The spread of tau tangles through the brain of a person who is coming down with Alzheimer’s disease correlates closely with his or her cognitive impairment, making this pathology a top therapeutic target these days. Even so, scientists still know little about what controls this process and how plaques promote it, a knowledge gap made painfully clear at the Alzheimer’s Association International Conference, held July 31 to August 4 virtually and in San Diego, California.

  • P-tau217 mediates the effect plaques exert on tangles.
  • Where tangles begin determines how fast they propagate through the brain.
  • Polygenic risk score accelerates tangle spread.

Taking a crack at the problem, several speakers shared the latest findings from tau PET studies, which are beginning to disentangle the various influences that come to bear on propagation. One talk implicated p-tau as a link between plaques and tangles; others focused on where tau aggregation starts, claiming its initial epicenters dictate the speed at which it travels through the brain. Genetic factors may underlie some of the heterogeneity in tangle accumulation as well. Overall, the emerging picture suggests manifold influences on tau pathology and the rate of disease progression.

“We are pretty sure the connectomic architecture of the brain dictates the spreading pattern of tau pathology in AD patients. Now we need to understand its modulators,” Nicolai Franzmeier of Ludwig-Maximilians University in Munich wrote to Alzforum. “We can use the tools we developed for predicting spreading patterns to zoom in and study what drives or attenuates tau spreading. This may give us more insight into how we could prevent it.”

Key Connections. One hypothesis holds that when tangles (red) form in hub regions (circles) of the brain, where many axonal highways meet, they are able to travel more rapidly to new areas, resulting in fast-advancing disease. [Courtesy of Nicolai Franzmeier.]

As people age, tangles accumulate in their entorhinal cortices and nearby regions, but in cognitively healthy people, tangles rarely move beyond that. Numerous PET studies have shown that amyloid plaques somehow unleash tangles, allowing them to rampage through the brain (Mar 2016 news; Aug 2016 news; Feb 2018 news). But exactly how do plaques spur tangle formation in distant brain regions? Some studies have suggested inflammation or synaptic connections as mediators (Sep 2021 news; Apr 2022 news). A better grasp of the mechanisms could help researchers design more targeted therapies.

Could the Culprit Be P-tau?
At AAIC, speakers offered many ideas. One early consequence of plaque formation is a rise in certain isoforms of phosphorylated tau, particularly p-tau217 and p-tau181, in cerebrospinal fluid and plasma (Aug 2019 conference news; Mar 2020 news; Jul 2020 conference news). Recently, researchers flagged p-tau231 as the earliest marker of amyloid aggregation (see related conference story).

Alexa Pichet Binette, working with Oskar Hansson of Lund University, Sweden, made a case that it is p-tau217 that brokers the relationship between plaques and tangles. In collaboration with Franzmeier, Pichet Binette investigated links between these two key pathologies in the BioFINDER-2 observational cohort. Her analysis included 204 amyloid-negative controls, 130 amyloid-positive people without dementia—half with MCI, half without—and 66 amyloid-positive with AD dementia.

Pichet Binette considered two possible ways in which a participant's amyloid load might influence his or her brain: via regional plaque accumulation or via p-tau217. Both related to the rise in their tau PET signal over time, but p-tau217 appeared to be the driving force. When both factors were entered into the model, the effect of amyloid dropped out statistically, leaving p-tau217 as the main predictor for the spread of tau tangles. It accounted for 54 percent of the association between plaques and tangles in non-demented participants.

This relationship between p-tau217 and tangles waned as disease advanced. In people with dementia, whose plaque load and soluble p-tau had plateaued, p-tau217 no longer had any effect on tangle accumulation. Metaphorically, p-tau217 may be the spark that lights the local fire of tangles, but once the fire is big enough, it spreads on its own through a self-fueling process, Franzmeier told Alzforum. The findings point to soluble p-tau217 as a potential therapeutic target in early, but not late, AD, Pichet Binette said. The article is available in preprint form (Binette et al., 2022). 

Meanwhile, Davina Biel in Franzmeier’s group went a step earlier, investigating how plaques boost p-tau in the first place. She focused on the microglial activation marker sTREM2, because it has been linked to the rise in p-tau (Jan 2016 news; Dec 2016 news; Pascoal et al., 2021). To examine longitudinal changes, Biel stratified data from 402 ADNI participants into three groups: 131 amyloid-negative controls, 70 people who were amyloid-positive by CSF but negative by PET, i.e., “early accumulators,” and 201 who were amyloid-positive by both, i.e., “late accumulators.” In ADNI CSF data, only p-tau181 was measured, as newer markers were not yet available.

Plaques were associated with elevated sTREM2 and p-tau181, but the nature of this relationship evolved with disease stage, as a statistical tool called mediation analysis showed. In early accumulators, sTREM2 mediated the effect plaques had on p-tau181. This implies that plaques prompt microglia to become active in ways that somehow stimulate phosphorylation of tau at position 181, or allow p-tau181's concentration to rise. However, in late accumulators, rather than boosting levels of p-tau181 further, sTREM2 seemed to weaken p-tau181's effect on hippocampal atrophy.

