This article was amended on January 10, 2020

Tau PET is prying open a window on when and where neurofibrillary tangles appear as Alzheimer’s progresses. At the 12th Clinical Trials on Alzheimer’s Disease Conference, held December 4–7 in San Diego, California, three presentations on next-generation tau tracers offered some detail on how tangles relate to plaque load and to cognition at different stages of the disease.

  • The amount of tau pathology varies widely among people with the same amyloid burden.
  • Baseline tau predicts the rate of tangle spread.
  • Cognitive decline lags behind tangle accumulation.

One surprise: Some people with MCI who were at the threshold of global amyloid positivity with florbetaben/Neuraceq already have positive PI-2620 tau PET scans. This would contradict scientists’ current sense, seen with flortaucipir/AV-1451, that scans turn positive around the time people become symptomatic, when amyloid is typically well-established. However, these are the early days of tau PET. The data shown at CTAD were cross-sectional, with the caveats that attend to such one-time comparisons. They varied widely from person to person, with a few people remaining tau-negative in the presence of a high global amyloid load. Partly, current data may reflect a lack of consensus on what constitutes a positive tau scan.

Meanwhile, longitudinal studies are starting to show that the more tangles a person has at his or her first scan, the quicker the pathology spreads, suggesting the baseline tau signal might help trialists find fast progressors. Neuropathology data have closely tied tangles to cognitive decline, but intriguingly, new PET data from a small longitudinal cohort hinted that there may be a time lag between the two. As more of these kinds of data roll in, scientists hope it will improve their ability to define the right timepoints for intervening with anti-amyloid or anti-tau drugs, and track their effect in trials.

Tau PET scans with next-generation tracer RO-948. [Courtesy of Gregory Klein at Roche and Oskar Hansson at Lund University, Sweden.]

Compared with the initial tau tracers, such as flortaucipir, the new ones tend to bind more strongly to tangles while ignoring other molecules, yielding a better signal-to-noise ratio (Apr 2017 conference news). This helps with tracking change over time.

One next-generation tracer is Life Molecular Imaging’s PI-2620, which appears to distinguish AD scans from those of healthy controls with little noise (Kroth et al., 2019; Mueller et al., 2019; Bullich et al., 2019). Eisai chose this tracer for its now-terminated Phase 3 MISSION AD program of the BACE inhibitor elenbecestat

In San Diego, LMI’s Andrew Stephens discussed baseline data from the program’s tau PET sub-study of 77 participants. All were amyloid-positive by a visual read of LMI’s florbetaben PET scans. Visual reads pick up early regional amyloid accumulation, before global amyloid scores turn positive. Participants’ average age was 76, and 43 percent of them carried an ApoE4 allele, a lower rate than is typical in AD trials. At baseline, they had mild cognitive impairment, with a CDR score of 0.5 and an average MMSE of 27.

Based on their tau scans, this population fell into three distinct groups, Stephens said. By visual assessment, 33 of the 77 people were tangle-negative, with barely any PI-2620 retention beyond that seen in healthy controls. In another 18, the tracer was taken up mainly in the hippocampus, parahippocampus, and fusiform gyrus—regions of early tau pathology that correspond to Braak stage 1/2. Nearly the same number, 20 people, had more extensive uptake in the neocortex, indicating stage 3 or later. The remaining seven people did not fit cleanly into any of these categories. “Tau deposition is quite heterogeneous, and we don’t fully understand why yet,” Stephens told Alzforum.

Stephens noted that a person’s age, sex, cognitive reserve, and genetic factors can affect his or her tangle accumulation. For example, at a given level of cognitive decline, older people tend to have fewer tangles than do younger ones, while people with high cognitive reserve have more tangles than do those with less reserve (Apr 2019 conference news). Other data suggest tangles accumulate faster in women, but not men, who carry an ApoE4 allele (Feb 2019 news; Nov 2019 news). 

In people who inherit a dominant Alzheimer’s mutation, flortaucipir indicates tangle spread into the cortex around the time of symptom onset. This is a faster tangle progression than in MISSION AD, where most of this MCI cohort had no cortical tangles (Aug 2017 conference news; Feb 2018 news). “We are beginning to define the amount of amyloid that is needed to see tracer accumulation, and we hope to extend these findings to learn what amyloid level is required for neocortical tau deposition,” Stephens wrote to Alzforum.

By quantifying tau uptake, not merely judging it with the naked eye, researchers picked up nine additional positive scans in the MISSION AD cohort. This resulted in a total of 47 positive scans, amounting to 60 percent of this MCI cohort. An audience member expressed the surprise of many when he asked why the percentage wasn’t higher. Previous work had reported 50 percent flortaucipir positivity in amyloid-positive but cognitively normal A4 trial participants—an earlier-stage population measured with a weaker tracer. Stephens said he does not know why the percentages are so similar in these different populations.

