Identical twins share the same womb, the same genome—and, it turns out, the same pattern of neurofibrillary tangles. This, according to a paper published January 12 in Brain. Led by Anouk den Braber and Pieter Jelle Visser at VU Amsterdam, the study compared the burden of tau tangles, and their regional distribution, among 39 pairs of identical twins who were in their 60s and 70s, some of whom tested positive for Aβ plaques.
- Among 39 sets of identical twins, tau accumulated in similar regions within each pair.
- A person’s tau-PET scan alone picked out his or her twin with 86 percent accuracy.
- Twins with discordant tau patterns also differed in amyloid status or lifestyle.
For most of the twins, tau deposited in both siblings in a strikingly similar pattern, so much so that the researchers were able to identify a person’s twin with 86 percent accuracy based solely on his or her tau-PET scan. Some twin pairs had discordant patterns of tau accumulation. Those were more likely seen in twins who differed in their Aβ status. Intriguingly, lifestyle factors also tracked with these differences, such that the twin who was less physically or socially active tended to have more tau tangles.
“I think the study is truly intriguing and novel,” commented Oskar Hansson of Lund University in Sweden. “It confirms that genetics plays a very important role in the pathogenesis of AD, and it indicates that genetic variations might also influence where in the brain tau fibrils tend to accumulate.”
Twin Power. Pairs of identical twins enrolled in the EMIF-AD PreclinAD cohort are helping scientists address how genetics and lifestyle each contribute to Alzheimer’s disease. [Courtesy of Pieter Jelle Visser, VU Amsterdam.]
Monozygotic twins are genetically identical, offering researchers the opportunity to tease apart genetic and environmental contributions to myriad traits and diseases. To explore this in AD, the researchers recruited 94 pairs of monozygotic twins from the Netherlands Twins Register. Together with 93 single individuals recruited from the Manchester and Newcastle Age and Cognitive Performance Research Cohort, the resulting cohort, dubbed EMIF-AD PreclinAD, included 285 cognitively normal participants over the age of 60 (Konijnenberg et al., 2018). At baseline, participants underwent amyloid-PET scans, functional and resting-state MRI, neuropsychological evaluations, blood sampling, and physical exams. The twin cohort volunteered for further tests, including CSF sampling, magnetoencephalography, optical coherence tomography, and retinal imaging. Four years later, participants returned for follow-up evaluations, as well as a tau-PET scan.
Previously, the researchers had reported remarkable concordance within twins for vascular risk factors, including white-matter hyperintensities, which have been correlated with cognitive decline (Ten Kate et al., 2018; Jan 2020 news). They also found that AD biomarkers, including amyloid and CSF phospho-tau, arose in a coordinated fashion in many twins, confirming that AD pathogenesis has a strong genetic component (Konijnenberg et al., 2019; Konijnenberg et al., 2021).
Still, genes weren’t everything, There were cases of discordance, for example where one twin accumulated amyloid plaques while the other didn’t. The scientists can now leverage these differences to learn how environmental factors might have influenced the onset and progression of AD in those twins.
But first, the authors wanted to know how genetics influences when and where tau tangles start to accumulate in a person’s brain. First author Emma Coomans and colleagues addressed these questions in the current study. Among the 78 participants, 15 had been amyloid-positive four years prior. Thirty-two twin pairs were concordant for amyloid status, including four pairs who were amyloid-positive and 28 who were amyloid-negative. Among the remaining seven pairs, only one twin tested positive for amyloid.
How about tau? Even by visual inspection of tau-PET scans, the researchers noticed that uptake of the flortaucipir tracer was similar, both in intensity and distribution, in most twin pairs. In quantitative analysis of tracer uptake, they found that global tau burden was more similar within a given twin pair than it was among other age-matched participants.
This was also true in specific brain regions, where twins had similar tau tangle burden in the entorhinal and neocortical regions—corresponding to Braak stage I and Braak V-VI, respectively. However, tau accumulation in the temporal composite regions—representing Braak III-IV—was no more similar between twins than it was among other age-matched participants. Might these within-twin-pair differences in tau accumulation relate to within-twin-pair differences in amyloid status? Indeed, when the researchers set aside the seven twin pairs who had been discordant for amyloid, tau accumulation strongly correlated in twins in all brain regions of interest, including Braak III-IV. In contrast, tau-tangle burden did not correlate in any region within amyloid-discordant twin pairs. The findings support the idea that Aβ deposition is strongly tied to patterns of subsequent tau tangle accumulation.
Identical Twin, Identical Tau? The distribution of tau tracer uptake is shown for two pairs of twins: one with similar (top) and one with discordant (bottom) tau tangle patterns. Twins with similar tau distributions are both amyloid-negative. One of the twins with dissimilar tau was amyloid positive (bottom left). [Courtesy of Coomans et al., Brain, 2022.]
The researchers also compared each participant’s distribution of tau tangles, voxel by voxel, to those of every other participant. They found the spatial distribution of tau tangles within most twin pairs more highly correlated than it was for non-twin pairings. Notably, for 86 percent of participants, spatial distribution of tau more strongly matched to their co-twin than to any other participant.
