Skip to main content

Advertisement

SpringerLink
Log in

Alzheimer’s disease is not “brain aging”: neuropathological, genetic, and epidemiological human studies

  • Review
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

Human studies are reviewed concerning whether “aging”-related mechanisms contribute to Alzheimer’s disease (AD) pathogenesis. AD is defined by specific neuropathology: neuritic amyloid plaques and neocortical neurofibrillary tangles. AD pathology is driven by genetic factors related not to aging per se, but instead to the amyloid precursor protein (APP). In contrast to genes involved in APP-related mechanisms, there is no firm connection between genes implicated in human “accelerated aging” diseases (progerias) and AD. The epidemiology of AD in advanced age is highly relevant but deceptively challenging to address given the low autopsy rates in most countries. In extreme old age, brain diseases other than AD approximate AD prevalence while the impact of AD pathology appears to peak by age 95 and decline thereafter. Many distinct brain diseases other than AD afflict older human brains and contribute to cognitive impairment. Additional prevalent pathologies include cerebrovascular disease and hippocampal sclerosis, both high-morbidity brain diseases that appear to peak in incidence later than AD chronologically. Because of these common brain diseases of extreme old age, the epidemiology differs between clinical “dementia” and the subset of dementia cases with AD pathology. Additional aging-associated mechanisms for cognitive decline such as diabetes and synapse loss have been linked to AD and these hypotheses are discussed. Criteria are proposed to define an “aging-linked” disease, and AD fails all of these criteria. In conclusion, it may be most fruitful to focus attention on specific pathways involved in AD rather than attributing it to an inevitable consequence of aging.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. (1997) Consensus recommendations for the postmortem diagnosis of Alzheimer’s disease. The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer’s Disease. Neurobiol Aging 18:S1–S2

  2. (2001) Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales. Neuropathology Group of the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS). Lancet 357:169–175

  3. (2007) Prevalence of stroke–United States, 2005. MMWR Morb Mortal Wkly Rep 56:469–474

  4. (1994) Sundt’s occlusive cerebrovascular disease. W.B. Saunders, Philadelphia

  5. Abner EL, Kryscio RJ, Schmitt FA et al (2011) “End-Stage” neurofibrillary tangle pathology in preclinical Alzheimer’s disease: fact or fiction? J Alzheimers Dis

  6. Abner EL, Schmitt FA, Mendiondo MS, Marcum JL, Kryscio RJ (2011) Vitamin E and all-cause mortality: a meta-analysis. Curr Aging Sci [Epub ahead of print]

  7. Adib-Samii P, Brice G, Martin RJ, Markus HS (2010) Clinical spectrum of CADASIL and the effect of cardiovascular risk factors on phenotype: study in 200 consecutively recruited individuals. Stroke 41:630–634

    Article  PubMed  Google Scholar 

  8. Ahtiluoto S, Polvikoski T, Peltonen M et al (2010) Diabetes, Alzheimer disease, and vascular dementia: a population-based neuropathologic study. Neurology 75:1195–1202

    Article  PubMed  CAS  Google Scholar 

  9. Ala TA, Beh GO, Frey WH 2nd (2000) Pure hippocampal sclerosis: a rare cause of dementia mimicking Alzheimer’s disease. Neurology 54:843–848

    PubMed  CAS  Google Scholar 

  10. Alafuzoff I, Arzberger T, Al-Sarraj S et al (2008) Staging of neurofibrillary pathology in Alzheimer’s disease: a study of the BrainNet Europe Consortium. Brain Pathol 18:484–496

    PubMed  Google Scholar 

  11. Albani D, Polito L, Forloni G (2010) Sirtuins as novel targets for Alzheimer’s disease and other neurodegenerative disorders: experimental and genetic evidence. J Alzheimers Dis 19:11–26

    PubMed  Google Scholar 

  12. Allen NB, Lichtman JH, Cohen HW et al (2008) Vascular disease among hospitalized multiple sclerosis patients. Neuroepidemiology 30:234–238

    Article  PubMed  Google Scholar 

  13. Altena E, Ramautar JR, Van Der Werf YD, Van Someren EJ (2010) Do sleep complaints contribute to age-related cognitive decline? Prog Brain Res 185:181–205

