Caroline Cassels

July 21, 2014

COPENHAGEN, Denmark — Tau protein in key brain areas of cognitively normal older individuals is strongly correlated to memory loss over time, preliminary research shows.

Dr. Keith Johnson

In the largest study of its kind reported to date, investigators at Harvard Medical School in Boston, Massachusetts, found that F18 T807 (Eli Lilly and Company), a novel positron emission tomography (PET) tau tracer that binds to tau in both the entorhinal cortex and the temporal neocortex, is related to episodic memory decline in normal older people.

"Our findings indicate the spread of tau, under the influence of, or in the presence of [beta amyloid], to widespread cortical regions may be the sign, the smoking gun, that cognitive impairment is imminent or already under way," said principal investigator Keith Johnson, MD, professor of radiology and neurology at Harvard and the director of molecular neuroimaging, Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital.

"We think this is very exciting because it will enable us to more efficiently develop therapies ― preventive therapies and treatment of actual Alzheimer's disease [AD] symptoms. We believe that in combination with other biomarkers that have been used in clinical trials, this technology will enable more efficient use of research dollars for developing these treatments and that this development will probably occur in individuals who do not have symptoms of cognitive impairment but may have image findings that place them at very much higher risk for the development of that impairment," added Dr. Johnson, who also codirects the Harvard Aging Brain Study and the neuroimaging program of the Massachusetts Alzheimer's Disease Research Center.

The study was presented at a press briefing here at the Alzheimer's Association International Conference (AAIC) 2014.

Closer to the Action

In addition to beta amyloid (Aβ) plaques, tau neurofibrillary tangles are hallmark pathologies of AD that are laid down many years before symptoms of cognitive decline present. However, until now, detection of tau in the brain has only been possible at autopsy.

A normal component of nerve cells, tau helps stabilize the internal neural transport system and supports architecture of neural cells. However, in dementia, the protein transforms and begins to accumulate in abnormal forms.

Previous research suggests that levels of tau in the brain may be more closely associated with cognitive decline in AD than Aβ, said Dr. Johnson.

Going into the study, the investigators hypothesized that tau was going to be "closer to the action" than Aβ and indicate incident impairment and that "when the tau compound binds to the sites in the brain, it was going to show us that these are the people that are about to have trouble or who have already started to have cognitive impairment."

The investigators' hypothesis bore out, and they found that there was a "highly significant" relationship between a worsening of memory performance and higher levels of T807 binding in the brain.

Identifying early buildup of these proteins in the brain, before cognitive decline occurs, may offer a road to early detection and diagnosis of AD and help identify candidates for prevention studies, investigators note.

PET ligands that are selective for tau have only been available for a year, and this study represents the beginning of research into the use of these tracers to image tau in live patients, said Dr. Johnson.

For the study, the researchers conducted PET scans using F18 T807 in 56 cognitively normal individuals whose median age was 72 years and who had undergone annual memory testing using the Selective Reminding Test (SRT) memory test during the previous 3 years.

Age, education, and Aβ status were entered as covariates.

The investigators found that longitudinal memory decline was associated with greater entorhinal (r-sq = 0.12; P < .0006) and inferior temporal (r-sq = 0.12; P < .0006) T807 binding.

The investigators report that the impact of tau on memory loss remained significant even in the presence of high Aβ.

Exciting New Technology

Commenting on the study, press conference moderator Ralph Nixon, MD, chair of the Alzheimer's Association Medical and Scientific Advisory Council, professor of psychiatry and cell biology, and director of research at the Center for Dementia Research at the Nathan S. Klein Institute for Psychiatric Research, said that the emerging neuroimaging technologies for tau are "exciting."

Dr. Ralph Nixon

If tau deposition turns out to be a very early event that is even closer to the phenomenon of cognitive decline and memory loss than Aβ, "this may allow us to track the progression and, in turn, assess the efficacy of clinical trials more effectively. We have more tools now to assess what might be the correlative of memory decline, so this may speed up the trials and really advance our ability to identify drugs," said Dr. Nixon.

Dr. Johnson and Dr. Nixon report no relevant financial relationships.

Alzheimer's Association International Conference (AAIC) 2014. Abstract F4-01-04 Presented July 16, 2014.


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