Immune response and endocytosis pathways are associated with the resilience against Alzheimer’s disease

Abstract Developing Alzheimer’s disease (AD) is influenced by multiple genetic variants that are involved in five major AD-pathways. Per individual, these pathways may differentially contribute to the modification of the AD-risk. The pathways involved in the resilience against AD have thus far been poorly addressed. Here, we investigated to what extent each molecular mechanism associates with (i) the increased risk of AD and (ii) the resilience against AD until extreme old age, by comparing pathway-specific polygenic risk scores (pathway-PRS). We used 29 genetic variants associated with AD to develop pathway-PRS for five major pathways involved in AD. We developed an integrative framework that allows multiple genes to associate with a variant, and multiple pathways to associate with a gene. We studied pathway-PRS in the Amsterdam Dementia Cohort of well-phenotyped AD patients (N = 1895), Dutch population controls from the Longitudinal Aging Study Amsterdam (N = 1654) and our unique 100-plus Study cohort of cognitively healthy centenarians who avoided AD (N = 293). Last, we estimated the contribution of each pathway to the genetic risk of AD in the general population. All pathway-PRS significantly associated with increased AD-risk and (in the opposite direction) with resilience against AD (except for angiogenesis, p < 0.05). The pathway that contributed most to the overall modulation of AD-risk was β-amyloid metabolism (29.6%), which was driven mainly by APOE-variants. After excluding APOE variants, all pathway-PRS associated with increased AD-risk (except for angiogenesis, p < 0.05), while specifically immune response (p = 0.003) and endocytosis (p = 0.0003) associated with resilience against AD. Indeed, the variants in these latter two pathways became the main contributors to the overall modulation of genetic risk of AD (45.5% and 19.2%, respectively). The genetic variants associated with the resilience against AD indicate which pathways are involved with maintained cognitive functioning until extreme ages. Our work suggests that a favorable immune response and a maintained endocytosis pathway might be involved in general neuro-protection, which highlight the need to investigate these pathways, next to β-amyloid metabolism.

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Immune response and endocytosis pathways are associated with the escape of Alzheimer’s Disease

10.1101/19009464 ◽

2019 ◽

Author(s):

Niccolò Tesi ◽

Sven J. van der Lee ◽

Marc Hulsman ◽

Iris E. Jansen ◽

Najada Stringa ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Immune Response ◽

Genetic Variants ◽

Genetic Risk ◽

Molecular Mechanisms ◽

Risk Scores ◽

Integrative Framework ◽

Amyloid Metabolism ◽

Population Controls

AbstractThe risk to develop and escape Alzheimer’s disease (AD) is influenced by a constellation of genetic variants, each associated with specific molecular pathways. Different pathways may differentially contribute to the modification of the AD-risk. We studied the molecular mechanisms that explain the extreme ends of the cognitive spectrum by comparing pathway-specific polygenic risk scores (pathway-PRS) in individuals with AD and those who escaped AD until old age. We used 29 genetic variants associated with AD to calculate pathway-PRS for five major pathways involved in AD. We developed an integrative framework that allows multiple genes to associate with a variant, and multiple pathways to associate with a gene. We studied pathway-PRS in patients with AD (N=1,909), population controls (N=1,654), and cognitively healthy centenarians who escaped AD (N=293). Last, we estimated the contribution of each pathway to the genetic risk of AD in the general population. All pathway-PRS significantly associated with increased AD-risk and escaping AD (p<0.05). The pathway that contributed the most to the overall modulation of AD-risk was b-amyloid metabolism (32%), driven mainly by APOE variants. After excluding APOE variants, all pathway-PRS associated with increased AD-risk (p<0.05), while specifically immune response (p=3.1×10−3) and endocytosis (p=3.8×10−4) associated with escaping AD. These pathways were the main contributors to the overall modulation of genetic risk of AD (41.3% and 21.4%, respectively). Our work suggests that immune response and endocytosis might be involved in general neuro-protective functions, and highlights the need to study these pathways, next to b-amyloid metabolism.