    Article  PubMed  Google Scholar 

  14. Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT (1992) Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease. Neurology 42:631–639

    PubMed  CAS  Google Scholar 

  15. Arvanitakis Z, Schneider JA, Wilson RS et al (2006) Diabetes is related to cerebral infarction but not to AD pathology in older persons. Neurology 67:1960–1965

    Article  PubMed  CAS  Google Scholar 

  16. Asiskovitch S (2010) Gender and health outcomes: the impact of healthcare systems and their financing on life expectancies of women and men. Soc Sci Med 70:886–895

    Article  PubMed  Google Scholar 

  17. Aubert G, Lansdorp PM (2008) Telomeres and aging. Physiol Rev 88:557–579

    Article  PubMed  CAS  Google Scholar 

  18. Baker LD, Cross DJ, Minoshima S et al (2011) Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes. Arch Neurol 68:51–57

    Article  PubMed  Google Scholar 

  19. Barker WW, Luis CA, Kashuba A et al (2002) Relative frequencies of Alzheimer disease, Lewy body, vascular and frontotemporal dementia, and hippocampal sclerosis in the State of Florida Brain Bank. Alzheimer Dis Assoc Disord 16:203–212

    Article  PubMed  Google Scholar 

  20. Bassi P, Sacco E (2009) Cancer and aging: the molecular pathways. Urol Oncol 27:620–627

    Article  PubMed  CAS  Google Scholar 

  21. Beach TG, Sue LI, Walker DG et al (2008) The Sun Health Research Institute Brain Donation Program: description and experience, 1987–2007. Cell Tissue Bank 9:229–245

    Article  PubMed  Google Scholar 

  22. Beekly DL, Ramos EM, Lee WW et al (2007) The National Alzheimer’s Coordinating Center (NACC) database: the Uniform Data Set. Alzheimer Dis Assoc Disord 21:249–258

    Article  PubMed  Google Scholar 

  23. Beekly DL, Ramos EM, van Belle G et al (2004) The National Alzheimer’s Coordinating Center (NACC) Database: an Alzheimer disease database. Alzheimer Dis Assoc Disord 18:270–277

    PubMed  Google Scholar 

  24. Beeri MS, Silverman JM, Davis KL et al (2005) Type 2 diabetes is negatively associated with Alzheimer’s disease neuropathology. J Gerontol A Biol Sci Med Sci 60:471–475

    PubMed  Google Scholar 

  25. Belbin O, Carrasquillo MM, Crump M et al (2010) Investigation of 15 of the top candidate genes for late-onset Alzheimer’s disease. Hum Genet

  26. Bennett DA, Schneider JA, Wilson RS et al (2005) Amyloid mediates the association of apolipoprotein E e4 allele to cognitive function in older people. J Neurol Neurosurg Psychiatry 76:1194–1199

    Article  PubMed  CAS  Google Scholar 

  27. Bennett DA, Wilson RS, Schneider JA et al (2003) Apolipoprotein E epsilon4 allele, AD pathology, and the clinical expression of Alzheimer’s disease. Neurology 60:246–252

    PubMed  CAS  Google Scholar 

  28. Bertram L, Lill CM, Tanzi RE (2010) The genetics of Alzheimer disease: back to the future. Neuron 68:270–281

    Article  PubMed  CAS  Google Scholar 

  29. Biere AL, Ostaszewski B, Zhao H et al (1995) Co-expression of beta-amyloid precursor protein (betaAPP) and apolipoprotein E in cell culture: analysis of betaAPP processing. Neurobiol Dis 2:177–187

    Article  PubMed  CAS  Google Scholar 

  30. Biffi A, Anderson CD, Desikan RS et al (2010) Genetic variation and neuroimaging measures in Alzheimer disease. Arch Neurol 67:677–685

    Article  PubMed  Google Scholar 

  31. Black RS, Sperling RA, Safirstein B et al (2010) A single ascending dose study of bapineuzumab in patients with Alzheimer disease. Alzheimer Dis Assoc Disord 24:198–203

