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...  Read more

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.

View all comments by Axel Schumacher

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...  Read more

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. Abstract

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. Abstract

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. Abstract

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. Abstract

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. Abstract

View all comments by Paul Coleman

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 and Scarpa S. Changes in Presenilin 1 gene methylation pattern in diet-induced B vitamin deficiency. Neurobiol Aging 2009. Abstract

View all comments by Andrea Fuso

Palsdottir et al. show in a fascinating analysis a major decrease in the age of death in carriers of hereditary cystatin C cerebral angiopathy (a L68Q mutation in the cystatin C gene) since the eighteenth century. The comparison with spouse lifespan is particularly striking because life expectancy of those surviving to adults was increasing at the same time as life expectancy of the L68Q carriers (“age of lethality penetrance”) was decreasing. In considering the possible environmental factors during these 200 years, the authors note the striking shift in diet composition, including a twofold greater carbohydrate intake (Fig. 7). It is also likely that the total caloric intake increased since the 1800s. Iceland suffered a major food shortage after the Viking age due to the increasingly cold climate: the population declined by about 35 percent and adult height shrank by two inches. As Einarsson (1573-1659) described it: "Formerly the earth produced all sorts of fruit, plants and roots. But now almost nothing grows.... Frost and cold torment people. The good years are rare.” The...  Read more

Palsdottir et al. show in a fascinating analysis a major decrease in the age of death in carriers of hereditary cystatin C cerebral angiopathy (a L68Q mutation in the cystatin C gene) since the eighteenth century. The comparison with spouse lifespan is particularly striking because life expectancy of those surviving to adults was increasing at the same time as life expectancy of the L68Q carriers (“age of lethality penetrance”) was decreasing. In considering the possible environmental factors during these 200 years, the authors note the striking shift in diet composition, including a twofold greater carbohydrate intake (Fig. 7). It is also likely that the total caloric intake increased since the 1800s. Iceland suffered a major food shortage after the Viking age due to the increasingly cold climate: the population declined by about 35 percent and adult height shrank by two inches. As Einarsson (1573-1659) described it: "Formerly the earth produced all sorts of fruit, plants and roots. But now almost nothing grows.... Frost and cold torment people. The good years are rare.” The eighteenth century Icelanders were plausibly still under severe caloric restriction, compounded by micronutrient deficiency. Even in the later nineteenth century with improving climate, Iceland was one of the poorest countries in Europe.

If this view is valid, then we may consider that caloric restriction was protective for cystatin C L68Q penetrance at an early age. In fact, caloric restriction is protective in various mouse models of brain amyloidosis, familial dominant Alzheimer mutant genes, and of aortic atherosclerosis (Finch, 2007, Chapter 3.2.2; Patel et al. 2005; Wang et al. 2005). There is thus good rationale to examine cystatin C L68Q and other angiopathic mutations for responses to caloric restriction in mouse models as a new approach to prevention.

References:
Einarsson O, quoted in http://www2.sunysuffolk.edu/mandias/lia/decline_of_vikings_iceland.html.

Finch CE. 2007. The Biology of Human Longevity. Inflammation, Nutrition, and Aging in the Evolution of Lifespans. Academic Press: San Diego.

Patel NV, Gordon MN, Connor KE, Good RA, Engelman RW, Mason J, Morgan DG,Morgan TE, Finch CE. 2005. Caloric restriction attenuates Abeta-deposition in Alzheimer transgenic models. Neurobiol Aging. 26:995-1000. Abstract

Wang J, Ho L, Qin W, Rocher AB, Seror I, Humala N, Maniar K, Dolios G, Wang R,Hof PR, Pasinetti GM. 2005. Caloric restriction attenuates beta-amyloid neuropathology in a mouse model of Alzheimer's disease. FASEB J. 19:659-61. Abstract

View all comments by Caleb (Tuck) Finch

Palsdottir et al. conducted extensive linkage disequilibrium and genealogical studies of patients with HCCAA (also called hereditary cerebral hemorrhage with amyloidosis, Icelandic type—HCHWA-I) and found a decrease in age at onset of the disease, and age at death, of mutation carriers during the nineteenth century. This decrease in age at death, from 65 years in carriers born in 1825 to the present-day average of about 30 years, occurred while an increase in lifespan was documented in the general population in Iceland. This decrease in lifespan paralleled a major change in diet, most significantly an increase in sugar and salt intake in Iceland.

