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Coomans EM, Tomassen J, Ossenkoppele R, Golla SS, den Hollander M, Collij LE, Weltings E, van der Landen S, Wolters EE, Windhorst AD, Barkhof F, de Geus EJ, Scheltens P, Visser PJ, van Berckel BN, den Braber A. Genetically identical twins show comparable tau PET load and spatial distribution. Brain. 2022 Jan 12; PubMed.
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Lund University
I think the study is truly intriguing and novel. The study 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.
However, only 15 (19 percent) of the included twins exhibited Aβ accumulation, and more cases will be needed to better understand how much of the genetic effects on tau accumulation are mediated by Aβ accumulation. Therefore, it will be very exciting to see future studies including more participants with AD, and preferably also individuals with more widespread tau pathology.
View all comments by Oskar HanssonUniversity of Pennsylvania
More so than the other hallmark pathology of Alzheimer's disease, Aβ, the distribution of tau pathology appears to determine where neurodegeneration will occur and what aspects of cognition are impaired (La Joie et al., 2020; Bejanin et al., 2017). In addition, autopsy and in vivo PET studies suggest the distribution of tau pathology differs substantially across individuals (Murray et al., 2011; Vogel et al., 2021). Understanding what causes these differences may be informative toward understanding the genesis of tau pathology.
How large a role does the genome play in determining individual differences in the timing and trajectory of tau pathology? This is one of the main underlying questions of this fascinating study by Emma Coomans and colleagues. The study examines the degree to which 78 cognitively unimpaired monozygotic twins show concordance in the magnitude and distribution of tau pathology, measured using positron emission tomography (PET). Coomans et al. find that the extent and distribution of tau pathology within twin-pairs is largely concordant, with discordance mainly stemming from twin pairs who also show discordant Aβ pathology.
Interestingly, twins with discordant tau magnitude still often showed a similar tau distribution. Looking across a full suite of environmental measures relevant to dementia, Coomans et al. find twin pairs with discordant pathology also tend to differ in their degree of depression, (health-related) social activity, and physical activity.
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, but that environmental factors may alter the disease timeline. This opens the door for future research to investigate links between genetic polymorphisms, brain gene expression, and regional vulnerability to AD pathology, hopefully paving the way toward individualized treatment.
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 to-be-determined aspects of one’s environment.
The study also provides opportunities to investigate other biological factors that might mediate twin-pair discordance. Are there brain-network properties that are present in more resilient twins? When during the lifespan do such differences emerge? This study inspires many very interesting questions that demand further investigation.
Other interesting findings abound in this well-executed study. The authors should be commended for collecting this rare and valuable dataset, and for providing an analysis rich in insight.
References:
Bejanin A, Schonhaut DR, La Joie R, Kramer JH, Baker SL, Sosa N, Ayakta N, Cantwell A, Janabi M, Lauriola M, O'Neil JP, Gorno-Tempini ML, Miller ZA, Rosen HJ, Miller BL, Jagust WJ, Rabinovici GD. Tau pathology and neurodegeneration contribute to cognitive impairment in Alzheimer's disease. Brain. 2017 Dec 1;140(12):3286-3300. PubMed.
La Joie R, Visani AV, Baker SL, Brown JA, Bourakova V, Cha J, Chaudhary K, Edwards L, Iaccarino L, Janabi M, Lesman-Segev OH, Miller ZA, Perry DC, O'Neil JP, Pham J, Rojas JC, Rosen HJ, Seeley WW, Tsai RM, Miller BL, Jagust WJ, Rabinovici GD. Prospective longitudinal atrophy in Alzheimer's disease correlates with the intensity and topography of baseline tau-PET. Sci Transl Med. 2020 Jan 1;12(524) PubMed.
Murray ME, Graff-Radford NR, Ross OA, Petersen RC, Duara R, Dickson DW. Neuropathologically defined subtypes of Alzheimer's disease with distinct clinical characteristics: a retrospective study. Lancet Neurol. 2011 Sep;10(9):785-96. PubMed.
Vogel JW, Young AL, Oxtoby NP, Smith R, Ossenkoppele R, Strandberg OT, La Joie R, Aksman LM, Grothe MJ, Iturria-Medina Y, Alzheimer’s Disease Neuroimaging Initiative, Pontecorvo MJ, Devous MD, Rabinovici GD, Alexander DC, Lyoo CH, Evans AC, Hansson O. Four distinct trajectories of tau deposition identified in Alzheimer's disease. Nat Med. 2021 May;27(5):871-881. Epub 2021 Apr 29 PubMed.
View all comments by Jacob VogelAmsterdam University Medical Center
It is not inconceivable that in the future, we will use the genome to predict, before symptoms occur, who is at risk of developing a specific neurodegenerative disease later in life. Therefore, it is reassuring that aspects of this genetic risk can be already be observed in the earliest tau stages.
In fact, it is interesting that the genetic component for distinct preclinical aspects of neurodegenerative diseases is substantial: this opens the way toward preclinical treatment, at the earliest stages, of those with an increased genetic risk of disease.
View all comments by Henne HolstegeMake a Comment
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