    Article  PubMed  CAS  Google Scholar 

  32. Blagosklonny MV (2009) Validation of anti-aging drugs by treating age-related diseases. Aging (Albany NY) 1:281–288

    CAS  Google Scholar 

  33. Blennow K, Bogdanovic N, Alafuzoff I, Ekman R, Davidsson P (1996) Synaptic pathology in Alzheimer’s disease: relation to severity of dementia, but not to senile plaques, neurofibrillary tangles, or the ApoE4 allele. J Neural Transm 103:603–618

    Article  PubMed  CAS  Google Scholar 

  34. Boche D, Denham N, Holmes C, Nicoll JA (2010) Neuropathology after active Abeta42 immunotherapy: implications for Alzheimer’s disease pathogenesis. Acta Neuropathol 120:369–384

    Article  PubMed  CAS  Google Scholar 

  35. Boche D, Donald J, Love S et al (2010) Reduction of aggregated Tau in neuronal processes but not in the cell bodies after Abeta42 immunisation in Alzheimer’s disease. Acta Neuropathol 120:13–20

    Article  PubMed  CAS  Google Scholar 

  36. Bordin P, Da Col PG, Peruzzo P et al (1999) Causes of death and clinical diagnostic errors in extreme aged hospitalized people: a retrospective clinical–necropsy survey. J Gerontol A Biol Sci Med Sci 54:M554–M559

    Article  PubMed  CAS  Google Scholar 

  37. Braak H, Braak E, Bohl J (1993) Staging of Alzheimer-related cortical destruction. Eur Neurol 33:403–408

    Article  PubMed  CAS  Google Scholar 

  38. Braak H, Del Tredici K (2011) The pathological process underlying Alzheimer’s disease in individuals under thirty. Acta Neuropathol 121:171–181

    Article  PubMed  Google Scholar 

  39. Braffman BH, Zimmerman RA, Trojanowski JQ et al (1988) Brain MR: pathologic correlation with gross and histopathology. 2. Hyperintense white-matter foci in the elderly. AJR Am J Roentgenol 151:559–566

    PubMed  CAS  Google Scholar 

  40. Brown WT, Kieras FJ, Houck GE Jr, Dutkowski R, Jenkins EC (1985) A comparison of adult and childhood progerias: Werner syndrome and Hutchinson–Gilford progeria syndrome. Adv Exp Med Biol 190:229–244

    PubMed  CAS  Google Scholar 

  41. Bu G (2009) Apolipoprotein E and its receptors in Alzheimer’s disease: pathways, pathogenesis and therapy. Nat Rev Neurosci 10:333–344

    Article  PubMed  CAS  Google Scholar 

  42. Burtner CR, Kennedy BK (2010) Progeria syndromes and ageing: what is the connection? Nat Rev Mol Cell Biol 11:567–578

    Article  PubMed  CAS  Google Scholar 

  43. Butterfield DA, Bush AI (2004) Alzheimer’s amyloid beta-peptide (1–42): involvement of methionine residue 35 in the oxidative stress and neurotoxicity properties of this peptide. Neurobiol Aging 25:563–568

    Article  PubMed  CAS  Google Scholar 

  44. Cacabelos R, Fernandez-Novoa L, Lombardi V, Kubota Y, Takeda M (2005) Molecular genetics of Alzheimer’s disease and aging. Methods Find Exp Clin Pharmacol 27(Suppl A):1–573

    PubMed  Google Scholar 

  45. Caselli RJ, Graff-Radford NR, Reiman EM et al (1999) Preclinical memory decline in cognitively normal apolipoprotein E-epsilon4 homozygotes. Neurology 53:201–207

    PubMed  CAS  Google Scholar 

  46. Castellani RJ, Zhu X, Lee HG et al (2007) Neuropathology and treatment of Alzheimer disease: did we lose the forest for the trees? Expert Rev Neurother 7:473–485

    Article  PubMed  CAS  Google Scholar 

  47. Chan DC (2006) Mitochondria: dynamic organelles in disease, aging, and development. Cell 125:1241–1252

    Article  PubMed  CAS  Google Scholar 

  48. Chong MS, Sahadevan S (2005) Preclinical Alzheimer’s disease: diagnosis and prediction of progression. Lancet Neurol 4:576–579

