Tau Linked to Subjective Cognitive Decline

Pauline Anderson

October 04, 2017

Tau deposition in the entorhinal cortex is linked to subjective cognitive decline (SCD), new research shows.

Investigators at Harvard Medical School in Boston, Massachusetts, found that the association between SCD and entorhinal cortical tauopathy was much stronger than the association between amyloid β (Aβ) and SCD.

"The paper is suggesting that there's not just a tie between subjective concerns and amyloid, but there's a tie between subjective concerns and tau as well," lead author, Rachel F. Buckley, PhD, research fellow, Massachusetts General Hospital and Harvard Medical School, Boston, and the Florey Institutes of Neuroscience and Mental Health, Melbourne, Australia, told Medscape Medical News.

"We're now building a lot more evidence that subjective concerns are definitely tapping into some kind of disease in the brain, even when people are asymptomatic in the sense that if you give them a memory test, they will perform quite well."

The study was published online October 2 in JAMA Neurology.

Clinically Healthy Participants

The entorhinal cortex is a tiny area located directly adjacent to the hippocampus. Tau deposition in this region is the earliest cortical involvement in the succession of tauopathy stages that, along with Aβ pathologic changes, is a hallmark of Alzheimer's disease (AD).

Researchers are becoming increasingly interested in the role of SCD in dementia. Patients with subjective concerns typically have been worried about their memory for at least a year, have noticed a gradual decline, and might also have a family history of dementia, said Dr Buckley.

The current thinking in the research community, said Keith Fargo, PhD, director of scientific programs and outreach, medical and scientific relations, Alzheimer's Association, is that SCD precedes mild cognitive impairment (MCI) and is part of the "smooth progression of disease" that leads to AD.

"If you notice cognitive decline, especially if you're concerned about it, that's a pretty good sign that you may be on the road to something more serious," Dr Fargo told Medscape Medical News.

But unlike MCI, SCD can't be detected on objective memory tests.

Now that SCD has been defined, at least as a concept, "researchers are beginning to look at what's underlying that, what's happening in the brain when a person is in this subjective cognitive decline period," said Dr Fargo.

Dr Buckley's research team is part of that investigation. The new study included 133 participants in the Harvard Aging Brain Study, mean age 76 years; 56.3% were women.

Participants were considered "clinically healthy" and so were free of cognitive impairment and didn't have elevated cardiovascular risks, such as a previous stroke, said Dr Buckley.

To create an SCD composite for study participants, researchers calculated the mean z-transformed subscales from three questionnaires: the Memory Functioning Questionnaire (the first 18 items of the General Frequency of Forgetting), the Everyday Cognitive battery (the Memory section from the self-report version), and the 7-item questionnaire adapted form the Structured Telephone Interview for Dementia Assessment.

Participants underwent flortaucipir F18 positron emission tomography (FTP-PET) to investigate tau, as well as Pittsburgh compound B carbon 11–labeled PET imaging to assess Aβ.

For FTP-PET, the researchers focused on two regions of interest: the entorhinal cortex and the inferior temporal cortex, an area that may represent the initial stages in the spread of tau pathology from the medial temporal lobe to the neocortex.

In these regions, investigators calculated the standardized uptake value ratio. For amyloid, they looked at the frontal, lateral, and retrosplenial tracer uptake summery distribution ratio. Greater numbers in their regression plots of the SCD composite and Aβ and tau indicated greater development of SCD.

The analysis showed that greater entorhinal cortical tau deposition was associated with significantly greater SCD (β = 0.35; 95% confidence interval [CI], 0.19 - 0.52; P < .001).

There was no significant association between SCD and inferior temporal cortex tau (P = .27). Greater SCD was also associated with Aβ burden (β = 0.24; 95% CI, 0.08 - 0.40; P = .005).

Very Early AD Marker?

The researchers used several increasingly complex models to determine the influence of tau and Aβ on SCD after accounting for covariates that included age, educational attainment, sex, depressive symptoms, and delay from neuropsychological testing to FTP-PET scanning.

When both aggregated proteins were simultaneously examined in a model, the effects of entorhinal tau remained, but the effects of Aβ were no longer significant.

"Our studies and those of others have shown that when you have subjective concerns, you tend to show a bit more amyloid in the brain, even when you're completely healthy memory-wise," said Dr Buckley.

"Here, we also found that amyloid was associated with subjective concerns, but if we included tau in our models, tau was swamping everything — the relationship of entorhinal cortical tau with subjective concerns was very, very strong."

The researchers conducted a post hoc whole-brain analysis. That exploratory investigation supported the notion that SCD was predominantly associated with greater tau burden in the entorhinal cortex.

"Taken together, we posit that our findings support SCD as an early behavioral manifestation of entorhinal cortical tauopathy," the authors write.

SCD may mark one of the earliest behavioral changes among increasing pathologic change in clinically healthy older adults, they add.

Doctors need to "pay attention" to patients expressing concern about their memory, as many already do, and possibly consider genetic testing, said Dr Buckley.

"If someone is worried about their memory, it's definitely a marker of something. Right now we think that in certain circumstances, that it's a very early marker for Alzheimer's disease risk."

While it could also be a marker for a range of other things, even some kind of mood disorder, "doctors should never discount the possibility that a memory concern presenting in their clinic is a potential marker for AD," said Dr Buckley.

However, it's too early to consider routine tau imaging in such patients, she said. Unlike amyloid imaging, which has been available for some 15 years, tau imaging is still in its infancy.

"We are still in the very early stages of learning how well these tracers work in a PET scanner," said Dr Buckley. She hopes such imaging will be ready for clinical use within the next 5 to 10 years.

"Important Advance"

In an accompanying editorial, Rik Ossenkoppele, PhD, Department of Neurology and Alzheimer Center, VU University Medical Center, Amsterdam, the Netherlands, and William J. Jagust, MD, Helen Wills Neuroscience Institute, University of California, Berkeley, said the study "is an important advance in our understanding of SCD."

However, they note "the interpretation is not straightforward because the independent variables," including Aβ and tau, and the dependent variable (SCD), are "complex and interrelated."

The editorialists noted that the construct of SCD is still evolving and that standards for its definition "are not universally agreed on."

Dr Ossenkoppele and Dr Jagust point out that many older individuals experience SCD and that physicians need better ways to assess this decline to more thoroughly evaluate and counsel patients.

This and other studies provide "mounting evidence" that SCD may be an early symptom of the accumulation of AD pathologic change.

"A better understanding of how each specific molecular pathologic change is expressed in association with SCD at different stages of the development of AD could lead to better methods of diagnosing AD at preclinical stages, selecting individuals for early clinical trials, and ultimately effectively treating AD at its earliest stages."

Dr Fargo said the authors are "world class" researchers who used "state of the art" methods.

Two novel aspects of the study are that it broached the concept of SCD, "which has only recently become measurable reliably," and used tau PET imaging, which is also relatively new, said Dr Fargo.

This research, he added, addresses an important question: For SCD, is it necessary to have both amyloid and tau?

"This paper shows that the strongest relationship is with tau in the entorhinal cortex; amyloid β can also play a role, but you certainly don't have to have both in order to have SCD."

If the study has any drawback, it's that it doesn't include "a random selection of people across the entire population" but instead a relatively small group drawn from an existing cohort, said Dr Fargo.

Dr Buckley has disclosed no relevant financial relationships. Dr Jagust reports serving as a consultant to Bioclinica, Genentech, Biogen, and Novartis.

JAMA Neurol. Published online October 2, 2017. Full text, Editorial

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