Skip to main content
Book cover

Advances in Geroscience pp 197–227Cite as

The Role of Aging in Alzheimer’s Disease

  • Chapter

Abstract

Cognitive function in humans declines in essentially all domains starting in the late 50s, and neurodegeneration and dementia seem to be inevitable in all but a few of those who survive to very old age. While age-related cognitive dysfunction and Alzheimer’s disease in humans are clearly distinct entities and seem to affect different brain regions, both show the telltale molecular and cellular changes that characterize tissue aging including abnormal proteostasis, loss in stem cell activity, and inflammation. Adding to the challenge of differentiating the two, Alzheimer’s disease is thought to begin up to 20 years before it manifests clinically and, accordingly, there is significant overlap between brain aging and the disease based on structural and functional brain imaging. This chapter will highlight commonalities and emphasize divergences between “normal” brain aging and Alzheimer’s disease and discuss novel approaches to understand the link between the two.

Keywords

  • Alzheimer’s
  • Aging
  • Proteostasis
  • Epigenetic
  • Inflammation
  • Geroscience

This is a preview of subscription content, access via your institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • DOI: 10.1007/978-3-319-23246-1_7
  • Chapter length: 31 pages
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
eBook
USD   169.00
Price excludes VAT (USA)
  • ISBN: 978-3-319-23246-1
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
Softcover Book
USD   219.99
Price excludes VAT (USA)
Hardcover Book
USD   219.99
Price excludes VAT (USA)
Learn about institutional subscriptions

References

  1. Yankner BA, Lu T, Loerch P (2008) The aging brain. Ann Rev Pathol Mech Dis 3:41–66. doi:10.1146/annurev.pathmechdis.2.010506.092044

    CAS  Google Scholar 

  2. Bishop NA, Lu T, Yankner BA (2010) Neural mechanisms of ageing and cognitive decline. Nature 464:529–535. doi:10.1038/nature08983

    PubMed Central  CAS  PubMed  Google Scholar 

  3. McKhann GM, Knopman DS, Chertkow H et al (2011) The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7:263–269. doi:10.1016/j.jalz.2011.03.005

    PubMed Central  PubMed  Google Scholar 

  4. Albert MS, DeKosky ST, Dickson D et al (2011) The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7:270–279. doi:10.1016/j.jalz.2011.03.008

    PubMed Central  PubMed  Google Scholar 

  5. Vos SJ, Verhey F, Frolich L et al (2015) Prevalence and prognosis of Alzheimer’s disease at the mild cognitive impairment stage. Brain. doi:10.1093/brain/awv029

    Google Scholar 

  6. Huang Y, Mucke L (2012) Alzheimer mechanisms and therapeutic strategies. Cell 148:1204–1222. doi:10.1016/j.cell.2012.02.040

    PubMed Central  CAS  PubMed  Google Scholar 

  7. Jack CR Jr, Holtzman DM (2013) Biomarker modeling of Alzheimer’s disease. Neuron 80:1347–1358. doi:10.1016/j.neuron.2013.12.003

    PubMed Central  CAS  PubMed  Google Scholar 

  8. Cohen AD, Klunk WE (2014) Early detection of Alzheimer’s disease using PiB and FDG PET. Neurobiol Dis 72:117–122. doi:10.1016/j.nbd.2014.05.001

    CAS  PubMed  Google Scholar 

  9. Okamura N, Harada R, Furumoto S et al (2014) Tau PET imaging in Alzheimer’s disease. Curr Neurol Neurosci Rep 14:500–507. doi:10.1007/s11910-014-0500-6

    PubMed  Google Scholar 

  10. Deary IJ, Corley J, Gow AJ et al (2009) Age-associated cognitive decline. Br Med Bull 92:135–152. doi:10.1093/bmb/ldp033

    PubMed  Google Scholar 

  11. Chadick JZ, Zanto TP, Gazzaley A (2014) Structural and functional differences in medial prefrontal cortex underlie distractibility and suppression deficits in ageing. Nat Commun 5:4223. doi:10.1038/ncomms5223

    PubMed Central  CAS  PubMed  Google Scholar 

  12. Hayden KM, Reed BR, Manly JJ et al (2011) Cognitive decline in the elderly: an analysis of population heterogeneity. Age Ageing 40:684–689. doi:10.1093/ageing/afr101

    PubMed Central  PubMed  Google Scholar 

  13. Tang YP, Shimizu E, Dube GR et al (1999) Genetic enhancement of learning and memory in mice. Nature 401:63–69. doi:10.1038/43432

    CAS  PubMed  Google Scholar 

  14. Cui Z, Feng R, Jacobs S et al (2013) Increased NR2A: NR2B ratio compresses long-term depression range and constrains long-term memory. Sci Rep 3:1036. doi:10.1038/srep01036

    PubMed Central  PubMed  Google Scholar 

  15. Chetelat G, La Joie R, Villain N et al (2013) Amyloid imaging in cognitively normal individuals, at-risk populations and preclinical Alzheimer’s disease. NeuroImage Clin 2:356–365. doi:10.1016/j.nicl.2013.02.006

    PubMed Central  PubMed  Google Scholar 

  16. Braak H, Braak E (1997) Frequency of stages of Alzheimer-related lesions in different age categories. NBA 18:351–357. doi:10.1016/S0197-4580(97)00056-0

    CAS  Google Scholar 

  17. Braak H, Thal DR, Ghebremedhin E, Del Tredici K (2011) Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J Neuropathol Exp Neurol 70:960–969. doi:10.1097/NEN.0b013e318232a379

    CAS  PubMed  Google Scholar 

  18. Barnes DE, Yaffe K (2011) The projected effect of risk factor reduction on Alzheimer’s disease prevalence. Lancet Neurol 10:819–828. doi:10.1016/S1474-4422(11)70072-2

    PubMed Central  PubMed  Google Scholar 

  19. McKee AC, Daneshvar DH (2015) The neuropathology of traumatic brain injury. Handb Clin Neurol 127:45–66. doi:10.1016/B978-0-444-52892-6.00004-0

    PubMed  Google Scholar 

  20. Erickson KI, Weinstein AM, Lopez OL (2012) Physical activity, brain plasticity, and Alzheimer’s disease. Arch Med Res 43:615–621. doi:10.1016/j.arcmed.2012.09.008

    PubMed Central  PubMed  Google Scholar 

  21. Wilson RS, Boyle PA, Yu L et al (2013) Life-span cognitive activity, neuropathologic burden, and cognitive aging. Neurology 81:314–321. doi:10.1212/WNL.0b013e31829c5e8a