    Article  PubMed  Google Scholar 

  49. Clavaguera F, Bolmont T, Crowther RA et al (2009) Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 11:909–913

    Article  PubMed  CAS  Google Scholar 

  50. Coker LH, Shumaker SA (2003) Type 2 diabetes mellitus and cognition: an understudied issue in women’s health. J Psychosom Res 54:129–139

    Article  PubMed  Google Scholar 

  51. Convit A, De Leon MJ, Tarshish C et al (1997) Specific hippocampal volume reductions in individuals at risk for Alzheimer’s disease. Neurobiol Aging 18:131–138

    Article  PubMed  CAS  Google Scholar 

  52. Corder EH, Saunders AM, Strittmatter WJ et al (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science (New York, NY) 261:921–923

    Article  CAS  Google Scholar 

  53. Corey-Bloom J, Sabbagh MN, Bondi MW et al (1997) Hippocampal sclerosis contributes to dementia in the elderly. Neurology 48:154–160

    PubMed  CAS  Google Scholar 

  54. Corrada MM, Brookmeyer R, Paganini-Hill A, Berlau D, Kawas CH (2010) Dementia incidence continues to increase with age in the oldest old: the 90+ study. Ann Neurol 67:114–121

    Article  PubMed  Google Scholar 

  55. Craft S (2009) The role of metabolic disorders in Alzheimer disease and vascular dementia: two roads converged. Arch Neurol 66:300–305

    Article  PubMed  Google Scholar 

  56. Crystal HA, Dickson D, Davies P et al (2000) The relative frequency of “dementia of unknown etiology” increases with age and is nearly 50% in nonagenarians. Arch Neurol 57:713–719

    Article  PubMed  CAS  Google Scholar 

  57. De Berardis G, D’Ettorre A, Graziano G et al (2011) The burden of hospitalization related to diabetes mellitus: a population-based study. Nutr Metab Cardiovasc Dis [Epub ahead of print]

  58. de Calignon A, Fox LM, Pitstick R et al (2010) Caspase activation precedes and leads to tangles. Nature 464:1201–1204

    Article  PubMed  CAS  Google Scholar 

  59. Debette S, Markus HS (2010) The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. Br Med J 341:c3666

    Article  Google Scholar 

  60. DeCarli C, Massaro J, Harvey D et al (2005) Measures of brain morphology and infarction in the Framingham heart study: establishing what is normal. Neurobiol Aging 26:491–510

    Article  PubMed  Google Scholar 

  61. Del Tredici K, Braak H (2008) Neurofibrillary changes of the Alzheimer type in very elderly individuals: neither inevitable nor benign: Commentary on “No disease in the brain of a 115-year-old woman”. Neurobiol Aging 29:1133–1136

    Article  PubMed  Google Scholar 

  62. Dickson DW, Crystal HA, Bevona C et al (1995) Correlations of synaptic and pathological markers with cognition of the elderly. Neurobiol Aging 16:285–298 (discussion 298–304)

    Google Scholar 

  63. Dickson DW, Davies P, Bevona C et al (1994) Hippocampal sclerosis: a common pathological feature of dementia in very old (> or =80 years of age) humans. Acta Neuropathol 88:212–221

    Article  PubMed  CAS  Google Scholar 

  64. Ding Q, Dimayuga E, Keller JN (2007) Oxidative stress alters neuronal RNA- and protein-synthesis: implications for neural viability. Free Radic Res 41:903–910

    Article  PubMed  CAS  Google Scholar 

  65. Dolan D, Troncoso J, Resnick SM et al (2010) Age, Alzheimer’s disease and dementia in the Baltimore Longitudinal Study of Ageing. Brain 133:2225–2231

