Search

By age 40 years, over 90% of adults with Down syndrome have Alzheimer's disease pathology and most progress to dementia. Despite having few systemic vascular risk factors, individuals with Down syndrome have elevated cerebrovascular disease markers that track with the clinical progression of Alzheimer's disease, suggesting a role of cerebrovascular disease that is hypothesized to be mediated by inflammatory factors. This study examined the pathways through which small vessel cerebrovascular disease contributes to Alzheimer's disease-related pathophysiology and neurodegeneration in adults with Down syndrome. One hundred eighty-five participants from the Alzheimer's Biomarkers Consortium-Down Syndrome [mean (SD) age = 45.2 (9.3) years] with available MRI and plasma biomarker data were included in this study. White matter hyperintensity (WMH) volumes were derived from T2-weighted fluid-attenuated inversion recovery MRI scans, and plasma biomarker concentrations of amyloid beta 42/40, phosphorylated tau 217, astrocytosis (glial fibrillary acidic protein) and neurodegeneration (neurofilament light chain) were measured with ultrasensitive immunoassays. We examined the bivariate relationships of WMH, amyloid beta 42/40, phosphorylated tau 217 and glial fibrillary acidic protein with age-residualized neurofilament light chain across Alzheimer's disease diagnostic groups. A series of mediation and path analyses examined statistical pathways linking WMH and Alzheimer's disease pathophysiology to promote neurodegeneration in the total sample and groups stratified by clinical diagnosis. There was a direct and indirect bidirectional effect through the glial fibrillary acidic protein of WMH on phosphorylated tau 217 concentration, which was associated with neurofilament light chain concentration in the entire sample. Amongst cognitively stable participants, WMH was directly and indirectly, through glial fibrillary acidic protein, associated with phosphorylated tau 217 concentration, and in those with mild cognitive impairment, there was a direct effect of WMH on phosphorylated tau 217 and neurofilament light chain concentrations. There were no associations of WMH with biomarker concentrations among those diagnosed with dementia. The findings from this cross-sectional study suggest that among individuals with Down syndrome, cerebrovascular disease promotes neurodegeneration by increasing astrocytosis and tau pathophysiology in the presymptomatic phases of Alzheimer's disease, but future studies will need to confirm these associations with longitudinal data. This work joins an emerging literature that implicates cerebrovascular disease and its interface with neuroinflammation as a core pathological feature of Alzheimer's disease in adults with Down syndrome., Competing Interests: O.H. has received consulting fees for AC Immune, Amylyx, ALZpath, BioArctic, Biogen, Cerveau, Eisai, Eli Lilly, Fujirebio, Merck, Novartis, Novo Nordisk, Roche, Sanofi and Siemens; S.Z. has received consulting fees from Lundbeck; D.M.W. has received consulting fees from Biohaven Therapeutics; E.H. has received consulting fees for Alzheon and Cyclo Therapeutics; A.M.B. has received consulting fees from Cogstate, Cognito Therapeutics, IQVIA, and Cognition Therapeutics., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Adults with Down syndrome are less likely to have hypertension than neurotypical adults. However, whether blood pressure measures are associated with brain health and clinical outcomes in this population has not been studied in detail. Here, we assessed whether pulse pressure is associated with markers of cerebrovascular disease and is linked to a diagnosis of dementia in adults with Down syndrome via structural imaging markers of cerebrovascular disease and atrophy. The study included participants with Down syndrome from the Alzheimer's Disease - Down Syndrome study ( n = 195, age = 50.6 ± 7.2 years, 44% women, 18% diagnosed with dementia). Higher pulse pressure was associated with greater global, parietal and occipital white matter hyperintensity volume but not with enlarged perivascular spaces, microbleeds or infarcts. Using a structural equation model, we found that pulse pressure was associated with greater white matter hyperintensity volume, which in turn was related to increased neurodegeneration, and subsequent dementia diagnosis. Pulse pressure is an important determinant of brain health and clinical outcomes in individuals with Down syndrome despite the low likelihood of frank hypertension., Competing Interests: M.M. is on the scientific advisory board of Brain Neurotherapy Bio, Davis Phinney Foundation for Parksinson’s and Alzheon. A.M.B. has received consulting/advisory fees from Cognition Therapeutics, Cognito Therapeutics and CogState and has a patent for technologies for white matter hyperintensity quantification (867566) issued., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