    PubMed Central  PubMed  Google Scholar 

  22. Michaelson DM (2014) APOE epsilon4: the most prevalent yet understudied risk factor for Alzheimer’s disease. Alzheimers Dement 10:861–868. doi:10.1016/j.jalz.2014.06.015

    PubMed  Google Scholar 

  23. Altmann A, Tian L, Henderson VW et al (2014) Sex modifies the APOE-related risk of developing Alzheimer disease. Ann Neurol 75:563–573. doi:10.1002/ana.24135

    PubMed Central  CAS  PubMed  Google Scholar 

  24. Yaffe K, Cauley J, Sands L, Browner W (1997) Apolipoprotein E phenotype and cognitive decline in a prospective study of elderly community women. Arch Neurol 54:1110–1114. doi:10.1001/archneur.1997.00550210044011

    CAS  PubMed  Google Scholar 

  25. De Jager PL, Shulman JM, Chibnik LB et al (2012) A genome-wide scan for common variants affecting the rate of age-related cognitive decline. NBA 33:1017.e1–15. doi:10.1016/j.neurobiolaging.2011.09.033

    Google Scholar 

  26. Brooks-Wilson AR (2013) Genetics of healthy aging and longevity. Hum Genet 132:1323–1338. doi:10.1007/s00439-013-1342-z

    PubMed Central  CAS  PubMed  Google Scholar 

  27. Dubal DB, Yokoyama JS, Zhu L et al (2014) Life extension factor klotho enhances cognition. Cell Reports 7(4):1065–1076. doi:10.1016/j.celrep.2014.03.076

    PubMed Central  CAS  PubMed  Google Scholar 

  28. Willcox BJ, Donlon TA, He Q et al (2008) FOXO3A genotype is strongly associated with human longevity. Proc Natl Acad Sci 105:13987–13992. doi:10.1073/pnas.0801030105

    PubMed Central  CAS  PubMed  Google Scholar 

  29. Fjell AM, McEvoy L, Holland D et al (2014) What is normal in normal aging? Effects of aging, amyloid and Alzheimer’s disease on the cerebral cortex and the hippocampus. Prog Neurobiol 117:20–40. doi:10.1016/j.pneurobio.2014.02.004

    PubMed Central  CAS  PubMed  Google Scholar 

  30. Fjell AM, Westlye LT, Grydeland H et al (2014) Accelerating cortical thinning: unique to dementia or universal in aging? Cereb Cortex 24:919–934. doi:10.1093/cercor/bhs379

    PubMed Central  PubMed  Google Scholar 

  31. Fraser MA, Shaw ME, Cherbuin N (2015) A systematic review and meta-analysis of longitudinal hippocampal atrophy in healthy human ageing. Neuroimage. doi:10.1016/j.neuroimage.2015.03.035

    PubMed  Google Scholar 

  32. Braak H, Alafuzoff I, Arzberger T et al (2006) Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol 112:389–404. doi:10.1007/s00401-006-0127-z

    PubMed Central  PubMed  Google Scholar 

  33. Jack CRJ, Petersen RC, O’Brien PC, Tangalos EG (1992) MR-based hippocampal volumetry in the diagnosis of Alzheimer’s disease. Neurology 42:183–188

    PubMed  Google Scholar 

  34. Kerchner GA, Hess CP, Hammond-Rosenbluth KE et al (2010) Hippocampal CA1 apical neuropil atrophy in mild Alzheimer disease visualized with 7-T MRI. Neurology 75:1381–1387

    PubMed Central  CAS  PubMed  Google Scholar 

  35. Chhatwal JP, Sperling RA (2012) Functional MRI of mnemonic networks across the spectrum of normal aging, mild cognitive impairment, and Alzheimer’s disease. J Alzheimers Dis 31:S155–S167. doi:10.3233/JAD-2012-120730

    PubMed Central  PubMed  Google Scholar 

  36. Dickerson BC, Sperling RA (2008) Functional abnormalities of the medial temporal lobe memory system in mild cognitive impairment and Alzheimer’s disease: insights from functional MRI studies. Neuropsychologia 46:1624–1635. doi:10.1016/j.neuropsychologia.2007.11.030

    PubMed Central  PubMed  Google Scholar 

  37. Palop JJ, Mucke L (2010) Amyloid-β–induced neuronal dysfunction in Alzheimer’s disease: from synapses toward neural networks. Nat Neurosci 13:812–818. doi:10.1038/nn.2583

    PubMed Central  CAS  PubMed  Google Scholar 

  38. Sanchez PE, Zhu L, Verret L et al (2012) Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer’s disease model. Proc Natl Acad Sci 109:E2895–E2903. doi:10.1073/pnas.1121081109

    PubMed Central  CAS  PubMed  Google Scholar 

  39. Vossel KA, Beagle AJ, Rabinovici GD et al (2013) Seizures and epileptiform activity in the early stages of Alzheimer disease. JAMA Neurol 70:1158–1166. doi:10.1001/jamaneurol.2013.136

    PubMed Central  PubMed  Google Scholar 

  40. Bakker A, Krauss GL, Albert MS et al (2012) Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment. Neuron 74:467–474. doi:10.1016/j.neuron.2012.03.023

    PubMed Central  CAS  PubMed  Google Scholar 

  41. Apostolova LG, Mosconi L, Thompson PM et al (2010) Subregional hippocampal atrophy predicts Alzheimer’s dementia in the cognitively normal. Neurobiol Aging 31:1077–1088. doi:10.1016/j.neurobiolaging.2008.08.008

    PubMed Central  PubMed  Google Scholar 

  42. La Joie R, Perrotin A, La Sayette de V et al (2013) Hippocampal subfield volumetry in mild cognitive impairment, Alzheimer’s disease and semantic dementia. Neuroimage Clin 3:155–162. doi:10.1016/j.nicl.2013.08.007

    PubMed Central  PubMed  Google Scholar 

  43. Yassa MA, Stark SM, Bakker A et al (2010) High-resolution structural and functional MRI of hippocampal CA3 and dentate gyrus in patients with amnestic Mild Cognitive Impairment. Neuroimage 51:1242–1252. doi:10.1016/j.neuroimage.2010.03.040

    PubMed Central  PubMed  Google Scholar 

  44. Yassa MA, Lacy JW, Stark SM et al (2011) Pattern separation deficits associated with increased hippocampal CA3 and dentate gyrus activity in nondemented older adults. Hippocampus 21:968–979. doi:10.1002/hipo.20808

    PubMed Central  PubMed  Google Scholar 

  45. Small SA, Schobel SA, Buxton RB et al (2011) A pathophysiological framework of hippocampal dysfunction in ageing and disease. Nat Rev Neurosci. doi:10.1038/nrn3085