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Genetic risk for Alzheimer's disease influences neuropathology via multiple biological pathways

10.1101/2020.07.16.20149658 ◽

2020 ◽

Author(s):

Eilis Hannon ◽

Gemma L Shireby ◽

Keeley Brookes ◽

Johannes Attems ◽

Rebecca Sims ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Genetic Variants ◽

Genetic Risk ◽

Cognitive Assessment ◽

Apoe Genotype ◽

Amyloid Plaques ◽

Polygenic Risk Score ◽

Polygenic Risk ◽

Β Amyloid

Alzheimer's disease is a highly heritable, common neurodegenerative disease characterised neuropathologically by the accumulation of β-amyloid plaques and tau-containing neurofibrillary tangles. In addition to the well-established risk associated with the APOE locus, there has been considerable success in identifying additional genetic variants associated with Alzheimer's disease. Major challenges in understanding how genetic risk influences the development of Alzheimer's disease are clinical and neuropathological heterogeneity, and the high level of accompanying comorbidities. We report a multimodal analysis integrating longitudinal clinical and cognitive assessment with neuropathological data collected as part of the Brains for Dementia Research (BDR) study to understand how genetic risk factors for Alzheimer's disease influence the development of neuropathology and clinical performance. 693 donors in the BDR cohort with genetic data, semi-quantitative neuropathology measurements, cognitive assessments and established diagnostic criteria were included in this study. We tested the association of APOE genotype and Alzheimer's disease polygenic risk score - a quantitative measure of genetic burden - with survival, four common neuropathological features in Alzheimer's disease brains (neurofibrillary tangles, β-amyloid plaques, Lewy bodies and TDP-43 proteinopathy), clinical status (clinical dementia rating) and cognitive performance (Mini-Mental State Exam, Montreal Cognitive Assessment). The APOE ϵ4 allele was significantly associated with younger age of death in the BDR cohort. Our analyses of neuropathology highlighted two independent pathways from APOE ϵ4, one where β-amyloid accumulation mediates the development of tauopathy, and a second characterized by direct effects on tauopathy independent of β-amyloidosis. Although we also detected association between APOE ϵ4 and dementia status and cognitive performance, these were all mediated by tauopathy, highlighting that they are a consequence of the neuropathological changes. Analyses of polygenic risk score identified associations with tauopathy and β-amyloidosis, which appeared to have both shared and unique contributions, suggesting that different genetic variants associated with Alzheimer's disease affect different features of neuropathology to different degrees. Taken together, our results provide insight into how genetic risk for Alzheimer's disease influences both the clinical and pathological features of dementia, increasing our understanding about the interplay between APOE genotype and other genetic risk factors.

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Continuous and Cyclic Progesterone Differentially Interact with Estradiol in the Regulation of Alzheimer-Like Pathology in Female 3×Transgenic-Alzheimer’s Disease Mice

Endocrinology ◽

10.1210/en.2009-1487 ◽

2010 ◽

Vol 151 (6) ◽

pp. 2713-2722 ◽

Cited By ~ 57

Author(s):

Jenna C. Carroll ◽

Emily R. Rosario ◽

Angela Villamagna ◽

Christian J. Pike

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Postmenopausal Women ◽

Transgenic Mouse Model ◽

Dependent Behavior ◽

Potential Efficacy ◽

Increased Risk ◽

Neural Interactions ◽

Β Amyloid ◽

Insight Into

Depletion of estrogens and progesterone at menopause has been linked to an increased risk for the development of Alzheimer’s disease (AD) in women. A currently controversial literature indicates that although treatment of postmenopausal women with hormone therapy (HT) may reduce the risk of AD, several parameters of HT may limit its potential efficacy and perhaps, even exacerbate AD risk. One such parameter is continuous vs. cyclic delivery of the progestogen component of HT. Recent experimental evidence suggests that continuous progesterone can attenuate neural actions of estradiol (E2). In the present study, we compared the effects of continuous and cyclic progesterone treatment in the presence and absence of E2 in ovariectomized 3×Tg-AD mice, a transgenic mouse model of AD. We found that ovariectomy-induced hormone depletion increases AD-like pathology in female 3×Tg-AD mice, including accumulation of β-amyloid, tau hyperphosphorylation, and impaired hippocampal-dependent behavior. E2 treatment alone prevents the increases in pathology. Continuous progesterone did not affect β-amyloid levels when delivered alone but blocked the Aβ-lowering action of E2. In contrast, cyclic progesterone significantly reduced β-amyloid levels by itself and enhanced rather than inhibited the E2 effects. These results provide new insight into the neural interactions between E2 and progesterone that may prove valuable in optimizing HT regimens in postmenopausal women.

