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INTRODUCTION: Protein‐based plasma assays provide hope for improving accessibility and specificity of molecular diagnostics to diagnose dementia. METHODS: Plasma was obtained from participants (N = 837) in our community‐based University of Kentucky Alzheimer's Disease Research Center cohort. We evaluated six Alzheimer's disease (AD)‐ and neurodegeneration‐related (Aβ40, Aβ42, Aβ42/40, p‐tau181, total tau, and NfLight) and five inflammatory biomarkers (TNF훼, IL6, IL8, IL10, and GFAP) using the SIMOA‐based protein assay platform. Statistics were performed to assess correlations. RESULTS: Our large cohort reflects previous plasma biomarker findings. Relationships between biomarkers to understand AD–inflammatory biomarker correlations showed significant associations between AD and inflammatory biomarkers suggesting peripheral inflammatory interactions with increasing AD pathology. Biomarker associations parsed out by clinical diagnosis (normal, MCI, and dementia) reveal changes in strength of the correlations across the cognitive continuum. DISCUSSION: Unique AD–inflammatory biomarker correlations in a community‐based cohort reveal a new avenue for utilizing plasma‐based biomarkers in the assessment of AD and related dementias. Highlights: Large community cohorts studying sex, age, and APOE genotype effects on biomarkers are few.It is unknown how biomarker–biomarker associations vary through aging and dementia.Six AD (Aβ40, Aβ42, Aβ42/40, p‐tau181, total tau, and NfLight) and five inflammatory biomarkers (TNFα, IL6, IL8, IL10, and GFAP) were used to examine associations between biomarkers.Plasma biomarkers suggesting increasing cerebral AD pathology corresponded to increases in peripheral inflammatory markers, both pro‐inflammatory and anti‐inflammatory.Strength of correlations, between pairs of classic AD and inflammatory plasma biomarker, changes throughout cognitive progression to dementia. [ABSTRACT FROM AUTHOR]

Vascular cognitive impairment and dementia (VCID) is the second most common form of dementia behind Alzheimer's disease (AD). It is estimated that 40% of AD patients also have some form of VCID. One promising therapeutic for AD is anti-Aβ immunotherapy, which uses antibodies against Aβ to clear it from the brain. While successful in clearing Aβ and improving cognition in mice, anti-Aβ immunotherapy failed to reach primary cognitive outcomes in several different clinical trials. We hypothesized that one potential reason the anti-Aβ immunotherapy clinical trials were unsuccessful was due to this high percentage of VCID comorbidity in the AD population. We used our unique model of VCID-amyloid comorbidity to test this hypothesis. We placed 9-month-old wild-type and APP/PS1 mice on either a control diet or a diet that induces hyperhomocysteinemia (HHcy). After being placed on the diet for 3 months, the mice then received intraperotineal injections of either IgG2a control or 3D6 for another 3 months. While we found that treatment of our comorbidity model with 3D6 resulted in decreased total Aβ levels, there was no cognitive benefit of the anti-Aβ immunotherapy in our AD/VCID mice. Further, microhemorrhages were increased by 3D6 in the APP/PSl/control but further increased in an additive fashion when 3D6 was administered to the APP/PSl/HHcy mice. This suggests that the use of anti-Aβ immunotherapy in patients with both AD and VCID would be ineffective on cognitive outcomes. [ABSTRACT FROM AUTHOR]

Introduction Vascular dementia is the second most common cause of dementia after Alzheimer's disease (AD). In addition, it is estimated that almost half of all AD patients have significant cerebrovascular disease co-morbid with their AD pathology. We hypothesized that cerebrovascular disease significantly impacts AD pathological progression. Methods We used a dietary model of cerebrovascular disease that relies on the induction of hyperhomocysteinemia (HHCy). HHCy is a significant clinical risk factor for stroke, cardiovascular disease and type 2 diabetes. In the current study we induced HHCy in APP/PS1 transgenic mice. Results While total beta-amyloid (Abeta) load is unchanged across groups, Congophilic amyloid deposition was decreased in the parenchyma and significantly increased in the vasculature as cerebral amyloid angiopathy (CAA; vascular amyloid deposition) in HHCy APP/PS1 mice. We also found that HHCy induced more microhemorrhages in the APP/PS1 than the wildtype mice and switched the neuroinflammatory phenotype from an M2a biased state to an M1 biased state. Associated with these changes was an induction of the MMP2 and MMP9 systems. Interestingly, after 6 months of HHCy, the APP/PS1 mice were cognitively worse than wildtype HHCy or APP/PS1 mice, indicative of an additive effect of the cerebrovascular pathology and the amyloid deposition. Conclusions These data show that cerebrovascular disease can significantly impact Abeta distribution in the brain, favoring vascular deposition. We predict that the presence of cerebrovascular disease with AD will have a significant impact on AD progression and efficacy of therapeutics. [ABSTRACT FROM AUTHOR]