    PubMed Central  PubMed  Google Scholar 

  46. Greicius MD, Srivastava G, Reiss AL, Menon V (2004) Default-mode network activity distinguishes Alzheimer’s disease from healthy aging: evidence from functional MRI. Proc Natl Acad Sci U S A 101:4637–4642. doi:10.1073/pnas.0308627101

    PubMed Central  CAS  PubMed  Google Scholar 

  47. Dennis EL, Thompson PM (2014) Functional brain connectivity using fMRI in aging and Alzheimer’s disease. Neuropsychol Rev 24:49–62. doi:10.1007/s11065-014-9249-6

    PubMed Central  PubMed  Google Scholar 

  48. López-Otín C, Blasco MA, Partridge L et al (2013) The hallmarks of aging. Cell 153:1194–1217. doi:10.1016/j.cell.2013.05.039

    PubMed Central  PubMed  Google Scholar 

  49. Pan L, Penney J, Tsai L-H (2014) Chromatin regulation of DNA damage repair and genome integrity in the central nervous system. J Mol Biol 426:3376–3388. doi:10.1016/j.jmb.2014.08.001

    CAS  PubMed  Google Scholar 

  50. Adamec E, Vonsattel JP, Nixon RA (1999) DNA strand breaks in Alzheimer’s disease. Brain Res 849:67–77

    CAS  PubMed  Google Scholar 

  51. Madabhushi R, Pan L, Tsai L-H (2014) DNA damage and its links to neurodegeneration. Neuron 83:266–282. doi:10.1016/j.neuron.2014.06.034

    CAS  PubMed  Google Scholar 

  52. Lu T, Pan Y, Kao S-Y et al (2004) Gene regulation and DNA damage in the ageing human brain. Nature 429:883–891. doi:10.1038/nature02661

    CAS  PubMed  Google Scholar 

  53. Suberbielle E, Sanchez PE, Kravitz AV et al (2013) Physiologic brain activity causes DNA double-strand breaks in neurons, with exacerbation by amyloid-β. Nat Neurosci 16:613–621. doi:10.1038/nn.3356

    PubMed Central  CAS  PubMed  Google Scholar 

  54. Ferron SR, Marques-Torrejon MA, Mira H et al (2009) Telomere shortening in neural stem cells disrupts neuronal differentiation and neuritogenesis. J Neurosci 29:14394–14407. doi:10.1523/JNEUROSCI.3836-09.2009

    CAS  PubMed  Google Scholar 

  55. Wolf SA, Melnik A, Kempermann G (2011) Physical exercise increases adult neurogenesis and telomerase activity, and improves behavioral deficits in a mouse model of schizophrenia. Brain Behav Immun 25:971–980. doi:10.1016/j.bbi.2010.10.014

    CAS  PubMed  Google Scholar 

  56. Ferron S (2004) Telomere shortening and chromosomal instability abrogates proliferation of adult but not embryonic neural stem cells. Development 131:4059–4070. doi:10.1242/dev.01215

    CAS  PubMed  Google Scholar 

  57. Eitan E, Hutchison ER, Mattson MP (2014) Telomere shortening in neurological disorders: an abundance of unanswered questions. Trends Neurosci 37:256–263. doi:10.1016/j.tins.2014.02.010

    PubMed Central  CAS  PubMed  Google Scholar 

  58. Panossian LA, Porter VR, Valenzuela HF et al (2003) Telomere shortening in T cells correlates with Alzheimer’s disease status. NBA 24:77–84

    CAS  Google Scholar 

  59. Roberts RO, Boardman LA, Cha RH et al (2014) Short and long telomeres increase risk of amnestic mild cognitive impairment. Mech Ageing Dev 141–142:64–69. doi:10.1016/j.mad.2014.10.002

    PubMed  Google Scholar 

  60. Jacobs EG, Epel ES, Lin J et al (2014) Relationship between leukocyte telomere length, telomerase activity, and hippocampal volume in early aging. JAMA Neurol 71:921–923. doi:10.1001/jamaneurol.2014.870

    PubMed  Google Scholar 

  61. Rolyan H, Scheffold A, Heinrich A et al (2011) Telomere shortening reduces Alzheimer’s disease amyloid pathology in mice. Brain 134:2044–2056. doi:10.1093/brain/awr133

    PubMed  Google Scholar 

  62. Flanary BE, Streit WJ (2004) Progressive teromere shortening occurs in cultured rat microglia, but not astrocytes. Glia 45(1):75–88. PMID 14648548

    Google Scholar 

  63. Mosher KI, Wyss-Coray T (2014) Microglial dysfunction in brain aging and Alzheimer’s disease. Biochem Pharmacol 88:594–604. doi:10.1016/j.bcp.2014.01.008

    PubMed Central  CAS  PubMed  Google Scholar 

  64. Spilsbury A, Miwa S, Attems J, Saretzki G (2015) The role of telomerase protein TERT in Alzheimer’s disease and in tau-related pathology in vitro. J Neurosci 35:1659–1674. doi:10.1523/JNEUROSCI.2925-14.2015

    PubMed Central  CAS  PubMed  Google Scholar 

  65. Kosik KS, Rapp PR, Raz N et al (2012) Mechanisms of age-related cognitive change and targets for intervention: epigenetics. J Gerontol A Biol Sci Med Sci 67:741–746. doi:10.1093/gerona/gls110

    PubMed Central  PubMed  Google Scholar 

  66. Ballas N, Mandel G (2005) The many faces of REST oversee epigenetic programming of neuronal genes. Curr Opin Neurobiol 15:500–506. doi:10.1016/j.conb.2005.08.015

    CAS  PubMed  Google Scholar 

  67. Lu T, Aron L, Zullo J et al (2014) REST and stress resistance in ageing and Alzheimer’s disease. Nature 507(7493):448–454. doi:10.1038/nature13163

    PubMed Central  CAS  PubMed  Google Scholar 

  68. Peleg S, Sananbenesi F, Zovoilis A et al (2010) Altered histone acetylation is associated with age-dependent memory impairment in mice. Science 328:753–756. doi:10.1126/science.1186088

    CAS  PubMed  Google Scholar 

  69. Pavlopoulos E, Jones S, Kosmidis S et al (2013) Molecular mechanism for age-related memory loss: the histone-binding protein RbAp48. Sci Transl Med 5:200ra115. doi:10.1126/scitranslmed.3006373

    PubMed  Google Scholar 

  70. Hernandez DG, Nalls MA, Gibbs JR et al (2011) Distinct DNA methylation changes highly correlated with chronological age in the human brain. Hum Mol Genet 20:1164–1172. doi:10.1093/hmg/ddq561

    PubMed Central  CAS  PubMed  Google Scholar 

  71. Lunnon K, Smith R, Hannon E et al (2014) Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer’s disease. Nat Neurosci 17:1164–1170. doi:10.1038/nn.3782