EGFR amplification in gliomas is commonly defined by an EGFR/CEP7 ratio of ≥2. In testing performed at a major reference laboratory, a small subset of patients had ≥5 copies of both EGFR and CEP7 yet were not amplified by the EGFR/CEP7 ratio and were designated high polysomy cases. To determine whether these tumors are more closely related to traditionally defined EGFR-amplified or nonamplified gliomas, a retrospective search identified 22 out of 1143 (1.9%) gliomas with an average of ≥5 copies/cell of EGFR and CEP7 with an EGFR/CEP7 ratio of <2 displaying high polysomy. Of these cases, 4 had insufficient clinicopathologic data to include in additional analysis, 15 were glioblastomas, 2 were IDH-mutant astrocytomas, and 1 was a high-grade glial neoplasm, NOS. Next-generation sequencing available on 3 cases demonstrated one with a TERT promoter mutation, TP53 mutations in all cases, and no EGFR mutations or amplifications, which most closely matched the nonamplified cases. The median overall survival times were 42.86, 66.07, and 41.14 weeks for amplified, highly polysomic, and nonamplified, respectively, and were not significantly different (p =  0.3410). High chromosome 7 polysomic gliomas are rare but our data suggest that they may be biologically similar to nonamplified gliomas., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc.)

People with dementia have an increase in brain inflammation, caused in part by innate and adaptive immune cells. However, it remains unknown whether dementia-associated diseases alter neuro-immune reflex arcs to impact the systemic immune system. We examined peripheral immune cells from a community-based cohort of older adults to test if systemic inflammatory cytokine signatures associated with early stages of cognitive impairment. Human peripheral blood mononuclear cells were cultured with monocyte or T-cell-targeted stimuli, and multiplex assays quantitated cytokines in the conditioned media. Following T-cell-targeted stimulation, cells from women with cognitive impairment produced lower amounts of T H 17 cytokines compared with cells from cognitively healthy women, while myeloid-targeted stimuli elicited similar amounts of cytokines from cells of both groups. This T H 17 signature correlated with the proportion of circulating CD4+ and CD8+ T cells and plasma glial fibrillary acidic protein and neurofilament light concentrations. These results suggest that decreases in T H 17 cytokines could be an early systemic change in women at risk for developing dementia. Amelioration of T H 17s cytokines in early cognitive impairment could, in part, explain the compromised ability of older adults to respond to vaccines or defend against infection., Competing Interests: The authors report no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

APOE is the largest genetic risk factor for late-onset Alzheimer disease (AD) with E4 conferring an increased risk for AD compared to E3. The ApoE protein can impact diverse pathways in the brain including neuroinflammation but the precise impact of ApoE isoforms on inflammation remains unknown. As microglia are a primary source of neuroinflammation, this study determined whether ApoE isoforms have an impact on microglial morphology and activation using immunohistochemistry and digital analyses. Analysis of ionized calcium-binding adaptor molecule 1 (Iba1) immunoreactivity indicated greater microglial activation in both the hippocampus and superior and middle temporal gyrus (SMTG) in dementia participants versus non-demented controls. Further, only an increase in activation was seen in E3-Dementia participants in the entire SMTG, whereas in the grey matter of the SMTG, only a diagnosis of dementia impacted activation. Specific microglial morphologies showed a reduction in ramified microglia in the dementia group. For rod microglia, a reduction was seen in E4-Control patients in the hippocampus whereas in the SMTG an increase was seen in E4-Dementia patients. These findings suggest an association between ApoE isoforms and microglial morphologies and highlight the importance of considering ApoE isoforms in studies of AD pathology., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Alzheimer disease (AD) is a neurodegenerative disease characterized by a cognitive decline leading to dementia. The most impactful genetic risk factor is apolipoprotein E (APOE). APOE-ε4 significantly increases AD risk, APOE-ε3 is the most common gene variant, and APOE-ε2 protects against AD. However, the underlying mechanisms of APOE-ε4 on AD risk remains unclear, with APOE-ε4 impacting many pathways. We investigated how the APOE isoforms associated with the neuroinflammatory state of the brain with and without AD pathology. Frozen brain tissue from the superior and middle temporal gyrus was analyzed from APOE-ε3/3 (n = 9) or APOE-ε4/4 (n = 10) participants with AD pathology and APOE-ε3/3 (n = 9) participants without AD pathology. We determined transcript levels of 757 inflammatory related genes using the NanoString Human Neuroinflammation Panel. We found significant pathways impaired in APOE-ε4/4-AD individuals compared to APOE-ε3/3-AD. Of interest, expression of genes related to microglial activation (SALL1), motility (FSCN1), epigenetics (DNMT1), and others showed altered expression. Additionally, we performed immunohistochemistry of P2RY12 to confirm reduced microglial activation. Our results suggest APOE-ε3 responds to AD pathology while potentially having a harmful long-term inflammatory response, while APOE-ε4 shows a weakened response to pathology. Overall, APOE isoforms appear to modulate the brain immune response to AD-type pathology., (© 2021 American Association of Neuropathologists, Inc. All rights reserved.)

