Neurofibrillary tangles spread from the hippocampus into the neocortex via axonal highways, but only after Aβ pushes them out the door. So claims a study published in Nature Neuroscience on February 5. Researchers led by Keith Johnson at Massachusetts General Hospital in Boston combined multiple imaging modalities to connect Aβ accumulation to an eroding axonal circuitry and tau accumulation outside the medial temporal lobe. They found that tau fibrils spread via synaptically linked regions, as opposed to those that are merely nearby. Tau did this mainly in people with elevated Aβ. Tau’s appearance outside of the hippocampus then coincided with the first inklings of memory problems.
- Researchers combined multiple imaging modalities to draw causal connections between AD pathology and cognition.
- Aβ plaques predicted a crumbling white-matter tract connecting the hippocampus to the posterior cingulate cortex. This in turn predicted accumulation of tau there.
- Tau accumulation in the PCC predicted a decline in memory.
“This study is a terrific example of translational neuroscience,” commented Rik Ossenkoppele of VU University Medical Center in Amsterdam. “[The findings] emphasize the importance of Aβ as a potential trigger for downstream effects, while tau pathology might be the actual driver of neurodegeneration and subsequent cognitive decline.”
Ever since Braak staging traced the insidious trajectory of tau tangles from the medial temporal lobe (mTL) out into the cortex, researchers have sought to understand what triggers this dangerous shift, and how it proceeds (see Research Timeline). Animal studies have implicated transsynaptic spread as tau’s travel mode of choice, and fingered Aβ as an instigator of the process (de Calignon et al., 2012; Ahmed et al., 2014; Pooler et al., 2015; Dec 2017 news). The recent advent of tau-PET tracers has allowed researchers to address these relationships in living people, and cross-sectional findings have so far revealed that the movement of tau pathology from the mTL into the cortex is a pathological event that Aβ may initiate (Mar 2016 news; Aug 2016 news).
To clinch causal connections between Aβ, tau, neural circuitry, and ultimately, memory problems (see graphic at left), first author Heidi Jacobs and colleagues made use of multimodal longitudinal data from the Harvard Aging Brain Study (HABS). At baseline, the study’s 256 participants were cognitively healthy and averaged 73.5 years old. Over the following seven years, participants underwent annual cognitive tests as well as multiple forms of brain imaging. These included amyloid-PET scans, magnetic resonance imaging (MRI) to assess hippocampal volume, and diffusion tensor imaging (DTI) to interrogate the integrity of white-matter tracts. After the third year of the study, researchers added PET imaging with the tau pathology-specific tracer flortaucipir to the mix.
First, they asked whether elevated Aβ correlated with hippocampal volume loss, which can serve as a proxy for neurodegeneration. They found that having neocortical Aβ accumulation based on PiB-PET uptake at baseline predicted steeper shrinkage of the hippocampus over the following six years. Though hippocampal volume loss can be attributed to factors other than AD pathology, the first tau-PET measurements taken in the entorhinal cortex between the third and fourth years of the study correlated tightly with the extent of hippocampal shrinkage at the nearest time point, suggesting hippocampal atrophy was indeed a rough proxy for tau pathology in this population.
The researchers next asked whether hippocampal atrophy would predict abnormalities in the hippocampal cingulum bundle. The HCB is a white-matter tract that projects from the hippocampus into the posterior cingulate cortex (PCC). They investigated this tract not only because it is easy to interrogate with DTI, but also because it represents a likely escape route for toxic forms of tau from the mTL. Interestingly, they found that low hippocampal volume at baseline predicted declining HCB diffusivity, an indicator of waning integrity, over time. In contrast, having a small hippocampus did not predict damage to the uncinate fasciculus. The UF is a white-matter tract close to the hippocampus, but does not innervate it. Notably, damage to the HCB did not predict hippocampal shrinkage, suggesting atrophy there preceded the white-matter damage.
Would crumbling HCB integrity coincide with the spread of tau pathology to the downstream PCC? Yes, according to tau PET data. The researchers reported that HCB damage at baseline predicted a steeper annual increase in PCC tau. Once again, white-matter abnormalities in the nearby, but unconnected, UF had no bearing on PCC tau. Furthermore, HCB abnormalities did not correlate with levels of tau in the inferior temporal cortex, a region adjacent to, but not tightly connected with, the hippocampus.
Strikingly, the researchers found that low HCB diffusivity only associated with a rise in PCC tau in people who already had elevated Aβ at baseline. The findings support a model in which Aβ triggers tau propagation along the HCB, which in turn leads to the accumulation of tau in the downstream PCC.
Path to Problems. Imaging uncovered links among amyloid, a damaged HCB fiber track, posterior cingulate tau, and memory (see boxes). High diffusivity in HCB (red line, bottom) correlated with memory decline in people who tested positive for amyloid and tau (right graph), but not negative (left graph). [Courtesy of Jacobs et al., Nature Neuroscience, 2018.]
