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The two hallmark pathologies of Alzheimer’s disease, amyloid plaques and tau tangles, play different roles in disease progression. Accumulating research suggests that amyloid plaques kick off the disease, precipitating the spread of tau, which then does the actual dirty work of harming neurons. At the Alzheimer’s Association International Conference 2017 held July 16–20 in London, researchers bolstered this theory with new data tying tangles to most types of cognitive decline. However, one talk bucked this trend by proposing a specific role for amyloid in semantic memory. In addition, researchers said that because tau, cortical atrophy, and amyloid all mingle together in Alzheimer’s disease, the presence of one biomarker can be used to predict the simultaneous presence of others. Some groups fashioned a preclinical AD signature from plaque-induced cortical thinning.

Tau and Cognitive Deficits. When AD patients (top row) voice concerns about their own cognitive abilities, they accumulate tau in frontal areas of the brain. When family members notice a memory change, tangles appear more posteriorly (bottom row). [Courtesy of Shannon Risacher, AAIC2017.]

Tau Drives Decline
Many talks at AAIC emphasized the connection between tangles and clinical decline. For example, Andrew Aschenbrenner of Washington University in St. Louis noted that markers of amyloid, tau tangles, and brain atrophy all predict future cognitive decline, though this does not prove that any of these pathologies cause decline. To pinpoint causation, Aschenbrenner and colleagues analyzed 104 older adults with an average age of 70, who ranged from cognitively healthy to mildly symptomatic. Participants were drawn from various aging studies at WashU, including the Adult Children and the Healthy Aging and Senile Dementia studies, who had undergone an average of five cognitive assessments over the course of six years. During this period, they underwent one florbetapir amyloid scan, one AV1451 tau scan, and one structural MRI to measure hippocampal volume.

As expected, abnormal values on any of these three imaging modalities correlated with later cognitive decline. However, when the researchers performed regression analyses to look for causal factors, they found that the tau signal alone accounted for all the cognitive decline in this cohort. Parsing tau’s effect on different cognitive domains in a cross-sectional analysis, the scientists found that tau as measured by PET most strongly affected episodic memory, then processing speed, executive function, and lastly semantic memory, Aschenbrenner said. A longitudinal analysis suggested a slightly different sequence of effects; over time, tau pathology appeared to hit processing speed the most, followed by executive function, episodic memory, and lastly semantic memory.

Taking this a step further, Shannon Risacher of the Indiana Alzheimer Disease Center in Indianapolis reported that tangles in different regions may exert distinct effects on cognition. She analyzed data from 36 amyloid-positive older adults in ADNI-2. Fifteen appeared cognitively healthy, four had memory concerns, and 17 mild cognitive impairment. All underwent an AV1451 tau scan. To assess cognitive function, the researchers analyzed the memory subscale from the Measurement of Everyday Cognition (ECog) test, which participants and informants separately completed (Farias et al., 2008). 

The researchers saw a surprising pattern. When participants themselves reported concerns about their cognition, they tended to have tau tangles in the frontal cortex, but not in posterior regions. When informants reported concerns but the participant appeared to have no insight, participants harbored tangles in the precuneus and parietal cortex but not in frontal regions.

Although the reason for the difference is unclear, Risacher speculated that people are most likely to notice when they have problems with executive function, which taxes the frontal cortex. On the other hand, informants might be more likely to notice memory problems caused by posterior tangles, she said. Other studies have reported that informant and self-concerns act as independent, additive risk factors for Alzheimer’s progression, reinforcing the idea that these two measures pick up different types of pathology.

In Risacher’s study, all participants had plaques in the medial temporal lobe (MTL). In another study, Anne Maass, working with Bill Jagust at the University of California, Berkeley, focused on what tau pathology in this region does to cognition. The MTL accumulates tangles early during normal aging; in fact, two-thirds of people over 60 have tangles in their MTL. While these tangles associate with poor episodic memory, it is unclear how that happens. Maass analyzed data from 83 cognitively normal people at an average age of 77 who participated in the Berkeley Aging Cohort Study. They underwent amyloid PiB and tau AV1451 PET, structural MRI, and took tests of episodic memory. Fifty-seven of the participants had at least one additional MRI and subsequent memory tests one to two years later. Tau scans were mostly acquired after the other data was collected.

In this cohort, tau tracer uptake in the MTL was the best predictor of baseline memory performance, accounting for 20 percent of the variance in these scores, Maass said. Notably, no other measure explained memory variance. Within the MTL, tangles in the entorhinal cortex and parahippocampal cortex most associated with poor baseline memory. Forty percent of the participants were amyloid-positive, but amyloid had no relationship to memory in this group, Maass noted. Moreover, MTL tau measures associated with memory decline and entorhinal atrophy over time. The data suggest that tau tangles underlie faltering memory even in normal aging, Maass concluded (Maass et al., 2017). 