    PubMed Central  CAS  PubMed  Google Scholar 

  72. De Jager PL, Srivastava G, Lunnon K et al (2014) Alzheimer’s disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci. Nat Neurosci 17:1156–1163. doi:10.1038/nn.3786

    PubMed Central  PubMed  Google Scholar 

  73. Lord J, Cruchaga C (2014) The epigenetic landscape of Alzheimer’s disease. Nat Neurosci 17:1138–1140. doi:10.1038/nn.3792

    CAS  PubMed  Google Scholar 

  74. Yu L, Chibnik LB, Srivastava GP et al (2015) Association of brain DNA methylation in SORL1, ABCA7, HLA-DRB5, SLC24A4, and BIN1With pathological diagnosis of Alzheimer disease. JAMA Neurol 72:15–24. doi:10.1001/jamaneurol.2014.3049

    PubMed  Google Scholar 

  75. Gjoneska E, Pfenning AR, Mathys H et al (2015) Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer’s disease. Nature 518:365–369. doi:10.1038/nature14252

    PubMed Central  CAS  PubMed  Google Scholar 

  76. Satoh J-I, Asahina N, Kitano S, Kino Y (2014) A comprehensive profile of ChIP-Seq-Based PU.1/Spi1 target genes in microglia. GRSB 8:127–13. doi:10.4137/GRSB.S19711

    PubMed Central  CAS  PubMed  Google Scholar 

  77. Bennett DA, Yu L, Yang J et al (2015) Epigenomics of Alzheimer’s disease. Transl Res 165:200–220. doi:10.1016/j.trsl.2014.05.006

    CAS  PubMed  Google Scholar 

  78. Zhang K, Schrag M, Crofton A et al (2012) Targeted proteomics for quantification of histone acetylation in Alzheimer’s disease. Proteomics 12:1261–1268. doi:10.1002/pmic.201200010

    CAS  PubMed  Google Scholar 

  79. Kim D, Nguyen MD, Dobbin MM et al (2007) SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer’s disease and amyotrophic lateral sclerosis. EMBO J 26:3169–3179. doi:10.1038/sj.emboj.7601758

    PubMed Central  CAS  PubMed  Google Scholar 

  80. Dobbin MM, Madabhushi R, Pan L et al (2013) SIRT1 collaborates with ATM and HDAC1 to maintain genomic stability in neurons. Nat Neurosci 16:1008–1015. doi:10.1038/nn.3460

    CAS  PubMed  Google Scholar 

  81. Huang PS, Son JH, Abbott LC, Winzer-Serhan UH (2011) Regulated expression of neuronal SIRT1 and related genes by aging and neuronal β2-containing nicotinic cholinergic receptors. Neuroscience 196:189–202. doi:10.1016/j.neuroscience.2011.09.007

    CAS  PubMed  Google Scholar 

  82. Cho SH, Chen JA, Sayed F et al (2015) SIRT1 deficiency in microglia contributes to cognitive decline in aging and neurodegeneration via epigenetic regulation of IL-1. J Neurosci 35:807–818. doi:10.1523/JNEUROSCI.2939-14.2015

    PubMed Central  PubMed  Google Scholar 

  83. Gapp K, Woldemichael BT, Bohacek J, Mansuy IM (2014) Reviewepigenetic regulation in neurodevelopment and neurodegenerative diseases. Neuroscience 264:99–111. doi:10.1016/j.neuroscience.2012.11.040

    CAS  PubMed  Google Scholar 

  84. Penner MR, Roth TL, Barnes CA, Sweatt JD (2010) An epigenetic hypothesis of aging-related cognitive dysfunction. Front Aging Neurosci. doi:10.3389/fnagi.2010.00009

    PubMed Central  PubMed  Google Scholar 

  85. Eckert A, Schmitt K, Götz J (2011) Mitochondrial dysfunction – the beginning of the end in Alzheimer’s disease? Separate and synergistic modes of tau and amyloid-β toxicity. Alzheimers Res Ther 3:15. doi:10.1186/alzrt74

    PubMed Central  CAS  PubMed  Google Scholar 

  86. Swerdlow RH (2011) Brain aging, Alzheimer’s disease, and mitochondria. BBA Mol Basis Dis 1812:1630–1639. doi:10.1016/j.bbadis.2011.08.012

    CAS  Google Scholar 

  87. Santos RX, Correia SC, Zhu X et al (2013) Mitochondrial DNA oxidative damage and repair in aging and Alzheimer’s disease. Antioxid Redox Signal 18:2444–2457. doi:10.1089/ars.2012.5039

    PubMed Central  CAS  PubMed  Google Scholar 

  88. Linnane AW, Marzuki S, Ozawa T, Tanaka M (1989) Mitochondrial DNA mutations as an important contributor to ageing and degenerative diseases. Lancet 1:642–645

    CAS  PubMed  Google Scholar 

  89. Mecocci P, MacGarvey U, Kaufman AE et al (1993) Oxidative damage to mitochondrial DNA shows marked age-dependent increases in human brain. Ann Neurol 34:609–616. doi:10.1002/ana.410340416

    CAS  PubMed  Google Scholar 

  90. Mecocci P, MacGarvey U, Beal MF (1994) Oxidative damage to mitochondrial DNA is increased in Alzheimer’s disease. Ann Neurol 36:747–751. doi:10.1002/ana.410360510

    CAS  PubMed  Google Scholar 

  91. Lin MT, Simon DK, Ahn CH et al (2002) High aggregate burden of somatic mtDNA point mutations in aging and Alzheimer’s disease brain. Hum Mol Genet 11:133–145

    CAS  PubMed  Google Scholar 

  92. Navarro A, Boveris A (2006) The mitochondrial energy transduction system and the aging process. AJP Cell Physiol 292:C670–C686. doi:10.1152/ajpcell.00213.2006

    Google Scholar 

  93. Selkoe DJ (2011) Alzheimer’s disease. Cold Spring Harb Perspect Biol 3:a004457. doi:10.1101/cshperspect.a004457

    PubMed Central  PubMed  Google Scholar 

  94. Bateman RJ, Munsell LY, Morris JC et al (2006) Human amyloid-β synthesis and clearance rates as measured in cerebrospinal fluid in vivo. Nat Med 12:856–861. doi:10.1038/nm1438

    PubMed Central  CAS  PubMed  Google Scholar 

  95. Krabbe G, Halle A, Matyash V et al (2013) Functional impairment of microglia coincides with beta-amyloid deposition in mice with Alzheimer-like pathology. PLoS One 8:e60921. doi:10.1371/journal.pone.0060921.s005