How does cognition fit into this cascade? That, after all, is what it’s all about. The scientists found that low white-matter integrity of the HCB at baseline predicted slippage of memory over the following six years, but not of executive function. They next classified participants as having either high or low PCC tau, based on a standardized PET uptake ratio of 1.28, and found that high tau drove the association between HCB integrity and memory decline. Narrowing things further, they found that among people with elevated PCC tau, the connection between HCB integrity and memory decline only occurred in those with elevated Aβ at baseline.
Jacobs told Alzforum that this imaging study cannot nail down specific molecular mechanisms of transsynaptic transfer of tau. That said, the findings do support the idea that neocortical Aβ aggregation somehow incites tau pathology to spread from the mTL into the cortex via synaptic connections, rather than through simple diffusion into nearby regions. Based on the changes in diffusivity the researchers observed in the HCB, they proposed that tau’s propagation through the tract somehow disrupted the structure of both axons and myelin along the way. However, they also acknowledged the possibility that neurodegeneration in the hippocampus, on top of tau’s trailblazing, could have caused the alterations in the connected white-matter tract.
Zeshan Ahmed of Eli Lilly in Surrey, England, who previously reported that tau spread transsynaptically in a mouse model of tauopathy, expressed excitement that the human findings aligned well with those in various animal models. “A greater understanding of the underlying mechanisms of disease progression in human patients opens doors to new therapeutic strategies, but also helps validate the in vivo models we use to develop much-needed therapies,” he told Alzforum.
Michel Goedert of the MRC Laboratory of Molecular Biology in Cambridge, England, agreed. Goedert also broached the question of how this Aβ-associated tau propagation relates to tau’s behavior in other tauopathies. “One must bear in mind that prion-like spreading of tau aggregates is also believed to be important in sporadic tauopathies that lack Aβ deposits, such as Pick’s disease and progressive supranuclear palsy,” he wrote. “Does it follow that the spreading of tau pathology is less effective in those diseases?”
Ahmed also wondered about propagation in other tauopathies, speculating that other triggers might substitute for Aβ in those cases. “Maybe some forms of tau are more likely to aggregate, or are more concentrated for some reason,” he said. Mutations in tau can cause tauopathies other than AD. Ahmed added that much is left to learn about exactly how tau transfers from one neuron to another, and thus how best to target this propagation. Interestingly, recent findings have implicated presynaptic tau, either in the context of dystrophic axons congregating around Aβ plaques, or within cells expressing mutant forms of tau that adhere to synaptic vesicles, as a pathological form that could facilitate propagation (Dec 2017 news; Feb 2018 news).
Jacobs and colleagues are continuing to collect longitudinal imaging and cognitive data on the HABS cohort, and plan to investigate tau’s propagation beyond the PCC should participants develop early AD. Given the connection between Aβ accumulation, the propagation of tau pathology, and subsequent memory problems, they proposed tau-PET imaging could serve as an additional outcome measure in Aβ-targeted trials.—Jessica Shugart
- Aβ Plaques: Breeding Ground for Toxic Tau?
- Tau PET Aligns Spread of Pathology with Alzheimer’s Staging
- Brain Imaging Suggests Aβ Unleashes the Deadly Side of Tau
- Tau Uses Synaptogyrin-3 to Clump Synaptic Vesicles
- de Calignon A, Polydoro M, Suárez-Calvet M, William C, Adamowicz DH, Kopeikina KJ, Pitstick R, Sahara N, Ashe KH, Carlson GA, Spires-Jones TL, Hyman BT. Propagation of tau pathology in a model of early Alzheimer's disease. Neuron. 2012 Feb 23;73(4):685-97. PubMed.
- Ahmed Z, Cooper J, Murray TK, Garn K, McNaughton E, Clarke H, Parhizkar S, Ward MA, Cavallini A, Jackson S, Bose S, Clavaguera F, Tolnay M, Lavenir I, Goedert M, Hutton ML, O'Neill MJ. A novel in vivo model of tau propagation with rapid and progressive neurofibrillary tangle pathology: the pattern of spread is determined by connectivity, not proximity. Acta Neuropathol. 2014 May;127(5):667-83. Epub 2014 Feb 16 PubMed.
- Pooler AM, Polydoro M, Maury EA, Nicholls SB, Reddy SM, Wegmann S, William C, Saqran L, Cagsal-Getkin O, Pitstick R, Beier DR, Carlson GA, Spires-Jones TL, Hyman BT. Amyloid accelerates tau propagation and toxicity in a model of early Alzheimer's disease. Acta Neuropathol Commun. 2015 Mar 24;3:14. PubMed.
No Available Further Reading
- Jacobs HI, Hedden T, Schultz AP, Sepulcre J, Perea RD, Amariglio RE, Papp KV, Rentz DM, Sperling RA, Johnson KA. Structural tract alterations predict downstream tau accumulation in amyloid-positive older individuals. Nat Neurosci. 2018 Mar;21(3):424-431. Epub 2018 Feb 5 PubMed.