Modifiable Risk Factors for Alzheimer’s Disease

Edwards, George A.; Gamez, Nazaret; Escobedo, Gabriel; Calderon, Olivia; Moreno-González, Inés

doi:10.3389/fnagi.2019.00146

Cited by 187 publications

(204 citation statements)

References 274 publications

(289 reference statements)

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“…Some of these genes include ABCA7, APOE, BIN1, CD2AP, CD33, CLU, CR1, EPHA1, MS4A4A/MS4A4E/MS4A6E, PICALM, and SORL1 (Barber 2012), of which a large proportion are immunological factors. .Modifiable risk factors for AD include inflammation, viral infections, Type 2 diabetes, vascular disorders, and hypertension (Edwards et al 2019;Stozická, Zilka, and Novák 2007). Among these risk factors, inflammation is considered as a central mechanism in AD and infectious agents like bacteria and viruses might play a critical role in sustaining chronic inflammation and inducing neuroinflammation in particular in subjects carrying the aforementioned genetic variants.…”

Section: Introductionmentioning

confidence: 99%

Systemic inflammation causes microglial dysfunction with a mixed AD-like pathology

Bathini

Dupanloup

Zenaro

et al. 2020

Preprint

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BackgroundAlzheimer’s disease (AD) is the primary cause of cognitive deficit in elderly humans. Late-onset AD (LOAD) is sporadic, multifactorial, non-Mendelian accounting at present for 95% of the cases in contrast to the genetic form. Risk factors for sporadic AD include Gene: Environment interactions. There is increasing evidence that lifestyle and environmental stress such as infection and chronic inflammation are underlying culprits of neurodegenerative dementia. To date, very few mouse models reproduce the pathophysiological progression of sporadic AD, while the majority of studies have employed transgenic animals reproducing the familial form.MethodsWe have re-engineered the Polyinosinic:polycytidylic acid (PolyI:C) sterile infection model in wildtype C57Bl6 mice to obtain chronic low-grade systemic inflammation. We have conducted a cross-sectional analysis of aging PolyI:C and Saline control mice (3 months, 6 months, 9 months and 16 months), taking the hippocampus as a reference brain region, based on its vulnerability, and compared the brain aging phenotype to AD progression in humans with mild AD, severe AD and Controls (CTL).ResultsWe found that PolyI:C mice display both peripheral and central inflammation with a peak at 6 months, associated with memory deficits. The hippocampus is characterized by a pronounced and progressive tauopathy. In PolyI:C brains, microglia undergo aging-dependent morphological rearrangements progressively adopting a phagocytic phenotype. Transcriptomic analysis reveals a profound change in gene expression over the course of aging, with a peak in differential expression at 9 months. We confirm that the proinflammatory marker Lcn2 is one of the genes with the strongest upregulation in PolyI:C mice upon aging. Validation in brains from patients with increasing severity of AD shows a general tendency of the genes to decline except for GFAP.ConclusionsThe PolyI:C model of sterile infection demonstrates that peripheral chronic inflammation is sufficient to cause neuropathological processes resembling a mixed-AD, with progressive tau hyperphosphorylation, changes in microglia morphology, and gene reprogramming reflecting the increased neuroinflammation and the loss of neuronal functionality seen to some extent in humans.

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Section: Introductionmentioning

confidence: 99%

Systemic inflammation causes microglial dysfunction with a mixed AD-like pathology

Bathini

Dupanloup

Zenaro

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Recent data shows that there exists a spectrum of genetic influences on AD development like common genetic variants with high risk for AD (SLC24A4, ZCWPW1, CELF1, FERMT2, HLA-DRB5/1, CASS4, INPP5D, MEF2C, NME8), rare genetic variants with low to high risk (AKAP9, AB13, PLCG2, SRCAP, TREM2) and other high-risk genes with moderate frequently expression (APOE4, SORL1) (Narayanan et al 2014;Campion, Charbonnier, and Nicolas 2019;Farrer et al 1997). Current investigations show the involvement of many modifiable risk factors for AD including inflammation, viral infections, Type 2 diabetes, vascular disorders, and hypertension (Edwards et al 2019;Stozická, Zilka, and Novák 2007). Among these risk factors, inflammation is considered as a central mechanism in AD and infectious agents like bacteria and viruses might play a critical role in sustaining chronic inflammation and inducing neuroinflammation.…”

Section: Introductionmentioning

confidence: 99%

Systemic Inflammation Causes Microglial Dysfunction with a Mixed AD-Like Pathology.

