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Introduction: Genetic studies have shown that variants in the microtubuleassociated protein tau (MAPT) gene, which encodes tau protein, can increase the risk for Alzheimer's disease (AD). Additionally, two haplotypes of the MAPT gene (H1 and H2) are associated with various neurodegenerative disorders, including AD. This study aimed to test the association of MAPT haplotypes (H1 and H2) and MAPT haplotype-tagging polymorphisms (rs1467967, rs242557, rs3785883, rs2471738, del-In9, rs7521) with AD. Methods: The study included 964 individuals: 113 with AD, 53 with mild cognitive impairment (MCI), 54 with other dementias, and 744 healthy controls. Results: The results showed that individuals carrying the A allele in the MAPT rs1467967 polymorphism, the GG genotype in the MAPT rs7521 polymorphism, and the G allele in the MAPT rs242557 polymorphism had worse performance on various neuropsychological tests. Carriers of the C allele in MAPT 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 MAPT rs2471738 polymorphism were more represented among patients with dementia and apolipoprotein E (APOE) 4 carriers. Carriers of the H2 MAPT haplotype had worse performance on various neuropsychological tests, consistent with our previous study, which associated the H2 MAPT haplotype with pathological levels of CSF AD biomarkers. Regarding the MAPT rs3785883 polymorphism, further research is needed since both the AA and GG genotypes were associated with pathological levels of CSF and plasma AD biomarkers. Discussion: In conclusion, further genetic studies are needed to elucidate the role of MAPT haplotypes and MAPT haplotype-tagging polymorphisms in the development of AD. [ABSTRACT FROM AUTHOR]

Lipids play crucial roles in the susceptibility and brain cellular responses to Alzheimer's disease (AD) and are increasingly considered potential soluble biomarkers in cerebrospinal fluid (CSF) and plasma. To delineate the pathological correlations of distinct lipid species, we conducted a comprehensive characterization of both spatially localized and global differences in brain lipid composition in AppNL‐G‐F mice with spatial and bulk mass spectrometry lipidomic profiling, using human amyloid‐expressing (h‐Aβ) and WT mouse brains controls. We observed age‐dependent increases in lysophospholipids, bis(monoacylglycerol) phosphates, and phosphatidylglycerols around Aβ plaques in AppNL‐G‐F mice. Immunohistology‐based co‐localization identified associations between focal pro‐inflammatory lipids, glial activation, and autophagic flux disruption. Likewise, in human donors with varying Braak stages, similar studies of cortical sections revealed co‐expression of lysophospholipids and ceramides around Aβ plaques in AD (Braak stage V/VI) but not in earlier Braak stage controls. Our findings in mice provide evidence of temporally and spatially heterogeneous differences in lipid composition as local and global Aβ‐related pathologies evolve. Observing similar lipidomic changes associated with pathological Aβ plaques in human AD tissue provides a foundation for understanding differences in CSF lipids with reported clinical stage or disease severity. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Brain perfusion and blood brain barrier (BBB) integrity are reduced in Alzheimer's disease (AD). We hypothesized that b‐amyloid (Aβ) induces dysfunction of pathways in vascular cells that regulate angiogenesis. Method: We performed single nucleus RNA sequencing (snRNAseq) of vascular cells isolated from post mortem samples from multiple cortical regions from AD patients (Braak V‐VI) and non‐diseased controls (NDC, Braak 0‐II). We developed a meta‐analytic approach to integrate these data with related publicly available datasets. We performed differential gene expression (DGE) analyses as a categorical comparison of AD vs NDC and as a confound‐controlled regression of transcriptomic alterations by regional total Aβ. We also performed cell‐specific gene co‐expression analyses identify modules differentially expressed in AD relative to NDC. Result: Our results describe differential expression of genes central to pathways sustaining angiogenesis, proliferation and migration of endothelial cells and the integrity of the BBB with either AD or greater pathological protein load. HIF1A and FGF2, proangiogenic molecules which both induce VEGF, are upregulated in EC, consistent the parenchymal hypoxic response shown repeatedly in prior studies. However, components of signalling pathways downstream of VEGFR2 are downregulated, suggesting a pathological block to angiogenesis with greater Aβ load. While the proangiogenic stimuli promote the expression of genes such as PPP3CA and ITPR1, coding for calcineurin, which contribute to VEGF signalling through the PLCγ‐Ca2+ signalling pathway are upregulated in AD, expression of RAC1 and RHOJ, which enable cellular migration and adhesion, is downregulated. While ANGPT2 expression is also upregulated, the angiopoietin receptor (TIE2, coded by TEK) is downregulated. Downregulation of ADAM10 in AD and upregulation of other NOTCH pathway genes with greater Aβ load suggests altered NOTCH signalling. Conclusion: Overall, a hypoxic tissue environment in AD is accompanied by dysfunctional angiogenesis related to Aβ load. Evidence for multiple sites of dysfunction were identified, involving impaired angiopoietin responses, vascular cell migration and NOTCH signaling. [ABSTRACT FROM AUTHOR]