    PubMed  Google Scholar 

  66. Droge W (2003) Oxidative stress and aging. Adv Exp Med Biol 543:191–200

    PubMed  CAS  Google Scholar 

  67. Dubois B, Feldman HH, Jacova C et al (2010) Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurol 9:1118–1127

    Article  PubMed  Google Scholar 

  68. Fang J, Alderman MH (2001) Trend of stroke hospitalization, United States, 1988–1997. Stroke 32:2221–2226

    Article  PubMed  CAS  Google Scholar 

  69. Ferenci P, Czlonkowska A, Merle U et al (2007) Late-onset Wilson’s disease. Gastroenterology 132:1294–1298

    Article  PubMed  CAS  Google Scholar 

  70. Fernando MS, Ince PG (2004) Vascular pathologies and cognition in a population-based cohort of elderly people. J Neurol Sci 226:13–17

    Article  PubMed  Google Scholar 

  71. Finch CE (2003) The biology of aging in model organisms. Alzheimer Dis Assoc Disord 17(Suppl 2):S39–S41

    Article  PubMed  CAS  Google Scholar 

  72. Frost B, Jacks RL, Diamond MI (2009) Propagation of tau misfolding from the outside to the inside of a cell. J Biol Chem 284:12845–12852

    Article  PubMed  CAS  Google Scholar 

  73. Gao S, Hendrie HC, Hall KS, Hui S (1998) The relationships between age, sex, and the incidence of dementia and Alzheimer disease: a meta-analysis. Arch Gen Psychiatry 55:809–815

    Article  PubMed  CAS  Google Scholar 

  74. Garde E, Mortensen EL, Krabbe K, Rostrup E, Larsson HB (2000) Relation between age-related decline in intelligence and cerebral white-matter hyperintensities in healthy octogenarians: a longitudinal study. Lancet 356:628–634

    Article  PubMed  CAS  Google Scholar 

  75. Gatz M, Reynolds CA, Fratiglioni L et al (2006) Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry 63:168–174

    Article  PubMed  Google Scholar 

  76. Giannakopoulos P, Gold G, Kovari E et al (2007) Assessing the cognitive impact of Alzheimer disease pathology and vascular burden in the aging brain: the Geneva experience. Acta Neuropathol 113:1–12

    Article  PubMed  Google Scholar 

  77. Giannakopoulos P, Hof PR, Michel JP, Guimon J, Bouras C (1997) Cerebral cortex pathology in aging and Alzheimer’s disease: a quantitative survey of large hospital-based geriatric and psychiatric cohorts. Brain Res Brain Res Rev 25:217–245

    Article  PubMed  CAS  Google Scholar 

  78. Giannattasio C, Poleggi A, Puopolo M et al (2008) Survival in Alzheimer’s disease is shorter in women carrying heterozygosity at codon 129 of the PRNP gene and no APOE epsilon 4 allele. Dement Geriatr Cogn Disord 25:354–358

    Article  PubMed  CAS  Google Scholar 

  79. Gold G, Bouras C, Kovari E et al (2000) Clinical validity of Braak neuropathological staging in the oldest-old. Acta Neuropathol 99:579–582 (discussion 583–574)

    Google Scholar 

  80. Gold G, Giannakopoulos P, Herrmann FR, Bouras C, Kovari E (2007) Identification of Alzheimer and vascular lesion thresholds for mixed dementia. Brain 130:2830–2836

    Article  PubMed  Google Scholar 

  81. Gold G, Kovari E, Herrmann FR et al (2005) Cognitive consequences of thalamic, basal ganglia, and deep white matter lacunes in brain aging and dementia. Stroke 36:1184–1188

    Article  PubMed  Google Scholar 

  82. Guo JL, Lee VM (2011) Seeding of normal tau by pathological tau conformers drives pathogenesis of Alzheimer-like tangles. J Biol Chem

  83. Hall CB, Verghese J, Sliwinski M et al (2005) Dementia incidence may increase more slowly after age 90: results from the Bronx Aging Study. Neurology 65:882–886

    Article  PubMed  CAS  Google Scholar 

  84. Harder A, Jendroska K, Kreuz F et al (1999) Novel twelve-generation kindred of fatal familial insomnia from Germany representing the entire spectrum of disease expression. Am J Med Genet 87:311–316

    Article  PubMed  CAS  Google Scholar 

  85. Harman D (2001) Aging: overview. Ann N Y Acad Sci 928:1–21

    Article  PubMed  CAS  Google Scholar 

  86. Haroutunian V, Schnaider-Beeri M, Schmeidler J et al (2008) Role of the neuropathology of Alzheimer disease in dementia in the oldest-old. Arch Neurol 65:1211–1217