This study has important significance for our understanding of factors that affect amyloid deposition as well as cerebral hemorrhages. Studies, mainly in animal models of amyloidosis, should be conducted to determine the role of carbohydrates and/or salt in either cerebral amyloid angiopathy (CAA) or cerebral hemorrhage. Carbohydrates have been related to both. Multiple studies have suggested a link between type 2 diabetes and...  Read more

Palsdottir et al. conducted extensive linkage disequilibrium and genealogical studies of patients with HCCAA (also called hereditary cerebral hemorrhage with amyloidosis, Icelandic type—HCHWA-I) and found a decrease in age at onset of the disease, and age at death, of mutation carriers during the nineteenth century. This decrease in age at death, from 65 years in carriers born in 1825 to the present-day average of about 30 years, occurred while an increase in lifespan was documented in the general population in Iceland. This decrease in lifespan paralleled a major change in diet, most significantly an increase in sugar and salt intake in Iceland.

This study has important significance for our understanding of factors that affect amyloid deposition as well as cerebral hemorrhages. Studies, mainly in animal models of amyloidosis, should be conducted to determine the role of carbohydrates and/or salt in either cerebral amyloid angiopathy (CAA) or cerebral hemorrhage. Carbohydrates have been related to both. Multiple studies have suggested a link between type 2 diabetes and stroke and that glucose lowering in high-risk patients would lower the risk of the disease. In addition, type 2 diabetes mellitus has been associated with a higher incidence of Alzheimer disease (AD). Excess consumption of sugar-sweetened beverages plays an important role in the epidemic of obesity, a major risk factor for type 2 diabetes mellitus. A study has shown that APP/PS1 transgenic mice that were provided with 10 percent sucrose-sweetened water had exacerbation of memory impairment and an increase in insoluble Aβ levels and deposition in the brain compared with control mice with no sucrose added to the water.

The Leu68Gln variant of cystatin C forms amyloid deposition in cerebral and spinal arteries and arterioles, leading to recurrent hemorrhagic strokes causing serious brain damage and eventually fatal stroke. In vessels affected by CAA, local muscle and elastic elements are lost and replaced by amyloid fibrils, thereby weakening the overall structure of the vessel. Consequently, it was suggested that CAA predisposes towards cerebral infarction and cerebral hemorrhage. However, CAA is usually asymptomatic and only a subpopulation is at high risk of hemorrhage. Several studies implicated non-fibrillar cystatin C in amyloid β-CAA-related hemorrhage. Therefore, it would be of great interest to study whether a change in carbohydrate consumption affects amyloid deposition and/or the occurrence of cerebral hemorrhages with significance not only for cystatin C-related cerebral amyloidosis, but also for AD and stroke.

View all comments by Efrat Levy

I am delighted that Wang and colleagues have done such a detailed analysis of the epigenome in LOAD. The results, especially the evidence of particularly marked epigenetic drifts in PS1 and APOE, are of great interest. The authors wisely point out, however, that there is an underlying methodological problem—variable shifts in subpopulation heterogeneity—and point out the need for follow-up studies using such methods as laser-assisted microdissection and single cell analysis.

While these results are likely to reflect, at least in part, variable environmental impacts, I am increasingly impressed with the potential role of stochastic events that can lead to epigenetic drifts in gene expression. There is enormous intra-specific variability in longevity within model organisms for which both genotype and environment appear to have been well controlled. This leads me to conclude that, while nature, nurture, and chance all play roles in modulating the rates of aging and the rates at which late-life disorders emerge, for the case of variations within a species, the...  Read more

I am delighted that Wang and colleagues have done such a detailed analysis of the epigenome in LOAD. The results, especially the evidence of particularly marked epigenetic drifts in PS1 and APOE, are of great interest. The authors wisely point out, however, that there is an underlying methodological problem—variable shifts in subpopulation heterogeneity—and point out the need for follow-up studies using such methods as laser-assisted microdissection and single cell analysis.

