclic adenosine monophosphate (cAMP) transmission. Furthermore, autophagic-lysosomal clearance is encouraged by upregulating transcription factor EB (TFEB), which lessens the pathogenic damage linked to AD. These results point to autophagy modification as a promising therapeutic approach, with the mTOR, AMPK, cAMP, and TFEB pathways being possible targets for drugs. Though much evidence is based on animal studies, these findings provide valuable insights into autophagy's role in AD pathology, offering promising directions for future research and drug development.

Estimating heritability has been fundamental in understanding the genetic contributions to complex disorders like late-onset Alzheimer's disease (LOAD), and provides a rationale for identifying genetic factors associated with disease susceptibility. While numerous studies have established substantial genetic contribution for LOAD, the interpretation of heritability estimates remains challenging. These challenges are further complicated by the binary nature of LOAD status, where estimation and interpretation require additional considerations. Through a systematic review, we identified LOAD heritability estimates from 6 twin studies and 17 genome-wide association studies, all conducted in populations of European ancestry. We demonstrate that these heritability estimates for LOAD vary considerably. The variation reflects not only differences in study design and methodological approaches but also the underlying study population characteristics. Our findings indicate that commonly cited heritability estimates, often treated as universal values, should be interpreted within specific population contexts and methodological frameworks.

Ependymal cells are multiciliated glial cells lining the ventricles of the mammalian brain. Their differentiation from progenitor cells involves cell enlargement and progresses through centriole amplification phases and ciliogenesis. These phases are accompanied by the sharp up-regulation of mTOR Complex 1 activity (mTORC1), a master regulator of macromolecule biosynthesis and cell growth, whose function in ependymal cell differentiation is unknown. We demonstrate that mTORC1 inhibition by rapamycin preserves the progenitor pool by reinforcing quiescence and preventing alternative cell cycle progression for centriole amplification. Overexpressing E2F4 and MCIDAS circumvents mTORC1-regulated processes, enabling centriole amplification despite rapamycin, and enhancing mTORC1 activity through positive feedback. Acute rapamycin treatment in multicentriolar cells during the late phases of differentiation causes centriole regrouping, indicating a direct role of mTORC1 in centriole dynamics. By phosphoproteomic and phosphomutant analysis, we reveal that the mTORC1-mediated phosphorylation of GAS2L1, a centrosomal protein that links actin and microtubule cytoskeletons, participates in centriole disengagement. This multilayered and sequential control of ependymal development by mTORC1, from the progenitor pool to centriolar function, has implications for pathophysiological conditions like aging and hydrocephalus-prone genetic diseases.

Until recently, the association between circulating adiponectin (ADPN) levels and the risk of Alzheimer's disease (AD) and Parkinson's disease (PD) remained unclear.

We utilized public data from the IEU GWAS database to conduct a two-sample bidirectional Mendelian randomization (MR) analysis and multiple sensitivity analyses. The MR analysis was performed using the aggregated data, with the genetic risk score (GRS) serving as an instrumental variable.

The MR analyses revealed no significant causal association between genetically determined ADPN levels and the risk of AD (ORIVW = 0.852, 95% confidence interval [CI]: 0.586-1.117, p = 0.235) or PD (ORIVW = 0.830, 95% CI: 0.780-1.156, p = 0.606). Conversely, neither AD nor PD demonstrated any causal association with ADPN levels. The GRS approach yielded similar results (p > 0.05). However, it exhibited a negative correlation with interleukin 1β (IL1β, βIVW = -0.31; 95% CI: -0.55 to -0.07, p = 0.011). The Cochrane's Q test and MR-PRESSO analysis revealed no evidence of pleiotropy.

Our findings provide no evidence to substantiate a causal relationship between ADPN levels and the risk of AD and PD or vice versa. However, elevated levels of ADPN may correlate with lower levels of IL1β.