    PubMed Central  CAS  PubMed  Google Scholar 

  96. Wyss-Coray T, Loike JD, Brionne TC et al (2003) Adult mouse astrocytes degrade amyloid-β in vitro and in situ. Nat Med 9:453–457. doi:10.1038/nm838

    CAS  PubMed  Google Scholar 

  97. Sagare AP, Bell RD, Zlokovic BV (2012) Neurovascular dysfunction and faulty amyloid -peptide clearance in Alzheimer disease. Cold Spring Harb Perspect Med 2:a011452. doi:10.1101/cshperspect.a011452

    PubMed Central  PubMed  Google Scholar 

  98. Saido T, Leissring MA (2012) Proteolytic degradation of amyloid -protein. Cold Spring Harb Perspect Med 2:a006379. doi:10.1101/cshperspect.a006379

    PubMed Central  PubMed  Google Scholar 

  99. LaFerla FM (2002) Calcium dyshomeostasis and intracellular signalling in Alzheimer’s disease. Nat Rev Neurosci 3:862–872. doi:10.1038/nrn960

    CAS  PubMed  Google Scholar 

  100. Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259

    CAS  PubMed  Google Scholar 

  101. Sultana R, Boyd-Kimball D, Poon HF et al (2006) Redox proteomics identification of oxidized proteins in Alzheimer’s disease hippocampus and cerebellum: an approach to understand pathological and biochemical alterations in AD. Neurobiol Aging 27:1564–1576. doi:10.1016/j.neurobiolaging.2005.09.021

    CAS  PubMed  Google Scholar 

  102. Petrucelli L, Dickson D, Kehoe K et al (2004) CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation. Hum Mol Genet 13:703–714. doi:10.1093/hmg/ddh083

    CAS  PubMed  Google Scholar 

  103. Riederer BM, Leuba G, Vernay A, Riederer IM (2011) The role of the ubiquitin proteasome system in Alzheimer’s disease. Exp Biol Med 236:268–276. doi:10.1258/ebm.2010.010327

    CAS  Google Scholar 

  104. Manavalan A, Mishra M, Feng L (2013) Brain site-specific proteome changes in aging-related dementia. Exp Mol Med 45:e39–17. doi:10.1038/emm.2013.76

    Google Scholar 

  105. Almeida CG (2006) Beta-amyloid accumulation impairs multivesicular body sorting by inhibiting the ubiquitin-proteasome system. J Neurosci 26:4277–4288. doi:10.1523/JNEUROSCI.5078-05.2006

    CAS  PubMed  Google Scholar 

  106. Dickey CA, Kamal A, Lundgren K et al (2007) The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins. J Clin Invest 117:648–658. doi:10.1172/JCI29715

    PubMed Central  CAS  PubMed  Google Scholar 

  107. O’Neill C (2013) PI3-kinase/Akt/mTOR signaling: impaired on/off switches in aging, cognitive decline and Alzheimer’s disease. Exp Gerontol 48:647–653. doi:10.1016/j.exger.2013.02.025

    Google Scholar 

  108. Caccamo A, Magrì A, Medina DX et al (2013) mTOR regulates tau phosphorylation and degradation: implications for Alzheimer’s disease and other tauopathies. Aging Cell 12:370–380. doi:10.1111/acel.12057

    PubMed Central  CAS  PubMed  Google Scholar 

  109. Spilman P, Podlutskaya N, Hart MJ et al (2010) Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-β levels in a mouse model of Alzheimer’s disease. PLoS One 5:e9979–8. doi:10.1371/journal.pone.0009979

    PubMed Central  PubMed  Google Scholar 

  110. Mrak R, Griffin WS, Graham DI (1997) Agin-associated changes in human brain. J Neuropathol Exp Neurol 56:1269–1275

    CAS  PubMed  Google Scholar 

  111. Brunk UT, Terman A (2002) The mitochondrial-lysosomal axis theory of aging: accumulation of damaged mitochondria as a result of imperfect autophagocytosis. Eur J Biochem 269:1996–2002. doi:10.1046/j.1432-1033.2002.02869.x

    CAS  PubMed  Google Scholar 

  112. Nixon RA, Cataldo AM, Mathews PM (2000) The endosomal-lysosomal system of neurons in Alzheimer’s disease pathogenesis: a review. Neurochem Res 25:1161–1172

    CAS  PubMed  Google Scholar 

  113. Nixon RA, Wegiel J, Kumar A et al (2005) Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J Neuropathol Exp Neurol 64:113–122

    PubMed  Google Scholar 

  114. Pickford F, Masliah E, Britschgi M et al (2008) The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J Clin Invest 118:2190–2199. doi:10.1172/JCI33585

    PubMed Central  CAS  PubMed  Google Scholar 

  115. Nilsson P, Loganathan K, Sekiguchi M et al (2013) Aβ secretion and plaque formation depend on autophagy. Cell Rep 5:61–69. doi:10.1016/j.celrep.2013.08.042

    CAS  PubMed  Google Scholar 

  116. Ash PEA, Vanderweyde TE, Youmans KL et al (2014) Pathological stress granules in Alzheimer’s disease. Brain Res 1584:52–58. doi:10.1016/j.brainres.2014.05.052

    PubMed Central  CAS  PubMed  Google Scholar 

  117. Castellani RJ, Gupta Y, Sheng B et al (2011) A novel origin for granulovacuolar degeneration in aging and Alzheimer’s disease: parallels to stress granules. Lab Invest 91:1777–1786. doi:10.1038/labinvest.2011.149

    PubMed Central  CAS  PubMed  Google Scholar 

  118. Vanderweyde T, Yu H, Varnum M et al (2012) Contrasting pathology of the stress granule proteins TIA-1 and G3BP in tauopathies. J Neurosci 32:8270–8283. doi:10.1523/JNEUROSCI.1592-12.2012

    PubMed Central  CAS  PubMed  Google Scholar 

  119. Altman J, Das GD (1965) Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol 124:319–335

    CAS  PubMed  Google Scholar 

  120. van Wijngaarden P, Franklin RJM (2013) Ageing stem and progenitor cells: implications for rejuvenation of the central nervous system. Development 140:2562–2575. doi:10.1242/dev.092262

    PubMed  Google Scholar 

  121. Eriksson PS, Perfilieva E, Björk-Eriksson T et al (1998) Neurogenesis in the adult human hippocampus. Nat Med 4:1313–1317. doi:10.1038/3305

    CAS  PubMed  Google Scholar 

  122. Spalding KL, Bergmann O, Alkass K et al (2013) Dynamics of hippocampal neurogenesis in adult humans. Cell 153:1219–1227. doi:10.1016/j.cell.2013.05.002

