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Defining how amyloid-β and pTau together lead to neurodegeneration is fundamental to understanding Alzheimer’s disease (AD). We used imaging mass cytometry to identify neocortical neuronal subtypes lost with AD in post-mortem brain middle temporal gyri from non-diseased and AD donors. Here we showed that L5,6 RORB + FOXP2 + and L3,5,6 GAD1 + FOXP2 + neurons, which accumulate amyloid-β intracellularly from early Braak stages, are selectively vulnerable to degeneration in AD, while L3 RORB + GPC5 + neurons, which accumulate pTau but not amyloid-β, are not lost even at late Braak stages. We discovered spatial associations between activated microglia and these vulnerable neurons and found that vulnerable RORB + FOXP2 + neuronal transcriptomes are enriched selectively for pathways involved in inflammation and glycosylation and, with progression to AD, also protein degradation. Our results suggest that the accumulation of intraneuronal amyloid-β, which is associated with glial inflammatory pathology, may contribute to the initiation of degeneration of these vulnerable neurons.

Genetic studies have shown that variants in the microtubule-associated protein tau ( ) gene, which encodes tau protein, can increase the risk for Alzheimer's disease (AD). Additionally, two haplotypes of the gene (H1 and H2) are associated with various neurodegenerative disorders, including AD. This study aimed to test the association of haplotypes (H1 and H2) and haplotype-tagging polymorphisms (rs1467967, rs242557, rs3785883, rs2471738, del-In9, rs7521) with AD. The study included 964 individuals: 113 with AD, 53 with mild cognitive impairment (MCI), 54 with other dementias, and 744 healthy controls. The results showed that individuals carrying the A allele in the rs1467967 polymorphism, the GG genotype in the rs7521 polymorphism, and the G allele in the rs242557 polymorphism had worse performance on various neuropsychological tests. Carriers of the C allele in rs2471738 polymorphism and CC homozygotes also showed worse performance on neuropsychological tests and pathological levels of several cerebrospinal fluid (CSF) biomarkers. However, T allele carriers in the rs2471738 polymorphism were more represented among patients with dementia and apolipoprotein E ( ) ɛ4 carriers. Carriers of the H2 haplotype had worse performance on various neuropsychological tests, consistent with our previous study, which associated the H2 haplotype with pathological levels of CSF AD biomarkers. Regarding the rs3785883 polymorphism, further research is needed since both the AA and GG genotypes were associated with pathological levels of CSF and plasma AD biomarkers. In conclusion, further genetic studies are needed to elucidate the role of haplotypes and haplotype-tagging polymorphisms in the development of AD.

Familial Alzheimer’s disease (fAD) mutations alter amyloid precursor protein (APP) cleavage by γ-secretase, increasing the proportion of longer amyloidogenic amyloid-β (Aβ) peptides. Using five control induced pluripotent stem cell (iPSC) lines and seven iPSC lines generated from fAD patients, we investigated the effects of mutations on the Aβ secretome in human neurons generated in 2D and 3D. We also analysed matched CSF, post-mortem brain tissue, and iPSCs from the same participant with the APP V717I mutation. All fAD mutation lines demonstrated an increased Aβ42:40 ratio relative to controls, yet displayed varied signatures for Aβ43, Aβ38, and short Aβ fragments. We propose four qualitatively distinct mechanisms behind raised Aβ42:40. (1) APP V717I mutations alter γ-secretase cleavage site preference. Whereas, distinct presenilin 1 (PSEN1) mutations lead to either (2) reduced γ-secretase activity, (3) altered protein stability or (4) reduced PSEN1 maturation, all culminating in reduced γ-secretase carboxypeptidase-like activity. These data support Aβ mechanistic tenets in a human physiological model and substantiate iPSC-neurons for modelling fAD.

