Mastroeni D, McKee A, Grover A, Rogers J, Coleman PD.
Epigenetic differences in cortical neurons from a pair of monozygotic twins discordant for Alzheimer's disease.
PLoS One. 2009;4(8):e6617.
PubMed.
There are many observations, including from our own laboratory, that indicate that epigenetic drift is likely to be a substantial mechanism predisposing individuals to LOAD and contributing to the course of disease. In this context, the study by Mastroeni et al. is a very interesting report, as we may gain more insight into epigenetic events in AD. However, in my opinion, the study presents a potentially unusual epigenetic phenotype in the affected co-twin. In a previous study from our group (Wang et al., 2008), we were able to show that most DNA methylation changes in AD brains are restricted to specific genes and are rather subtle. In this new study of discordant twins, the authors found significant global demethylation in the affected brain areas of the AD twin. In general, such rare monozygotic twins discordant for a disease offer a great opportunity to study molecular events that may contribute to a predisposition or the development of a complex disease such as AD. And indeed, this observation is highly interesting as it demonstrates clearly that epigenetic mechanisms are affected in AD. However, the intricacy is that, similar to epigenetic studies in cancer, we look at the endpoint of the disease, where it is difficult to establish if the observed epigenetic phenotype is the cause or the result of the disease. In this case, the global demethylation in the affected brain areas may indicate that specific components of the epigenetic machinery (such as DNA maintenance methylation) were inactivated, which in turn could indicate that the observed epigenetic patterns are rather the result of the course of the disease.
In addition, we also see that merely measuring DNA methylation levels in postmortem brain samples of AD patients with a long AD history may not be enough in the long run, as we primarily observe the endpoint of the disease. In this case, the affected twin had lived already more than 16 years with the disease. Hence, it is important to identify epigenetic events that happen during very early stages of AD, or even before AD symptoms occur in the first place! It may also be necessary to study the age effects that are evident in AD. For example, in our study, we identified a notably age-specific epigenetic drift in AD patients, supporting a potential role of epigenetic effects in the development of the disease. The occurrence of early epigenetic changes in a significant subset of younger AD patients may be indicative of AD-specific epigenetic abnormalities predisposing to AD. It seems that specific genes in the human brain have a higher likelihood of developing abnormal epigenetic patterns, meaning they are epigenetically unstable. Such metastability could be due to vulnerable chromosomal regions, to environmentally induced changes affecting specific pathways in the brain, but also simply to stochastic fluctuations. For example, we found that some genes that participate in amyloid-β processing (PSEN1, ApoE) and methylation homeostasis (MTHFR, DNMT1) show a significant interindividual epigenetic variability, which may contribute to LOAD predisposition. For the present study on the twins, this could potentially indicate that the affected twin may have had an unfavorable epigenetic event affecting the DNMT1 or MTHFR gene, thereby interrupting methylation homeostasis in certain areas of the brain.
It is noteworthy, though, that the non-affected twin also shows weak signs of AD pathology, indicating that he also may have been predisposed to AD. It seems likely that, had he lived longer, he might have developed AD symptoms as well. Such observations in AD twins are not new; from older twin studies we know that the onset of AD in identical twins can differ by more than 20 years. Rather than genetic causes, epigenetic factors are probably much better suited to explain the observed anomalies in AD, as individual people may acquire aberrant epigenetic patterns during many developmental stages. It is important to note that it is unlikely that age-dependent epigenetic drift will manifest itself by switching AD susceptibility genes completely on or off, as observed in the affected twins in this study. That is true especially if the majority of changes are due to stochastic fluctuations, which could be more common than is generally assumed.
One important finding of this study is that epigenetic abnormalities were restricted to certain brain tissues. This finding could indicate, again, that the observed methylation patterns are the result of the disease and not the cause. On the other hand, it is also plausible that epigenetic events happened during early tissue differentiation stages, predisposing the twins to AD, because later environmental factors (such as work-related chemical exposures) are unlikely to affect only specific brain areas, but rather the whole brain. Small epimutations in the critical genes may be tolerated to a certain degree and merely reflect the range of interindividual variance. Environmental factors could be the triggers that push an epigenome across the disease threshold with the result that the brain starts to malfunction (see also “Epigenetic theory of late onset AD” in Wang et al., 2008). In future twin studies, it may be helpful to study additional tissues outside the affected brain, to learn when during the development of a human being critical epimutations occur and how the environment affects these events.