    PubMed Central  CAS  PubMed  Google Scholar 

  123. Göritz C, Frisén J (2012) Neural stem cells and neurogenesis in the adult. Cell Stem Cell 10:657–659. doi:10.1016/j.stem.2012.04.005

    PubMed  Google Scholar 

  124. Lazarov O, Mattson MP, Peterson DA et al (2010) When neurogenesis encounters aging and disease. Trends Neurosci 33:569–579. doi:10.1016/j.tins.2010.09.003

    PubMed Central  CAS  PubMed  Google Scholar 

  125. Mu Y, Gage FH (2011) Adult hippocampal neurogenesis and its role in Alzheimer’s disease. Mol Neurodeg 6:85. doi:10.1186/1750-1326-6-85

    Google Scholar 

  126. Ming G-L, Song H (2011) Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 70:687–702. doi:10.1016/j.neuron.2011.05.001

    PubMed Central  CAS  PubMed  Google Scholar 

  127. Fuentealba LC, Obernier K, Alvarez-Buylla A (2012) Adult neural stem cells bridge their niche. Stem Cell 10:698–708. doi:10.1016/j.stem.2012.05.012

    CAS  Google Scholar 

  128. Molofsky AV, Slutsky SG, Joseph NM et al (2006) Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature 443:448–452. doi:10.1038/nature05091

    PubMed Central  CAS  PubMed  Google Scholar 

  129. Molofsky AV, Pardal R, Iwashita T et al (2003) Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 425:962–967. doi:10.1038/nature02060

    PubMed Central  CAS  PubMed  Google Scholar 

  130. Renault VM, Rafalski VA, Morgan AA et al (2009) FoxO3 regulates neural stem cell homeostasis. Cell Stem Cell 5:527–539. doi:10.1016/j.stem.2009.09.014

    PubMed Central  CAS  PubMed  Google Scholar 

  131. Ma DK, Jang M-H, Guo JU et al (2009) Neuronal activity-induced Gadd45b promotes epigenetic DNA demethylation and adult neurogenesis. Science 323:1074–1077. doi:10.1126/science.1166859

    PubMed Central  CAS  PubMed  Google Scholar 

  132. Hsieh J, Nakashima K, Kuwabara T et al (2004) Histone deacetylase inhibition-mediated neuronal differentiation of multipotent adult neural progenitor cells. Proc Natl Acad Sci U S A 101:16659–16664. doi:10.1073/pnas.0407643101

    PubMed Central  CAS  PubMed  Google Scholar 

  133. Gao Z, Ure K, Ding P et al (2011) The master negative regulator REST/NRSF controls adult neurogenesis by restraining the neurogenic program in quiescent stem cells. J Neurosci 31:9772–9786. doi:10.1523/JNEUROSCI.1604-11.2011

    PubMed Central  CAS  PubMed  Google Scholar 

  134. Trejo JL, Carro E, Torres-Aleman I (2001) Circulating insulin-like growth factor I mediates exercise-induced increases in the number of new neurons in the adult hippocampus. J Neurosci 21:1628–1634

    CAS  PubMed  Google Scholar 

  135. Fabel K, Fabel K, Tam B et al (2003) VEGF is necessary for exercise-induced adult hippocampal neurogenesis. Eur J Neurosci 18:2803–2812. doi:10.1046/j.1460-9568.2003.03041.x

    PubMed  Google Scholar 

  136. Villeda SA, Luo J, Mosher KI et al (2011) The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477:90–94. doi:10.1038/nature10357

    PubMed Central  CAS  PubMed  Google Scholar 

  137. Shen Q, Wang Y, Kokovay E et al (2008) Adult SVZ stem cells lie in a vascular niche: a quantitative analysis of niche cell-cell interactions. Cell Stem Cell 3:289–300. doi:10.1016/j.stem.2008.07.026

    PubMed Central  CAS  PubMed  Google Scholar 

  138. Tavazoie M, Van der Veken L, Silva-Vargas V et al (2008) A specialized vascular niche for adult neural stem cells. Cell Stem Cell 3:279–288. doi:10.1016/j.stem.2008.07.025

    CAS  PubMed  Google Scholar 

  139. Palmer TD, Willhoite AR, Gage FH (2000) Vascular niche for adult hippocampal neurogenesis. J Comp Neurol 425:479–494

    CAS  PubMed  Google Scholar 

  140. van Praag H, Kempermann G, Gage FH (1999) Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci 2:266–270. doi:10.1038/6368

    PubMed  Google Scholar 

  141. van Praag H, Kempermann G, Gage FH (2000) Neural consequences of environmental enrichment. Nat Rev Neurosci 1:191–198. doi:10.1038/35044558

    PubMed  Google Scholar 

  142. Aberg MAI, Waern M, Nyberg J et al (2012) Cardiovascular fitness in males at age 18 and risk of serious depression in adulthood: Swedish prospective population-based study. Br J Psychiatry. doi:10.1192/bjp.bp.111.103416

    PubMed  Google Scholar 

  143. Knöchel C, Oertel-Knöchel V, O’Dwyer L et al (2012) Cognitive and behavioural effects of physical exercise in psychiatric patients. Prog Neurobiol 96:46–68. doi:10.1016/j.pneurobio.2011.11.007

    PubMed  Google Scholar 

  144. Larson EB, Wang L, Bowen JD et al (2006) Exercise is associated with reduced risk for incident dementia among persons 65 years of age and older. Ann Intern Med 144:73–81

    PubMed  Google Scholar 

  145. Villeda SA, Plambeck KE, Middeldorp J et al (2014) Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med 20:659–663. doi:10.1038/nm.3569

    PubMed Central  CAS  PubMed  Google Scholar 

  146. Katsimpardi L, Litterman NK, Schein PA et al (2014) Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science 344:630–634. doi:10.1126/science.1251141

    PubMed Central  CAS  PubMed  Google Scholar 

  147. Paliouras GN, Hamilton LK, Aumont A et al (2012) Mammalian target of rapamycin signaling is a key regulator of the transit-amplifying progenitor pool in the adult and aging forebrain. J Neurosci 32:15012–15026. doi:10.1523/JNEUROSCI.2248-12.2012

    CAS  PubMed  Google Scholar 

  148. Monje ML, Toda H, Palmer TD (2003) Inflammatory blockade restores adult hippocampal neurogenesis. Science 302:1760–1765. doi:10.1126/science.1088417

    CAS  PubMed  Google Scholar 

  149. Iosif RE (2006) Tumor necrosis factor receptor 1 is a negative regulator of progenitor proliferation in adult hippocampal neurogenesis. J Neurosci 26:9703–9712. doi:10.1523/JNEUROSCI.2723-06.2006