The brain is a highly plastic organ that continually receives and integrates signals to generate functional and structural changes and homeostatic adaptations throughout life. Alterations in some signaling pathways that mediate these responses can impact brain plasticity, accelerate brain aging and potentially lead to neurodegeneration. There is substantial evidence that two important signaling pathways activated by neurotrophins, nonacronymic (VGF) and brain-derived neurotrophic factor (BDNF), are involved in substantial functions stimulating neuronal growth, differentiation, and circuit establishment during development and neuronal maintenance and plasticity in the mature brain. In this review, we present evidence that these two pathways and their interactions are central players in cognitive performance and alterations in pathological aging, particularly in conditions such as Alzheimer's disease (AD). Finally, we suggest specific avenues for future research on the basis of recent findings suggesting these molecules are diagnostic biomarkers and putative therapeutic tools to prevent, delay or improve AD neuropathology.

Epigenomic profiling of the brain has largely been done on bulk tissues, limiting our understanding of cell type-specific epigenetic changes in disease states. Here, we introduce cell type-specific histone acetylation score (CHAS), a computational tool for inferring cell type-specific signatures in bulk brain H3K27ac profiles. We applied CHAS to >300 H3K27ac chromatin immunoprecipitation sequencing samples from studies of Alzheimer's disease, Parkinson's disease, autism spectrum disorder, schizophrenia, and bipolar disorder in bulk postmortem brain tissue. In addition to recapitulating known disease-associated shifts in cellular proportions, we identified cell type-specific biological insights into brain-disorder-associated regulatory variation. In most cases, genetic risk and epigenetic dysregulation targeted different cell types, suggesting independent mechanisms. For instance, genetic risk of Alzheimer's disease was exclusively enriched within microglia, while epigenetic dysregulation predominantly fell within oligodendrocyte-specific H3K27ac regions. In addition, reanalysis of the original datasets using CHAS enabled identification of biological pathways associated with each neurological and psychiatric disorder at cellular resolution.

Cognitive resilience (CR) contributes to the variability in risk for developing and progressing in Alzheimer's disease (AD) among individuals. Beyond genetics, recent studies highlight the critical role of lifestyle factors in enhancing CR and delaying cognitive decline. DNA methylation (DNAm), an epigenetic mechanism influenced by both genetic and environmental factors, including CR-related lifestyle factors, offers a promising pathway for understanding the biology of CR. We studied DNAm changes associated with the Resilience Index (RI), a composite measure of lifestyle factors, using blood samples from the Healthy Brain Initiative (HBI) cohort. After corrections for multiple comparisons, our analysis identified 19 CpGs and 24 differentially methylated regions significantly associated with the RI, adjusting for covariates age, sex, APOE ε4, and immune cell composition. The RI-associated methylation changes are significantly enriched in pathways related to lipid metabolism, synaptic plasticity, and neuroinflammation, and highlight the connection between cardiovascular health and cognitive function. By identifying RI-associated DNAm, our study provided an alternative approach to discovering future targets and treatment strategies for AD, complementary to the traditional approach of identifying disease-associated variants directly. Furthermore, we developed a Methylation-based Resilience Score (MRS) that successfully predicted future cognitive decline in an external dataset from the Alzheimer's Disease Neuroimaging Initiative (ADNI), even after accounting for age, sex, APOE ε4, years of education, baseline diagnosis, and baseline MMSE score. Our findings are particularly relevant for a better understanding of epigenetic architecture underlying cognitive resilience. Importantly, the significant association between baseline MRS and future cognitive decline demonstrated that DNAm could be a predictive marker for AD, laying the foundation for future studies on personalized AD prevention.