While similarities in the landscape of tau tangles between twins predominated, there were also some differences. Could environmental factors play a role in those? To find out, the investigators asked whether within-pair tau differences correlated with within-pair differences in lifestyle factors. They had data including scores on the geriatric depression scale, the physical activity scale for the elderly, as well as self-reported involvement in social activities. Indeed, twins who were less physically or socially active, or who had more depressive symptoms, were likelier to bear a greater burden of tau tangles than their siblings. These associations held, at least in some regions of the brain, even when the researchers corrected for amyloid status. This suggested that lifestyle at least partly influences tau accumulation independent from amyloid.
Together, the findings suggest that genetics plays a strong part not only in the overall burden of tau tangles, but in their regional distribution. This genetic contribution was true even among people without amyloid, in whom tau deposition was confined to the medial temporal lobe. How might genetics dictate exactly where tau starts to tangle? The answer may come down to risk, noted Visser. Perhaps genetic background dictates which regions are more vulnerable to tau accumulation, he said.
Importantly, while nature clearly plays a strong hand in dictating when and where tau accumulates, nurture—i.e., lifestyle factors—also partly determines when AD pathogenesis starts. Future studies should help tease out if differences in tau deposition within twin pairs are merely a matter of stage—i.e., the same cascade occurs in both twins but starts at different age, or whether the twins are on different trajectories entirely. Visser noted that at baseline, 14 twin pairs had been discordant for amyloid. Of those, only seven remained in the study for the tau-PET follow-up scan. Of those seven pairs, three had become concordant for amyloid upon follow-up, raising the possibility that they were at different stages along the same disease trajectory. However, the amyloid status at follow-up was not used in the current study.
“While performed in a relatively small, cross-sectional sample, the early returns from this study support the idea that the genome influences regional vulnerability to tau accumulation,” commented Jacob Vogel of the University of Pennsylvania in Philadelphia. “At the same time, the study provides a hopeful message that one’s genome does not fully determine the fate of one’s brain, suggesting that the onset of dementia might be delayed by modifying aspects of one’s environment,” he wrote. Indeed, the findings support the broad conclusions from numerous studies suggesting that leading a healthy life can stave off dementia (Jul 2014 news; Mar 2018 news; Aug 2021 news). “This study inspires many very interesting questions that demand further investigation,” Vogel added.
Visser said ongoing studies will measure plasma biomarkers—both Aβ and p-tau—in stored blood samples taken from volunteers in the National Twin Register for 10 years prior to when they joined the PreclinAD study. This will teach him more about how genetics influence when, and if, AD biomarkers become positive. Importantly, Visser hopes to boost the power of this study by retrospectively measuring plasma biomarkers of participants in the Netherlands Twins Register cohort who never enrolled in PreclinAD.
Other twin cohorts are also investigating the heritability of AD, and have so far found at least moderate similarities within twin pairs in the presence of amyloid plaques (Lindgren et al., 2021; Koncz et al., 2021).—Jessica Shugart
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Konijnenberg E, Carter SF, Ten Kate M, den Braber A, Tomassen J, Amadi C, Wesselman L, Nguyen HT, van de Kreeke JA, Yaqub M, Demuru M, Mulder SD, Hillebrand A, Bouwman FH, Teunissen CE, Serné EH, Moll AC, Verbraak FD, Hinz R, Pendleton N, Lammertsma AA, van Berckel BN, Barkhof F, Boomsma DI, Scheltens P, Herholz K, Visser PJ.
The EMIF-AD PreclinAD study: study design and baseline cohort overview.
Alzheimers Res Ther. 2018 Aug 4;10(1):75.
Ten Kate M, Sudre CH, den Braber A, Konijnenberg E, Nivard MG, Cardoso MJ, Scheltens P, Ourselin S, Boomsma DI, Barkhof F, Visser PJ.
White matter hyperintensities and vascular risk factors in monozygotic twins.
Neurobiol Aging. 2018 Jun;66:40-48. Epub 2018 Feb 10
Konijnenberg E, den Braber A, Ten Kate M, Tomassen J, Mulder SD, Yaqub M, Teunissen CE, Lammertsma AA, van Berckel BN, Scheltens P, Boomsma DI, Visser PJ.
Association of amyloid pathology with memory performance and cognitive complaints in cognitively normal older adults: a monozygotic twin study.
Neurobiol Aging. 2019 May;77:58-65. Epub 2019 Jan 21
Konijnenberg E, Tomassen J, den Braber A, Ten Kate M, Yaqub M, Mulder SD, Nivard MG, Vanderstichele H, Lammertsma AA, Teunissen CE, van Berckel BN, Boomsma DI, Scheltens P, Tijms BM, Visser PJ.
Onset of Preclinical Alzheimer Disease in Monozygotic Twins.
Ann Neurol. 2021 May;89(5):987-1000. Epub 2021 Mar 4
Lindgren N, Kaprio J, Karjalainen T, Ekblad L, Helin S, Karrasch M, Teuho J, Rinne JO, Vuoksimaa E.
Episodic memory and cortical amyloid pathology: PET study in cognitively discordant twin pairs.
Neurobiol Aging. 2021 Dec;108:122-132. Epub 2021 Sep 3
Koncz R, Thalamuthu A, Wen W, Catts VS, Dore V, Lee T, Mather KA, Slavin MJ, Wegner EA, Jiang J, Trollor JN, Ames D, Villemagne VL, Rowe CC, Sachdev PS, Older Australian Twins Study collaborative team.
The heritability of amyloid burden in older adults: the Older Australian Twins Study.
J Neurol Neurosurg Psychiatry. 2021 Dec 17;
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