Then What’s Amyloid Doing?
Does amyloid play any role in the progression of symptoms? Several imaging studies have suggested that cortical amyloid seems to unleash tau, allowing it to spread from the medial temporal lobe into surrounding regions and kicking off neurodegeneration (Jul 2016 newsAug 2016 news; Jun 2017 news). At AAIC, Keith Johnson of Massachusetts General Hospital, Boston, underscored this finding. He noted that in multiple cohorts of healthy elderly people, including those in the Harvard Aging Brain Study, the Mayo Clinic Study of Aging, and the National Alzheimer’s Coordinating Center database, neocortical tau appears to interact with amyloid plaques to bring on hypometabolism and bring down memory. In particular, temporal lobe tau associates with waning metabolism in the posterior cingulate, but only when cortical amyloid is also there, Johnson said.

Beyond amyloid’s role in precipitating tau pathology, does it do anything to harm memory by itself? Perhaps, according to Kate Papp at Brigham and Women’s Hospital, Boston. Papp previously found that semantic memory, which stores factual knowledge, declines in cognitively normal older adults who have amyloid plaques (Papp et al., 2015). This was notable because unlike episodic memory, which wanes with age, semantic memory tends to increase with healthy aging. It was unclear what type of pathology caused this form of memory to drop in preclinical AD. To investigate, Papp compared episodic and semantic memory in 74 cognitively healthy participants in the Harvard Aging Brain Study whose average age was 78. All had PiB and AV1451 PET scans.

Papp found that the extent of amyloid plaques, but not of tau tangles, correlated with worse semantic memory. Something about how semantic memory is stored could render it more susceptible to amyloid, Papp speculated. Some researchers believe that semantic memory is processed in a distributed neocortical network, which could leave it vulnerable to the effects of widespread neocortical Aβ, she suggested. Next she plans to examine longitudinal and brain network data to see if the plaque-semantic memory effect holds up, and what might explain it.

Because of the close relationship between plaques, tangles, and cortical neurodegeneration, the latter can be used as a surrogate for the former, other speakers noted. Aylin Dincer, working with Tammie Benzinger at WashU, analyzed structural MRI data from participants with and without amyloid plaques in the Dominantly Inherited Alzheimer Network (DIAN) to derive a specific signature of AD-related cortical thinning. She found thinning in amyloid-positive people, who were also the mutation carriers, primarily in the posterior regions of the brain, such as the precuneus and lateral parietal lobes. Because DIAN participants are young, this signature was not confounded by age-related brain volume loss. When Dincer looked for this AD signature in a cohort of cognitively normal elderly seen at the Knight ADRC at WashU, it only turned up in those with brain amyloid and/or cognitive impairment. In fact, this thinning signature better predicted amyloid status than did hippocampal volume, Dincer said, noting that hippocampal shrinkage is not specific to AD.

Paula Petrone of Barcelonaβeta Brain Research Center, Spain, described a complementary approach. She used structural MRI and diffusion tensor imaging, which measures axonal integrity, to derive an AD signature from 96 ADNI participants and 87 elderly patients seen at the Hospital Clinic of Barcelona. Both groups included cognitively healthy controls as well as people with preclinical, prodromal, and full-blown AD. Using machine-learning techniques, the researchers found a set of 45 structural features, 43 from DTI scans and two from MRI, that best predicted whether people had amyloid plaques. This AD signature was 84 percent accurate, suggesting it could serve as a prescreening tool in place of expensive PET scans, Petrone suggested. She calculated DTI could save about 75 percent of screening costs over PET for clinical trials. Petrone noted, however, that the signature performs best in younger cohorts with fewer age-related changes. In future work, she plans to include cognitive and genetic biomarkers to try to improve its performance. —Madolyn Bowman Rogers


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News Citations

  1. CSF and Brain Markers Highlight Different Facets of Dementia
  2. Do Temporal Lobe Tangles and Cortical Plaques Together Bring on Alzheimer’s?
  3. Brain Imaging Suggests Aβ Unleashes the Deadly Side of Tau
  4. Analysis of PET Scans Suggests Link Between Amyloid and Tau

Paper Citations

  1. . The measurement of everyday cognition (ECog): scale development and psychometric properties. Neuropsychology. 2008 Jul;22(4):531-44. PubMed.
  2. . Comparison of multiple tau-PET measures as biomarkers in aging and Alzheimer's disease. Neuroimage. 2017 Aug 15;157:448-463. Epub 2017 Jun 3 PubMed.
  3. . Biomarker Validation of a Decline in Semantic Processing in Preclinical Alzheimer's Disease. Neuropsychology. 2015 Nov 23; PubMed.

Further Reading