How did tau uptake among these people relate to their amyloid burden? For context, healthy young controls average a florbetaben amyloid load of 1.16 SUVR using LMI’s methodology, with cerebellar gray matter as the reference region. Regional accumulation begins two standard deviations above that, at 1.25 SUVR, or 12 centiloids, Stephens said. He will present new florbetaben research at upcoming meetings, showing that 12 centiloids is where amyloid accumulation can first be detected. A previous histopathology study of florbetaben in end-of-life subjects had set a cutoff for global amyloid positivity at 1.48 SUVR, about 35 centiloids. Stephens noted that this study included only people who had moderate dementia or worse, and so this cutoff may not capture everyone at earlier disease stages. The range between 12 and 35 centiloids thus defines a “gray zone,” where regional amyloid has begun to build up but the global score is not yet positive.

In the MISSION AD sub-study, the three people whose global amyloid score was below the gray zone were all tau-negative, Stephens reported at CTAD. “This shows that in Alzheimer’s, there is no PI-2620 accumulation in the absence of detectable amyloid,” he said. Among those in the amyloid gray zone, one in five had a positive tau scan, and they all had amyloid burdens toward the high end of the gray zone. At intermediate levels of amyloid plaque, half the MISSION participants were tau-positive. Among those with high global amyloid loads, 80 percent were tau-positive.

Were there regional patterns? Yes. The higher a person’s global amyloid load, the more tau-tracer uptake he or she had in regions known to succumb to AD early—hippocampus, parahippocampus, fusiform gyrus, amygdala, inferior temporal cortex. In this cohort, as expected, amyloid and tau tracer uptake were less correlated in parietal cortex, a region affected later in disease than the 0.5 CDR stage. The researchers are currently gathering longitudinal tau PET data as MISSION AD participants come for their final visits.

Other talks at CTAD offered a glimpse at longitudinal data. The Swedish BioFINDER2 study, which tracks biomarker change over time, uses Roche’s next-generation tracer RO-948 to follow participants. In San Diego, Gregory Klein and colleagues at Roche presented data from the first 51 participants who were scanned at baseline and one-year follow-up. They spanned the disease spectrum, with nine of them amyloid-negative and cognitively healthy, 14 amyloid-positive and cognitively healthy, 18 amyloid-positive with MCI, and 7 amyloid-positive with AD dementia. There were also three outliers who were amyloid-negative but cognitively impaired.

Among this cohort, tau PET scans diverged sharply according to whether a person was amyloid-negative or -positive. For amyloid-negative participants, baseline tau tracer uptake was low and did not rise over the course of a year. If anything, the RO-948 signal dipped slightly at follow-up. For amyloid-positive participants, the baseline tau signal was higher, as expected, and it rose over the following year. The more tau a person had at baseline, the more it rose, suggesting that high baseline tau could be used as a criteria for selecting trial participants. Klein and colleagues did not quantify exactly how many of the amyloid-positive MCI group were tau-positive, but he noted that roughly half of them fell below a tau PET SUVR of 1.3, considered the threshold for positivity with RO-948. These proportions are consistent with those seen in BioFINDER1 with flortaucipir, he noted (Ossenkoppele et al., 2018). “What truly defines tau positivity is still a subject of discussion in the tau PET community,” he told Alzforum.

Where the tau signal rose depended on disease stage. For cognitively normal people with brain amyloid, tau went up in Braak 1/2 regions. For the MCI group, it went up in Braak 3/4 regions, and for people with AD dementia, in Braak 5/6. Curiously, for people with dementia, tau tracer uptake fell slightly in Braak 1/2 regions over the course of a year, perhaps due to neuron death there.

Klein said that compared with flortaucipir, RO-948 has less off-target binding in brain structures up close to Braak 1/2 regions, particularly in the choroid plexus sitting atop the hippocampus. This, he believes, may allow this tracer to better detect longitudinal change in people at the preclinical stage of disease (Smith et al., 2019). It may also explain why the longitudinal effect size for tracer uptake change in this group was greater than that published using AV-1451, Klein told Alzforum (Jack et al., 2018). 

He believes the combination of high sensitivity in Braak 1/2 regions and setting a baseline tau cutoff as an inclusion criteria could enable clinical trials to use tau PET as an outcome measure. “This could be a game-changer for designing clinical trials targeting a preclinical AD population, where prior sample-size estimates have been too large to be practical using a tau PET endpoint,” Klein wrote to Alzforum.