References:
Wang SC, Oelze B, Schumacher A.
Age-specific epigenetic drift in late-onset Alzheimer's disease.
PLoS One. 2008;3(7):e2698.
PubMed.
Dr. Schumacher’s commentary about our paper makes a number of valid points that, in their totality, emphasize that there is much still to be learned about epigenetics with regard to the normally aging and Alzheimer brain. For example, he refers to “epigenetic drift” and “stochastic fluctuations,” phrases that imply a random process. We, on the other hand, prefer to use the term “life events,” which implies a causal connection between specific events and epigenetic consequences. Such causal connection is consistent with the work of Fuso et al. (2008), which shows that “PS1 and BACE genes can be upregulated even in vivo by B vitamin deficiency, a condition that limits methylation activity.” Of course, what is missing here is the demonstration that the experimental B vitamin deficiency led to decreased DNA methylation (or other epigenetic regulator) of the specific genes affected in their animals.
The hypothesis that life events, rather than a stochastic process, influence epigenetic phenomena is also consistent with the comment in Fraga et al. (2005) that similarities in the epigenome of the identical twins they studied was related to the amount of time they spent together. In a stochastic process one would expect that time only would determine similarity/dissimilarity, rather than time spent together.
Of course, an influence of life events and a stochastic process are not mutually exclusive (e.g., Poulsen et al., 2007). Further research is needed to determine the role that each may play in the epigenetics of aging and Alzheimer disease.
Dr. Schumacher also raises the appropriate issue of whether epigenetic changes in AD are a result or a cause of the disease. It appears to us that this is more complicated than an either/or proposition. For example, data indicate that the APP gene can be methylated (West et al., 1995) and also that Aβ induces epigenetic effects (Chen et al., 2009). Again, further research is needed to resolve this issue.
Dr. Schumacher raises other important areas needing further research, including the elucidation of epigenetic events during the very early stages of AD and their relationship to age effects “that are evident in AD.”
References:
Chen KL, Wang SS, Yang YY, Yuan RY, Chen RM, Hu CJ.
The epigenetic effects of amyloid-beta(1-40) on global DNA and neprilysin genes in murine cerebral endothelial cells.
Biochem Biophys Res Commun. 2009 Jan 2;378(1):57-61.
PubMed.
Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, Heine-Suñer D, Cigudosa JC, Urioste M, Benitez J, Boix-Chornet M, Sanchez-Aguilera A, Ling C, Carlsson E, Poulsen P, Vaag A, Stephan Z, Spector TD, Wu YZ, Plass C, Esteller M.
Epigenetic differences arise during the lifetime of monozygotic twins.
Proc Natl Acad Sci U S A. 2005 Jul 26;102(30):10604-9.
PubMed.
Fuso A, Nicolia V, Cavallaro RA, Ricceri L, D'Anselmi F, Coluccia P, Calamandrei G, Scarpa S.
B-vitamin deprivation induces hyperhomocysteinemia and brain S-adenosylhomocysteine, depletes brain S-adenosylmethionine, and enhances PS1 and BACE expression and amyloid-beta deposition in mice.
Mol Cell Neurosci. 2008 Apr;37(4):731-46.
PubMed.
Poulsen P, Esteller M, Vaag A, Fraga MF.
The epigenetic basis of twin discordance in age-related diseases.
Pediatr Res. 2007 May;61(5 Pt 2):38R-42R.
PubMed.
West RL, Lee JM, Maroun LE.
Hypomethylation of the amyloid precursor protein gene in the brain of an Alzheimer's disease patient.
J Mol Neurosci. 1995;6(2):141-6.
PubMed.
After reading with great interest the comment by Dr. Schumacher and the response by Dr. Coleman, I'd like to point out that the demonstration that B vitamin deficiency led to decreased DNA methylation (missing in our 2008 paper) was actually given in our recent paper on PS1 promoter demethylation (Fuso et al., 2009).
I completely agree with the conclusion that there is much more to understand in the area of epigenetic changes in LOAD. It seems to me of great importance that different approaches are applied by different groups to investigate this topic.
References:
Fuso A, Nicolia V, Pasqualato A, Fiorenza MT, Cavallaro RA, Scarpa S.