Background: APOE is the largest genetic risk factor for late‐onset Alzheimer's disease (AD) with the APOE‐e4 allele conferring an increased risk for AD compared to the APOE‐ e3 allele. While APOE in the brain is a lipid transporter produced by astrocytes, research has shown that APOE can impact diverse biochemical pathways. Interestingly, APOE isoforms have also been shown to modulate levels of neuroinflammation in the brain, yet the exact impact on inflammation remains unknown. As microglia are considered to be a primary source of brain inflammation, this study explores how APOE isoforms impact microglial morphology and activation state in human brains. Method: Two methods were used in this study to assess the impact of APOE isoforms on microglia in human brain sections. First, NanoString Digital Spatial Profiling (DSP) was used to investigate protein levels of inflammatory markers specific for microglia on fixed tissue in the hippocampus with AD pathology in both APOE‐ e3 (n=7) and APOE‐ e4 (n=8) subjects. Immunohistochemistry (IHC) was then performed using samples from APOE‐ e3/3 (n=33 control n=23 AD), APOE‐ e4/4 (n=19 AD), and APOE‐e3/4 (n=15 control) subjects from the University of Kentucky AD Research Center. IBA‐1 IHC was used to investigate microglial activation and morphology differences between APOE isoforms. Result: Using both DSP and IHC, the results indicate that APOE isoforms play a role in the microglial changes seen in the presence of AD pathology‐ both in activation state and morphology. The DSP experiments showed significant changes in microglial markers throughout the hippocampal region between APOE‐ e3 and APOE‐ e4. Of interest, in APOE‐e3 subjects, we show an alteration of the microglial phenotype based on pathology level, however, in APOE‐e4 subjects, this change due to pathology is reduced. Additionally, in the IHC experiments we found changes in microglial morphology and activation that parallel those seen in DSP. Conclusion: The findings from this study suggest that with APOE‐ e3, microglia are able to respond in the presence of AD pathology. By contrast, APOE‐ e4 microglia cannot produce an appropriate response to AD pathology. Overall, these findings help highlight the role of the APOE isoforms in AD and neuroinflammation. [ABSTRACT FROM AUTHOR]

Background: Vascular contributions to cognitive impairment and dementia (VCID) are one of the leading causes of dementia. High levels of plasma homocysteine or hyperhomocysteinemia has been characterized as a risk factor for VCID however, the mechanism underlying this connection remains elusive. I hypothesize that hyperhomocysteinemia initiates a pro‐inflammatory cascade that increases the activity of matrix metalloproteinase 9 (MMP9) causing perivascular astrocytes to dissociate from their vessels, leading to blood brain barrier dysfunction and the progression toward VCID pathology. Method: For in vivo studies, C57BL6 WT mice were placed on a control diet or a diet deficient in folate, vitamins B6 and B12 and enriched in methionine to induce hyperhomocysteinemia for 6, 10, 14, or 18 weeks. Immunohistochemistry and gene expression analysis were used to determine neuroinflammatory changes while histology was used to identify changes in astrocytic end‐feet proteins and microhemorrhages. Gel zymography was used to assess proteinase activity of MMP9. Behavior was assessed using the 2‐day radial arm water maze. For in vitro, experiments, primary astrocytes obtained from both WT and MMP9 null mice were placed in a co‐culture model with WT primary endothelial cells. Trans‐endothelial electrical resistance measurements were used to assess blood brain barrier integrity in response to homocysteine in vitro. Result: After 6 weeks of diet administration, we saw a significant increase in gene expression of TNFα, IL‐1β, IL‐6 and IL‐12α. This was followed by increases in MMP transcription and proteinase activity seen at 10 weeks on diet. Also, beginning at the 10‐week time point, cognitive deficits became detectable, which coincided with significant disruptions between astrocytic end‐feet and the cerebrovasculature. Finally, there was a significant increase in the number of microhemorrhages after 14 weeks on diet. In vitro, astrocytes showed an increase in MMP9 after 48 hours of homocysteine treatment. Conclusion: Collectively, our findings suggest that astrocytic MMP9 may play an integral role in the mechanism associating homocysteine induced neuroinflammation with vascular pathogenesis leading to VCID. Continued study of the cell specificity and mechanism of MMP9 mediated vascular pathology will allow us to systematically target the various stages of disease and ultimately prevent the progression of VCID. [ABSTRACT FROM AUTHOR]

