Alzheimer's disease is a condition characterized by amyloid aggregation, chronic inflammation in brain tissue, and tau aggregation, these aspects of the condition progressing at different paces and interacting with one another in complex ways that are yet to be fully understood. Amyloid aggregation is widely thought to be the initial, triggering pathology. Tau aggregation is found in the later stages of Alzheimer's disease, once cell death begins in earnest, and the evidence suggests that this form of pathology is driven by chronic inflammation in the brain. Removal of senescent supporting cells in the brain, thereby reducing inflammatory signaling, can reverse tau aggregation in mouse models of the condition, for example.
The failure of treatments that clear amyloid aggregates to improve patient outcomes in clinical trials has led to a growing debate over how the various aspects of Alzheimer's disease fit together to produce the progression from mild cognitive impairment to full blown dementia. Perhaps amyloid is a side-effect of chronic inflammation, or simply no longer important to the progression of the condition once matters have progressed to the point of sustained inflammation and tau aggregation. Researchers are now looking more closely at addressing chronic inflammation and tau aggregation either instead of or in addition to clearance of amyloid. The evidence, such as that noted below, continues to support this change in strategy.
Many researchers are now taking a second look at tau protein, once dismissed as simply a "tombstone" marking dying cells, and investigating whether tau may in fact be an important biological driver of Alzheimer's disease. In contrast to amyloid, which accumulates widely across the brain, sometimes even in people with no symptoms, autopsies of Alzheimer's patients have revealed that tau is concentrated precisely where brain atrophy is most severe, and in locations that help explain differences in patients' symptoms (in language-related areas vs. memory-related regions, for example).
"No one doubts that amyloid plays a role in Alzheimer's disease, but more and more tau findings are beginning to shift how people think about what is actually driving the disease. Still, just looking at postmortem brain tissue, it has been hard to prove that tau tangles cause brain degeneration and not the other way around. One of our group's key goals has been to develop non-invasive brain imaging tools that would let us see whether the location of tau buildup early in the disease predicts later brain degeneration."
Researchers recruited 32 participants with early clinical stage Alzheimer's disease, all of whom received PET scans using two different tracers to measure levels of amyloid protein and tau protein in their brains. The participants also received MRI scans to measure their brain's structural integrity, both at the start of the study, and again in follow-up visits one to two years later.
The researchers found that overall tau levels in participants' brains at the start of the study predicted how much degeneration would occur by the time of their follow up visit (on average 15 months later). Moreover, local patterns of tau buildup predicted subsequent atrophy in the same locations with more than 40 percent accuracy. In contrast, baseline amyloid-PET scans correctly predicted only 3 percent of future brain degeneration. "Seeing that tau buildup predicts where degeneration will occur supports our hypothesis that tau is a key driver of neurodegeneration in Alzheimer's disease."
β-Amyloid plaques and tau-containing neurofibrillary tangles are the two neuropathological hallmarks of Alzheimer's disease (AD) and are thought to play crucial roles in a neurodegenerative cascade leading to dementia. Both lesions can now be visualized in vivo using positron emission tomography (PET) radiotracers, opening new opportunities to study disease mechanisms and improve patients' diagnostic and prognostic evaluation.
In a group of 32 patients at early symptomatic AD stages, we tested whether β-amyloid and tau-PET could predict subsequent brain atrophy measured using longitudinal magnetic resonance imaging acquired at the time of PET and 15 months later. Quantitative analyses showed that the global intensity of tau-PET, but not β-amyloid-PET, signal predicted the rate of subsequent atrophy, independent of baseline cortical thickness. Additional investigations demonstrated that the specific distribution of tau-PET signal was a strong indicator of the topography of future atrophy at the single patient level and that the relationship between baseline tau-PET and subsequent atrophy was particularly strong in younger patients.
This data supports disease models in which tau pathology is a major driver of local neurodegeneration and highlight the relevance of tau-PET as a precision medicine tool to help predict individual patient's progression and design future clinical trials.