On November 3, 1906, at the 37th Meeting of South-West German Psychiatrists in Tübingen, Germany, clinical psychiatrist and neuroanatomist Alois Alzheimer reported “a peculiar severe disease process of the cerebral cortex." Alzheimer talked about a 51-year-old woman named Auguste Deter, whom he treated for paranoia, memory disturbance and confusion until her death five years after being admitted to the Institution for the Mentally Ill and Epileptics in Frankfurt. After performing a post-mortem, he noted distinctive plaques and neurofibrillary tangles in the brain.
Though not a household name, Auguste Deter is considered the first Alzheimer's patient. Her post-mortem revealed what are now established as the pathological hallmarks of Alzheimer's disease: tau tangles and amyloid plaque.
Today, according to the World Health Organization, more than 55 million people live with dementia worldwide. Alzheimer's contributes to 60–70% of cases1.
Tau and Amyloid Beta: It's complicated
“We know that amyloid comes first," says Dominic Walsh, Ph.D., Vice President and head of Biogen's Neurodegenerative Diseases Unit. “So, it's natural to think that amyloid drives tau pathology to some extent, but the relationship between the two is much more complex."
“While there is certainly a precursor-product relationship, we must not underestimate the role of tau in driving toxicity in amyloid beta (Aβ)," he says.
For years, Alzheimer's disease researchers focused on the two proteins separately, divided into two factions, says Dominic: the "baptists," who believed in the amyloid-beta hypothesis, and the "tauists," advocating for tau's role. Today, it is well understood that the two are interconnected. Indeed, for a person to be diagnosed with Alzheimer's disease (AD), both pathologies must be present.
While many neurological disorders are linked to abnormal tau protein accumulation, termed “tauopathies," what sets AD apart is the unique progression and distribution of tau in the brain.
Dominic Walsh, Ph.D., Vice President and head of Biogen's Neurodegenerative Diseases Unit
"Alzheimer's disease is one that we consider an Aβ-driven tauopathy," says Dominic. And while amyloid-beta plaques begin to form years before symptoms of AD begin to manifest, the appearance of tau tangles is more closely tied to symptom onset.
Tau accumulates in the form of large intracellular aggregates known as neurofibrillary tangles.
“They start in the entorhinal cortex, spread through the hippocampus into the medial temporal lobe, and then in the more cortical regions," says Dominic.
The pattern tau follows as it spreads through the brain “almost dictates the symptoms a patient presents with," he says.
"It starts in the regions of the brain that are most involved in learning and memory, so that's the first symptom that you see. As it spreads it affects regions that are involved in executive function, which is when you start seeing impairment in a person's ability to make good decisions," says Dominic.
Over the past few years, we have seen promising results from approved drugs targeting Aβ, with more expected to come. And according to Dominic, this is due to decades of work that focused on Aβ. These successes have reinvigorated a field that has been filled with disappointments for years.
But tau is much more complicated than Aβ, he says. “It is an intracellular protein with multiple binding partners. It also undergoes a host of post-translational modifications, making it challenging to pinpoint the precise form of the protein that causes the disease."
Tau acts both on an intracellular and extracellular level, can have a different negative effect when it is or isn't aggregated and can act as an enabler of certain forms of toxicity. And while its role under normal circumstances is not well understood, studies in animal models and data from human biobanks have shown that both animals and humans can thrive with reduced tau levels, free of any neurological disease.
For Dominic, who joined Biogen after spending much of his career in academic research, this complexity does not mean that it's not possible to develop potential treatments. In fact, this was the primary driver for him to make the move to industry.
“I believe that while there's more we can discover about the mechanism of the disease, I don't think that mechanistic understanding and understanding the precise toxic form of tau is necessary in order to develop effective therapies," he says. “We know that tau is a 'bad guy,' so we can focus on developing agents that can inhibit its expression. For me, it came down to the fact that I could continue to work on interesting things, untangling the unanswered questions, or I could work on something that could actually benefit people in the near term."
Two primary strategies that have emerged to date include antisense oligonucleotides (ASOs) and antibodies. ASOs enter cells and inhibit tau production at its source, potentially reducing tau's transfer between cells. In contrast, antibodies interact with tau outside the cell, requiring a precise understanding of the tau variant contributing to disease progression.
Our understanding of Alzheimer's disease has advanced significantly since Alois Alzheimer's discovery more than 100 years ago. “Biomarker and longitudinal studies have revolutionized the field," says Dominic. “Thanks to imaging, we now know that amyloid aggregates build up in the brain years before symptom onset."
If removing amyloid can potentially slow down the progression of the disease, then would removing tau stop progression altogether? And depending on whether there is a dynamic process within the cell that allows it to recover, could the disease reverse and lead to symptom improvement?
Answering these questions will require commitment, says Dominic.
“It will take multiple shots at the goal, but if we stick to our understanding of the disease and keep our focus on human biology, we will ultimately come up with multiple treatments that target tau and are efficacious for Alzheimer's disease," he says.