Neurogenetic contributions to amyloid beta and tau spreading in the human cortex

Sepulcre, Jorge; Grothe, Michel J.; Uquillas, Federico d’Oleire; Ortiz-Terán, Laura; Diez, Ibai; Yang, Hyun‐Sik; Jacobs, Heidi I.L.; Hanseeuw, Bernard; Li, Quanzheng; El-Fakhri, Georges; Sperling, Reisa A.; Johnson, Keith A.

doi:10.1038/s41591-018-0206-4

Cited by 149 publications

(151 citation statements)

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“…Together, it is thus possible that functional connectivity of fast tau accumulating regions may facilitate the spread of tau to their closely connected neighbors. An alternative explanation is, that network-forming regions show similar susceptibility for developing tau pathology: Specifically, previous studies have shown that similar gene expression is found among functionally connected regions 31,32 , where similar gene expression across brain regions is associated with shared susceptibility to develop AD pathology, including amyloid, tau and neurodegeneration [33][34][35] . Thus, it is possible that the association between functional connectivity and tau accumulation rates is in part determined by shared genetic susceptibility for developing tau pathology.…”

Section: Discussionmentioning

confidence: 99%

Functional brain architecture is associated with the rate of tau accumulation in Alzheimer’s disease

2020

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In Alzheimer's diseases (AD), tau pathology is strongly associated with cognitive decline. Preclinical evidence suggests that tau spreads across connected neurons in an activitydependent manner. Supporting this, cross-sectional AD studies show that tau deposition patterns resemble functional brain networks. However, whether higher functional connectivity is associated with higher rates of tau accumulation is unclear. Here, we combine resting-state fMRI with longitudinal tau-PET in two independent samples including 53 (ADNI) and 41 (BioFINDER) amyloid-biomarker defined AD subjects and 28 (ADNI) vs. 16 (Bio-FINDER) amyloid-negative healthy controls. In both samples, AD subjects show faster tau accumulation than controls. Second, in AD, higher fMRI-assessed connectivity between 400 regions of interest (ROIs) is associated with correlated tau-PET accumulation in corresponding ROIs. Third, we show that a model including baseline connectivity and tau-PET is associated with future tau-PET accumulation. Together, connectivity is associated with tau spread in AD, supporting the view of transneuronal tau propagation.

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Section: Discussionmentioning

confidence: 99%

Functional brain architecture is associated with the rate of tau accumulation in Alzheimer’s disease

2020

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“…Spatial gene expression patterns in the human brain have been studied to unravel the pathogenic mechanisms underlying amyloid-β and tau pathology progression in Alzheimer’s disease, revealing proteins that co-aggregate with amyloid-β and tau, and protein homeostasis components 13,14 . Interestingly, by integrating Allen Human Brain Atlas (AHBA) gene expression data 15 with magnetic resonance imaging of PD patients, the regional expression pattern of MAPT and SNCA was associated with loss of functional connectivity in PD 16 , and regional expression of synaptic transfer genes was related to regional gray matter atrophy in PD 17 .…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic signatures of brain regional vulnerability to Parkinson’s disease

Keo

Mahfouz

Ingrassia

et al. 2019

Preprint

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25The molecular mechanisms underlying the caudal-to-rostral progression of Lewy body pathology in 26Parkinson's disease (PD) remain poorly understood. Here, we aimed to unravel transcriptomic signatures 27 across brain regions involved in Braak Lewy body stages in non-neurological controls and PD donors. 28Using human postmortem brain datasets of non-neurological adults from the Allen Human Brain Atlas, we 29 identified expression patterns related to PD progression, including genes found in PD genome-wide 30 associations studies: SNCA, ZNF184, BAP1, SH3GL2, ELOVL7, and SCARB2. We confirmed these 31 patterns in two datasets of non-neurological subjects (Genotype-Tissue Expression project and UK Brain 32 Expression Consortium) and found altered patterns in two datasets of PD patients. Additionally, co-33 expression analysis across vulnerable regions identified two modules associated with dopamine 34 synthesis, the motor and immune system, blood-oxygen transport, and contained microglial and 35 endothelial cell markers, respectively. Alterations in genes underlying these region-specific functions may 36 contribute to the selective regional vulnerability in PD brains. 37 38 3 Background 39 Parkinson's disease (PD) is characterized by a temporal caudal-rostral progression of Lewy body (LB) 40 pathology across a selected set of nuclei in the brain 1 . The distribution pattern of LB pathology is divided 41 into six Braak stages based on accumulation of the protein α-synucleinthe main component of LBs and 42 Lewy neuritesin the brainstem, limbic and neocortical regions 1 . Different hypotheses have been 43 brought forward to explain the evolving LB pathology across the brain, including: retrograde transport of 44 pathological α-synuclein via neuroanatomical networks, α-synuclein's prion-like behavior, and cell-or 45 region-autonomous factors 2,3 . Yet, the mechanisms underlying the selective vulnerability of brain regions 46 to LB pathology remains poorly understood, limiting the ability to diagnose and treat PD. 47 Multiplications of the SNCA gene encoding α-synuclein are relatively common in autosomal dominant PD 48and SNCA dosage has been linked to the severity of PD 4,5 . For other PD-associated variants, e.g. GBA 49and LRRK2, their role in progressive α-synuclein accumulation is less clear, although they have been 50 associated with mitochondrial (dys)function and/or protein degradation pathways [6][7][8] . On the other hand, 51 transcriptomic changes between PD and non-neurological controls of selected brain regions, e.g. the 52 substantia nigra, have identified several molecular mechanisms underlying PD pathology, including 53 synaptic vesicle endocytosis [9][10][11] . However, post-mortem human brain tissue of well-characterized PD 54 patients and controls is scarce, usually focuses on a select number of brain regions, and have a limited 55 coverage of patients with different Braak LB stages, resulting in low concordance of findings across 56 different studies 12 . 57Spatial gene expression patterns in the human ...