    Article  PubMed  Google Scholar 

  87. Harras A (1995) Tapping the SEER database. Cancer Pract 3:184–186

    PubMed  CAS  Google Scholar 

  88. Hayflick L (2007) Biological aging is no longer an unsolved problem. Ann N Y Acad Sci 1100:1–13

    Article  PubMed  CAS  Google Scholar 

  89. Heitner J, Dickson D (1997) Diabetics do not have increased Alzheimer-type pathology compared with age-matched control subjects. A retrospective postmortem immunocytochemical and histofluorescent study. Neurology 49:1306–1311

    PubMed  CAS  Google Scholar 

  90. Herrup K (2010) Reimagining Alzheimer’s disease—an age-based hypothesis. J Neurosci 30:16755–16762

    Article  PubMed  CAS  Google Scholar 

  91. Hof PR, Bussiere T, Gold G et al (2003) Stereologic evidence for persistence of viable neurons in layer II of the entorhinal cortex and the CA1 field in Alzheimer disease. J Neuropathol Exp Neurol 62:55–67

    PubMed  Google Scholar 

  92. Hof PR, Glannakopoulos P, Bouras C (1996) The neuropathological changes associated with normal brain aging. Histol Histopathol 11:1075–1088

    PubMed  CAS  Google Scholar 

  93. Holliday R (1997) Understanding ageing. Philos Trans R Soc Lond B Biol Sci 352:1793–1797

    Article  PubMed  CAS  Google Scholar 

  94. Holmes C, Boche D, Wilkinson D et al (2008) Long-term effects of Abeta42 immunisation in Alzheimer’s disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet 372:216–223

    Article  PubMed  CAS  Google Scholar 

  95. Huttenlocher PR (1979) Synaptic density in human frontal cortex—developmental changes and effects of aging. Brain Res 163:195–205

    Article  PubMed  CAS  Google Scholar 

  96. Imhof A, Kovari E, von Gunten A et al (2007) Morphological substrates of cognitive decline in nonagenarians and centenarians: a new paradigm? J Neurol Sci

  97. Iseki E, Tsunoda S, Suzuki K et al (2002) Regional quantitative analysis of NFT in brains of non-demented elderly persons: comparisons with findings in brains of late-onset Alzheimer’s disease and limbic NFT dementia. Neuropathology 22:34–39

    Article  PubMed  Google Scholar 

  98. Janson J, Laedtke T, Parisi JE et al (2004) Increased risk of type 2 diabetes in Alzheimer disease. Diabetes 53:474–481

    Article  PubMed  CAS  Google Scholar 

  99. Jellinger K (2000) Pure hippocampal sclerosis: a rare cause of dementia mimicking Alzheimer’s disease. Neurology 55:739–740

    PubMed  CAS  Google Scholar 

  100. Jellinger KA (2009) Criteria for the neuropathological diagnosis of dementing disorders: routes out of the swamp? Acta Neuropathol 117:101–110

    Article  PubMed  Google Scholar 

  101. Jellinger KA (1994) Hippocampal sclerosis: a common pathological feature of dementia in very old humans. Acta Neuropathol 88:599

    Article  PubMed  CAS  Google Scholar 

  102. Jellinger KA (2008) The pathology of “vascular dementia”: a critical update. J Alzheimers Dis 14:107–123

    PubMed  CAS  Google Scholar 

  103. Jellinger KA, Attems J (2010) Is there pure vascular dementia in old age? J Neurol Sci 299:150–154

    Article  PubMed  Google Scholar 

  104. Jellinger KA, Attems J (2007) Neuropathological evaluation of mixed dementia. J Neurol Sci 257:80–87

    Article  PubMed  CAS  Google Scholar 

  105. Jellinger KA, Attems J (2010) Prevalence and pathology of vascular dementia in the oldest-old. J Alzheimers Dis 21:1283–1293

    PubMed  Google Scholar 

  106. Jellinger KA, Attems J (2010) Prevalence of dementia disorders in the oldest-old: an autopsy study. Acta Neuropathol 119:421–433

