Assessing amyloid-β, tau, and glial features in Lothian Birth Cohort 1936 participants post-mortem

Tzioras, Makis; Easter, Jacqueline; Harris, Sarah E.; McKenzie, Chris-Anne; Smith, Colin; Deary, Ian J.; Henstridge, Christopher M.; Spires‐Jones, Tara L.

doi:10.19185/matters.201708000003

Cited by 3 publications

(6 citation statements)

References 44 publications

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“…Other than for AgeAccel Grim , epigenetic age acceleration was found to be significantly higher in the hippocampus than in BA17. Reactive microglial burdens, identified through CD68 immunostaining, were additionally found to be higher in the hippocampus, consistent with previous findings in a smaller sample of the LBC1936 cohort (Tzioras et al, 2017). However, the only association identified between the DNAm signatures (age acceleration or inflammation proxies) and microglial load was a positive association with the mean brain-based DNAm AgeAccel Pheno .…”

Section: Discussionsupporting

confidence: 90%

A comparison of blood and brain‐derived ageing and inflammation‐related DNA methylation signatures and their association with microglial burdens

Stevenson

McCartney

Gadd

et al. 2022

Eur J of Neuroscience

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Inflammation and ageing-related DNA methylation patterns in the blood have been linked to a variety of morbidities, including cognitive decline and neurodegenerative disease. However, it is unclear how these blood-based patterns relate to patterns within the brain and how each associates with central cellular profiles. In this study, we profiled DNA methylation in both the blood and in five post mortem brain regions (BA17, BA20/21, BA24, BA46 and hippocampus) in 14 individuals from the Lothian Birth Cohort 1936. Microglial burdens were additionally quantified in the same brain regions. DNA methylation

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Section: Discussionsupporting

confidence: 90%

A comparison of blood and brain‐derived ageing and inflammation‐related DNA methylation signatures and their association with microglial burdens

Stevenson

McCartney

Gadd

et al. 2022

Eur J of Neuroscience

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“…Interestingly, these age-associated astrocyte changes were reduced in mice lacking microglial secreted cytokines, indicating important interactions between microglia and astrocytes during ageing 55 . In support of the translational relevance of these age-associated changes observed in mice, we observed differences in the distribution of microglia and astrocytes in different brain regions in healthy aged human brain 56 , suggesting that regional differences in the ageing of glia could contribute to selective vulnerability in age-related neurodegenerative diseases such as AD. In a recent mouse study profiling the translatome of microglia, ageing, APP/PS1 overexpression and P301L tau overexpression all induced a similar network of translational changes strongly implicating APOE in driving a network of changes resulting in production of the cytokines CCL3 and CCL4 (REF.…”

Section: Inflammation and The Immune Responsesupporting

confidence: 67%

“…Non-demented individuals from the Lothian Birth Cohort in their ninth decade oflife exhibit a faster rate of cognitive decline if they are APOE4 positive than those with APOE2 or APOE3 alleles 136 . Future work on the well-characterized Lothian Birth Cohort subjects will help to clarify the role of factors such as APOE in cognitive ageing through deep phenotyping of genetic, psychosocial and neuropathological factors 56,137,138 .…”

Section: Cellular Interactions In Synapse Lossmentioning

confidence: 99%

Beyond the neuron–cellular interactions early in Alzheimer disease pathogenesis

2019

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The symptoms of Alzheimer disease reflect a loss of neural circuit integrity in the brain, but neurons do not work in isolation. Emerging evidence suggests that the intricate balance of interactions between neurons, astrocytes, microglia and vascular cells required for healthy brain function becomes perturbed during the disease, with early changes likely protecting neural circuits from damage, followed later by harmful effects when the balance cannot be restored. Moving beyond a neuronal focus to understand the complex cellular interactions in Alzheimer disease and how these change throughout the course of the disease may provide important insight into developing effective therapeutics.

