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

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

This is very interesting. I am wondering how to relate those findings to the roles of folate in brain function and cognitive aging in humans.

Folate provides one carbon group to methylate DNA and other substrates. In population-based studies, low folate has been associated with poor cognitive performance, and trial results suggest that supplementation of folate and other B vitamins could slow down cognitive decline and brain atrophy. Optimizing folate status could be a potential preventive measure for dementia.

References:
Feng L, Ng TP, Chuah L, Niti M, Kua EH. Homocysteine, folate, and vitamin B-12 and cognitive performance in older Chinese adults: findings from the Singapore Longitudinal Ageing Study. Am J Clin Nutr. 2006 Dec;84(6):1506-12. Abstract

Durga J, van Boxtel MP, Schouten EG, Kok FJ, Jolles J, Katan MB, Verhoef P. Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. Lancet. 2007 Jan 20;369(9557):208-16. Abstract

Smith AD, Smith SM, de Jager CA, Whitbread P, Johnston C, Agacinski G, Oulhaj A, Bradley KM, Jacoby R, Refsum H. Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial. PLoS One. 2010;5(9):e12244. Abstract

Feng L. Oral folic acid and vitamin B-12 supplementation to prevent cognitive decline. Am J Clin Nutr. 2012 May;95(5):1289-90; author reply 1290. Abstract

View all comments by Lei Feng