Introduction: Protein-based plasma assays provide hope for improving accessibility and specificity of molecular diagnostics to diagnose dementia., Methods: Plasma was obtained from participants (N = 837) in our community-based University of Kentucky Alzheimer's Disease Research Center cohort. We evaluated six Alzheimer's disease (AD)- and neurodegeneration-related (Aβ40, Aβ42, Aβ42/40, p-tau181, total tau, and NfLight) and five inflammatory biomarkers (TNF𝛼, IL6, IL8, IL10, and GFAP) using the SIMOA-based protein assay platform. Statistics were performed to assess correlations., Results: Our large cohort reflects previous plasma biomarker findings. Relationships between biomarkers to understand AD-inflammatory biomarker correlations showed significant associations between AD and inflammatory biomarkers suggesting peripheral inflammatory interactions with increasing AD pathology. Biomarker associations parsed out by clinical diagnosis (normal, MCI, and dementia) reveal changes in strength of the correlations across the cognitive continuum., Discussion: Unique AD-inflammatory biomarker correlations in a community-based cohort reveal a new avenue for utilizing plasma-based biomarkers in the assessment of AD and related dementias., Highlights: Large community cohorts studying sex, age, and APOE genotype effects on biomarkers are few. It is unknown how biomarker-biomarker associations vary through aging and dementia. Six AD (Aβ40, Aβ42, Aβ42/40, p-tau181, total tau, and NfLight) and five inflammatory biomarkers (TNFα, IL6, IL8, IL10, and GFAP) were used to examine associations between biomarkers. Plasma biomarkers suggesting increasing cerebral AD pathology corresponded to increases in peripheral inflammatory markers, both pro-inflammatory and anti-inflammatory. Strength of correlations, between pairs of classic AD and inflammatory plasma biomarker, changes throughout cognitive progression to dementia., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Vascular contributions to cognitive impairment and dementia (VCID) are a leading cause of dementia. An underappreciated, modifiable risk factor for VCID is hyperhomocysteinemia (HHcy), defined by elevated levels of plasma homocysteine, most often due to impaired B vitamin absorption in aged persons. Studies aimed at identifying neuropathologic features and gene expression profiles associated with HHcy have been lacking., Methods: A subset of research volunteers from the University of Kentucky Alzheimer's Disease Research Center longitudinal cohort came to autopsy and had ante mortem plasma homocysteine levels available. Brain tissue and blood plasma drawn closest to death were used to measure homocysteine and related metabolites in the current pilot study. Genetic expression profiles of inflammatory markers were evaluated using the Human Neuroinflammation NanoString panel. Further analyses included an evaluation of plasma homocysteine effects on amyloid beta, tau, ionized calcium-binding adaptor molecule 1, and glial fibrillary acidic protein immunohistochemistry in the frontal and occipital cortices. Analytes and other study outcomes were evaluated in relation to ante mortem HHcy status: We identified 13 persons with normal ante mortem plasma homocysteine levels (<14 µmol/L) and 18 who had high plasma homocysteine levels (≥14 µmol/L)., Results: Participants with HHcy demonstrated increased levels of several plasma homocysteine cycle metabolites such as total cysteine, S-adenosyl-homocysteine, cystathionine, and choline. Inflammatory gene expression profiles showed a general downregulation in the setting of elevated plasma homocysteine. HHcy was associated with more and longer microglial processes, but smaller and fewer astrocytes, especially in participants of older age at death. HHcy in older participants was also associated with occipital cortex microhemorrhages and increased severity of atherosclerosis throughout the cerebral vasculature., Conclusions: Increased plasma homocysteine and older age were associated with the downregulation of inflammatory gene expression markers in association with significant glial and vascular pathology changes. Impaired immune function is a plausible mechanism by which HHcy increases cerebrovascular damage leading to impaired cognitive function., Competing Interests: The authors declare they have no conflicts of interest. Author disclosures are available in the supporting information., (© 2022 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)