Over the course of most common neurodegenerative diseases the amygdala accumulates pathologically misfolded proteins. Misfolding of 1 protein in aged brains often is accompanied by the misfolding of other proteins, suggesting synergistic mechanisms. The multiplicity of pathogenic processes in human amygdalae has potentially important implications for the pathogenesis of Alzheimer disease, Lewy body diseases, chronic traumatic encephalopathy, primary age-related tauopathy, and hippocampal sclerosis, and for the biomarkers used to diagnose those diseases. Converging data indicate that the amygdala may represent a preferential locus for a pivotal transition from a relatively benign clinical condition to a more aggressive disease wherein multiple protein species are misfolded. Thus, understanding of amygdalar pathobiology may yield insights relevant to diagnoses and therapies; it is, however, a complex and imperfectly defined brain region. Here, we review aspects of amygdalar anatomy, connectivity, vasculature, and pathologic involvement in neurodegenerative diseases with supporting data from the University of Kentucky Alzheimer's Disease Center autopsy cohort. Immunohistochemical staining of amygdalae for Aβ, Tau, α-synuclein, and TDP-43 highlight the often-coexisting pathologies. We suggest that the amygdala may represent an "incubator" for misfolded proteins and that it is possible that misfolded amygdalar protein species are yet to be discovered., (© 2017 American Association of Neuropathologists, Inc. All rights reserved.)

Understanding the pathophysiologic mechanisms underlying Alzheimer disease relies on knowledge of disease onset and the sequence of development of brain pathologies. We present a comprehensive analysis of early and progressive changes in a mouse model that demonstrates a full spectrum of characteristic Alzheimer disease-like pathologies. This model demonstrates an altered immune redox state reminiscent of the human disease and capitalizes on data indicating critical differences between human and mouse immune responses, particularly in nitric oxide levels produced by immune activation of the NOS2 gene. Using the APPSwDI(+)/(+)mNos2(-/-) (CVN-AD) mouse strain, we show a sequence of pathologic events leading to neurodegeneration,which include pathologically hyperphosphorylated tau in the perforant pathway at 6 weeks of age progressing to insoluble tau, early appearance of β-amyloid peptides in perivascular deposits around blood vessels in brain regions known to be vulnerable to Alzheimer disease, and progression to damage and overt loss in select vulnerable neuronal populations in these regions. The role of species differences between hNOS2 and mNos2 was supported by generating mice in which the human NOS2 gene replaced mNos2. When crossed with CVN-AD mice, pathologic characteristics of this new strain (APPSwDI(+)/(-)/HuNOS2(tg+)/(+)/mNos2(-/-)) mimicked the pathologic phenotypes found in the CVN-AD strain.

The APOE-ε4 allele correlates with increased risk of Alzheimer disease (AD) and increased parenchymal amyloid plaques. We tested how the APOE genotype correlated with cerebral amyloid angiopathy (CAA) by analyzing 371 brains for parenchymal and meningeal CAA in 4 brain regions (frontal, parietal, temporal, and occipital neocortex). The overall severity of CAA was highest in the occipital lobe. APOE-ε4/4 brains (n = 22) had the highest levels of CAA across regions. In the occipital lobe, nearly all APOE-ε4/4 cases were scored with the highest level of CAA (meninges, 95% of cases; parenchyma, 81%). In this brain region as in others, APOE-ε3/4 brains (n = 115) showed consistently less CAA than APOE-ε4/4 brains (meninges, 43%; parenchyma, 43%). APOE-ε3/3 brains (n = 182) showed even less CAA (meninges, 19%; parenchyma, 19%). Interestingly, APOE-ε2/3 cases (n = 42) had more CAA than APOE-ε3/3 (meninges, 44%; parenchyma, 32%), despite a reduced risk for AD in the APOE-ε2/3 individuals. APOE-ε4/4 brains also had the fewest regions without CAA, whereas APOE-ε3/3 brains had the most. Ordinal regression analyses demonstrated significant impacts of APOE-ε2 and APOE-ε4 on CAA at least in some brain regions. These data demonstrate that APOE genotype correlations with Aβ deposition in CAA only incompletely correspond to other AD-linked brain pathologies.