Background: Coding variants in the microglial TREM2 ectodomain differentially (R47H> R62H) increase the risk of Alzheimer's disease (AD). To define mechanisms responsible in glia and neurons, we aimed to characterise neuropathology and transcriptomic responses in heterozygotes for these TREM2 variant alleles and for common allele homozygotes (CV) in non‐diseased (n = 16) and AD (n = 42) brain cortical tissue from 58 donors. Method: Using immunohistochemistry (IHC) and imaging mass cytometry (IMC), we characterised neocortical b‐amyloid and AT8/PHF1 pTau pathology with CV (n = 30) and the R47H (n = 11) or R62H (n = 17) TREM2 carriers. We performed single nuclear RNA sequencing to test for the differential gene expression (DGE) in TREM2 and CV cortical tissues with greater 4G8+ b‐amyloid‐ or PHF1+ pTau‐immunostaining. Result: There was a two‐fold increase in 4G8+, a three‐fold reduction in AT8+ but no change in PHF1+ immunostaining with AD in both variants versus CV. We found a reduced expression of genes associated with TREM2 function in R47H carriers relative to CV however enhanced microglial activation in R62H carriers. This was associated with an up‐regulation of pathways such as 'neuroinflammation signalling pathway' in R62H not seen in R47H. CV astrocytes had little DGE with increasing pathology however both variants (R47H>R62H) had an increased proportion of differentially expressed genes suggestive of a heightened activation state. R47H and R62H astrocytes impacted pathways had opposing actions such as 'synaptogenesis signalling pathway' and 'PDGF signalling' pathways downregulated in R47H but upregulated in R62H. Neuronal gene expression changes were evident in all variants, however greatly enhanced in R47H in response to 4G8+ b‐amyloid. With increasing PHF1+ pTau gene expression changes were mainly seen in R47H. Excitatory and inhibitory neurons both exhibited DGE in R47H carriers and impacted pathways centred around those involved in 'synaptogenesis signalling pathway', 'SNARE signalling pathway' and 'synaptic long term depression'. Conclusion: This analysis identified novel disease‐associated transcriptomic differences in the glial response to TREM2 and the secondary neuronal responses that can explain differences in the genetic AD risk conferred by these two TREM2 risk variants. [ABSTRACT FROM AUTHOR]

Background: Ageing is the greatest risk factor for Alzheimer's disease (AD). While accumulation of senescent cells is one of the major hallmarks of ageing, the effect of the senescence burden is yet to be explored in AD. The aims of this study were to i) quantify senescent microglia, oligodendrocyte and astrocyte in human brain in AD, ii) determine the driver of cell senescence in AD, and iii) AD pathology associated senescence. Method: We multiplexed Image Mass Cytometry (IMC) to co‐localise cell type markers (IBA1, OLIG2, GFAP), senescence markers (GLB1 and p16) and β‐amyloid (4G8) to detect senescence in tissues from Middle Temporal Gyrus (MTG) of 10 AD and 10 non‐disease control (NDC). We also generated snRNA‐seq from three different brain regions of the same subject namely Entorhinal (EC), MTG (Mid‐temporal Cortex) and Somatosensory Cortex (SSC) of 9 AD and 9 NDC. We performed geneset enrichment analysis using a set of curated senescence associated genesets in snRNA‐seq using AUcell and dream (variancePartition). We further performed trajectory analysis using Monocle3 to characterise β‐amyloid associated senescence signatures in the snRNAseq data. Result: More than 25% microglia, oligodendrocyte and astrocyte were positive for GLB1 in AD brains while only around 5% glia showed GLB1 expression in NDC. Around 25% peri‐plaque microglia within 10 µm around β‐amyloid plaques in AD showed expression of GLB1 while only 3% of microglia >10 µm had associated senescence markers. Senescence genes were significantly upregulated in AD compared to NDC and were positively correlated with increase amyloid densities in all three glial cells (not in neurons). Trajectories of the glial nuclei described increased expression of pathways related to replicative senescence, cellular activation and stress response in microglia and oxidative stress in oligodendroglia, and astrocyte. Senescence gene signatures were positively associated with both β‐amyloid and pTau. Conclusion: Our results highlight the high burden of senescent glia and provide evidence for distinct mechanisms of senescence in microglia (both replicative and stress‐induced) relative to oligodendroglia and astrocyte (stress‐induced) in AD. Both β‐amyloid and pTau associated increase in senescence gene signatures suggest that senescence is an important feature in the late stage of AD. [ABSTRACT FROM AUTHOR]