Tangles Before Cognitive Decline? Uptake of tau tracer GTP1 rises early in disease, while memory slips later. [Courtesy of Robby Weimer, Genentech.]

A second longitudinal tau PET study presenting at CTAD tied tangle spread to cognition. Robby Weimer and colleagues at Genentech followed 72 people for 18 months using their in-house next-generation tracer GTP1 (Sanabria-Bohórquez et al., 2019). In a previous cross-sectional study, uptake of this tracer correlated with worse memory (Teng et al., 2019). The new longitudinal study comprised 27 people with prodromal, 19 with mild, and 16 with moderate AD, along with 10 cognitively healthy controls. Everyone with AD had a positive amyloid scan.

The data again tightly linked tangles to cognitive decline, but with a temporal lag, i.e., tau PET changed before cognition slipped. For healthy controls, the tau PET signal fell slightly at 18 months, just as in BioFINDER, while cognitive scores on the CDR-SB and ADAS-Cog13 stayed flat. For the prodromal group, tau tracer uptake rose slightly, about 0.05 SUVR, while cognitive scores barely moved. The mild AD group had a similar bump in tracer signal as the prodromals, but their cognition worsened by five points on the ADAS-Cog13 and three on the CDR-SB. For those with moderate AD, GTP1 uptake rose the most, about 0.1 SUVR, while their cognition worsened at about the same rate as in the mild group.

Weimer sees two possible explanations for the apparent delay between rising tau PET and declining cognition. It could reflect a physiological phenomenon, where tangle accumulation precedes synaptic or neuronal damage by some period of time. Or it could be a result of ceiling effects in the cognitive measures used, which may lack the sensitivity to detect early changes. “Evaluation of atrophy from this study, which is ongoing, will help delineate these differences and provide insight into the pathophysiology of disease,” Weimer wrote to Alzforum. He noted that with the current dataset, he cannot quantify the time lag in terms of months or years.

Regionally, data from the longitudinal Genentech cohort resembled that from the BioFINDER2, with Braak stage 1/2 regions changing the most at the prodromal stage, and 5/6 changing the most in moderate AD. People with mild AD gained tau signal in all Braak regions over one year.

Weimer noted that a person’s baseline GTP1signal predicted by how much he or she would worsen on the CDR-SB and ADAS-Cog13 over the following year, whereas his or her rate of tau PET change did not. In other words, tangle pathology at baseline better predicted progression than did the rate of tangle spread. Tau PET could be used for disease staging and as a biomarker of progression, Weimer suggested.

He noted that just as in MISSION AD and BioFINDER2, his group saw a range of tau pathology among prodromal patients. They have not yet defined a positivity cutoff for GTP1. “For all the tracers, we will need larger longitudinal datasets for cognitively normal, MCI, and AD patients before we can fully explore the relationship between baseline tau pathology and disease progression. That information will help define tau positivity,” Weimer wrote.

Regarding other next-generation tau tracers, there is also Merck’s entrant, MK-6240. The only data at CTAD on it on came from the aducanumab sub-study (Dec 2019 conference news). There were no presentations on Janssen’s JNJ-067, currently in a Phase 1 trial.

Meanwhile, researchers led by Alex Whittington and Roger Gunn at the imaging services company Invicro, London, presented a new method for quantifying tau tracer uptake by calculating both global and local tau loads. In cross-sectional analyses, the new measure, TauIQ, arrived at a larger effect size than did SUVR for distinguishing between control and AD scans. For flortaucipir, the effect size was 17 percent larger with TauIQ than with SUVR, while for GTP1, it was 24 to 49 percent larger. In longitudinal scans, TauIQ showed a greater increase over a year than did SUVR. For example, in people with high GTP1 uptake at baseline, TauIQ went up 0.7 standard deviations in a year, compared with 0.45 for SUVR. The use of TauIQ could facilitate clinical trials, the authors suggested.—Madolyn Bowman Rogers

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References

News Citations

  1. Next-Generation Tau PET Tracers Strut Their Stuff
  2. News From the PET Front: Early Amyloid Networks and Tau Mystery
  3. Is a Woman’s Brain More Susceptible to Tau Pathology?
  4. ApoE4 and Tau in Alzheimer’s: Worse Than We Thought? Especially in Women
  5. Data from DIAN Revise Familiar Biomarker Trajectories
  6. In Familial Alzheimer’s, Tau Creeps into Cortex as Symptoms Show
  7. Exposure, Exposure, Exposure? At CTAD, Aducanumab Scientists Make a Case

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External Citations

  1. longitudinal study
  2. Phase 1

Further Reading