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...  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

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

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