Cerebrovascular disease promotes tau pathology in Alzheimer’s disease

Abstract

Small vessel cerebrovascular disease, visualized as white matter hyperintensities on T2-weighted MRI, contributes to the clinical presentation of Alzheimer’s disease. However, the extent to which cerebrovascular disease represents an independent pathognomonic feature of Alzheimer's disease or directly promotes Alzheimer’s pathology is unclear. The purpose of this study was to examine the association between white matter hyperintensities and plasma levels of tau and to determine if white matter hyperintensities and tau levels interact to predict Alzheimer’s disease diagnosis. To confirm that cerebrovascular disease promotes tau pathology, we examined tau fluid biomarker concentrations and pathology in a mouse model of ischemic injury. Three hundred ninety-one participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI; 74.5 ± 7.1 years of age) were included in this cross-sectional analysis. Participants had measurements of plasma total-tau, CSF beta amyloid, and white matter hyperintensities, and were diagnosed clinically as Alzheimer’s disease (n = 97), mild cognitive impairment (n = 186), or cognitively normal control (n = 108). We tested the relationship between plasma tau concentration and white matter hyperintensity volume across diagnostic groups. We also examined the extent to which white matter hyperintensity volume, plasma tau, amyloid positivity status, and the interaction between white matter hyperintensities and plasma tau correctly classifies diagnostic category. Increased white matter hyperintensity volume was associated with higher plasma tau concentration, particularly among those diagnosed clinically with Alzheimer’s disease. Presence of brain amyloid and the interaction between plasma tau and white matter hyperintensity volume distinguished Alzheimer’s disease and mild cognitive impairment participants from controls with 77.6% and 63.3% accuracy, respectively. In 63 ADNI participants who came to autopsy (82.33 ± 7.18 age at death) we found that higher degrees of arteriosclerosis were associated with higher Braak staging, indicating a positive relationship between cerebrovascular disease and neurofibrillary pathology. In a transient middle cerebral artery occlusion (tMCAo) mouse model, aged mice that received tMCAo, but not sham surgery, had increased plasma and CSF tau concentrations, induced myelin loss, and hyperphosphorylated tau pathology in the ipsilateral hippocampus and cerebral hemisphere. These findings demonstrate a relationship between cerebrovascular disease, operationalized as white matter hyperintensities, and tau levels, indexed in the plasma, suggesting that hypoperfusive injury promotes tau pathology. This potential causal association is supported by the demonstration that transient cerebral artery occlusion induces white matter damage, increases biofluidic markers of tau, and promotes cerebral tau hyperphosphorylation in older adult mice.

Impairments in Brain Bioenergetics in Aging and Tau Pathology: A Chicken and Egg Situation?

“…No changes were detected regarding Aβ pathology. Similar observations were done in AD patients, in which cerebral hypoperfusion appeared to have a causative link with tau pathology but not Aβ pathology [47,48]. Intriguingly, brain aging is also marked by hypoperfusion due to the decrease in cerebral blood flow and the loss of BBB integrity [12][13][14], which may lead to deficits in nutrient import, including glucose, into the brain.…”

“…Evidence has been linking disturbances in brain metabolism and tau pathology. For instance, studies have shown that cerebral hypoperfusion, which impairs brain energy metabolism, leads to an increase in tau abnormal phosphorylation in different animal models [45][46][47]. In the 3xTgAD model of AD, cerebral hypoperfusion (caused by unilateral common carotid artery occlusion) induced a significant increase in tau phosphorylation in the hippocampus of 3-month-old animals compared to controls (sham-operated mice) [45].…”

Involvement of cerebrovascular abnormalities in the pathogenesis and progression of Alzheimer’s disease: an adrenergic approach

“…Brain amyloid burden and the interaction between plasma tau and white matter of hyperintensity could distinguish AD and MCI patients from controls, with accuracies as 77.6% and 63.3%, respectively. Moreover, increased tau levels in plasma and CSF and hyperphosphorylated tau level in the ipsilateral hippocampus and cerebral hemisphere were observed in aged mice subjected to transient focal cerebral ischemia [ 68 ]. All these findings suggested cerebrovascular dysfunctions could induce and promote tau pathology in AD.…”

Choriocapillaris Changes Are Correlated With Disease Duration and MoCA Score in Early-Onset Dementia

“…Moreover, EOD is a good model to study the factors interacting with both dementia and the aging process, such as the vascular factor, whose contribution is often questioned in the dementia pathogenesis since the vessels are also undergoing degeneration during the aging process. Recent reports (Zlokovic, 2011;Laing et al, 2020) have shown that microvascular influences affecting cerebral microcirculation may contribute to the pathogenesis of dementia. Reports have also suggested that decreased cerebral blood flow occurs before the onset of clinical dementia which was trailed by decreased amyloid-beta clearance resulting in neurotoxicity (Kalaria et al, 2012; making the possibility of vascular factor as a pre-clinical dementia biomarker.…”