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

Abstract

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.

Human astrocytes and microglia show augmented ingestion of synapses in Alzheimer’s disease via MFG-E8

“…We also assessed internalization of synapses by microglia using Syn1 colocalization with the microglial lysosomal marker CD68 ( Figure 2 A), which was also confirmed by super-resolution Airyscan microscopy ( Figure S1 E). CD68 labels both microglia and macrophages, and in the cortical neuropil regions examined from our cases, we observed that CD68-positive cells were also positive for IBA1 and the microglial marker TMEM119 24 , 25 ( Figure S1 G). We found a significant increase in the volume of colocalization between CD68 and Syn1 in AD compared with aged controls (p = 0.0024) and in AD compared with midlife controls (p = 0.0096), suggesting increased synaptic ingestion by microglia in disease ( Figure 2 B).…”

“…Interestingly, women had significantly more synaptic ingestion by astrocytes when normalized to GFAP burden (p = 0.015). To confirm synaptic ingestion by astrocytes with a sub-diffraction limit technique, we re-analyzed a recently published array tomography dataset, 24 and confirmed at sub-synaptic resolution that synapses are within GFAP-positive astrocytes ( Figures S1 J and S1K).

Figure 1 Astrocytes ingest more synapses in Alzheimer’s disease compared with midlife and aged controls (A) Confocal images of immunostaining with orthogonal views (left) and three-dimensional reconstructions of stacks (right) of midlife control, aged control, and Alzheimer’s disease showing ingestion of synapsin 1 (Syn1, green) by astrocytes (GFAP, magenta) in human brain sections.

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Considerations for biomarker strategies in clinical trials investigating tau-targeting therapeutics for Alzheimer’s disease

“…This suggests that further evidence is required to establish what these biomarkers truly represent and their utility as surrogate biomarkers with degree of reduction required in the specific context of each therapeutic modality, epitope and mechanism of action (discussed in further sections of this review). Recent evidence suggests that some phosphorylated tau fluid biomarkers may in part reflect synaptic dysfunction via accumulation and release of oligomeric phosphorylated tau, and also plaque-associated dystrophic neurites that contain oligomeric phosphorylated tau [ 71 , 72 ].…”

Towards early diagnosis of Alzheimer’s disease: advances in immune-related blood biomarkers and computational approaches

“…In addition, it has been shown that GFAP levels in both CSF and plasma correlate with cognitive and biological measures of AD progression. For instance, elevated plasma and GFAP levels are associated with lower cognitive performance and steeper cognitive decline ( 59 , 60 ). Moreover, recent studies have shown that higher GFAP plasma levels correlate particularly with amyloid burden measured both by CSF and amyloid-PET quantification in opposition to Tau burden ( 46 , 61 , 62 ).…”