One of the many challenges presented by Alzheimer’s disease is that different patients decline at very different rates. A recent study suggests differences in tau, the protein that makes up the neurofibrillary tangles in Alzheimer’s pathology, may help explain this observation between individuals. Among the authors are two members of the Cure Alzheimer’s Fund Research Leadership Group—Dr. Bradley Hyman, who led the research, and Dr. Rudy Tanzi, both of Massachusetts General Hospital. The results appeared in the August 2020 issue of Nature Medicine.
Scientists have recognized that the development of symptoms of the disease correlates better with the accumulation of tau tangles than with the accumulation of amyloid-beta plaques, which typically peaks before symptoms emerge. Previous reports have shown that while amyloid-beta plaques are present as early as 20 years before Alzheimer’s symptoms appear, tau tangle appear and spread coincident with the progression of cognitive decline.
Now, thanks to the study detailed in the Nature Medicine report, clues emerge as to why some people deteriorate faster than others. The researchers had a cohort of generous patients who shared their clinical history, undertook regular cognitive testing, and donated their brains after they died. Thanks to this group, the researchers were able to closely study the disease progression of 32 patients with “typical AD”: the participants had an Alzheimer’s diagnosis, confirmed with pathology after they died—i.e., amyloid plaques and extensive tau tangles. They found striking variability in age of onset of the disease, rate of decline, and the number of years the participants lived with Alzheimer’s disease. Among these 32 individuals, the age of onset ranged between 45 and 81 years, and the time spent with the disease until death also varied from as little as five years to as many as 19 years. The patients’ rate of cognitive decline was evaluated through annual neuropsychological testing, called the clinical dementia rating scale sum of boxes (CDR-SOB). The test provided a score with a range of zero for no cognitive impairment to a maximum of 18 for severe dementia. Within the group of 32 patients, some individuals reached the maximum score in as few as six years and others in as many as 17 years; however, in a few, the rate of decline was prolonged, and cognition never worsened to the maximum score.
To determine if disease progression correlated with the state of tau protein, the researchers performed a series of biochemical experiments on tau from each participant’s postmortem samples. Previous research has shown that misfolded tau – such as the tau in Alzheimer’s neurofibrillary tangles – can trigger otherwise structurally healthy tau to misfold in turn. Drs. Hyman and Tanzi sought to assess whether tau from different patients with different disease trajectories might differ in its capacity to affect other tau in this manner.
The results suggest that tau indeed had variable seeding ability as judged by a biosensor assay: i.e., in samples from some patients, diseased tau was better at attracting and aggregating otherwise non-diseased tau from the assay. Patients with the APOE4 genetic variant—the strongest genetic risk factor for AD—had tau with high seeding capabilities. The researchers also found that more vigorous seeding activity correlated with a steeper rate of decline, as determined by the CDR-SOB test; high seeding and steeper rate of decline also had a relationship to younger onset of Alzheimer’s disease.
As the scientists further explored why some forms of tau can be more effective at seeding than others, they found that variations in certain modifications of the tau protein appeared to associate with higher seeding activity and worse clinical outcomes.
To demonstrate the future translational value of their findings, the scientists tested commercially available lab tau antibodies in cell culture models for their ability to reduce tau seeding; some antibodies were more effective than others, suggesting they bound preferentially to the forms of tau more likely to cause tangles. This result has potential implications for future anti-tau immunotherapy.
Identifying differences in tau among patients and the impact on the rates of the severity of the progression of Alzheimer’s sheds light on the potential for better prognostics and personalized therapy in the fight against the disease. Much like in the treatment of cancer, where individual therapies are targeted to each specific patient, this paper puts forward the notion that future therapies for Alzheimer’s disease may require approaches customized for each individual.
For further reading about the study, please check out the AlzForum coverage following this link: