Fig. 4

Hypothesized intersection of amyloid-β and tau pathology in cortex and their influence on soluble p-tau release into plasma. We propose parallel processes occur for amyloid-β plaque (Left) and neurofibrillary tangle (Right) pathologies with an intersection (Middle) in the AD brain that impacts phospho-tau release into plasma. The hypothesized intersection is influenced by data from the cortex and may not apply to limbic regions, as the current study and others [49] observed a weaker relationship between limbic neuropathology and plasma p-tau levels. Plaque-mediated route: The locus coeruleus is highly vulnerable in the AD brain and is considered the earliest site of phospho-tau accumulation [50]. This noradrenergic hub nucleus (mid-sagittal brain, blue spot) sends projections throughout the brain [43] and is thought to influence amyloid-β plaque deposition through a mechanistic effect on glial disturbance [44]. Based upon available evidence that amyloid-β deposition induces a hyperactivation of neurons [51, 52], we speculate that the amyloid-β-mediated impact on soluble p-tau release is a result of increased neuronal activity that stimulates and enhances release of p-tau into the extracellular space [53, 54]. The association observed in the current study between lower locus coeruleus neuron counts and higher plasma p-tau levels is hypothesized to be mediated through noradrenergic deficiencies leading to increased leakage of blood-brain barrier [55] enhancing release of p-tau into plasma. Tangle-mediated route: The nucleus basalis of Meynert acts as a cholinergic hub (coronal brain, pink spot) that supplies acetylcholine to the cortex and is thought to influence cortical tangle accumulation through cholinergic deficiencies leading to neuronal dysfunction [45, 46, 56]. We did not observe an association between nucleus basalis of Meynert neuron count and plasma p-tau levels, which may suggest the resultant neuronal dysfunction from decreased acetylcholine does not affect p-tau release. The current study and others [4, 49] observed a strong relationship between severity of neurofibrillary tangle accumulation and plasma p-tau, which we speculate may result from neuronal injury [57] as tangles mature through their lifespan [58, 59]. Amyloid-β plaque accumulation does not associate with cognitive decline when accounting for tau pathology [60, 61], however we and others previously showed plasma p-tau to associate with cognitive decline [1, 3, 8, 9, 47, 48]. To evaluate both neuropathologic and soluble plasma p-tau contribution to cognitive decline, the current study utilized regression modeling. The results suggest that underlying tangle accumulation in the brain (Braak stage), but neither amyloid-β deposition (Thal phase) nor soluble plasma p-tau levels predict cognitive decline when modeled simultaneously. Acronyms: Aβ amyloid-β, AD Alzheimer’s disease, LC locus coeruleus, nbM nucleus basalis of Meynert, p-tau phosphorylated tau, T threonine. Created with BioRender.com