Franzmeier presented this work in San Diego. He said the findings hint that microglial activation could be harmful at early stages of AD, but possibly protective later. This seems to contradict previous cross-sectional data, including some from Franzmeier, that report less cognitive decline in amyloid-positive people with high sTREM2, suggesting microglia activity helps early in disease (Aug 2019 news; Mar 2022 news). The issue is murky, however, with another longitudinal study linking sTREM2 to faster atrophy in preclinical AD (Apr 2020 conference news). Franzmeier noted that protective effects of sTREM2 have mostly been seen in people who already have symptoms of AD and thus are later in the disease trajectory. Moreover, microglia may have mixed effects, curbing plaque growth while boosting p-tau. More research will be needed to disentangle microglia’s effects at different stages, and reconcile these cross-sectional and longitudinal findings. “It’s highly complex, and we are just starting to understand how microglia play into AD biomarker and clinical trajectories,” Franzmeier told Alzforum.

Location, Location, Location
P-tau217 might somehow promote tangles, but that still does not explain how tangles spread in stereotyped patterns through a person's brain. Other talks in San Diego dissected the anatomy of tau propagation. Deborah Schoonhoven, working with Alida Gouw of Amsterdam UMC in the Netherlands, tested three models, one each for functional connections, structural connections, or diffusion through gray matter. Schoonhoven used data from 82 participants in the Amsterdam Dementia Cohort. All reported memory problems, but 25 were amyloid-negative, 16 were amyloid-positive and unimpaired on normed tests, 16 had amyloid-positive MCI, and 25 had AD dementia.

Schoonhoven constructed models of each potential pathway of tangle spread, then used those to predict how aggregated tau would spread in each participant’s brain based on where their tangles were at baseline. Functional connectivity maps for each participant were derived from magnetoencephalography, which records the magnetic fields produced by electrical activity in the brain. Schoonhoven compared the model predictions to actual tau PET scans from each person.

The functional connectivity model was most accurate, with a correlation of r=0.58 with the scan. The other two models both correlated at r=0.45, showing a weaker relationship. This suggests that both are involved, but functional relationships between brain regions are more important than structural ones in determining tau spread. Schoonhoven noted that functional connections always require a structural underpinning, but functional mapping provides another layer of information by showing which brain connections are most active and firing together most often. Thus, functional maps vary slightly from structural ones.

Curiously, some previous work had reached the opposite conclusion, finding a primary role for structural over functional connections (May 2020 news). Schoonhoven said methodological differences between the studies, such as the use of magnetoencephalography in hers, might explain the apparent contradiction. She acknowledged that her findings do not preclude that tau aggregates physically pass between axonal connections. Instead, the functional data simply suggest that neuronal activity plays a key role in promoting spread, she told Alzforum. Previous studies have recorded an increase in tau release upon neuronal stimulation (e.g., Feb 2014 news).

For his part, Franzmeier homed in on the role of brain hubs. He said that observational studies suggest that tangles spread at different rates in different people, and show some variability in their pattern of spread. Could the deciding factor be where tangles start? Franzmeier hypothesized that if tau first aggregated in a less-connected brain region, tangles would spread slowly, whereas if the aggregates first deposited in a highly connected hub, they would run like wildfire through the brain.

To identify hub regions, he mapped brain connectivity using resting-state fMRI data from 1,000 participants in the Human Connectome Project. Then he compared longitudinal tau PET scans from 242 ADNI and 57 BioFINDER participants against this map.

As predicted, when tangles in symptomatic AD patients were in hubs, the person’s subsequent tau PET signal increased more rapidly over time. Younger participants were more likely to have tangles in hub regions, while older participants tended to have them in limbic regions. Franzmeier believes this makes sense, because hub regions are crucial for complex cognitive processes, and therefore people with tangles in these areas are likely to show symptoms at a younger age.

In these cohorts, mediation analyses showed that the presence of tangles in hub regions was responsible for the faster accumulation of abnormal tau in younger than older symptomatic participants (Frontzkowski et al., 2022). Previous studies already noticed this age effect, where tau pathology is less pronounced in older people with AD (e.g., Apr 2018 conference news). Franzmeier noted that the big question remains: Why does tau aggregation start in distinct brain regions in different people?

Do Our Genes Have a Hand in This?
One driver behind the variability of tangle spread could be genetics. Anna Rubinski, working with Michael Ewers of Ludwig-Maximilians University, examined the role of known AD risk factors in tau pathology. Ewers’ group had previously tied a BIN1 risk variant to faster spread, and a protective klotho variant to slower (Franzmeier et al., 2021; Neitzel et al., 2021). To look at genetic factors more broadly, Rubinski computed a polygenic risk score (PGS) from 85 GWAS SNPs tied to AD, excluding APOE. In a cohort of 231 ADNI participants, having a higher AD PGS correlated with more rapid increase in one’s cortical tau PET signal at all Braak stages after 1. This genetic acceleration effect was stronger in people who had more plaque.