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Neurobiological substrates underlying the effect of genomic risk for depression on the conversion of amnestic mild cognitive impairment

Brain ◽

10.1093/brain/awy277 ◽

2018 ◽

Vol 141 (12) ◽

pp. 3457-3471 ◽

Cited By ~ 7

Author(s):

Jiayuan Xu ◽

Qiaojun Li ◽

Wen Qin ◽

Mulin Jun Li ◽

Chuanjun Zhuo ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Major Depressive Disorder ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Depressive Disorder ◽

Genetic Variants ◽

Amnestic Mild Cognitive Impairment ◽

Risk Scores ◽

Major Depressive

Abstract Depression increases the conversion risk from amnestic mild cognitive impairment to Alzheimer’s disease with unknown mechanisms. We hypothesize that the cumulative genomic risk for major depressive disorder may be a candidate cause for the increased conversion risk. Here, we aimed to investigate the predictive effect of the polygenic risk scores of major depressive disorder-specific genetic variants (PRSsMDD) on the conversion from non-depressed amnestic mild cognitive impairment to Alzheimer’s disease, and its underlying neurobiological mechanisms. The PRSsMDD could predict the conversion from amnestic mild cognitive impairment to Alzheimer’s disease, and amnestic mild cognitive impairment patients with high risk scores showed 16.25% higher conversion rate than those with low risk. The PRSsMDD was correlated with the left hippocampal volume, which was found to mediate the predictive effect of the PRSsMDD on the conversion of amnestic mild cognitive impairment. The major depressive disorder-specific genetic variants were mapped into genes using different strategies, and then enrichment analyses and protein–protein interaction network analysis revealed that these genes were involved in developmental process and amyloid-beta binding. They showed temporal-specific expression in the hippocampus in middle and late foetal developmental periods. Cell type-specific expression analysis of these genes demonstrated significant over-representation in the pyramidal neurons and interneurons in the hippocampus. These cross-scale neurobiological analyses and functional annotations indicate that major depressive disorder-specific genetic variants may increase the conversion from amnestic mild cognitive impairment to Alzheimer’s disease by modulating the early hippocampal development and amyloid-beta binding. The PRSsMDD could be used as a complementary measure to select patients with amnestic mild cognitive impairment with high conversion risk to Alzheimer’s disease.

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CYP46A1 variants influence Alzheimer’s disease risk and brain cholesterol metabolism

European Psychiatry ◽

10.1016/j.eurpsy.2008.12.005 ◽

2009 ◽

Vol 24 (3) ◽

pp. 183-190 ◽

Cited By ~ 22

Author(s):

Heike Kölsch ◽

Dieter Lütjohann ◽

Frank Jessen ◽

Julius Popp ◽

Frank Hentschel ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Genetic Risk ◽

Cholesterol Metabolism ◽

Disease Risk ◽

Brain Cholesterol ◽

Increased Risk ◽

Csf Levels ◽

Interaction Term ◽

Gene Variability

AbstractBackgroundCholesterol 24S-hydroxylase (CYP46) catalyzes the conversion of cholesterol to 24S-hydroxycholesterol, the primary cerebral cholesterol elimination product. Only few gene variations in CYP46 gene (CYP46A1) have been investigated for their relevance as genetic risk factors of Alzheimer’s disease (AD) and results are contradictory.MethodsWe performed a gene variability screening in CYP46A1 and investigated the effect of gene variants on the risk of AD and on CSF levels of cholesterol and 24S-hydroxycholesterol.ResultsTwo of the identified 16 SNPs in CYP46A1 influenced AD risk in our study (rs7157609: p = 0.016; rs4900442: p = 0.019). The interaction term of both SNPs was also associated with an increased risk of AD (p = 0.006). Haplotypes including both SNPs were calculated and haplotype G–C was identified to influence the risk of AD (p = 0.005). AD patients and non-demented controls, who were carriers of the G–C haplotype, presented with reduced CSF levels of 24S-hydroxycholesterol (p = 0.001) and cholesterol (p < 0.001).ConclusionOur results suggest that CYP46A1 gene variations might act as risk factor for AD via an influence on brain cholesterol metabolism.