Alzheimer's disease (AD) remains a significant global health challenge, characterized by its progressive neurodegeneration and cognitive decline. The urgent need for early diagnosis and effective treatment necessitates the identification of reliable biomarkers that can illuminate the underlying pathophysiology of AD. This review provides a comprehensive overview of the latest advancements in biomarker research, focusing on their applications in diagnosis, prognosis, and therapeutic development. We delve into the multifaceted landscape of AD biomarkers, encompassing molecular, imaging, and fluid-based markers. The integration of these biomarkers, including amyloid-β and tau proteins, neuroimaging modalities, cerebrospinal fluid analysis, and genetic risk factors, offers a more nuanced understanding of AD's complex etiology. By leveraging the power of precision medicine, biomarker-driven approaches can enable personalized treatment strategies and enhance diagnostic accuracy. Moreover, this review highlights the potential of biomarker research to accelerate drug discovery and development. By identifying novel therapeutic targets and monitoring disease progression, biomarkers can facilitate the evaluation of experimental treatments and ultimately improve patient outcomes. In conclusion, this review underscores the critical role of biomarkers in advancing our comprehension of AD and driving the development of effective interventions. By providing a comprehensive overview of the current state-of-the-art, this work aims to inspire future research and contribute to the goal of conquering AD.

Virtually all individuals aged 65 or older develop at least early pathology of Alzheimer's disease (AD), yet most lack disease-causing mutations in APP, PSEN, or MAPT, and many do not carry the APOE4 risk allele. This raises questions about AD development in the general population. Although transcriptional dysregulation has not traditionally been a hallmark of AD, recent studies reveal significant epigenomic changes in late-onset AD (LOAD) patients. We show that altered expression of the LOAD biomarker phosphoglycerate dehydrogenase (PHGDH) modulates AD pathology in mice and human brain organoids independent of its enzymatic activity. PHGDH has an uncharacterized role in transcriptional regulation, promoting the transcription of inhibitor of nuclear factor kappa-B kinase subunit alpha (IKKa) and high-mobility group box 1 (HMGB1) in astrocytes, which suppress autophagy and accelerate amyloid pathology. A blood-brain-barrier-permeable small-molecule inhibitor targeting PHGDH's transcriptional function reduces amyloid pathology and improves AD-related behavioral deficits. These findings highlight transcriptional regulation in LOAD and suggest therapeutic strategies beyond targeting familial mutations.

Both schizophrenia (SCZ) and Alzheimer's disease (AD) are highly heritable brain disorders. Despite of the observed comorbidity and shared psychosis and cognitive decline between the two disorders, the genetic risk architecture shared by SCZ and AD remains largely unknown. Based on summary statistics of the currently available largest genome-wide association studies for SCZ (n = 130,644) and AD (n = 455,258) in individuals of European ancestry, we conducted conditional/conjunctional false discovery rate (FDR) analysis to enhance the statistical power for discovering more genetic associations with SCZ or AD and to detect the common genetic variants shared by both disorders. We found shared genetic architecture in SCZ conditioned on AD and vice versa across different levels of significance, indicating polygenic overlap. We found 268 (78 novel) SCZ-only and 125 (55 novel) AD-only SNPs at conditional FDR < 0.01, and 16 lead SNPs shared by SCZ and AD at conjunctional FDR < 0.05. Only half of the shared SNPs showed concordant effect direction, which was consistent with the modest genetic correlation (r = 0.097; P = 0.026) between the two disorders. This study provides evidence for polygenic overlap between SCZ and AD, suggesting the existence of the shared molecular genetic mechanisms, which may inform therapeutic targets that are applicable for both disorders.

The concept of brain age (BA) describes an integrative imaging marker of brain health, often suggested to reflect aging processes. However, the degree to which cross-sectional MRI features, including BA, reflect past, ongoing, and future brain changes across different tissue types from macro- to microstructure remains controversial. Here, we use multimodal imaging data of 39,325 UK Biobank participants, aged 44-82 years at baseline and 2,520 follow-ups within 1.12-6.90 years to examine BA changes and their relationship to anatomical brain changes. We find insufficient evidence to conclude that BA reflects the rate of brain aging. However, modality-specific differences in brain ages reflect the state of the brain, highlighting diffusion and multimodal MRI brain age as potentially useful cross-sectional markers.