    Article  PubMed  Google Scholar 

  107. Jicha GA, Parisi JE, Dickson DW et al (2008) Age and apoE associations with complex pathologic features in Alzheimer’s disease. J Neurol Sci 273:34–39

    Article  PubMed  CAS  Google Scholar 

  108. Josephs KA, Whitwell JL, Knopman DS et al (2008) Abnormal TDP-43 immunoreactivity in AD modifies clinicopathologic and radiologic phenotype. Neurology 71:743–749

    Article  PubMed  Google Scholar 

  109. Jun G, Naj AC, Beecham GW et al (2010) Meta-analysis confirms CR1, CLU, and PICALM as alzheimer disease risk loci and reveals interactions with APOE genotypes. Arch Neurol 67:1473–1484

    Article  PubMed  Google Scholar 

  110. Jyrkka J, Enlund H, Lavikainen P, Sulkava R, Hartikainen S (2011) Association of polypharmacy with nutritional status, functional ability and cognitive capacity over a three-year period in an elderly population. Pharmacoepidemiol Drug Saf [Epub ahead of print]

  111. Kang DE, Pietrzik CU, Baum L et al (2000) Modulation of amyloid beta-protein clearance and Alzheimer’s disease susceptibility by the LDL receptor-related protein pathway. J Clin Invest 106:1159–1166

    Article  PubMed  CAS  Google Scholar 

  112. Katzman R, Kawas C (1994) The epidemiology of dementia and Alzheimer disease. In: Terry RD (ed) Alzheimer disease. Raven Press, New York, pp 105–122

    Google Scholar 

  113. Kirkwood TB (2011) Systems biology of ageing and longevity. Philos Trans R Soc Lond B Biol Sci 366:64–70

    Article  PubMed  Google Scholar 

  114. Knight JA (2000) The biochemistry of aging. Adv Clin Chem 35:1–62

    Article  PubMed  CAS  Google Scholar 

  115. Knopman DS, Parisi JE, Salviati A et al (2003) Neuropathology of cognitively normal elderly. J Neuropathol Exp Neurol 62:1087–1095

    PubMed  CAS  Google Scholar 

  116. Krach C, Velkoff VA (1999) Centenarians in the United States. Current Population Reports, vol. Series P23-199RV, US Dept of Health and Human Services/NIH, US Dept of Commerce/Census Bureau, Washington, DC

  117. Kudlow BA, Kennedy BK (2006) Aging: progeria and the lamin connection. Curr Biol 16:R652–R654

    Article  PubMed  CAS  Google Scholar 

  118. Kukull WA, Higdon R, Bowen JD et al (2002) Dementia and Alzheimer disease incidence: a prospective cohort study. Arch Neurol 59:1737–1746

    Article  PubMed  Google Scholar 

  119. Kulminski AM, Culminskaya I, Ukraintseva SV et al (2011) Trade-off in the effects of the apolipoprotein E polymorphism on the ages at onset of CVD and cancer influences human lifespan. Aging Cell [Epub ahead of print]

  120. Langlois NE (2006) The use of histology in 638 coronial post-mortem examinations of adults: an audit. Med Sci Law 46:310–320

    Article  PubMed  Google Scholar 

  121. Lassmann H, Fischer P, Jellinger K (1993) Synaptic pathology of Alzheimer’s disease. Ann N Y Acad Sci 695:59–64

    Article  PubMed  CAS  Google Scholar 

  122. Lauderback CM, Kanski J, Hackett JM et al (2002) Apolipoprotein E modulates Alzheimer’s Abeta(1–42)-induced oxidative damage to synaptosomes in an allele-specific manner. Brain Res 924:90–97

    Article  PubMed  CAS  Google Scholar 

  123. Launer LJ (2011) Counting dementia: there is no one “best” way. Alzheimers Dement 7:10–14

    Article  PubMed  Google Scholar 

  124. Lemere CA, Blusztajn JK, Yamaguchi H et al (1996) Sequence of deposition of heterogeneous amyloid beta-peptides and APO E in Down syndrome: implications for initial events in amyloid plaque formation. Neurobiol Dis 3:16–32