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“…Several pathological changes in the brain, typically seen in Alzheimer’s disease (AD) can also be observed in late-adulthood individuals without dementia. Post-mortem studies of those without dementia report the accumulation of hyperphosphorylated tau into neurofibrillary tangles, the build-up of amyloid-beta (Aβ) into plaques 5 , 6 and the presence of GFAP (reflecting neuroinflammation). 6 , 7 Biomarkers reflecting the pathological hallmarks of Alzheimer’s disease 8-10 such as plasma phosphorylated tau 181 (p-tau181) and plasma Aβ (both Aβ40, Aβ42 and the Aβ42/40 ratio) have been investigated as biomarkers associated with cognitive function.…”

Section: Introductionmentioning

confidence: 99%

“…Post-mortem studies of those without dementia report the accumulation of hyperphosphorylated tau into neurofibrillary tangles, the build-up of amyloid-beta (Aβ) into plaques 5 , 6 and the presence of GFAP (reflecting neuroinflammation). 6 , 7 Biomarkers reflecting the pathological hallmarks of Alzheimer’s disease 8-10 such as plasma phosphorylated tau 181 (p-tau181) and plasma Aβ (both Aβ40, Aβ42 and the Aβ42/40 ratio) have been investigated as biomarkers associated with cognitive function. Plasma p-tau181 levels are elevated in AD relative to controls, 11 , 12 and studies report a negative correlation with cognitive function across the Alzheimer’s-spectrum.…”

Section: Introductionmentioning

confidence: 99%

Predictive blood biomarkers and brain changes associated with age-related cognitive decline

Saunders

Pozzolo

Heslegrave

et al. 2023

Brain Communications

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Growing evidence supports the use of plasma levels of tau phosphorylated at threonine 181 (p-tau181), amyloid-β, neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) as promising biomarkers for Alzheimer’s disease. While these blood biomarkers are promising for distinguishing people with Alzheimer’s disease from healthy controls, their predictive validity for age-related cognitive decline without dementia remains unclear. Further, while p-tau181 is a promising biomarker, the distribution of this phospho-epitope of tau in the brain is unknown. Here, we tested whether plasma levels of p-tau181, amyloid-β, NfL, and GFAP predict cognitive decline between ages 72 and 82 in 195 participants in the Lothian Birth Cohorts 1936 study of cognitive ageing. We further examined post-mortem brain samples from temporal cortex to determine the distribution of p-tau181 in the brain. Several forms of p-tau have been shown to contribute to synapse degeneration in Alzheimer’s disease, which correlates closely with cognitive decline in this form of dementia, but to date there have not been investigations of whether p-tau181 is found in synapses in Alzheimer’s disease or healthy ageing brain. It was also previously unclear whether p-tau181 accumulated in dystrophic neurites around plaques which could contribute to tau leakage to the periphery due to impaired membrane integrity in dystrophies. Brain homogenate and biochemically enriched synaptic fractions were examined with western blot to examine p-tau181 levels between groups (n = 10-12 per group), and synaptic and astrocytic localisation of p-tau181 were examined using array tomography (n = 6-15 per group), and localisation of p-tau181 in plaque-associated dystrophic neurites with associated gliosis were examined with standard immunofluorescence (n = 8-9 per group). Elevated baseline plasma p-tau181, NfL, and GFAP predicted steeper general cognitive decline during ageing. Further, increasing p-tau181 over time predicted general cognitive decline in females only. Change in plasma p-tau181 remained a significant predictor of g factor decline when taking into account Alzheimer’s disease polygenic risk score, indicating the increase of blood p-tau181 in this cohort was not only due to incipient Alzheimer’s disease. P-tau181 was observed in synapses and astrocytes in both healthy ageing and Alzheimer’s disease brain. We observed that a significantly higher proportion of synapses contain p-tau181 in Alzheimer’s disease relative to aged controls. Aged controls with pre-morbid lifetime cognitive resilience had significantly more p-tau181 in GFAP-positive astrocytes than those with pre-morbid lifetime cognitive decline. Further, p-tau181 was found in dystrophic neurites around plaques and in some neurofibrillary tangles. The presence of p-tau181 in plaque-associated dystrophies may be a source of leakage of tau out of neurons that eventually enters the blood. Together, these data indicate that plasma p-tau181, NfL, and GFAP may be useful biomarkers of age-related cognitive decline, and that efficient clearance of p-tau181 by astrocytes may promote cognitive resilience.

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Assessing amyloid-β, tau, and glial features in Lothian Birth Cohort 1936 participants post-mortem

Cited by 3 publications

References 44 publications

A comparison of blood and brain‐derived ageing and inflammation‐related DNA methylation signatures and their association with microglial burdens

A comparison of blood and brain‐derived ageing and inflammation‐related DNA methylation signatures and their association with microglial burdens

Beyond the neuron–cellular interactions early in Alzheimer disease pathogenesis

Predictive blood biomarkers and brain changes associated with age-related cognitive decline

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