Background: Autosomal dominant familial Alzheimer's disease (ADAD), caused by APP, PSEN1 and PSEN2 mutations, is clinically and pathologically similar to sporadic AD, with both typically presenting with memory impairment. However as in sporadic AD, atypical phenotypes and neuropathological heterogeneity occur, including variable vascular Aβ deposition as cerebral amyloid angiopathy (CAA). Investigating relationships between clinical, genetic and neuropathological heterogeneity in ADAD may provide insights into pathophysiological pathways relevant to AD in general. Methods: 256 symptomatic individuals from ADAD families seen at our Centre were included in a survival analysis, with detailed clinical phenotype data available for 138 (101 PSEN1, 37 APP). 33 of these individuals underwent brain donation (24 PSEN1, 9 APP), all demonstrating end‐stage AD pathology. Frontal and occipital cortex sections were stained immunohistochemically for Aβ and vessel counts used to determine the proportion of cortical and leptomeningeal blood vessels affected by CAA. Results: Age at onset was, on average, seven years younger for PSEN1 than APP mutations and was influenced by mutation much more than survival was. Atypical (non‐amnestic) cognitive presentations with initial behavioral, language, dyscalculic or dysexecutive symptoms, and atypical clinical features (pyramidal, extrapyramidal and cerebellar signs) were more common in PSEN1 than APP cases, particularly those with post‐codon 200 mutations. Atypical cognitive presentations were associated with longer survival. There was some indication that APOE4 carriers had longer survival and that this effect may be restricted to PSEN1. In the post‐mortem cohort, atypical cognitive presentations occurred in 15%. Additional neurological features comprised myoclonus (45%), seizures (21%), pyramidal signs (21%) and extrapyramidal signs (15%), one individual had cerebellar signs. Increased frontal cortical and leptomeningeal CAA occurred in individuals with pyramidal and extrapyramidal signs, and in PSEN1 post‐codon 200 compared to pre‐codon 200 mutations. Atypical cognitive presentations were associated with increased frontal cortical CAA. Conclusions: Phenotypic heterogeneity in ADAD is influenced by causative gene and mutation type, and atypical clinical presentations are associated with increased CAA. Exploring mechanisms by which certain mutations drive Aβ deposition towards the vasculature, and how these may be impacted by other genetic factors and by therapies targeting Aβ, is an important direction for future research. [ABSTRACT FROM AUTHOR]

In vitro studies of autosomal dominant Alzheimer's disease implicate longer amyloid-β peptides in disease pathogenesis; however, less is known about the behaviour of these mutations in vivo. In this cross-sectional cohort study, we used liquid chromatography-tandem mass spectrometry to analyse 66 plasma samples from individuals who were at risk of inheriting a mutation or were symptomatic. We tested for differences in amyloid-β (Aβ)42:38, Aβ42:40 and Aβ38:40 ratios between presenilin 1 (PSEN1) and amyloid precursor protein (APP) carriers. We examined the relationship between plasma and in vitro models of amyloid-β processing and tested for associations with parental age at onset. Thirty-nine participants were mutation carriers (28 PSEN1 and 11 APP). Age- and sex-adjusted models showed marked differences in plasma amyloid-β between genotypes: higher Aβ42:38 in PSEN1 versus APP (P < 0.001) and non-carriers (P < 0.001); higher Aβ38:40 in APP versus PSEN1 (P < 0.001) and non-carriers (P < 0.001); while Aβ42:40 was higher in both mutation groups compared to non-carriers (both P < 0.001). Amyloid-β profiles were reasonably consistent in plasma and cell lines. Within the PSEN1 group, models demonstrated associations between Aβ42:38, Aβ42:40 and Aβ38:40 ratios and parental age at onset. In vivo differences in amyloid-β processing between PSEN1 and APP carriers provide insights into disease pathophysiology, which can inform therapy development. [ABSTRACT FROM AUTHOR]