Familial Alzheimer's disease (FAD) is caused by autosomal dominant mutations in the PSEN1, PSEN2 or APP genes, giving rise to considerable clinical and pathological heterogeneity in FAD. Here we investigate variability in clinical data and the type and distribution of Aβ pathologies throughout the cortical layers of different FAD mutation cases. Brain tissue from 20 FAD cases [PSEN1 pre‐codon 200 (n = 10), PSEN1 post‐codon 200 (n = 6), APP (n = 4)] were investigated. Frontal cortex sections were stained immunohistochemically for Aβ, and Nissl to define the cortical layers. The frequency of different amyloid‐beta plaque types was graded for each cortical layer and the severity of cerebral amyloid angiopathy (CAA) was determined in cortical and leptomeningeal blood vessels. Comparisons were made between FAD mutations and APOE4 status, with associations between pathology, clinical and genetic data investigated. In this cohort, possession of an APOE4 allele was associated with increased disease duration but not with age at onset, after adjusting for mutation sub‐group and sex. We found Aβ pathology to be heterogeneous between cases although Aβ load was highest in cortical layer 3 for all mutation groups and a higher Aβ load was associated with APOE4. The PSEN1 post‐codon 200 group had a higher Aβ load in lower cortical layers, with a small number of this group having increased cotton wool plaque pathology in lower layers. Cotton wool plaque frequency was positively associated with the severity of CAA in the whole cohort and in the PSEN1 post‐codon 200 group. Carriers of the same PSEN1 mutation can have differing patterns of Aβ deposition, potentially because of differences in risk factors. Our results highlight possible influences of APOE4 genotype, and PSEN1 mutation type on Aβ deposition, which may have effects on the clinical heterogeneity of FAD. An investigation of the frequency and distribution of the Aβ pathologies throughout the cortical layers of different familial Alzheimer's disease mutations cases. The frequency of different Aβ plaque types were graded for each cortical layer and the severity of cerebral amyloid angiopathy was determined in cortical and leptomeningeal blood vessels.

Brain perfusion and blood-brain barrier (BBB) integrity are reduced early in Alzheimer’s disease (AD). We performed single nucleus RNA sequencing of vascular cells isolated from AD and non-diseased control brains to characterise pathological transcriptional signatures responsible for this. We show that endothelial cells (EC) are enriched for expression of genes associated with susceptibility to AD. Increased β-amyloid is associated with BBB impairment and a dysfunctional angiogenic response related to a failure of increased pro-angiogenic HIF1A to increased VEGFA signalling to EC. This is associated with vascular inflammatory activation, EC senescence and apoptosis. Our genomic dissection of vascular cell risk gene enrichment provides evidence for a role of EC pathology in AD and suggests that reducing vascular inflammatory activation and restoring effective angiogenesis could reduce vascular dysfunction contributing to the genesis or progression of early AD. Vascular pathology may play important early role in Alzheimer’s disease (AD). Here, the authors show that β-amyloid induces transcriptomic signatures associated with accelerated apoptosis, impaired function and AD risk in human brain microvasculature.

Aging is associated with cell senescence and is the major risk factor for AD. We characterized premature cell senescence in postmortem brains from non-diseased controls (NDC) and donors with Alzheimer’s disease (AD) using imaging mass cytometry (IMC) and single nuclear RNA (snRNA) sequencing (> 200,000 nuclei). We found increases in numbers of glia immunostaining for galactosidase beta (> fourfold) and p16 INK4A (up to twofold) with AD relative to NDC. Increased glial expression of genes related to senescence was associated with greater β-amyloid load. Prematurely senescent microglia downregulated phagocytic pathways suggesting reduced capacity for β-amyloid clearance. Gene set enrichment and pseudo-time trajectories described extensive DNA double-strand breaks (DSBs), mitochondrial dysfunction and ER stress associated with increased β-amyloid leading to premature senescence in microglia. We replicated these observations with independent AD snRNA-seq datasets. Our results describe a burden of senescent glia with AD that is sufficiently high to contribute to disease progression. These findings support the hypothesis that microglia are a primary target for senolytic treatments in AD.