The same PGS was also associated with faster cognitive decline. This was only partially mediated by its effect on tangle propagation, suggesting that genetic factors may exert independent effects on cognition. A PGS comprising 85 AD risk SNPs likely reflects multiple mechanisms.

What about APOE4? This risk allele has been linked to tau pathology in transgenic mice (Sep 2017 news; Apr 2021 news). Beyond that, however, few studies have tied ApoE to tau thus far, whereas ample evidence exists for its effect on amyloid deposition. Elizabeth Mormino of Stanford University, Palo Alto, California, used data from 392 amyloid-positive, cognitively healthy participants in the A4 secondary prevention solanezumab trial to dissect the effect of this gene on tangles. In this cohort, 207 people had at least one E4 allele, and 31 an E2 allele.

The E4 carriers accumulated more tangles in multiple brain regions, particularly the medial temporal lobe, than did E3 homozygotes, while E2 carriers had less tau burden compared to E3s. Surprisingly, little of this effect was mediated by amyloid plaques. Instead, APOE4 appeared to directly affect tangle burden, in agreement with the mouse data. That said, E2's power to lower tangles was greater than E4's sway toward more tangles, as seen in 13 participants who carried both alleles. This highlights APOE2 as a key protective mechanism, Mormino said.

Exactly how APOE alleles affect tangles remains to be determined. Although amyloid is the strongest driver of aberrant tau accumulation, APOE may directly influence tau clearance, with E4 promoting and E2 diminishing tangles in amyloid-positive people, Mormino suggested.

In the bigger picture, Mormino believes it will be important to learn why tangle spread is so heterogenous from one person to another, and why even within an individual’s brain, some regions are spared. “It is striking that many amyloid-positive, clinically unimpaired individuals have low levels of tau. It is possible that these individuals have protective factors that prevent or slow downstream tau accumulation. Understanding resilient individuals and resilient brain regions could pave the way for preventative strategies,” Mormino wrote to Alzforum.

One such case, that of Aliria Rosa Piedrahita de Villegas, was discussed in San Diego. Her APOE3 Christchurch mutation protected her from otherwise certain autosomal-dominant AD for nearly 30 years; in part, it seems, by keeping tangles at bay (see related conference story).—Madolyn Bowman Rogers


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News Citations

  1. Tau PET Aligns Spread of Pathology with Alzheimer’s Staging
  2. Brain Imaging Suggests Aβ Unleashes the Deadly Side of Tau
  3. Imaging Clinches Causal Connections between Aβ, Tau, Circuitry, and Cognition
  4. PET Firms Up Amyloid Cascade: Plaques, Inflammation, Tangles
  5. From Near and Far, Aβ Beckons Tau to Tangle in the Cortex
  6. Move Over Aβ, CSF P-Tau Tells Us There’s Plaque in the Brain
  7. Different CSF Phospho-Taus Match Distinct Changes in Brain Pathology
  8. Plasma p-Tau217 Set to Transform Alzheimer’s Diagnostics
  9. Head-to-Head Study Confirms Plasma p-Tau231 Rises First in Early AD
  10. TREM2 Goes Up in Spinal Fluid in Early Alzheimer’s
  11. Paper Alert: Slotting TREM2 into Alzheimer’s Pathogenesis
  12. In Alzheimer’s, More TREM2 Is Good for You
  13. Robust TREM2 Expression May Delay Alzheimer’s Disease
  14. Does Alzheimer’s Start in the Heart of the Cholinergic System?
  15. Simulating Tangle Spread Along Axons, Scientists Predict Tau PET Patterns
  16. Neurons Release Tau in Response to Excitation
  17. News From the PET Front: Early Amyloid Networks and Tau Mystery
  18. ApoE4 Makes All Things Tau Worse, From Beginning to End
  19. Squelching ApoE in Astrocytes of Tau-Ravaged Mice Dampens Degeneration
  20. In Brain With Christchurch Mutation, More ApoE3 Means Fewer Tangles

Paper Citations

  1. . Amyloid-associated increases in soluble tau is a key driver in accumulation of tau aggregates and cognitive decline in early Alzheimer. medRxiv, January 08, 2022. medRxiv
  2. . Microglial activation and tau propagate jointly across Braak stages. Nat Med. 2021 Sep;27(9):1592-1599. Epub 2021 Aug 26 PubMed. Correction.
  3. . Earlier Alzheimer's disease onset is associated with tau pathology in brain hub regions and facilitated tau spreading. Nat Commun. 2022 Aug 20;13(1):4899. PubMed.
  4. . The BIN1 rs744373 Alzheimer's disease risk SNP is associated with faster Aβ-associated tau accumulation and cognitive decline. Alzheimers Dement. 2021 Jun 1; PubMed.
  5. . KL-VS heterozygosity is associated with lower amyloid-dependent tau accumulation and memory impairment in Alzheimer's disease. Nat Commun. 2021 Jun 22;12(1):3825. PubMed.

Further Reading