Researchers led by Yakeel Quiroz at Massachusetts General Hospital in Boston have used PET imaging to measure both Aβ and tau deposition in members of a large Colombian kindred affected by an autosomal-dominant Alzheimer’s disease mutation. On average, family members who inherit the mutation develop symptoms by the age of 44. In the February 12 JAMA Neurology, Quiroz and colleagues report that Aβ starts to accumulate in the neocortices of carriers 10 to 15 years prior, whereas tau deposits emerge in the medial temporal lobe about six years prior and spread from there into the cortex even later, once people start to have trouble with memory. The new findings support the idea that Aβ instigates the spread of tau pathology beyond the medial temporal lobe, and that this spreading process is intimately connected with the cognitive manifestations of AD. Co-author Keith Johnson and colleagues recently came to the same conclusion after analyzing longitudinal data from people with late-onset AD (Feb 2018 news).
- A cross-sectional study measured Aβ, tau, and cognition in the Colombian PSEN1 E280A kindred.
- In carriers, Aβ rose 15 years prior to expected symptom onset, while tau rose up to six years prior in the medial temporal lobe.
- Tau pathology invaded the cortex mostly in symptomatic people.
“This [study] helps us to better understand the preclinical trajectory of this early onset autosomal-dominant disease tightly linked to amyloid overproduction as its driving force,” commented Samuel Lockhart of Wake Forest University in Winston-Salem, North Carolina.
“This study adds to a growing appreciation for the utility of biomarkers in identifying preclinical AD,” said Samantha Burnham of Commonwealth Scientific and Industrial Research Organization in Canberra, Australia. She added that the close association between tau accumulation and cognitive symptoms suggests that tau PET imaging might be a useful marker of treatment response in clinical studies.
Research from several groups has shown conclusively that the pathological process of AD begins many years prior to the first signs of forgetfulness. Understanding more about the preclinical course of the disease is crucial for the development of biomarkers and effective treatments. People with autosomal-dominant AD mutations are destined to have AD, and people who inherit the same mutation tend to have similar ages at onset. An estimated 1,800 people in and around the Colombian city of Medellín carry the PSEN1 E280A mutation. Most develop mild cognitive impairment (MCI) due to AD between the ages of 43–45 and dementia before they turn 50 (Acosta-Baena et al., 2011). Hundreds of these family members have volunteered for longitudinal studies, which have yielded invaluable information on AD biomarkers (Jan 2015 news).
In the current study, Quiroz added tau PET imaging to the roster of analyses, making this the largest tau-PET imaging study on people with a single ADAD mutation to date. Twenty-four members of the kindred traveled from Colombia to Boston to undergo brain scans at Massachusetts General Hospital. They averaged 38 years old, and included 12 cognitively normal noncarriers, as well as 12 carriers, of whom nine were cognitively normal and three had MCI.
The researchers first assessed levels of Aβ accumulation based on the distribution volume ratio (DVR) of the PET ligand PiB, using the cerebellum as a reference. None of the noncarriers had any signs of elevated Aβ, nor did the youngest carrier, who was 28. The other 11 carriers all had evidence of Aβ accumulation, with seven reaching the brain-wide threshold for positivity—a PiB DVR of at least 1.2. The extent of Aβ accumulation increased with advancing age of the carriers, and the three carriers with MCI had the highest burden of Aβ. The plaque distribution resembled patterns reported in people with late-onset AD (LOAD), with preferential PiB binding in the posterior cingulate, precuneus, parietotemporal, frontal, and basal ganglia regions.
Quiroz next assessed tau accumulation, comparing the average standard uptake value ratios (SUVR) of 18F-flortaucipir, formerly called AV1451, in different regions of the brain. She told Alzforum that while the field has not yet agreed upon a standard threshold for tau accumulation, they chose an SUVR of 1.3 as a working threshold for this study. None of the noncarriers showed signs of elevated tau deposition in the medial temporal lobe (mTL) or elsewhere, regardless of their age. Tau deposits are often detected in the mTL of aging people; however, all of the noncarriers were 55 or younger, most in their 30s or 40s.
Likewise, little flortaucipir stuck in the mTL of the six mutation carriers who were under age 38. However, five of the six carriers who were 38 or older had evidence of tau accumulation in the mTL. Of these five, four also had substantial tau deposition in the cortex, most notably in the inferior and lateral temporo-parietal, the parieto-occipital, the posterior cingulate cortex, and in the precuneus. The three people with MCI had cortical tau, as did one cognitively normal mutation carrier. People with elevated cortical tau also had the highest degree of cortical Aβ accumulation.
Aβ Begets Tau. PET imaging of Aβ (left panels) and tau (right panels) in unimpaired (top) and impaired (bottom) mutation carriers. Both pathologies become more extensive after symptoms appear. [Courtesy of Quiroz et al., JAMA Neurology, 2018.]
Among mutation carriers, the amount of tau accumulation in the entorhinal cortex and in the inferior temporal lobe correlated with poorer performance on memory tests, and this held true even among the nine presymptomatic carriers.