While these results are likely to reflect, at least in part, variable environmental impacts, I am increasingly impressed with the potential role of stochastic events that can lead to epigenetic drifts in gene expression. There is enormous intra-specific variability in longevity within model organisms for which both genotype and environment appear to have been well controlled. This leads me to conclude that, while nature, nurture, and chance all play roles in modulating the rates of aging and the rates at which late-life disorders emerge, for the case of variations within a species, the "800-pound gorilla" may well be chance, including varying patterns of epigenetic drift. This is in striking contrast to the dominating role of the constitutional genome in the modulation of lifespan and late-life disorders between species. A question of great interest is the implications that one might derive from evidence that random variations in gene expression have deep evolutionary roots (e.g., in bacteria). Given unpredictable environments, it might be adaptive for a population to have not only genetic heterogeneity but also epigenetic heterogeneity. Perhaps LOAD is an antagonistic pleiotropic byproduct of a class of gene action that has beneficial effects on younger, reproducing populations; the price we pay may be unlucky members of our aging population who have had their epigenetic changes drift in the wrong directions. I hope to live long enough to test my more general quasi-group-selectionist hypothesis!

View all comments by George M. Martin

Methylation changes in AD are becoming more and more studied. The paper by Mastroeni and colleagues evidences that changes in DNA methylation are particularly evident in specific (sensitive) neurons.

It is very good that different researchers apply different strategies to study this feature: protein methylation (Sontag et al., 2008; Zhou et al., 2008), DNA methylation of specific AD loci in post-mortem brains (Mastroeni et al., 2009; Wang et al., 2008), DNA methylation in aging (Siegmund et al., 2007), methylation metabolism in AD models (Fuso et al., 2008).

Future developments on this topic will certainly help to clarify some aspects of the multifactorial basis of AD.

References:
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. Abstract

Mastroeni D, Grover A, Delvaux E, Whiteside C, Coleman PD, Rogers J. Epigenetic changes in Alzheimer's disease: Decrements in DNA methylation. Neurobiol Aging. 2008 Dec 29. Abstract

Siegmund KD, Connor CM, Campan M, Long TI, Weisenberger DJ, Biniszkiewicz D, Jaenisch R, Laird PW, Akbarian S. DNA methylation in the human cerebral cortex is dynamically regulated throughout the life span and involves differentiated neurons. PLoS ONE. 2007 Sep 19;2(9):e895. Abstract

Sontag JM, Nunbhakdi-Craig V, Montgomery L, Arning E, Bottiglieri T, Sontag E. Folate deficiency induces in vitro and mouse brain region-specific downregulation of leucine carboxyl methyltransferase-1 and protein phosphatase 2A B(alpha) subunit expression that correlate with enhanced tau phosphorylation. J Neurosci. 2008 Nov 5;28(45):11477-87. Abstract

Wang SC, Oelze B, Schumacher A. Age-specific epigenetic drift in late-onset Alzheimer's disease. PLoS ONE. 2008 Jul 16;3(7):e2698. Abstract

Zhou XW, Gustafsson JA, Tanila H, Bjorkdahl C, Liu R, Winblad B, Pei JJ. Tau hyperphosphorylation correlates with reduced methylation of protein phosphatase 2A. Neurobiol Dis. 2008 Sep;31(3):386-94. Abstract

View all comments by Andrea Fuso

The Bjornsson et al. study provides further evidence that DNA methylation differences between individuals increase with age. However, the study not only confirms this principle, but shows that genetic factors play a role in inter-individual methylation differences. It highlights the complexities when studying DNA methylation in aging. While it is thought that "environmental" factors such as alcohol, diet, perhaps medications, etc., play a role in modifying DNA methylation patterns in the genome, genetic factors could play a role as well. Recently, we identified in a postmortem brain study 2/50 gene loci that showed significant alterations in Alzheimer's subjects, as compared to controls (Siegmund et al., 2007). Interestingly, the changes in the Alzheimer's cohort, in terms of DNA methylation, appeared to reflect an acceleration of normal aging. Therefore, one could assume that the findings of Bjornsson et al. will be of great interest for aging-related disorders, including Alzheimer disease.

View all comments by Schahram Akbarian

These are indeed highly interesting papers.

To add to the story of epigenetic influences in the aging process, a new and fascinating study was published in PLoS ONE. The group around Axel Schumacher et al. at the Technical University Munich/Germany could show that people with late-onset Alzheimer disease have indeed an increased “epigenetic drift” in genes that may be responsible for some of the observed phenotypes. Additionally, the group found that some genes that participate in amyloid-β processing and methylation homeostasis show a significant interindividual epigenetic variability, which may contribute to disease predisposition. The observed epigenetic pattern would complement and support the aforementioned data, showing that the changes in the Alzheimer brain appeared to reflect an acceleration of normal aging. This could indicate that everybody has a certain likelihood of developing the disease.

