Knowledge gaps in Alzheimer's disease immune biomarker research

Morgan, David; Mielke, Michelle M.

doi:10.1002/alz.12342

Cited by 14 publications

(6 citation statements)

References 113 publications

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“…The relationship between inflammatory proteins and AD-related outcomes also varies by disease stage [ 7 ]. Some inflammatory proteins are elevated in the asymptomatic phase of AD, whereas others may only become abnormal when individuals develop MCI or dementia [ 4 ]. Importantly, elevations in several inflammatory cytokines, such as IFN-γ and IL-12p70, which influence Th1-macrophage activation, have shown a protective effect on AD-related neurocognitive outcomes [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

The role of peripheral inflammatory insults in Alzheimer’s disease: a review and research roadmap

Walker

Page

Terrando

et al. 2023

Mol Neurodegeneration

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Peripheral inflammation, defined as inflammation that occurs outside the central nervous system, is an age-related phenomenon that has been identified as a risk factor for Alzheimer’s disease. While the role of chronic peripheral inflammation has been well characterized in the context of dementia and other age-related conditions, less is known about the neurologic contribution of acute inflammatory insults that take place outside the central nervous system. Herein, we define acute inflammatory insults as an immune challenge in the form of pathogen exposure (e.g., viral infection) or tissue damage (e.g., surgery) that causes a large, yet time-limited, inflammatory response. We provide an overview of the clinical and translational research that has examined the connection between acute inflammatory insults and Alzheimer’s disease, focusing on three categories of peripheral inflammatory insults that have received considerable attention in recent years: acute infection, critical illness, and surgery. Additionally, we review immune and neurobiological mechanisms which facilitate the neural response to acute inflammation and discuss the potential role of the blood–brain barrier and other components of the neuro-immune axis in Alzheimer’s disease. After highlighting the knowledge gaps in this area of research, we propose a roadmap to address methodological challenges, suboptimal study design, and paucity of transdisciplinary research efforts that have thus far limited our understanding of how pathogen- and damage-mediated inflammatory insults may contribute to Alzheimer’s disease. Finally, we discuss how therapeutic approaches designed to promote the resolution of inflammation may be used following acute inflammatory insults to preserve brain health and limit progression of neurodegenerative pathology.

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Section: Introductionmentioning

confidence: 99%

The role of peripheral inflammatory insults in Alzheimer’s disease: a review and research roadmap

Walker

Page

Terrando

et al. 2023

Mol Neurodegeneration

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“…Alzheimer's disease (AD) is the most common neurodegenerative disease affecting the elderly population and is the sixth leading cause of death in the United States [154,155]. Promising outcomes in preclinical studies have not always yielded positive clinical outcomes [156].…”

Section: Alzheimer's Diseasementioning

confidence: 99%

Humanized Mice for Infectious and Neurodegenerative disorders

et al. 2021

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Humanized mice model human disease and as such are used commonly for research studies of infectious, degenerative and cancer disorders. Recent models also reflect hematopoiesis, natural immunity, neurobiology, and molecular pathways that influence disease pathobiology. A spectrum of immunodeficient mouse strains permit long-lived human progenitor cell engraftments. The presence of both innate and adaptive immunity enables high levels of human hematolymphoid reconstitution with cell susceptibility to a broad range of microbial infections. These mice also facilitate investigations of human pathobiology, natural disease processes and therapeutic efficacy in a broad spectrum of human disorders. However, a bridge between humans and mice requires a complete understanding of pathogen dose, co-morbidities, disease progression, environment, and genetics which can be mirrored in these mice. These must be considered for understanding of microbial susceptibility, prevention, and disease progression. With known common limitations for access to human tissues, evaluation of metabolic and physiological changes and limitations in large animal numbers, studies in mice prove important in planning human clinical trials. To these ends, this review serves to outline how humanized mice can be used in viral and pharmacologic research emphasizing both current and future studies of viral and neurodegenerative diseases. In all, humanized mouse provides cost-effective, high throughput studies of infection or degeneration in natural pathogen host cells, and the ability to test transmission and eradication of disease.

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“…The soluble form of TREM2 (sTREM2) was shown to be increased in the CSF of mild cognitive impairment (MCI) and AD patients compared to controls, probably reflecting a TREM2-dependent microglia response [ 10 – 14 ]. Additional fluid biomarkers capturing the dynamics of disease-associated microglia and its specificity toward AD are needed to understand the disease etiology or monitor the effects of treatments [ 4 , 15 – 17 ].…”

Section: Introductionmentioning

confidence: 99%

Neuroinflammatory CSF biomarkers MIF, sTREM1, and sTREM2 show dynamic expression profiles in Alzheimer’s disease

Hok‐A‐Hin

Campo

Boiten

et al. 2023

J Neuroinflammation

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Background There is a need for novel fluid biomarkers tracking neuroinflammatory responses in Alzheimer’s disease (AD). Our recent cerebrospinal fluid (CSF) proteomics study revealed that migration inhibitory factor (MIF) and soluble triggering receptor expressed on myeloid cells 1 (sTREM1) increased along the AD continuum. We aimed to assess the potential use of these proteins, in addition to sTREM2, as CSF biomarkers to monitor inflammatory processes in AD. Methods We included cognitively unimpaired controls (n = 67, 63 ± 9 years, 24% females, all amyloid negative), patients with mild cognitive impairment (MCI; n = 92, 65 ± 7 years, 47% females, 65% amyloid positive), AD (n = 38, 67 ± 6 years, 8% females, all amyloid positive), and DLB (n = 50, 67 ± 6 years, 5% females, 54% amyloid positive). MIF, sTREM1, and sTREM2 levels were measured by validated immunoassays. Differences in protein levels between groups were tested with analysis of covariance (corrected for age and sex). Spearman correlation analysis was performed to evaluate the association between these neuroinflammatory markers with AD-CSF biomarkers (Aβ42, tTau, pTau) and mini-mental state examination (MMSE) scores. Results MIF levels were increased in MCI (p < 0.01), AD (p < 0.05), and DLB (p > 0.05) compared to controls. Levels of sTREM1 were specifically increased in AD compared to controls (p < 0.01), MCI (p < 0.05), and DLB patients (p > 0.05), while sTREM2 levels were increased specifically in MCI compared to all other groups (all p < 0.001). Neuroinflammatory proteins were highly correlated with CSF pTau levels (MIF: all groups; sTREM1: MCI, AD and DLB; sTREM2: controls, MCI and DLB). Correlations with MMSE scores were observed in specific clinical groups (MIF in controls, sTREM1 in AD, and sTREM2 in DLB). Conclusion Inflammatory-related proteins show diverse expression profiles along different AD stages, with increased protein levels in the MCI stage (MIF and sTREM2) and AD stage (MIF and sTREM1). The associations of these inflammatory markers primarily with CSF pTau levels indicate an intertwined relationship between tau pathology and inflammation. These neuroinflammatory markers might be useful in clinical trials to capture dynamics in inflammatory responses or monitor drug–target engagement of inflammatory modulators.

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Knowledge gaps in Alzheimer's disease immune biomarker research

Cited by 14 publications

References 113 publications

The role of peripheral inflammatory insults in Alzheimer’s disease: a review and research roadmap

The role of peripheral inflammatory insults in Alzheimer’s disease: a review and research roadmap

Humanized Mice for Infectious and Neurodegenerative disorders

Neuroinflammatory CSF biomarkers MIF, sTREM1, and sTREM2 show dynamic expression profiles in Alzheimer’s disease

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