Bathini

Dupanloup

Zennaro

et al. 2020

Preprint

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Background Alzheimer's disease (AD) is the primary cause of cognitive deficit in elderly humans. Late-onset AD (LOAD) is sporadic, multifactorial, non-Mendelian accounting at present for 95% of the cases in contrast to the genetic form. Risk factors for sporadic AD include Gene: Environment interactions. There is increasing evidence that lifestyle and environmental stress such as infection and chronic inflammation are underlying culprits of neurodegenerative dementia. To date, very few mouse models reproduce the pathophysiological progression of sporadic AD, while the majority of studies have employed transgenic animals reproducing the familial form. Methods We have re-engineered the Polyinosinic:polycytidylic acid (PolyI:C) sterile infection model in wildtype C57Bl6 mice to obtain chronic low-grade systemic inflammation. We have conducted a cross-sectional analysis of aging PolyI:C and Saline control mice (3 months, 6 months, 9 months and 16 months), taking the hippocampus as a reference brain region, based on its vulnerability, and compared the brain aging phenotype to AD progression in humans with mild AD, severe AD and Controls (CTL). Results We found that PolyI:C mice display both peripheral and central inflammation with a peak at 6 months, associated with memory deficits. The hippocampus is characterized by a pronounced and progressive tauopathy. In PolyI:C brains, microglia undergo aging-dependent morphological rearrangements progressively adopting a phagocytic phenotype. Transcriptomic analysis reveals a profound change in gene expression over the course of aging, with a peak in differential expression at 9 months. We confirm that the proinflammatory marker Lcn2 is one of the genes with the strongest upregulation in PolyI:C mice upon aging. Validation in brains from patients with increasing severity of AD shows a general tendency of the genes to decline except for GFAP. Conclusions The PolyI:C model of sterile infection demonstrates that peripheral chronic inflammation is sufficient to cause neuropathological processes resembling a mixed-AD, with progressive tau hyperphosphorylation, changes in microglia morphology, and gene reprogramming reflecting the increased neuroinflammation and the loss of neuronal functionality seen to some extent in humans.

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“…There is a rich literature on possible mechanisms linking NPS to dementia. The relationship may be directly causal, in that NPS lead to dementia . This might occur by activation of the neuroendocrine axis or through deposition of β‐amyloid .…”

Section: Introductionmentioning

confidence: 99%

“…The relationship may be directly causal, in that NPS lead to dementia. 13 This might occur by activation of the neuroendocrine axis 14 or through deposition of β-amyloid. 15,16 The NPS may also share a common cause with dementia; essentially, the NPS are a noncognitive symptom of the same underlying pathology.…”

mentioning

confidence: 99%

Trajectories of neuropsychiatric symptoms over time in healthy volunteers and risk of MCI and dementia

Leoutsakos

Wise

Smith

2019

Int J Geriat Psychiatry

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Objectives To identify subtypes of neuropsychiatric symptom (NPS) course among cognitively normal individuals and to assess the association between these subtypes and hazard of later mild cognitive impairment (MCI) or dementia diagnosis. Methods We modeled neuropsychiatric inventory questionnaire (NPI‐Q) scores from 4184 volunteers over approximately 4 years using growth mixture models, generating latent classes of trajectory. We then fit Cox proportional hazard models to determine if membership in trajectory classes was associated with increased hazard of diagnosis of MCI or dementia. Results We identified four trajectory classes: the majority of the sample (65%) would be expected to belong to a class with consistently low or zero NPS. The next most prevalent class, (16%) showed a decrease over time in NPI‐Q total score but, compared with the majority class had an almost threefold increase in hazard of MCI or dementia (HR: 2.92; 95% CI: 1.82‐4.68). Another class (14%) showed an increase in NPS over time and was also associated with greater hazard of MCI or dementia (HR: 3.96; CI: 2.61‐6.03). The smallest class (5%) had high and fluctuating NPI‐Q total scores and had the greatest hazard (HR: 4.57; CI: 2.72‐7.63). Conclusion We have demonstrated that it is possible to identify meaningful groups of NPS trajectories and that trajectory of NPS can convey information beyond a single cross‐sectional measure. While even those whose NPS improved were at increased hazard of MCI or dementia, hazard increased as a function of the severity of the NPS trajectory.

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Modifiable Risk Factors for Alzheimer’s Disease

Cited by 187 publications

References 274 publications

Systemic inflammation causes microglial dysfunction with a mixed AD-like pathology

Systemic inflammation causes microglial dysfunction with a mixed AD-like pathology

Systemic Inflammation Causes Microglial Dysfunction with a Mixed AD-Like Pathology.

Trajectories of neuropsychiatric symptoms over time in healthy volunteers and risk of MCI and dementia

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