How Biochemical Pathways for Disease May be Triggered by Early-Life Events

  • Debomoy K. Lahiri
  • Bryan Maloney
  • Nasser H. Zawia


Alzheimer’s disease (AD) is the most common form of dementia among the elderly and usually appears late in adult life. It is presently uncertain when process of this disease starts and how long these pathobiochemical processes take to develop. Therefore, we address the timing and nature of triggers that lead to AD. To explain the etiology of AD, we propose a “Latent Early-life Associated Regulation” (LEARn) model which postulates latent expression of specific genes triggered at the developmental stage of life. This model integrates both the neuropathological features (e.g., amyloid-loaded plaques and tau-laden tangles) and environmental conditions (e.g., diet, metal exposure, and hormones) associated with AD. In the LEARn model, environmental agents could perturb gene regulation in a long-term fashion, beginning at early developmental stages, but these perturbations would not have pathological results until significantly later in life. The LEARn model operates through the regulatory region (promoter) of the gene, specifically through changes in methylation and oxidation status within the promoter of specific genes. The LEARn model combines genetic and environmental risk factors to explain the etiology of the most common, sporadic, form of AD.


LEARn Model Epigenetic Drift Concentrate Apple Juice Childhood Weight Gain Perturb Gene Expression 
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  1. 1.
    Hebert LE, Scherr PA, Bienias JL (2003) Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch Neurol 60:1119–1122PubMedCrossRefGoogle Scholar
  2. 2.
    Plassman BL, Langa KM, Fisher GG (2007) Prevalence of dementia in the United States: the aging, demographics, and memory study. Neuroepidemiology 29:125–132PubMedCrossRefGoogle Scholar
  3. 3.
    Alzheimer’s Association (2008) Alzheimer’s Disease Facts and FiguresGoogle Scholar
  4. 4.
    Sambamurti K, Suram A, Venugopal C (2006) A partial failure of membrane protein turnover may cause Alzheimer’s disease: a new hypothesis. Curr Alzheimer Res 3:81–90PubMedCrossRefGoogle Scholar
  5. 5.
    Lahiri DK, Wavrant De-Vrieze F, Ge Y-W (2005) Characterization of two APP gene promoter polymorphisms that appear to influence risk of late-onset Alzheimer’s disease. Neurobiol Aging 26:1329–1341PubMedCrossRefGoogle Scholar
  6. 6.
    Maloney B, Ge Y-W, Alley GM (2007) Important differences between human and mouse APOE gene promoters with implications for Alzheimer’s disease. J Neurochem 103:1237–1257PubMedCrossRefGoogle Scholar
  7. 7.
    Bellingham SA, Lahiri DK, Maloney B (2004) Copper depletion down-regulates expression of the Alzheimer’s disease amyloid-beta precursor protein gene. J Biol Chem 279:20378–20386PubMedCrossRefGoogle Scholar
  8. 8.
    Lahiri DK, Maloney B, Basha MR (2007) How and when environmental agents and dietary factors affect the course of Alzheimer’s disease: the “LEARn” model (Latent Early Associated Regulation) may explain the triggering of AD. Curr Alzheimer Res 4:219–228PubMedCrossRefGoogle Scholar
  9. 9.
    Basha MR, Wei W, Bakheet SA (2005) The fetal basis of amyloidogenesis: exposure to lead and latent overexpression of amyloid precursor protein and beta-amyloid in the aging brain. J Neurosci 25:823–829PubMedCrossRefGoogle Scholar
  10. 10.
    Wu J, Basha MR, Brock B (2008) Alzheimer’s disease (AD)-like pathology in aged monkeys after infantile exposure to environmental metal lead (Pb): evidence for a developmental origin and environmental link for AD. J Neurosci 28:3–9PubMedCrossRefGoogle Scholar
  11. 11.
    Barker DJ, Eriksson JG, Forsen T (2002) Fetal origins of adult disease: strength of effects and biological basis. Int J Epidemiol 31:1235–1239PubMedCrossRefGoogle Scholar
  12. 12.