    CAS  PubMed  Google Scholar 

  150. Koo JW, Duman RS (2008) IL-1β is an essential mediator of the antineurogenic and anhedonic effects of stress. Proc Natl Acad Sci U S A 105:751–756

    PubMed Central  CAS  PubMed  Google Scholar 

  151. Kaneko N, Kudo K, Mabuchi T et al (2006) Suppression of cell proliferation by interferon-alpha through interleukin-1 production in adult rat dentate gyrus. Neuropsychopharmacology 31:2619–2626. doi:10.1038/sj.npp.1301137

    CAS  PubMed  Google Scholar 

  152. Scheibel RS, Valentine AD, O’Brien S, Meyers CA (2004) Cognitive dysfunction and depression during treatment with interferon-alpha and chemotherapy. J Neuropsychiatry Clin Neurosci 16:185–191. doi:10.1176/appi.neuropsych.16.2.185

    CAS  PubMed  Google Scholar 

  153. Hilsabeck RC, Hassanein TI, Ziegler EA et al (2005) Effect of interferon-alpha on cognitive functioning in patients with chronic hepatitis C. J Int Neuropsychol Soc 11:16–22. doi:10.1017/S1355617705050022

    CAS  PubMed  Google Scholar 

  154. Moriyama M, Fukuhara T, Britschgi M et al (2011) Complement receptor 2 is expressed in neural progenitor cells and regulates adult hippocampal neurogenesis. J Neurosci 31:3981–3989. doi:10.1523/JNEUROSCI.3617-10.2011

    PubMed Central  CAS  PubMed  Google Scholar 

  155. Baruch K, Ron-Harel N, Gal H et al (2013) CNS-specific immunity at the choroid plexus shifts toward destructive Th2 inflammation in brain aging. Proc Natl Acad Sci. doi:10.1073/pnas.1211270110

    PubMed Central  PubMed  Google Scholar 

  156. Vasudevan AR (2006) Eotaxin and obesity. J Clin Endocrinol Metab 91:256–261. doi:10.1210/jc.2005-1280

    CAS  PubMed  Google Scholar 

  157. Choi KM, Kim JH, Cho GJ et al (2007) Effect of exercise training on plasma visfatin and eotaxin levels. Eur J Endocrinol 157:437–442. doi:10.1530/EJE-07-0127

    CAS  PubMed  Google Scholar 

  158. Jin K, Peel AL, Mao XO et al (2004) Increased hippocampal neurogenesis in Alzheimer’s disease. Proc Natl Acad Sci U S A 101:343–347. doi:10.1073/pnas.2634794100

    PubMed Central  CAS  PubMed  Google Scholar 

  159. Haughey NJ, Nath A, Chan SL et al (2002) Disruption of neurogenesis by amyloid beta-peptide, and perturbed neural progenitor cell homeostasis, in models of Alzheimer’s disease. J Neurochem 83:1509–1524

    CAS  PubMed  Google Scholar 

  160. Verret L, Jankowsky JL, Xu GM et al (2007) Alzheimer’s-type amyloidosis in transgenic mice impairs survival of newborn neurons derived from adult hippocampal neurogenesis. J Neurosci 27:6771–6780. doi:10.1523/JNEUROSCI.5564-06.2007

    PubMed Central  CAS  PubMed  Google Scholar 

  161. López-Toledano MA, Shelanski ML (2007) Increased neurogenesis in young transgenic mice overexpressing human APP(Sw, Ind). J Alzheimers Dis 12:229–240

    PubMed  Google Scholar 

  162. Wen PH, Shao X, Shao Z et al (2002) Overexpression of wild type but not an FAD mutant presenilin-1 promotes neurogenesis in the hippocampus of adult mice. Neurobiol Dis 10:8–19. doi:10.1006/nbdi.2002.0490

    CAS  PubMed  Google Scholar 

  163. Hu WT, Holtzman DM, Fagan AM et al (2012) Plasma multianalyte profiling in mild cognitive impairment and Alzheimer disease. Neurology 79:897–905. doi:10.1212/WNL.0b013e318266fa70

    PubMed Central  CAS  PubMed  Google Scholar 

  164. Ray S, Britschgi M, Herbert C et al (2007) Classification and prediction of clinical Alzheimer’s diagnosis based on plasma signaling proteins. Nat Med 13:1359–1362. doi:10.1038/nm1653

    CAS  PubMed  Google Scholar 

  165. Johnstone D, Milward EA, Berretta R et al (2012) Multivariate protein signatures of pre-clinical Alzheimer’s disease in the Alzheimer’s disease neuroimaging initiative (ADNI) plasma proteome dataset. PLoS One 7:e34341. doi:10.1371/journal.pone.0034341.t009

    PubMed Central  CAS  PubMed  Google Scholar 

  166. Hye A, Riddoch-Contreras J, Baird AL et al (2014) Plasma proteins predict conversion to dementia from prodromal disease. Alzheimers Dement 10:799–807.e2. doi:10.1016/j.jalz.2014.05.1749

    PubMed Central  PubMed  Google Scholar 

  167. Soares HD, Potter WZ, Pickering E et al (2012) Plasma biomarkers associated with the apolipoprotein E genotype and Alzheimer disease. Arch Neurol 69(10):1310–1317. doi:10.1001/archneurol.2012.1070

    PubMed Central  PubMed  Google Scholar 

  168. Britschgi M, Rufibach K, Huang SL et al (2011) Modeling of pathological traits in Alzheimer’s disease based on systemic extracellular signaling proteome. Mol Cell Proteomics 10(M111):008862

    PubMed  Google Scholar 

  169. Kiddle SJ, Thambisetty M, Simmons A et al (2012) Plasma based markers of [11C] PiB-PET brain amyloid burden. PLoS One 7:e44260. doi:10.1371/journal.pone.0044260.t003

    PubMed Central  CAS  PubMed  Google Scholar 

  170. Hye A, Lynham S, Thambisetty M et al (2006) Proteome-based plasma biomarkers for Alzheimer’s disease. Brain 129:3042–3050. doi:10.1093/brain/awl279

    CAS  PubMed  Google Scholar 

  171. Franceschi C, Campisi J (2014) Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci 69:S4–S9. doi:10.1093/gerona/glu057

    PubMed  Google Scholar 

  172. Dubal DB, Zhu L, Sanchez PE et al (2015) Life extension factor klotho prevents mortality and enhances cognition in hAPP transgenic mice. J Neurosci 35:2358–2371. doi:10.1523/JNEUROSCI.5791-12.2015

    PubMed Central  CAS  PubMed  Google Scholar 

  173. Wyss-Coray T (2006) Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat Med 12:1005–1015. doi:10.1038/nm1484

    CAS  PubMed  Google Scholar 

  174. Lucin KM, Wyss-Coray T (2009) Immune activation in brain aging and neurodegeneration: too much or too little? Neuron 64:110–122. doi:10.1016/j.neuron.2009.08.039