Introduction: Alzheimer's disease (AD) is the most common neurodegenerative dementia and its cause is unknown. In rare cases AD can be caused by mutations in the PSEN1, PSEN2 or APP gene and this form of AD is termed familial Alzheimer's disease (FAD). While the genetic cause is determined, there is considerable heterogeneity in terms of clinical presentation and pathological appearance at post-mortem. Previously it has been suggested pathological features of FAD may influence clinical features. It has also been suggested that FAD mutations may influence both pathological and clinical features. Common features of AD may also play a role in FAD, such as microglial activation and the influence of genetic modifiers of disease, such as APOE. The aims of this thesis were to investigate the associations of Aβ pathology (including CAA) and microglial load to age at onset and disease duration. Investigate histological profiles of Aβ pathologies (including CAA) and microglial load and the associations between these pathologies in genetic causes of FAD and APOE genotypes. Observe the contribution of specific Aβ peptide species to the histological profiles of Aβ pathology, and the association of these peptide with FAD and APOE genotypes. Generate and differentiate FAD patient derived iPSC to neuronal cultures to assess the association of FAD mutation with Aβ peptide profiles and PSEN1 maturity in a neuronal model of FAD. We hypothesise that histological features and Aβ peptide profiles will segregate with FAD mutation location, while microglial phenotype will associate with specific Aβ pathologies. Additionally, we predict the Aβ profiles observed in FAD cell lines will reflect histological profiles of Aβ aggregation. Materials and Methods: Nissl staining was performed on the frontal cortex of 20 FAD cases from the Queen Square Brain Bank (QSBB) (PSEN1 mutation carriers n=16, 10 pre-codon 200, 6 post-codon 200 and APP mutation carriers n=4). Cortical layers were delineated and serial sections immunohistochemically stained with antibodies against Aβ, Iba1, CD68 and CR3/43 and a subset were also stained for Tau. Aβ plaque type, load (% area stained), proportion of Aβ positive cerebral amyloid angiopathy (CAA), and microglial load were analysed per cortical layer. Additionally, in frontal and occipital cortex tissue from the 20 QSBB cases and an additional 21 FAD cases from the Institute of Psychiatry, Psychology and Neuroscience (combined total n=41, PSEN1 mutation carriers n=31, 20 pre-codon 200, 11 post-codon 200 and APP mutation carriers n=10) the proportion and severity of cortical and leptomeningeal CAA were investigated via vessel counts. In the temporal and occipital cortex of the 20 QSBB cases, IHC with Aβ isoform specific antibodies was conducted to investigate genetic contribution to isoform specific pathology. Finally, 5 induced pluripotent stem cell (iPSC) lines from FAD patients were generated. Four FAD lines and two control lines were differentiated into cortical neurons to investigate Aβ isoform production via ELISA and PSEN1 protein levels and maturity were assessed. Results: Clinical features in this FAD cohort were influenced by both FAD mutation and APOE status. Pathological Aβ deposits showed variability across cortical layers, and specific features were more associated with distinct mutations. Microglial phenotype did not differ by FAD mutation group or APOE status however associations with Aβ pathologies were observed. CAA differed between mutations groups, while APOE4 genotype had a non-significant effect of CAA pathology in FAD. Analysis of Aβ production from FAD iPSC derived cortical neurons showed that Aβ production differed not only compared to control cell lines but compared to other independent PSEN1 mutations. This could be the result of changes to PSEN1 maturation. Conclusions: It was shown that there is pathological heterogeneity in FAD of which some aspects associate with specific FAD mutation subgroup. For instance, greater Aβ and CWP frequency in the lower layers in the PSEN1 post-codon 200 group as well as greater proportion and severity of CAA. Correlations between plaques, CAA and microglia indicate contribution of clearance mechanisms to histological features observed in FAD, which can differ by mutation group. Specifically, CD68 was generally associated with greater CAA and reduced Aβ pathology. In the cellular models, specific FAD mutations, particularly those post-codon 200, affect Aβ peptide ratios, which associates with observed pathological heterogeneity and suggests that differences in the aggregation and clearance of these peptides modifies the histological appearance of Aβ pathology. Combined with the observed effect of APOE genotype on disease duration, peptide profiles and CAA severity, this may contribute to the differences in clinical aspects of FAD.

