Tau Molecular Diversity Contributes to Clinical Heterogeneity of Alzheimer's Disease
Key findings
- This study investigated whether the characteristics of tau may differ among individuals with "typical" Alzheimer's disease
- In brain samples taken from 32 deceased subjects, there was marked person-to-person heterogeneity in tau bioactivity, conformation, and biochemical and biophysical properties
- Tau bioactivity correlated with the rate of cognitive decline as scored during life on the Clinical Dementia Rating scale
- The tau samples responded differently to a panel of diverse anti-tau antibodies, suggesting that individualized anti-tau immunotherapy might someday be possible
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Tauopathies such as progressive supranuclear palsy, Pick's disease and Alzheimer's disease (AD) are characterized by seeding (aggregation) of tau protein into disease-specific conformations in the brain. During the course of AD, tau can undergo a variety of modifications, including phosphorylation.
In a report published in Nature Medicine, Bradley T. Hyman, MD, PhD, director of the Alzheimer’s disease research unit at the MassGeneral Institute for Neurodegenerative Disease (MIND), and Simon Dujardin, PhD, a research fellow in his laboratory at Massachusetts General Hospital, and colleagues report that characteristics of phosphorylated tau differ not just between tauopathies but also within AD, and these differences may explain the clinical heterogeneity of the disease.
Study Details
Study subjects included 32 people who were diagnosed with "typical" AD before and after death. Over a minimum of three annual research visits at Mass General, they had completed the Clinical Dementia Rating (CDR) scale. The researchers extracted and evaluated tau from each participant's frontal cortices.
Results
There was marked person-to-person heterogeneity in:
- Tau seeding bioactivity (amount of seeding per unit of tau), with differences up to tenfold
- Tau conformation
- Biochemical and biophysical properties of tau
Some post-translational modification sites, although not all, were associated with both greater tau seeding and worse clinical outcomes. They also found that the greater the tau bioactivity, the greater the rate of clinical AD progression (CDR sum of boxes score).
A Potential Therapeutic Strategy
Suppression of tau has been proposed as a therapeutic strategy in AD. In 15 of the 32 subjects, the researchers explored immunotherapy with seven commercially available antibodies that recognize a range of tau epitopes.
None of the antibodies fully depleted tau bioactivity in subject samples, but those that recognize pathologic forms of tau were the most consistently effective.
In many forms of cancer, the recognition of different molecular drivers has made it possible to devise individualized therapeutic approaches. AD, too, may have different molecular drivers, and subclassification of patients may someday enable personalized medicine for them as well.
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