    PubMed Central  CAS  PubMed  Google Scholar 

  175. McGeer PL, McGeer E, Rogers J, Sibley J (1990) Anti-inflammatory drugs and Alzheimer disease. Lancet 335:1037

    CAS  PubMed  Google Scholar 

  176. Côté S, Carmichael P-H, Verreault R et al (2012) Nonsteroidal anti-inflammatory drug use and the risk of cognitive impairment and Alzheimer’s disease. Alzheimers Dement 8:219–226. doi:10.1016/j.jalz.2011.03.012

    PubMed  Google Scholar 

  177. Vlad SC, Miller DR, Kowall NW, Felson DT (2008) Protective effects of NSAIDs on the development of Alzheimer disease. Neurology 70:1672–1677. doi:10.1212/01.wnl.0000311269.57716.63

    PubMed Central  CAS  PubMed  Google Scholar 

  178. Holmes C, Cunningham C, Zotova E et al (2011) Proinflammatory cytokines, sickness behavior, and Alzheimer disease. Neurology 77:212–218. doi:10.1212/WNL.0b013e318225ae07

    PubMed Central  CAS  PubMed  Google Scholar 

  179. Holmes C, Cunningham C, Zotova E et al (2009) Systemic inflammation and disease progression in Alzheimer disease. Neurology 73:768–774. doi:10.1212/WNL.0b013e3181b6bb95

    PubMed Central  CAS  PubMed  Google Scholar 

  180. Coppé J-P, Patil CK, Rodier F et al (2008) Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. Plos Biol 6:e301. doi:10.1371/journal.pbio.0060301

    PubMed Central  Google Scholar 

  181. Salminen A, Ojala J, Kaarniranta K et al (2011) Astrocytes in the aging brain express characteristics of senescence-associated secretory phenotype. Eur J Neurosci 34:3–11. doi:10.1111/j.1460-9568.2011.07738.x

    PubMed  Google Scholar 

  182. Podtelezhnikov AA, Tanis KQ, Nebozhyn M et al (2011) Molecular insights into the pathogenesis of Alzheimer’s disease and its relationship to normal aging. PLoS One 6:e29610. doi:10.1371/journal.pone.0029610

    PubMed Central  CAS  PubMed  Google Scholar 

  183. Zhang B, Gaiteri C, Bodea L-G et al (2013) Integrated systems approach identifies genetic nodes and networks in late-onset alzheimer’s disease. Cell 153:707–720. doi:10.1016/j.cell.2013.03.030

    Google Scholar 

  184. Linnartz B, Neumann H (2012) Microglial activatory (immunoreceptor tyrosine-based activation motif)- and inhibitory (immunoreceptor tyrosine-based inhibition motif)-signaling receptors for recognition of the neuronal glycocalyx. Glia. doi:10.1002/glia.22359

    PubMed  Google Scholar 

  185. Jonsson T, Stefansson H, Steinberg S et al (2013) Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med 368:107–116. doi:10.1056/NEJMoa1211103

    PubMed Central  CAS  PubMed  Google Scholar 

  186. Guerreiro R, Wojtas A, Bras J et al (2013) TREM2 variants in Alzheimer’s disease. N Engl J Med 368:117–127. doi:10.1056/NEJMoa1211851

    PubMed Central  CAS  PubMed  Google Scholar 

  187. Naj AC, Jun G, Beecham GW et al (2011) Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset alzheimer’s disease. Nat Genet 43:436–441. doi:10.1038/ng.801

    Google Scholar 

  188. Hollingworth P, Harold D, Sims R et al (2011) Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat Genet 43:429–435. doi:10.1038/ng.803

    PubMed Central  CAS  PubMed  Google Scholar 

  189. Lambert J-C, Ibrahim-Verbaas CA, Harold D et al (2013) Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet 45(12):1452–1458. doi:10.1038/ng.2802

    PubMed Central  CAS  PubMed  Google Scholar 

  190. Zhang G, Li J, Purkayastha S et al (2013) Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH. Nature 497:211–216. doi:10.1038/nature12143

    PubMed Central  CAS  PubMed  Google Scholar 

  191. den Dunnen WFA, Brouwer WH, Bijlard E et al (2008) No disease in the brain of a 115-year-old woman. Neurobiol Aging 29:1127–1132. doi:10.1016/j.neurobiolaging.2008.04.010

    Google Scholar 

  192. Katsel P, Tan W, Haroutunian V (2009) Gain in brain immunity in the oldest-old differentiates cognitively normal from demented individuals. PLoS One 4:e7642. doi:10.1371/journal.pone.0007642.t009

    PubMed Central  PubMed  Google Scholar 

  193. Ron-Harel N, Schwartz M (2009) Immune senescence and brain aging: can rejuvenation of immunity reverse memory loss? Trends Neurosci 32:367–375. doi:10.1016/j.tins.2009.03.003

    CAS  PubMed  Google Scholar 

  194. Lampron A, Gosselin D, Rivest S (2011) Targeting the hematopoietic system for the treatment of Alzheimer’s disease. Brain Behav Immun 25(Suppl 1):S71–S79. doi:10.1016/j.bbi.2010.12.018

    PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the Department of Veterans Affairs (T.W.-C.), and the NIA (AG045034 (T.W.-C.)).

Editor: Bradley Wise, National Institute on Aging (NIA), NIH.

Author information

Authors and Affiliations

  1. Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA

    Geoffrey A. Kerchner & Tony Wyss-Coray

  2. Center for Tissue Regeneration, Repair and Restoration, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA

    Tony Wyss-Coray

Authors
  1. Geoffrey A. Kerchner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tony Wyss-Coray
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tony Wyss-Coray .

Editor information

Editors and Affiliations

  1. National Inst. of Aging Division of Aging Biology, National Institutes of Health, Bethesda, Maryland, USA

    Felipe Sierra

  2. National Inst on Aging/ National Inst of Health, Division of Aging Biology, Bethesda, Maryland, USA

    Ronald Kohanski

Rights and permissions

Reprints and Permissions

Copyright information

© 2016 Springer International Publishing

About this chapter

Cite this chapter

Kerchner, G.A., Wyss-Coray, T. (2016). The Role of Aging in Alzheimer’s Disease. In: Sierra, F., Kohanski, R. (eds) Advances in Geroscience. Springer, Cham. https://doi.org/10.1007/978-3-319-23246-1_7

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-23246-1_7

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-23245-4

  • Online ISBN: 978-3-319-23246-1

  • eBook Packages: MedicineMedicine (R0)