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  various metrics, such as astrocytosis, were due to both sex chromosomes and gonads, and/or the interaction between them, as in aged FCG mice cytokine expression and gliosis.
Discussion: These data demonstrate a complex relationship between immune cell activation and the sex chromosomes and gonads, with implications for how the immune cells respond to AD-related processes. Conclusions: Our data suggest that sex chromosomes and gonadally- derived circulating sex hormones each influence AD-related neuroinflammatory processes. These in turn contribute to divergent patterns of disease onset and progression.
Background: Anxiety concurrent with subjective cognitive decline (SCD), a preclinical stage of Alzheimer’s disease (AD), associates with faster progression to dementia. Yet, the mechanism is unclear. We tested the hypothesis that anxiety in SCD correlates with cerebral blood flow (CBF) abnormalities. We focused on the anterior cerebral artery (ACA) and anterior choroidal artery (ACHA), vessels supplying the prefrontal cortex and hippocampal head, respectively, key areas of the anxiogenic network.
Materials and Methods: Consecutive participants (n = 17) in the NYU Alzheimer’s Disease Research Center with SCD underwent florbetaben amyloid PET MRI, with arterial spin labeling sequence to measure CBF. Visualization and quantification of CBF was performed using CereFlowTM V1.0. Global amyloid burden was quantified as the standard value uptake ratio over the cortex. Self-reported anxiety and depression were quantified via the Beck Anxiety Inventory and Beck Depression Inventory. Monotonic associations were measured using Spearman or Pearson correlation, as appropriate. Means were compared using t-test. Results: There was a statistically significant positive correlation between CBF and anxiety in the ACA (p = 0.0077) and ACHA (p = 0.0249), but not with depression. There was no difference in CBF between APOE4 carriers and non-carriers. There was no correlation of global amyloid burden with CBF nor with anxiety.
Discussion: These results suggest that anxiety may be driven by elevated CBF. This hyperfusion may reflect increased cortical metabolic demand from hyperexcitability or direct vascular mechanisms. Lack of correlation to global amyloid deposition suggests a role for amyloid forms not measured by PET or, more interestingly, non-amyloid processes.
Conclusions: Anxiety in preclinical AD correlates with increased blood flow to anxiogenic regions, independent of PET-measured amyloid and APOE4. This motivates exploration of amyloid-independent mechanisms on cerebral blood flow in preclinical AD that may mediate anxiety and its relationship to accelerated progression to dementia.
Glial and vascular contributions to neurodegenerative diseases
Anxiety associates with cerebral hyperperfusion in preclinical Alzheimer disease
Anup Deshpande1, Henry Rusinek1, Arjun Masurkar1
1NYU School Of Medicine, New York, USA
Unbiased classification of the human brain proteome resolves distinct clinical and pathophysiological subtypes of cognitive impairment
Lenora Higginbotham1, E. Kathleen Carter1, Eric B. Dammer1, Erik C. B. Johnson1, Duc M. Duong1, Luming Yin1, Philip L.
De Jager2, David A. Bennett3, James J. Lah1, Allan I. Levey1, Nicholas T. Seyfried1
1Emory University School of Medicine, Atlanta, USA 2Columbia University Taub Institute, New York, USA 3Rush University Medical Center, Chicago, USA
 Background: Increasing evidence indicates the hallmark amyloid and tau deposition of Alzheimer’s disease (AD) represents only a fraction of its complex and heterogenous pathophysiology. Molecular subtyping using large-scale -omic strategies can resolve this biological heterogeneity and advance diagnostic and therapeutic precision. Methods: Postmortem dorsolateral prefrontal cortex tissues from the Religious Orders Study and Rush Memory and Aging Project with clinical diagnoses of no cognitive impairment (NCI, n=220), mild cognitive impairment (MCI, n=173), and AD (n=204) were analyzed by quantitative mass spectrometry. Using the clustering algorithm MONET M1, cognitively impaired cases were classified based on individual proteomic profiles.
Results: Approximately 8,000 proteins were quantified across all cases. Clustering of MCI and AD cases resolved three proteomic classes of cognitive impairment, termed A, B, and C. Applying a systems-based organization to these profiles highlighted divergent biological trends, and phenotypic characterization of each class identified key differences in genetic, clinical, and pathological features. Class A featured the most neurologically preserved proteomic profile, mirroring NCI cases in levels of synaptic, metabolic, and inflammatory proteins. In contrast, Class C displayed the most neurodegenerative proteomic profile with decreased synaptic markers and exceptionally elevated inflammatory signatures. Accordingly, Class A featured the slowest rates of cognitive decline and lowest neuropathological burden, while Class C harbored more aggressive cognitive deterioration, heightened neuropathology, and elevated genetic AD risk. Class B featured an intermediate proteomic profile, excepting remarkably high levels of numerous synaptic markers. Yet, these neuronal signatures offered Class B no distinct advantages in disease phenotype, as it strongly mirrored Class C in clinicopathological features.
Conclusion: Large-scale proteomic clustering of the MCI and AD brain resolved three subtypes characterized by diverse genetic, molecular, and phenotypic differences. Further investigation of these classes and their unique molecular signatures promises to meaningfully impact diagnostic classification, disease prognostication, and precision therapeutics.
Background: Mechanisms driving cerebrovascular decline during aging and in disease are poorly understood. Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in the folate/methionine/ homocysteine pathway. Variants in MTHFR, notably 677C>T, have been associated with Alzheimer’s disesase (AD) and vascular dementia. Approximately 30% of individuals carry at least one copy of MTHFR677C>T, causing a 50% decrease in MTHFR enzyme efficiency. Reduced efficiency can lead to high levels of homocysteine in blood, resulting in vascular inflammation and increased risk for cerebrovascular damage. We hypothesize that brain-specific vascular expression of MTHFR677C>T in cerebrovasculature drives damaging effects.
The 677C>T variant in methylenetetrahydrofolate reductase causes morphological and functional cerebrovascular deficits in mice
Alaina Reagan1, Karen Christensen2, Jill Meyer3, Jonathan Peters3, Lucas Figueiredo3, Scott Persohn3, Amanda Bedwell3, Kierra Eldridge3, Racheal Speedy3, Rima Rozen2, Michael Sasner1, Paul Territo3, Gareth Howell1
1The Jackson Laboratory, Bar Harbor, USA
2McGill University, Montreal, Canada
3Indiana University School of Medicine, Indianapolis, USA

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