Changes in Presenilin 1 gene methylation pattern in diet-induced B vitamin deficiency.
Neurobiol Aging. 2011 Feb;32(2):187-99.
PubMed.
Comments
Klinikum rechts der Isar
There are many observations, including from our own laboratory, that indicate that epigenetic drift is likely to be a substantial mechanism predisposing individuals to LOAD and contributing to the course of disease. In this context, the study by Mastroeni et al. is a very interesting report, as we may gain more insight into epigenetic events in AD. However, in my opinion, the study presents a potentially unusual epigenetic phenotype in the affected co-twin. In a previous study from our group (Wang et al., 2008), we were able to show that most DNA methylation changes in AD brains are restricted to specific genes and are rather subtle. In this new study of discordant twins, the authors found significant global demethylation in the affected brain areas of the AD twin. In general, such rare monozygotic twins discordant for a disease offer a great opportunity to study molecular events that may contribute to a predisposition or the development of a complex disease such as AD. And indeed, this observation is highly interesting as it demonstrates clearly that epigenetic mechanisms are affected in AD. However, the intricacy is that, similar to epigenetic studies in cancer, we look at the endpoint of the disease, where it is difficult to establish if the observed epigenetic phenotype is the cause or the result of the disease. In this case, the global demethylation in the affected brain areas may indicate that specific components of the epigenetic machinery (such as DNA maintenance methylation) were inactivated, which in turn could indicate that the observed epigenetic patterns are rather the result of the course of the disease.
In addition, we also see that merely measuring DNA methylation levels in postmortem brain samples of AD patients with a long AD history may not be enough in the long run, as we primarily observe the endpoint of the disease. In this case, the affected twin had lived already more than 16 years with the disease. Hence, it is important to identify epigenetic events that happen during very early stages of AD, or even before AD symptoms occur in the first place! It may also be necessary to study the age effects that are evident in AD. For example, in our study, we identified a notably age-specific epigenetic drift in AD patients, supporting a potential role of epigenetic effects in the development of the disease. The occurrence of early epigenetic changes in a significant subset of younger AD patients may be indicative of AD-specific epigenetic abnormalities predisposing to AD. It seems that specific genes in the human brain have a higher likelihood of developing abnormal epigenetic patterns, meaning they are epigenetically unstable. Such metastability could be due to vulnerable chromosomal regions, to environmentally induced changes affecting specific pathways in the brain, but also simply to stochastic fluctuations. For example, we found that some genes that participate in amyloid-β processing (PSEN1, ApoE) and methylation homeostasis (MTHFR, DNMT1) show a significant interindividual epigenetic variability, which may contribute to LOAD predisposition. For the present study on the twins, this could potentially indicate that the affected twin may have had an unfavorable epigenetic event affecting the DNMT1 or MTHFR gene, thereby interrupting methylation homeostasis in certain areas of the brain.
It is noteworthy, though, that the non-affected twin also shows weak signs of AD pathology, indicating that he also may have been predisposed to AD. It seems likely that, had he lived longer, he might have developed AD symptoms as well. Such observations in AD twins are not new; from older twin studies we know that the onset of AD in identical twins can differ by more than 20 years. Rather than genetic causes, epigenetic factors are probably much better suited to explain the observed anomalies in AD, as individual people may acquire aberrant epigenetic patterns during many developmental stages. It is important to note that it is unlikely that age-dependent epigenetic drift will manifest itself by switching AD susceptibility genes completely on or off, as observed in the affected twins in this study. That is true especially if the majority of changes are due to stochastic fluctuations, which could be more common than is generally assumed.
One important finding of this study is that epigenetic abnormalities were restricted to certain brain tissues. This finding could indicate, again, that the observed methylation patterns are the result of the disease and not the cause. On the other hand, it is also plausible that epigenetic events happened during early tissue differentiation stages, predisposing the twins to AD, because later environmental factors (such as work-related chemical exposures) are unlikely to affect only specific brain areas, but rather the whole brain. Small epimutations in the critical genes may be tolerated to a certain degree and merely reflect the range of interindividual variance. Environmental factors could be the triggers that push an epigenome across the disease threshold with the result that the brain starts to malfunction (see also “Epigenetic theory of late onset AD” in Wang et al., 2008). In future twin studies, it may be helpful to study additional tissues outside the affected brain, to learn when during the development of a human being critical epimutations occur and how the environment affects these events.