The SH2-containing inositol phosphatase (SHIP) has become an actively researched therapeutic target for a number of disorders, including Alzheimer's Disease, Graft-vs-Host disease, obesity and cancer. Analogs of the aminosteroid SHIP inhibitor 3α-aminocholestane (3AC) have been synthesized and tested. Analogs with improved water solubility have been identified. Deletion of the C17 alkyl group from the cholestane skeleton improves water solubility, however these compounds inhibit both SHIP1 and SHIP2. Enzyme kinetics imply that these molecules are competitive inhibitors of SHIP, binding at a site near where the substrate binds to the phosphatase. A model of the binding of the inhibitors within the active site of SHIP1 is proposed to explain the structure activity studies. Overall this work provides more water soluble aminosteroid pan-SHIP1/2 inhibitors that can be used for future studies of SHIP activity.

Introduction: Transcriptional regulation is an important process wherein non-protein coding enhancer sequences play a key role in determining cell type identity and phenotypic diversity. In neural tissue, these gene regulatory processes are crucial for coordinating a plethora of interconnected and regionally specialized cell types, ensuring their synchronized activity in generating behavior. Recognizing the intricate interplay of gene regulatory processes in the brain is imperative, as mounting evidence links neurodevelopment and neurological disorders to non-coding genome regions. While genome-wide association studies are swiftly identifying non-coding human disease-associated loci, decoding regulatory mechanisms is challenging due to causal variant ambiguity and their specific tissue impacts. Methods: Massively parallel reporter assays (MPRAs) are widely used in cell culture to study the non-coding enhancer regions, linking genome sequence differences to tissue-specific regulatory function. However, widespread use in animals encounters significant challenges, including insufficient viral library delivery and library quantification, irregular viral transduction rates, and injection site inflammation disrupting gene expression. Here, we introduce a systemic MPRA (sysMPRA) to address these challenges through systemic intravenous AAV viral delivery. Results: We demonstrate successful transduction of the MPRA library into diverse mouse tissues, efficiently identifying tissue specificity in candidate enhancers and aligning well with predictions from machine learning models. We highlight that sysMPRA effectively uncovers regulatory effects stemming from the disruption of MEF2C transcription factor binding sites, single-nucleotide polymorphisms, and the consequences of genetic variations associated with late-onset Alzheimer's disease. Conclusion: SysMPRA is an effective library delivering method that simultaneously determines the transcriptional functions of hundreds of enhancers in vivo across multiple tissues.

The urgent need for safe and effective therapies for Alzheimer's disease (AD) has spurred a growing interest in repurposing existing drugs to treat or prevent AD. In this study, we combined multi-omics and clinical data to investigate possible repurposing opportunities for AD. We performed transcriptome-wide association studies (TWAS) to construct gene expression signatures of AD from publicly available GWAS summary statistics, using both transcriptome prediction models for 49 tissues from the Genotype-Tissue Expression (GTEx) project and microglia-specific models trained on eQTL data from the Microglia Genomic Atlas (MiGA). We then identified compounds capable of reversing the AD-associated changes in gene expression observed in these signatures by querying the Connectivity Map (CMap) drug perturbation database. Out of >2,000 small-molecule compounds in CMap, aspirin emerged as the most promising AD repurposing candidate. To investigate the longitudinal effects of aspirin use on AD, we collected drug exposure and AD coded diagnoses from three independent sources of real-world data: electronic health records (EHRs) from Vanderbilt University Medical Center (VUMC) and the National Institutes of Health All of Us Research Program, along with national healthcare claims from the MarketScan Research Databases. In meta-analysis of EHR data from VUMC and All of Us , we found that aspirin use before age 65 was associated with decreased risk of incident AD (hazard ratio=0.76, 95% confidence interval [CI]: 0.64-0.89, P =0.001). Consistent with the findings utilizing EHR data, analysis of claims data from MarketScan revealed significantly lower odds of aspirin exposure among AD cases compared to matched controls (odds ratio=0.32, 95% CI: 0.28-0.38, P <0.001). Our results demonstrate the value of integrating genetic and clinical data for drug repurposing studies and highlight aspirin as a promising repurposing candidate for AD, warranting further investigation in clinical trials.