Introduction Alzheimer's disease (AD) is the world leading cause of dementia. Early detection of AD is essential for faster and more efficacious usage of therapeutics and preventive measures. Even though it is well known that one ε4 allele of apolipoprotein E gene increases the risk for sporadic AD five times, and that two ε4 alleles increase the risk 20 times, reliable genetic markers for AD are not yet available. Previous studies have shown that microtubule‐associated protein tau (MAPT) gene polymorphisms could be associated with increased risk for AD. Methods The present study included 113 AD patients and 53 patients with mild cognitive impairment (MCI), as well as nine healthy controls (HC) and 53 patients with other primary causes of dementia. The study assessed whether six MAPT haplotype‐tagging polymorphisms (rs1467967, rs242557, rs3785883, rs2471738, del–In9, and rs7521) and MAPT haplotypes are associated with AD pathology, as measured by cerebrospinal fluid (CSF) AD biomarkers amyloid β1–42 (Aβ1–42), total tau (t‐tau), tau phosphorylated at epitopes 181 (p‐tau181), 199 (p‐tau199), and 231 (p‐tau231), and visinin‐like protein 1 (VILIP‐1). Results Significant increases in t‐tau and p‐tau CSF levels were found in patients with AG and AA MAPT rs1467967 genotype, CC MAPT rs2471738 genotype and in patients with H1H2 or H2H2 MAPT haplotype. Conclusions These results indicate that MAPT haplotype‐tagging polymorphisms and MAPT haplotypes should be further tested as potential genetic biomarkers of AD. Sporadic Alzheimer's disease (AD) is the most common secondary tauopathy. We used AD biomarkers in cerebrospinal fluid to increase statistical power of identifying MAPT (tau) gene variants that may increase the likelihood of dementia. In the Croatian cohort studied, we confirmed an association of MAPT rs2471738 polymorphisms with AD pathology and demonstrated a novel risk allele (C‐allele) in MAPT rs1467967 as well as an increased risk for AD in subjects with H1H2 or H2H2 MAPT haplotype. These results have relevance for understanding and use of genetic biomarkers of AD.

The Omix pipeline offers an integration and analysis framework for multiomics intended to preprocess, analyse, and visualise multimodal data flexibly to address various research questions. From biomarker discovery and patient stratification to the investigation of complex biological processes, Omix empowers researchers to derive valuable insights from omics data. Using Alzheimer’s Disease (AD) bulk proteomics and transcriptomics datasets generated from two distinct regions derived from post-mortem brains, we demonstrate the utility of Omix in generating an integrated pseudo-temporal multi-omics profile of AD. Omix is implemented as a software package in R. The code for the Omix package is available at https://github.com/eleonoreschneeg/Omix. Reference documentation and online tutorials are available at https://eleonore-schneeg.github.io/Omix. All code is open-source and available under the GNU General Public License v3.0 (GPL-3). eleonore.schneegans17@imperial.ac.uk, johanna.jackson@imperial.ac.uk

Synapse loss is the greatest correlate of cognitive impairment in Alzheimer's Disease (AD) and offers a therapeutic avenue alongside disease-modifying therapies. However, the events preceding synapse loss in the human condition have not been well characterised. In this study, we describe a pseudotemporal profile of alterations in the synaptic proteome prior to excitatory synapse loss in human post-mortem brain AD tissue using synapse proteomics and synaptome mapping techniques. In a region with early-stage disease pathology, the most predominant changes were pre-synaptic and featured changes in metabolism and exocytosis. In a mid-stage disease state, alongside initial synapse loss, there was a dominance of inhibitory synaptic changes. In a region with late-stage disease pathology and profound synapse loss, post-synaptic changes were most prevalent with a range of canonical synaptic transmission pathways reduced and differential excitatory synapse subtype pathology. Synapse loss was associated with changes in astrocytic proteins which were enriched for those at peri-synaptic astrocytic processes, including an upregulation of complement activation and endocytosis; a signature that differed from the astrocyte cytosolic proteome. Taken together, this provides evidence of a cascade of events leading to synapse loss with multiple points for therapeutic intervention to alleviate cognitive decline in AD. Data are available via ProteomeXchange with identifier PXD056052.Competing Interest StatementPMM has received consultancy fees from Roche, Celgene, and Neurodiem. He has received honoraria or speakers' fees from Novartis and Biogen and has received research or educational funds from Biogen and Novartis. JSJ has received speakers' fees from Eli Lilly and research funds from Biogen.