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“…The asymmetrical progression of Alzheimer's disease neuropathology in different brain regions may reflect selective neuronal vulnerabilities local to each region (Mattson and Magnus, 2006;Saxena and Caroni, 2011;Wu et al, 2014;Schmitz and Nathan Spreng, 2016). However, evidence in both mouse models of Alzheimer's disease (De Calignon et al, 2012;Liu et al, 2012) and in human Alzheimer's disease patients (Schmitz et al, 2018;Sepulcre et al, 2018) indicates that neuropathology also spreads across anatomically and functionally connected brain regions. It is therefore possible that pathologies arising from selective neuronal vulnerability local to a given brain region might precede and predispose the subsequent spread of pathology across networks (Warren et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Basal forebrain volume reliably predicts the cortical spread of Alzheimer’s degeneration

Fernández-Cabello

Kronbichler

Dijk

et al. 2019

Preprint

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Alzheimer's disease neuropathology is thought to spread across anatomically and functionally connected brain regions. However, the precise sequence of spread remains ambiguous. The prevailing model posits that Alzheimer's neurodegeneration starts in the entorhinal cortices, before spreading to temporoparietal cortex. Challenging this model, we previously provided evidence that degeneration within the nucleus basalis of Meynert (NbM), a subregion of the basal forebrain heavily populated by cortically projecting cholinergic neurons, precedes and predicts entorhinal degeneration (Schmitz and Spreng, 2016). There have been few systematic attempts at directly comparing staging models using in vivo longitudinal biomarker data, and determining if these comparisons generalize across independent samples. Here we addressed the sequence of pathological staging in Alzheimer's disease using two independent samples of the Alzheimer's Disease Neuroimaging Initiative (N1 = 284; N2 = 553) with harmonized CSF assays of amyloid (Aβ) and hyperphosphorylated tau (pTau), and longitudinal structural MRI data over two years.We derived measures of gray matter degeneration in a priori NbM and the entorhinal regions of interest. To examine the spreading of degeneration, we used a predictive modelling strategy which tests whether baseline gray matter volume in a seed region accounts for longitudinal change in a target region. We demonstrated that predictive pathological spread favored the NbM→entorhinal over the entorhinal→NbM model. This evidence generalized across the independent samples (N1: r=0.20, p=0.03; N2: r=0.37, p<0.001). We also showed that CSF concentrations of pTau/Aβ moderated the observed predictive relationship, consistent with evidence in rodent models of an underlying trans-synaptic mechanism of pathophysiological spread (t826=2.55, p=0.01). The moderating effect of CSF was robust to additional factors, including clinical diagnosis (t826=1.65, p=0.49). We then applied our predictive modelling strategy to an exploratory whole-brain voxelwise analysis to examine the spatial specificity of the NbM→entorhinal model. We found that smaller baseline NbM volumes predicted greater degeneration in localized regions of the entorhinal and perirhinal cortices. By contrast, smaller baseline entorhinal volumes predicted degeneration in the medial temporal cortex, recapitulating the prevailing staging model. Our findings suggest that degeneration of the basal forebrain cholinergic projection system is a robust and reliable upstream event of entorhinal and neocortical degeneration, calling into question the prevailing view of Alzheimer's disease pathogenesis.3

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Neurogenetic contributions to amyloid beta and tau spreading in the human cortex

Cited by 149 publications

References 70 publications

Functional brain architecture is associated with the rate of tau accumulation in Alzheimer’s disease

Functional brain architecture is associated with the rate of tau accumulation in Alzheimer’s disease

Transcriptomic signatures of brain regional vulnerability to Parkinson’s disease

Basal forebrain volume reliably predicts the cortical spread of Alzheimer’s degeneration

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