Alzheimer's disease is both an amyloidosis and a tauopathy. The dysfunction and death of neurons is driven by rising levels of amyloid-β and altered forms of tau, both of which form solid deposits in brain tissue. The accumulation of misfolded proteins and metabolic waste in this way is characteristic of aged tissues and happens to everyone, but in Alzheimer's patients the process is far more pronounced, the solid aggregates far more abundant. The relationship between these aggregates and the death of neurons is very complex, and at some levels the details still much debated, involving a cascade of intermediary interactions and proteins. There is plenty of room for new theory and new discoveries. In an open access paper I noticed recently, and linked below, researchers provide evidence for the progression of Alzheimer's to be more than just an additive consequence of amyloid and, separately, tau. The two forms of aggregrate and the consequences of their presence interact with one another to make the outcome worse than that.
This should probably not be all that surprising. All of our biological systems interact with one another, directly and indirectly, and at all scales, whether considering nanoscale processes inside a single cell or macroscopic process linking the behaviors of organs. Consider the effects of changing blood pressure and the number of different organs impacted, for example. When it comes to the forms of cell and tissue damage that cause aging, these too interact with one another. To pick one example, the declining effectiveness of the immune system accelerates the contribution of cellular senescence to aging, allowing ever more of these unwanted cells to linger rather than be destroyed. In turn senescent cells create greater levels of chronic inflammation, making the immune system more dysfunctional than it would otherwise be. Similar interactions are either known or there to be found between other classes of damage: mitochondrial DNA deletions; cross-linking in the extracellular matrix; and so forth. This synergy between forms of damage, creating a downward spiral of accelerating malfunction and breakage, is prevalent in all complex systems, not just in our biology.
What does all this mean for ongoing work on producing a viable therapy for Alzheimer's disease? It is already clear that both amyloid-β and tau aggregates should be cleared, with amyloid clearance somewhat ahead of tau clearance at the present time. The dominant strategy of immunotherapy has proven to be a far greater challenge to implement than desired, with the first tangible, promising results in human trails only recently achieved. One thing to consider is that, depending on the degree of synergy, the first successful therapy for amyloid-β clearance may be more effective than hoped, even though it leaves all of the tau in place. It may also mean that a combination of poor therapies that only partially impact both amyloid-β and tau might be worth trying, even though each on its own isn't effective enough to move beyond trials. That said, one of the other major challenges in treat Alzheimer's is that more than half of the patients suffer from other forms of dementia as well, commonly vascular dementia, and that distinct pathology may well mask many of the benefits produced by clearance of amyloid or tau. Repairing the later stages of neurodegeneration is a challenging business, all things considered.
Alzheimer disease (AD) is characterized by the progressive accumulation of extracellular amyloid-β (Aβ) plaques, intracellular inclusions of hyperphosphorylated tau in tangles, and neuronal degeneration. The most widely accepted model of AD progression proposes a cascade of neuropathological events in which abnormal levels of Aβ, neurofibrillary tangles, and neurodegeneration precede dementia. The idea of pathophysiological progression was incorporated by the criterion for predementia phase of AD, which recognizes that the coexistence of abnormal Aβ and neurodegeneration biomarkers better identify mild cognitive impairment (MCI) patients who will progress to dementia. This notion has been supported by recent observations demonstrating that MCI Aβ+ individuals with neurodegenerative changes have higher rates of neuropsychological decline as compared with MCI biomarker negative participants. Yet a key question that remains unanswered is whether the highest rate of progression to dementia in MCI Aβ+ individuals with downstream cascade abnormalities is due to a synergistic effect between the coexistent brain pathologies or simply the sum of their deleterious effects.
Given the emphasis of the current literature on the combination of Aβ and neuronal degeneration biomarkers, the clinical fate of MCI patients with abnormal Aβ plus p-tau proteins is scarcely known. The importance of characterizing the synergistic effect between Aβ and p-tau on the development of dementia goes beyond the understanding of the mechanisms of disease progression. Determination of such synergism has immediate implications for the population enrichment of clinical trials testing anti-amyloid or anti-tau therapy. For example, if Aβ and p-tau synergistically determine dementia, the enrichment of clinical trial populations with carriers of both pathologies would increase the rate of clinical progression without loss of therapeutic effectiveness. Conversely, if Aβ and p-tau simply add their deleterious effects on cognitive decline, carriers of both pathologies would lead to a reduced therapeutic effectiveness of an intervention targeting only one of these proteinopathies, given the residual effect of the untreated protein on the clinical course of the disease.
Although several studies have shown that Aβ and p-tau independently predict disease progression, a hypothetical framework proposes that both proteinopathies synergistically potentiate downstream neurodegeneration. The presence of such a synergism would suggest that the effect of Aβ and p-tau on the progression of AD taken together is greater than the sum of their separate effects at the same level. In fact, recent findings from our laboratory support this framework showing that the synergistic effect between brain Aβ and p-tau rather than neurodegeneration drives AD-related metabolic decline in a cognitively normal population. Similarly, in vivo studies conducted in controls have suggested that p-tau modulates the link between Aβ and brain atrophy or behavioral changes, whereas animal model literature has demonstrated a synergistic effect between Aβ and p-tau peptides, leading to downstream synaptic and neuronal dysfunctions.
Here, in a longitudinal analysis conducted in amnestic MCI individuals, we tested the hypothesis that the synergism between Aβ aggregation and tau hyperphosphorylation determines progression from amnestic MCI to AD dementia. In this study, we found that amnestic MCI Aβ+/p-tau+ individuals had the highest rate of cognitive decline and progression to dementia, as compared to all other biomarker groups. Remarkably, our regression models confirmed that a synergistic rather than additive effect between Aβ and p-tau determined greater cognitive decline and clinical progression in amnestic MCI Aβ+/p-tau+. Furthermore, we found that only among amnestic MCI Aβ+/p-tau+ individuals, did the baseline values of Aβ and p-tau biomarkers predict cognitive and clinical impairments.
Overall, our results suggest the synergism between Aβ and p-tau as an important element involved in the progression from amnestic MCI to AD dementia. This finding extends previous studies conducted in cognitively normal persons demonstrating that the synergism between Aβ and p-tau determines functional and structural abnormalities. This study revealed that the link between Aβ levels and progression to AD dementia depends on the p-tau status. This finding sheds light on the literature showing conflicting results reporting the association between Aβ and cognition. From a clinical perspective, if replicated, such a synergism has important implications in understanding the dynamics of progression to dementia. From a therapeutic perspective, one can derive important predictions from the existence of a synergistic interaction between Aβ and p-tau in AD. For example, one can predict that therapeutic interventions targeting either Aβ or p-tau pathology might similarly mitigate AD progression. Furthermore, the same synergistic model implies better effectiveness of a combined therapeutic approach targeting both, Aβ and p-tau, pathological pathways.