Late-onset Alzheimer's disease (LOAD) has a complex genomic architecture with risk variants in multiple pathways, including the endolysosomal network (ELN). Whether genetic risk in specific pathways correlates with corresponding biological dysfunction remains largely unknown. We developed an endolysosomal pathway-specific polygenic risk score (ePRS) using 13 established AD GWAS loci containing ELN genes. We investigated the association between ePRS and AD neuropathology, then examined cell-specific endolysosomal morphology and transcriptomic profiles in post-mortem dorsolateral prefrontal cortex samples from donors stratified by ePRS burden. We found that the ePRS was significantly associated with AD diagnosis and neuropathological measures, comparable to a pathway-agnostic PRS despite representing far fewer loci. High ePRS correlated with increased neuronal endosome volume, number and perinuclear aggregation, as well as enlarged microglial lysosomes, independent of AD pathology. Single-nucleus RNA sequencing revealed cell-type transcriptomic changes associated with ePRS status, including glutamatergic signaling, protein homeostasis, responses to DNA damage and immune function. Neurons, astrocytes, oligodendrocytes, and microglia showed varied gene expression patterns associated with ePRS burden. Conclusions: This study provides evidence that AD genetic risk variants harboring ELN genes correlate with endolysosomal dysfunction in human brain tissue. These findings suggest that pathway-specific genetic risk contributes to corresponding cellular pathology in AD and nominates candidate mechanisms by which ELN AD variants contribute to pathogenesis.

Recent studies show that patients with Alzheimer's disease (AD) harbor specific methylation marks in the brain that, if accessible, could be used as epigenetic biomarkers. Liquid biopsy enables the study of circulating cell-free DNA (cfDNA) fragments originated from dead cells, including neurons affected by neurodegenerative processes. Here, we isolated and epigenetically characterized plasma cfDNA from 35 patients with AD and 35 cognitively healthy controls by using the Infinium® MethylationEPIC BeadChip array. Bioinformatics analysis was performed to identify differential methylation positions (DMPs) and regions (DMRs), including APOE ε4 genotype stratified analysis. Plasma pTau181 (Simoa) and cerebrospinal fluid (CSF) core biomarkers (Fujirebio) were also measured and correlated with differential methylation marks. Validation was performed with bisulfite pyrosequencing and bisulfite cloning sequencing. Epigenome-wide cfDNA analysis identified 102 DMPs associated with AD status. Most DMPs correlated with clinical cognitive and functional tests including 60% for Mini-Mental State Examination (MMSE) and 80% for Global Deterioration Scale (GDS), and with AD blood and CSF biomarkers. In silico functional analysis connected 30 DMPs to neurological processes, identifying key regulators such as SPTBN4 and APOE genes. Several DMRs were annotated to genes previously reported to harbor epigenetic brain changes in AD (HKR1, ZNF154, HOXA5, TRIM40, ATG16L2, ADAMST2) and were linked to APOE ε4 genotypes. Notably, a DMR in the HKR1 gene, previously shown to be hypermethylated in the AD hippocampus, was validated in cfDNA from an orthogonal perspective. These results support the feasibility of studying cfDNA to identify potential epigenetic biomarkers in AD. Thus, liquid biopsy could improve non-invasive AD diagnosis and aid personalized medicine by detecting epigenetic brain markers in blood.