References:
Wang SC, Oelze B, Schumacher A. Age-specific epigenetic drift in late-onset Alzheimer's disease. PLoS ONE. 2008;3(7):e2698. Abstract

View all comments by Jutta Bremer

The article by Roe et al. is a strong contribution to the literature of two fields—cancer and AD. But while the field will benefit from having access to the data and the analyses reported, the article and the accompanying editorial bring up two questions in my mind.

The first is a solely theoretical one. In their accompanying tables, the authors cite the ApoE profiles of the two groups (those getting cancer and those getting dementia) but unfortunately do not comment on the data itself. This is frustrating, because the strong correlation between carrying one or two ApoE4 alleles and elevated AD risk means a potential insight into mechanism has slipped through their fingers. The sample size is large enough that they should replicate the often-observed AD/ApoE4 connection in their dementia population. But then, according to their hypothesis, the cancer data should go the other way, i.e., ApoE4 genotype should be protective. The 4/4 numbers are small, but seem adequate given that increased risk of AD for this group has been estimated to be above 10-fold. I don't see this...  Read more

The article by Roe et al. is a strong contribution to the literature of two fields—cancer and AD. But while the field will benefit from having access to the data and the analyses reported, the article and the accompanying editorial bring up two questions in my mind.

The first is a solely theoretical one. In their accompanying tables, the authors cite the ApoE profiles of the two groups (those getting cancer and those getting dementia) but unfortunately do not comment on the data itself. This is frustrating, because the strong correlation between carrying one or two ApoE4 alleles and elevated AD risk means a potential insight into mechanism has slipped through their fingers. The sample size is large enough that they should replicate the often-observed AD/ApoE4 connection in their dementia population. But then, according to their hypothesis, the cancer data should go the other way, i.e., ApoE4 genotype should be protective. The 4/4 numbers are small, but seem adequate given that increased risk of AD for this group has been estimated to be above 10-fold. I don't see this effect in the paper’s cancer table, although I do see it (in the expected direction) in the dementia table. If my cursory impression is true, and there is no ApoE4-cancer linkage, it would hint that the cancer/AD connection is working off a parallel biological mechanism that is independent of the ApoE mechanism. And since it is widely believed that ApoE cannot account for all cases of sporadic AD, this could be a very important insight.

My second comment is both theoretical and personal. On behalf of the many laboratories (Herrup, Arendt, Davies, Lamb, Neve, Copani, Chun, Slack, Park, Potter, Greene, Benes, Dawson, Julien, Bowser, Sharp, Rakic, Smith and Perry, and probably others) that have labored hard over the past 15 years to repeatedly demonstrate the linkage between loss of cell cycle control in adult nerve cells and the onset of neurodegeneration in AD and other diseases, I wish to express our concern that neither the authors of the study nor the writers of the editorial mentioned this rapidly growing body of work and how it relates to their findings. In bringing up Pin1, which is more closely associated with DNA damage than with cell cycle regulation, they also ignore the excellent work on the association between mutations in DNA repair enzymes and developmental nerve cell death (e.g., ATM, ATR, Mre11, Nbs1, etc.). I mention this partly out of personal pride, but mostly because it raises a potentially important theoretical question about mechanism. In every case, DNA damage and/or loss of nerve cell cycle control is associated with increased nerve cell death. Therefore, on first principles we might expect that the correlation between AD and cancer (also accompanied by DNA damage and a loss of cell cycle control) would be positive, not negative as reported here. Even putting aside my obvious personal interest, I suggest that the lack of discussion of this point by the authors is an opportunity missed.

View all comments by Karl Herrup

One molecular mechanism that could explain this is sodium. In the Hypothesis Factory (1) I explain how repeated osmotic swelling of the brain resulting from hyponatremia could be a root cause of Alzheimer’s. It is widely believed that a high-salt diet is somehow responsible for a higher rate of stomach cancer. This may explain why the Japanese have a higher rate of stomach cancer coincident with a lower rate of Alzheimer’s.

References:
1. Could Hyponatremia Be the Root Cause of Alzheimer's?

View all comments by Gregory Marlow