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Alzheimer’s disease genetic risk and sleep phenotypes: association with more slow-waves and daytime sleepiness

10.1101/2020.02.26.20027912 ◽

2020 ◽

Author(s):

Vincenzo Muto ◽

Ekaterina Koshmanova ◽

Pouya Ghaemmaghami ◽

Mathieu Jaspar ◽

Christelle Meyer ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Young Adults ◽

Genetic Variants ◽

Daytime Sleepiness ◽

Sleep Disturbances ◽

Cognitive Disorders ◽

Risk Scores ◽

Polygenic Risk ◽

Genome Wide

AbstractSleep disturbances and genetic variants have been identified as risk factors for Alzheimer’s disease. Whether genome-wide polygenic risk scores (PRS) for AD associate with sleep phenotypes in young adults, decades before typical AD symptom onset, is currently not known. We extensively phenotyped sleep under different sleep conditions and compute whole-genome Polygenic Risk Scores (PRS) for AD in a carefully selected homogenous sample of healthy 363 young men (22.1 y ± 2.7) devoid of sleep and cognitive disorders. AD PRS was associated with more slow wave energy, i.e. the cumulated power in the 0.5-4 Hz EEG band, a marker of sleep need, during habitual sleep and following sleep loss. Furthermore higher AD PRS was correlated with higher habitual daytime sleepiness. These results imply that sleep features may be associated with AD liability in young adults, when current AD biomarkers are typically negative, and reinforce the idea that sleep may be an efficient intervention target for AD.

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Investigating the role of APOE: limitations of human pluripotent stem cell-derived cerebral organoids

10.1101/2020.11.30.405654 ◽

2020 ◽

Author(s):

Damián Hernández ◽

Louise A. Rooney ◽

Maciej Daniszewski ◽

Lerna Gulluyan ◽

Helena H. Liang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cell Line ◽

Human Fibroblasts ◽

Susceptibility Gene ◽

Tau Phosphorylation ◽

Isogenic Lines ◽

Apoe Ε4 ◽

Increased Risk ◽

Β Amyloid

SummaryApolipoprotein E (APOE) is the most important susceptibility gene for late onset of Alzheimer’s disease, with the presence of APOE-ε4 associated with increased risk of developing Alzheimer’s disease. Here, we reprogrammed human fibroblasts from individuals with different APOE-ε genotypes into induced pluripotent stem cells, and generated isogenic lines with different APOE profiles. We then differentiated these into cerebral organoids for six months and assessed the suitability of this in vitro system to measure APOE, β amyloid, and Tau phosphorylation levels. We identified intra- and inter-variabilities in the organoids’ cell composition. Using the CRISPR-edited APOE isogenic lines, we observed more homogenous cerebral organoids, and similar levels of APOE, β amyloid, and Tau between the isogenic lines, with the exception of one site of Tau phosphorylation which was higher in the APOE-ε4/ε4 organoids. These data describe that pathological hallmarks of AD are observed in cerebral organoids, and that their variation is mainly independent of the APOE-ε status of the cells, but associated with the high variability of cerebral organoid differentiation. It demonstrates that the batch-to-batch and cell-line-to-cell-line variabilities need to be considered when using cerebral organoids.

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A Multiomics Approach to Heterogeneity in Alzheimer’s Disease: Focused Review and Roadmap

10.1101/19008615 ◽

2019 ◽

Author(s):

AmanPreet Badhwar ◽

G. Peggy McFall ◽

Shraddha Sapkota ◽

Sandra E. Black ◽

Howard Chertkow ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Genetic Risk ◽