    Takiguchi M, Achanzar WE, Qu W (2003) Effects of cadmium on DNA-(Cytosine-5) methyltransferase activity and DNA methylation status during cadmium-induced cellular transformation. Exp Cell Res 286:355–365PubMedCrossRefGoogle Scholar
  13. 13.
    Fowler BA, Whittaker MH, Lipsky M (2004) Oxidative stress induced by lead, cadmium and arsenic mixtures: 30-day, 90-day, and 180-day drinking water studies in rats: an overview. Biometals 17:567–568PubMedCrossRefGoogle Scholar
  14. 14.
    Campos AC, Molognoni F, Melo FH (2007) Oxidative stress modulates DNA methylation during melanocyte anchorage blockade associated with malignant transformation. Neoplasia 9:1111–1121PubMedCrossRefGoogle Scholar
  15. 15.
    Valinluck V, Tsai HH, Rogstad DK (2004) Oxidative damage to methyl-CpG sequences inhibits the binding of the methyl-CpG binding domain (MBD) of methyl-CpG binding protein 2 (MeCP2). Nucleic Acids Res 32:4100–4108PubMedCrossRefGoogle Scholar
  16. 16.
    Dobosy JR and Selker EU (2001) Emerging connections between DNA methylation and histone acetylation. Cell Mol Life Sci 58:721–727PubMedCrossRefGoogle Scholar
  17. 17.
    Wu J, Basha MR, Brock B (2008) Alzheimer’s disease (AD)-like pathology in aged monkeys after infantile exposure to environmental metal lead (Pb): evidence for a developmental origin and environmental link for AD. J Neurosci 28:3–9PubMedCrossRefGoogle Scholar
  18. 18.
    Bjornsson HT, Sigurdsson MI, Fallin MD (2008) Intra-individual change over time in DNA methylation with familial clustering. JAMA 299:2877–2883PubMedCrossRefGoogle Scholar
  19. 19.
    Galic MA, Riazi K, Heida JG (2008) Postnatal inflammation increases seizure susceptibility in adult rats. J Neurosci 28:6904–6913PubMedCrossRefGoogle Scholar
  20. 20.
    Knudson AG, Jr. (1971) Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 68:820–823PubMedCrossRefGoogle Scholar
  21. 21.
    Lu T, Pan Y, Kao SY (2004) Gene regulation and DNA damage in the ageing human brain. Nature 429:883–891PubMedCrossRefGoogle Scholar
  22. 22.
    Whitelaw NC and Whitelaw E (2006) How lifetimes shape epigenotype within and across generations. Hum Mol Genet 15:R131–R137PubMedCrossRefGoogle Scholar
  23. 23.
    van Vliet J, Oates NA and Whitelaw E (2007) Epigenetic mechanisms in the context of complex diseases. Cell Mol Life Sci 64:1531–1538PubMedCrossRefGoogle Scholar
  24. 24.
    Lahiri DK, and Maloney B (2006) Genes are not our destiny: the somatic epitype bridges between the genotype and the phenotype. Nat Rev Neurosci 7:doi:10.1038/nrn2022-c1Google Scholar
  25. 25.
    Bolin CM, Basha R, Cox D (2006) Exposure to lead and the developmental origin of oxidative DNA damage in the aging brain. Faseb J 20:788–790PubMedGoogle Scholar
  26. 26.
    De la Burde B,and Choat MS (1972) Does asymptomatic lead exposure in children have latent sequelae? J Pediatr 81:1088–1091PubMedCrossRefGoogle Scholar
  27. 27.
    Chan A and Shea TB (2006) Supplementation with apple juice attenuates presenilin-1 overexpression during dietary and genetically-induced oxidative stress. J Alzheimers Dis 10:353–358PubMedGoogle Scholar
  28. 28.
    Lahiri DK, Chen D, Ge YW (2004) Dietary supplementation with melatonin reduces levels of amyloid beta-peptides in the murine cerebral cortex. J Pineal Res 36:224–231PubMedCrossRefGoogle Scholar
  29. 29.
    Buehlmeyer K, Doering F, Daniel H (2008) Alteration of gene expression in rat colon mucosa after exercise. Ann Anat 190:71–80PubMedCrossRefGoogle Scholar
  30. 30.
    Kivipelto M,and Solomon A (2008) Alzheimer’s disease – the ways of prevention. J Nutr Health Aging 12:89S–94SPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Debomoy K. Lahiri
    • 1
  • Bryan Maloney
  • Nasser H. Zawia
  1. 1.Department of Psychiatry and of Medical & Molecular Genetics MemberIndiana University School of Medicine Institute of Psychiatric ResearchIndianapolisUSA

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