“By studying mutation carriers at various stages of the disease cascade, the authors provide one of the first comprehensive views of the pattern of AV1451 binding in ADAD,” commented Eric McDade of Washington University in St. Louis. “Importantly, this work supports many of the studies in sporadic AD by indicating that AV1451 binding is absent in those without fibrillar Aβ plaques, and that once symptoms begin, AV1451 binding increases in limbic/paralimbic cortices and then spreads to heteromodal cortices with increased symptoms.”
While Quiroz’s analysis is the largest tau PET study on carriers of a single ADAD mutation, preliminary findings from the Dominantly Inherited Alzheimer’s Network (DIAN) reported tau distribution in 14 symptomatic carriers, 20 asymptomatic carriers, and 16 noncarriers (Aug 2017 conference news). Similar to Quiroz, the DIAN researchers also found that Aβ started accumulating more than a decade prior to estimated symptom onset, but the two studies differed slightly with respect to the timing of tau pathology in the mTL. In DIAN, that first began around the age at onset.
Why the difference? Quiroz speculated that by studying carriers of just a single AD mutation, she teased out the relationship between tau accumulation and disease stage more precisely than can be done in a more heterogeneous cohort comprising dozens of mutations in APP and the presenilins. Others noted that that small number of participants must be kept in mind. In Quiroz’s paper, three of the five mutation carriers with entorhinal tau accumulation were symptomatic, and one of the two asymptomatic carriers was younger than 40, leaving only one asymptomatic, tau-positive person who was six years away from age of onset. However, Quiroz told Alzforum that up to now, a total of 42 members of the Colombian kindred have had flortaucipir imaging to date, and the timing of tau accumulation in the mTL has held at around six years before disease onset.
To Michel Grothe of the German Center for Neurodegenerative Diseases in Rostock, the appearance of tau pathology in the mTL in people without neocortical tangles was the most striking result of the paper. He pointed out that the existence of age-related tauopathy in the mTL has blurred the connections between Aβ and mTL tau pathology in people with LOAD. However, in PSEN1 E280A carriers, any tau pathology can be assumed to be a direct consequence of the overproduction of Aβ caused by the mutation, since they are so young. “This underlines the high potential of cerebral amyloidosis to facilitate the accumulation of medial temporal tau pathology, even in the absence of initial age-related tau changes to act upon,” he wrote to Alzforum. “Given the strikingly low levels of amyloid deposits in the medial temporal lobe in both autosomal-dominant and sporadic forms of AD, this effect is likely to be mediated by remote mechanisms that remain to be elucidated.”
How does this PET data tie in with changes in soluble tau in the CSF? In a joint commentary alongside Quiroz’s paper, McDade and Randall Bateman, also at WashU, pointed out that in the DIAN cohort, the concentration of tau in the cerebrospinal fluid rises more than a decade before estimated symptom onset (Jul 2012 news). This early elevation of CSF tau has also been reported in the PSEN1 E280A carriers (Fleisher et al., 2015). “Taken together, these [CSF and PET] findings suggest a modified pathobiological cascade of AD, with tau in cerebrospinal fluid changing 10–15 years before neurofibrillary tau pathology begins,” they wrote.
Both the DIAN and Colombian tau PET imaging studies came to similar conclusions about cortical tau—it largely appeared in people with symptoms, and the precuneus and posterior cingulate took on heavy tau burdens, as did the inferior temporal region. A recent DIAN study also found that the precuneus was the earliest region to accumulate Aβ and to have metabolic and structural changes (Gordon et al., 2018). McDade therefore suggested that in the future, it will be important to understand how tau accumulation in these posterior regions relates to Aβ accumulation, and to specific changes in cognition. Quiroz added that longitudinal studies of the Colombian kindred will track the trajectory of tau in the cortex.
Will these findings in ADAD help researchers understand the trajectory of LOAD? Michael Donohue of the University of Southern California in San Diego believes that despite the obvious limitation of small sample size, Quiroz’s study supports a strong congruence between the two forms of AD. “The findings are strikingly consistent with prospective and retrospective studies of LOAD and other studies of ADAD,” he wrote. “Namely, the finding that Aβ pathology is apparent approximately 15 years prior to symptom onset, and tau pathologies are apparent approximately six years prior to symptom onset, is consistent with other studies in LOAD. The importance of this consistency is to support our hope that future findings in ADAD might translate to LOAD and vice versa.”
Lockhart thinks this study of young ADAD mutation carriers will help researchers distinguish between the effects of central AD pathology and the myriad comorbidities that affect people with LOAD. “Results like those presented here help demonstrate the background of amyloid-driven, tau-mediated neurodegeneration that may be present in patients with LOAD but may interact with other injurious processes to negatively impact cognition and function,” he wrote to Alzforum. “This enables us to be able to better investigate, for example, how elevated vascular risk factors may contribute to tau pathology in late life above and beyond the contributions of amyloid pathology.”—Jessica Shugart
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