New Drugs ◽

Data Driven ◽

Risk Scores ◽

Multiple Levels ◽

Multimodal Biomarkers ◽

Design And Testing ◽

Key Pathways

AbstractEtiological and clinical heterogeneity is increasingly recognized as a common characteristic of Alzheimer’s disease and related dementias. This heterogeneity complicates diagnosis, treatment, and the design and testing of new drugs. An important line of research is discovery of multimodal biomarkers that will facilitate the targeting of subpopulations with homogeneous pathophysiological signatures. High-throughput ‘omics’ are unbiased data driven techniques that probe the complex etiology of Alzheimer’s disease from multiple levels (e.g. network, cellular, and molecular) and thereby account for pathophysiological heterogeneity in clinical populations. This review focuses on data reduction analyses that identify complementary disease-relevant perturbations for three omics techniques: neuroimaging-based subtypes, metabolomics-derived metabolite panels, and genomics-related polygenic risk scores. Neuroimaging can track accrued neurodegeneration and other sources of network impairments, metabolomics provides a global small-molecule snapshot that is sensitive to ongoing pathological processes, and genomics characterizes relatively invariant genetic risk factors representing key pathways associated with Alzheimer’s disease. Following this focused review, we present a roadmap for assembling these multiomics measurements into a diagnostic tool highly predictive of individual clinical trajectories, to further the goal of personalized medicine in Alzheimer’s disease.

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Plasma neurofilament light as a longitudinal biomarker of neurodegeneration in Alzheimer’s disease

Brain Science Advances ◽

10.1177/2096595820902582 ◽

2019 ◽

Vol 5 (2) ◽

pp. 94-105 ◽

Cited By ~ 1

Author(s):

Ya-Nan Ou ◽

Hao Hu ◽

Zuo-Teng Wang ◽

Wei Xu ◽

Lan Tan ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Rate Of Change ◽

Neurofilament Light ◽

Cox Proportional Hazards Models ◽

Increased Risk ◽

Β Amyloid ◽

Longitudinal Biomarker

Objective: To examine whether plasma neurofilament light (NFL) might be a potential longitudinal biomarker for Alzheimer’s disease (AD). Methods: A total of 835 individuals from the Alzheimer’s Disease Neuroimaging Initiative were involved. Correlations of the rate of change in plasma NFL with cerebrospinal fluid biomarkers, cognition, and brain structure were investigated. Cox proportional hazards models were used to assess the associations between quartiles of plasma NFL and the risk of AD conversion. Results: Participants were further divided into β amyloid-positive (Aβ+) versus β amyloid-negative (Aβ−), resulting in five biomarker group combinations, which are CN Aβ−, CN Aβ+, MCI Aβ−, MCI Aβ+ and AD Aβ+. Plasma NFL concentration markedly increased in the five groups longitudinally ( p < 0.001) with the greatest rate of change in AD Aβ+ group. The rate of change in plasma NFL was associated with cognitive deficits and neuroimaging hallmarks of AD over time ( p < 0.005). Compared with the bottom quartile, the top quartile of change rate was associated with a 5.41-fold increased risk of AD (95% CI = 1.83−16.01) in the multivariate model. Conclusion: Our finding implies the potential of plasma NFL as a longitudinal noninvasive biomarker in AD.

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Clusterin accumulates in synapses in Alzheimer’s disease and is increased in apolipoprotein E4 carriers

Brain Communications ◽

10.1093/braincomms/fcz003 ◽

2019 ◽

Vol 1 (1) ◽

Cited By ~ 11

Author(s):

Rosemary J Jackson ◽

Jamie Rose ◽

Jane Tulloch ◽

Chris Henstridge ◽

Colin Smith ◽

...

Keyword(s):

Risk Factors ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Beta ◽

Genetic Risk ◽

Genetic Risk Factors ◽

Data Link ◽

Increased Risk ◽

Synapse Degeneration ◽

Models Of Disease

Abstract One of the major challenges in developing effective therapeutic strategies for Alzheimer’s disease is understanding how genetic risk factors contribute to neurodegeneration. The apolipoprotein epsilon 4 isoform (APOE4) and variants in the Clusterin (CLU) gene (also known as apolipoprotein J) are associated with increased risk of developing Alzheimer’s. Our previous work demonstrated that APOE4 exacerbates synapse degeneration and synaptic accumulation of toxic oligomeric amyloid beta in human Alzheimer’s and mouse models of disease. Here, we observe clusterin in synapses in human Alzheimer's disease brain. The percentage of synapses containing clusterin is higher in APOE4 carriers than APOE3 carriers. Furthermore, we observe oligomeric amyloid beta accumulation within synapses containing clusterin which is also higher in APOE4 carriers. These data link two genetic risk factors with synapse degeneration in Alzheimer’s and support a potential role for clusterin working with APOE in causing synaptic damage.

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