References:
Wang SC, Oelze B, Schumacher A. Age-specific epigenetic drift in late-onset Alzheimer's disease. PLoS One. 2008;3(7):e2698. PubMed.
Banner Research Institute
Dr. Schumacher’s commentary about our paper makes a number of valid points that, in their totality, emphasize that there is much still to be learned about epigenetics with regard to the normally aging and Alzheimer brain. For example, he refers to “epigenetic drift” and “stochastic fluctuations,” phrases that imply a random process. We, on the other hand, prefer to use the term “life events,” which implies a causal connection between specific events and epigenetic consequences. Such causal connection is consistent with the work of Fuso et al. (2008), which shows that “PS1 and BACE genes can be upregulated even in vivo by B vitamin deficiency, a condition that limits methylation activity.” Of course, what is missing here is the demonstration that the experimental B vitamin deficiency led to decreased DNA methylation (or other epigenetic regulator) of the specific genes affected in their animals.
The hypothesis that life events, rather than a stochastic process, influence epigenetic phenomena is also consistent with the comment in Fraga et al. (2005) that similarities in the epigenome of the identical twins they studied was related to the amount of time they spent together. In a stochastic process one would expect that time only would determine similarity/dissimilarity, rather than time spent together.
Of course, an influence of life events and a stochastic process are not mutually exclusive (e.g., Poulsen et al., 2007). Further research is needed to determine the role that each may play in the epigenetics of aging and Alzheimer disease.
Dr. Schumacher also raises the appropriate issue of whether epigenetic changes in AD are a result or a cause of the disease. It appears to us that this is more complicated than an either/or proposition. For example, data indicate that the APP gene can be methylated (West et al., 1995) and also that Aβ induces epigenetic effects (Chen et al., 2009). Again, further research is needed to resolve this issue.
Dr. Schumacher raises other important areas needing further research, including the elucidation of epigenetic events during the very early stages of AD and their relationship to age effects “that are evident in AD.”
References:
Chen KL, Wang SS, Yang YY, Yuan RY, Chen RM, Hu CJ. The epigenetic effects of amyloid-beta(1-40) on global DNA and neprilysin genes in murine cerebral endothelial cells. Biochem Biophys Res Commun. 2009 Jan 2;378(1):57-61. PubMed.
Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, Heine-Suñer D, Cigudosa JC, Urioste M, Benitez J, Boix-Chornet M, Sanchez-Aguilera A, Ling C, Carlsson E, Poulsen P, Vaag A, Stephan Z, Spector TD, Wu YZ, Plass C, Esteller M. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A. 2005 Jul 26;102(30):10604-9. PubMed.
Fuso A, Nicolia V, Cavallaro RA, Ricceri L, D'Anselmi F, Coluccia P, Calamandrei G, Scarpa S. B-vitamin deprivation induces hyperhomocysteinemia and brain S-adenosylhomocysteine, depletes brain S-adenosylmethionine, and enhances PS1 and BACE expression and amyloid-beta deposition in mice. Mol Cell Neurosci. 2008 Apr;37(4):731-46. PubMed.
Poulsen P, Esteller M, Vaag A, Fraga MF. The epigenetic basis of twin discordance in age-related diseases. Pediatr Res. 2007 May;61(5 Pt 2):38R-42R. PubMed.
West RL, Lee JM, Maroun LE. Hypomethylation of the amyloid precursor protein gene in the brain of an Alzheimer's disease patient. J Mol Neurosci. 1995;6(2):141-6. PubMed.
Sapienza University of Rome
After reading with great interest the comment by Dr. Schumacher and the response by Dr. Coleman, I'd like to point out that the demonstration that B vitamin deficiency led to decreased DNA methylation (missing in our 2008 paper) was actually given in our recent paper on PS1 promoter demethylation (Fuso et al., 2009).
I completely agree with the conclusion that there is much more to understand in the area of epigenetic changes in LOAD. It seems to me of great importance that different approaches are applied by different groups to investigate this topic.
References:
Fuso A, Nicolia V, Pasqualato A, Fiorenza MT, Cavallaro RA, Scarpa S. Changes in Presenilin 1 gene methylation pattern in diet-induced B vitamin deficiency. Neurobiol Aging. 2011 Feb;32(2):187-99. PubMed.
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