Mutations in presenilin 1 (PSEN1) or presenilin 2 (PSEN2), the catalytic subunit of γ-secretase, cause familial Alzheimer's disease (fAD). We hypothesized that mutations in PSEN1 reduce Notch signaling and alter neurogenesis. Expression data from developmental and adult neurogenesis show relative enrichment of Notch and γ-secretase expression in stem cells, whereas expression of APP and β-secretase is enriched in neurons. We observe premature neurogenesis in fAD iPSCs harboring PSEN1 mutations using two orthogonal systems: cortical differentiation in 2D and cerebral organoid generation in 3D. This is partly driven by reduced Notch signaling. We extend these studies to adult hippocampal neurogenesis in mutation-confirmed postmortem tissue. fAD cases show mutation-specific effects and a trend toward reduced abundance of newborn neurons, supporting a premature aging phenotype. Altogether, these results support altered neurogenesis as a result of fAD mutations and suggest that neural stem cell biology is affected in aging and disease. • In neurogenesis, PSEN1 expression is enriched in progenitors, as it is for APP in neurons • Inhibiting β-secretase has little effect on neurogenesis, contrary to γ-secretase • Familial Alzheimer's disease mutations in PSEN1 cause premature neurogenesis • Trend toward fewer newborn neurons in familial AD postmortem hippocampi Arber et al. employ human iPSC neurogenesis to model adult hippocampal neurogenesis, investigating familial Alzheimer's disease (fAD) mutations. In contrast to APP , PSEN1 and γ-secretase components are enriched in neural progenitors and mutations drive premature neurogenesis. Postmortem fAD hippocampi show corresponding trends toward altered neurogenesis. [ABSTRACT FROM AUTHOR]

Background: Familial Alzheimer's disease (fAD) is caused by mutations inPSEN1, PSEN2and APP. PSEN1forms the catalytic core of g‐secretase, a membrane protease which cleaves numerous substrates including APP and Notch. We have previously shown that our panel of fAD patient‐derived iPSCs show altered APP processing and Abgeneration. Here we investigated whether mutations led to altered Notch cleavage in neural precursors. We hypothesised that reduced Notch cleavage in fAD lines would promote premature differentiation during iPSC neuronal differentiation and during adult hippocampal neurogenesis. Methods: We generated 2D cortical neurons and 3D cerebral organoids from a panel of 14 donor‐derived iPSC lines (5 controls, 2 APPmutation lines and 7 PSEN1mutation lines). Neurogenesis was quantified via the proportion of neural precursors versus the number of post‐mitotic neurons at timepoints of neural commitment. In addition, we quantified newly generated neurons in the post‐mortem hippocampus of 3 control brains and 7 brains derived from fAD mutation carriers. Results: We describe a small, yet reproducible premature differentiation phenotype in lines containing mutations in PSEN1during in vitro neurogenesis. This is, at least in part, due to reduced Notch signalling; which drives terminal differentiation. These findings are corroborated in independent orthogonal iPSC systems, namely 2D neurogenesis and 3D organoid differentiation. Using immunohistochemistry against b‐III‐tubulin, we describe robust, quantifiable neurogenesis in post‐mortem tissue. Results are suggestive of mutation‐specific effects and also a premature ageing phenotype in fAD tissue. Conclusion: These findings reveal insights into the functional outcomes of fAD mutations. Mutations in PSEN1, but not APP, alter Notch signalling in neural precursors, which in turn drives premature terminal differentiation. Premature differentiation and mutation‐specific differences both necessitate careful consideration for drug design and patient stratification. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]