The SORL1 gene encodes the sortilin-related receptor protein SORLA, a sorting receptor that regulates endo-lysosomal trafficking of various substrates. Loss of function variants in SORL1 are causative for Alzheimer's disease (AD) and decreased expression of SORLA has been repeatedly observed in human AD brains. SORL1 is highly expressed in the central nervous system, including in microglia, the tissue-resident immune cells of the brain. Loss of SORLA leads to enlarged lysosomes in hiPSC-derived microglia-like cells (hMGLs). However, how SORLA deficiency contributes to lysosomal dysfunction in microglia and how this contributes to AD pathogenesis is not known. In this study, we show that loss of SORLA results in decreased lysosomal degradation and lysosomal enzyme activity due to altered trafficking of lysosomal enzymes in hMGLs. Phagocytic uptake of fibrillar amyloid beta 1-42 and synaptosomes is increased in SORLA-deficient hMGLs, but due to reduced lysosomal degradation, these substrates aberrantly accumulate in lysosomes. An alternative mechanism of lysosome clearance, lysosomal exocytosis, is also impaired in SORL1-deficient microglia, which may contribute to an altered immune response. Overall, these data suggest that SORLA has an important role in the proper trafficking of lysosomal hydrolases in hMGLs, which is critical for microglial function. This further substantiates the microglial endo-lysosomal network as a potential novel pathway through which SORL1 may increase AD risk and contribute to the development of AD. Additionally, our findings may inform the development of novel lysosome and microglia-associated drug targets for AD.

Apolipoprotein E ε4 (APOE ε4) bring the higher risk of Alzheimer' Disease (AD). It is essential to evaluate whether the diagnostic performances and critical values of cerebrospinal fluid (CSF) biomarkers are influenced by APOE ε4, which has guiding significance for the clinical practical application.

The differences in CSF biomarkers and their performances between APOE ε4 carriers and non-carriers in distinguishing AD, mild cognitive impairment (MCI) and preclinical AD from normal controls (NCs) were analyzed. The receiver operating characteristic (ROC) curves were generated to compare the area under the curve (AUC) between APOE ε4 carriers and non-carriers, as well as the critical values corresponding Youden Index.

In a cross sectional convenience sample of 1610 participants, lower Aβ42 and Aβ42/Aβ40 and higher p-Tau 181/Aβ42 in CSF were observed among APOE ε4 carriers than non-carriers in NC, MCI, and AD groups (P< 0.05). The performance of CSF p-tau/Aβ42 in distinguishing MCI from NC among APOE ε4 carriers was superior to non-carriers [AUC: 0.714 (95%CI: 0.673- 0.752) vs 0.600 (95%CI: 0.564- 0.634), P< 0.001], although it was similar in distinguishing AD from NC between APOE ε4 carriers and non-carriers [AUC: 0.874 (95%CI: 0.835-0.906) vs 0.876 (95%CI: 0.843- 0.904)]. In the longitudinal cohort of 254 participants, the association of CSF Aβ42, Aβ42/Aβ40 and p-Tau181/Aβ42 with cognitive decline were stronger in APOE ε4 carriers compared to non-carriers (P< 0.05). Meanwhile, the critical values were different depending on APOE genotype.

The CSF level of p-Tau181/Aβ42 was significantly different between APOE ε4 carriers and non-carriers at different stages of AD. The results indicate that the performances of CSF biomarkers are influenced by APOE ε4, which should be considered in the practical application.

Sorting protein-related receptor containing class A repeats (SORLA) is an intracellular trafficking receptor encoded by the Alzheimer's disease (AD) gene SORL1 (sortilin-related receptor 1). Recent findings argue that altered expression in microglia may underlie the genome-wide risk of AD seen with some SORL1 gene variants, however, the functional significance of the receptor in microglia remains poorly explained. Using unbiased omics and targeted functional analyses in iPSC-based human microglia, we identified a crucial role for SORLA in sensitizing microglia to pro-inflammatory stimuli. We show that SORLA acts as a sorting factor for the pattern recognition receptor CD14, directing CD14 exposure on the cell surface and priming microglia to stimulation by pro-inflammatory factors. Loss of SORLA in gene-targeted microglia impairs proper CD14 sorting and blunts pro-inflammatory responses. Our studies indicate an important role for SORLA in shaping the inflammatory brain milieu, a biological process important to local immune responses in AD.

