Tau tangles predicted the location of brain atrophy in people with mild Alzheimer’s disease a year in advance, a small longitudinal imaging study showed.
Baseline tau PET patterns in people with early symptomatic Alzheimer’s predicted how much neurodegeneration would occur a median of 15 months later, reported Renaud La Joie, PhD, of the University of California San Francisco (UCSF), and co-authors.
The match between baseline tau and subsequent neurodegeneration patterns was “remarkably predictive, not only at the group level, but at the individual patient level,” noted co-author Gil Rabinovici, MD, also of UCSF.
“You could predict where atrophy would occur from patient to patient in a very specific way,” he told MedPage Today. “We think this provides evidence that tau is actually spreading upstream of neurodegeneration and a major driver of Alzheimer’s disease.”
The study involved 32 patients in early clinical stages of Alzheimer’s disease who had mild cognitive impairment or mild dementia and a positive amyloid-beta scan. All patients had structural MRI and positron emission tomography (PET) with Pittsburgh compound B to determine amyloid and flortaucipir to assess tau at the baseline visit and a second MRI at follow-up a median of 15 months later. Average age was 64 at baseline; 21 participants were women and 11 were men.
At the group level, longitudinal atrophy was greater in regions that had higher baseline tau. These patients also developed more severe cortical atrophy, independent of baseline cortical thickness.
Tau patterns predicted about 40% of subsequent atrophy — “a very strong number when you’re looking at neuroimaging correlates,” Rabinovici said — and predictive value differed by age.
“Among people who had an early age of onset of Alzheimer’s disease, the predictive value of tau approached nearly 60%,” Rabinovici noted. “It may be that younger patients have a purer form of Alzheimer’s disease with less co-pathologies.”
The predictive value of amyloid was not significant at this stage of Alzheimer’s disease. “There’s obviously been a lot of focus on amyloid as the cause of Alzheimer’s disease and the primary drug target,” Rabinovici noted. “But it’s been known for several decades that the clinical symptoms of the disease correlate much more strongly with the distribution burden of neurofibrillary tangles than they do with amyloid plaques.”
“The major controversy is whether tau tangles are just representative of cell dysfunction and neuron death — are they just tombstones? — or whether they are really a driver of the disease,” he added. “With tau imaging, we can test these questions prospectively in vivo.”
Because brain atrophy is linked closely to clinical disease progression, the findings “are encouraging for the potential use of tau PET for personalized medicine approaches and for improving clinical trials,” observed Rik Ossenkoppele, PhD, of Lund University in Sweden, who wasn’t involved with the study.
“This study also emphasizes that once the symptomatic stage of Alzheimer’s disease is reached, tau pathology is a key factor involved in further disease progression, while the role of amyloid-beta at this stage seems limited,” Ossenkoppele told MedPage Today.
The study needs to be replicated in a larger sample, Rabinovici noted. Meanwhile, the researchers will follow the cognitive trajectories of these 32 patients as their Alzheimer’s disease progresses. “We’ll have to see whether these patterns translate into predicting specific cognitive changes,” he said.
“If we could provide a more accurate prognosis in both the rate of change and the quality of change, that would be very valuable to patients and families,” he pointed out. “It will also be valuable in clinical trial design. You could potentially improve your power to assess a drug’s clinical benefit by looking at individual patient trajectories, as opposed to the group level of analysis we currently do.”
Disclaimer
This study was supported by the Alzheimer’s Association, NIH’s National Institute on Aging, the Tau Consortium, and the California Department of Health Services.
Researchers reported relationships with Eli Lilly, Genentech, Merck, Biogen Idec, Bristol-Myers Squibb, ExpertConnect, Grifols, the John Douglas French Foundation, Tau Consortium, the National Institute for Health Research Cambridge Biomedical Research Centre, the American Brain Foundation, Bioclinica, Novartis Pharmaceuticals, Avid Radiopharmaceuticals, GE Healthcare, Life Molecular Imaging, Axon Neurosciences, Roche, and Eisai.
Primary Source
Science Translational Medicine