Decreases in body mass index (BMI) may be early consequences of Alzheimer's disease (AD) pathophysiological changes. Previous research in the UK Biobank estimated that AD-related genes began affecting BMI around age 47. We assessed whether this result could be replicated using longitudinal data in an independent cohort.

Using All of Us (AOU) (N = 197,619, aged 30+) data, we estimated linear mixed models for associations of Z-scored AD-Genetic Risk Score (AD-GRS) with BMI, stratified by decade of age. We calculated the earliest age at which AD-GRS was associated with differences in BMI using cross-validated models adjusted for demographics.

Higher AD-GRS was statistically associated with lower BMI in participants aged 60-70 (b = -0.060 [-0.113, -0.007]). Best fitting models suggested the inverse association of AD-GRS and BMI emerged beginning at ages 47-54.

AD genes accelerate age-related weight loss starting in middle age.

Understanding when physiological changes from amyloid pathology begin is key for AD prevention. Our findings indicate that AD-associated genes accelerate midlife weight loss, starting between 47 and 54 years. AD prevention research should consider that disease pathology likely begins by middle age.

Although large-scale genetic association studies have proven useful for the delineation of neurodegenerative disease processes, we still lack a full understanding of the pathologic mechanisms of these diseases, resulting in few appropriate treatment options and diagnostic challenges. To mitigate these gaps, the Neurodegenerative Disease Knowledge Portal (NDKP) was created as an open-science initiative with the aim to aggregate, enable analysis, and display all available genomic datasets of neurodegenerative disease, while protecting the integrity and confidentiality of the underlying datasets. The portal contains 218 genomic datasets, including genotyping and sequencing studies, of individuals across 10 different phenotypic groups, including neurologic conditions such as Alzheimer disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson disease. In addition to securely hosting large genomic datasets, the NDKP provides accessible workflows and tools to effectively use the datasets and assist in the facilitation of customized genomic analyses. Here, we summarize the genomic datasets currently included within the portal, the bioinformatics processing of the datasets, and the variety of phenotypes captured. We also present example use cases of the various user interfaces and integrated analytic tools to demonstrate their extensive utility in enabling the extraction of high-quality results at the source, for both genomics experts and those in other disciplines. Overall, the NDKP promotes open science and collaboration, maximizing the potential for discovery from the large-scale datasets researchers and consortia are expending immense resources to produce and resulting in reproducible conclusions to improve diagnostic and therapeutic care for patients with neurodegenerative disease.

White matter (WM) microstructure is essential for brain function but deteriorates with age and in neurodegenerative conditions such as Alzheimer's disease (AD). Diffusion MRI, enhanced by advanced bi-tensor models accounting for free water (FW), enables in vivo quantification of WM microstructural differences.

To evaluate how AD genetic risk factors affect limbic WM microstructure - crucial for memory and early impacted in disease - we conducted linear regression analyses in a cohort of 2,614 non-Hispanic White aging adults (aged 50.12 to 100.85 years). The study evaluated 36 AD risk variants across 26 genes, the association between AD polygenic scores (PGSs) and WM metrics, and interactions with cognitive status.

AD PGSs, variants in TMEM106B, PTK2B, WNT3, and apolipoprotein E (APOE), and interactions involving MS4A6A were significantly linked to WM microstructure.

These findings implicate AD-related genetic factors related to neurodevelopment (WNT3), lipid metabolism (APOE), and inflammation (TMEM106B, PTK2B, MS4A6A) that contribute to alternations in WM microstructure in older adults.

AD risk variants in TMEM106B, PTK2B, WNT3, and APOE genes showed distinct associations with limbic FW-corrected WM microstructure metrics. Interaction effects were observed between MS4A6A variants and cognitive status. PGS for AD was associated with higher FW content in the limbic system.