    Article  PubMed  CAS  Google Scholar 

  125. Leverenz JB, Agustin CM, Tsuang D et al (2002) Clinical and neuropathological characteristics of hippocampal sclerosis: a community-based study. Arch Neurol 59:1099–1106

    Article  PubMed  Google Scholar 

  126. Leverenz JB, Yu CE, Schellenberg GD (1998) Aging-associated neuropathology in Werner syndrome. Acta Neuropathol 96:421–424

    Article  PubMed  CAS  Google Scholar 

  127. Lovell MA, Markesbery WR (2007) Oxidative damage in mild cognitive impairment and early Alzheimer’s disease. J Neurosci Res 85:3036–3040

    Article  PubMed  CAS  Google Scholar 

  128. Lovell MA, Markesbery WR (2008) Oxidatively modified RNA in mild cognitive impairment. Neurobiol Dis 29:169–175

    Article  PubMed  CAS  Google Scholar 

  129. Lowe VJ, Kemp BJ, Jack CR Jr et al (2009) Comparison of 18F-FDG and PiB PET in cognitive impairment. J Nucl Med 50:878–886

    Article  PubMed  Google Scholar 

  130. Luchsinger JA (2010) Diabetes, related conditions, and dementia. J Neurol Sci 299:35–38

    Article  PubMed  Google Scholar 

  131. Mancuso C, Scapagini G, Curro D et al (2007) Mitochondrial dysfunction, free radical generation and cellular stress response in neurodegenerative disorders. Front Biosci 12:1107–1123

    Article  PubMed  CAS  Google Scholar 

  132. Martin GM (2005) Genetic modulation of senescent phenotypes in Homo sapiens. Cell 120:523–532

    Article  PubMed  CAS  Google Scholar 

  133. Martin GM (1989) Genetic modulation of the senescent phenotype in Homo sapiens. Genome 31:390–397

    Article  PubMed  CAS  Google Scholar 

  134. Masliah E (1995) Mechanisms of synaptic dysfunction in Alzheimer’s disease. Histol Histopathol 10:509–519

    PubMed  CAS  Google Scholar 

  135. Matsuzaki T, Sasaki K, Tanizaki Y et al (2010) Insulin resistance is associated with the pathology of Alzheimer disease: the Hisayama study. Neurology 75:764–770

    Article  PubMed  CAS  Google Scholar 

  136. Mayeux R, Reitz C, Brickman AM et al (2011) Operationalizing diagnostic criteria for Alzheimer’s disease and other age-related cognitive impairment—Part 1. Alzheimers Dement 7:15–34

    Article  PubMed  Google Scholar 

  137. McKee AC, Cantu RC, Nowinski CJ et al (2009) Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J Neuropathol Exp Neurol 68:709–735

    Article  PubMed  Google Scholar 

  138. McNaughton D, Knight W, Guerreiro R et al (2010) Duplication of amyloid precursor protein (APP), but not prion protein (PRNP) gene is a significant cause of early onset dementia in a large UK series. Neurobiol Aging [Epub ahead of print]

  139. Mirra SS, Heyman A, McKeel D et al (1991) The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 41:479–486

    PubMed  CAS  Google Scholar 

  140. Mizutani T, Shimada H (1992) Neuropathological background of twenty-seven centenarian brains. J Neurol Sci 108:168–177

    Article  PubMed  CAS  Google Scholar 

  141. Montine TJ (2011) Prevalence estimates for latent neurodegenerative disease. Toxicol Pathol 39:99–102

    Article  PubMed  Google Scholar 

  142. Morrison JH, Hof PR (2007) Life and death of neurons in the aging cerebral cortex. Int Rev Neurobiol 81:41–57

    Article  PubMed  CAS  Google Scholar 

  143. Mungas D, Reed BR, Ellis WG, Jagust WJ (2001) The effects of age on rate of progression of Alzheimer disease and dementia with associated cerebrovascular disease. Arch Neurol 58:1243–1247

    Article  PubMed  CAS  Google Scholar 

  144. Myers RH, Schaefer EJ, Wilson PW et al (1996) Apolipoprotein E epsilon4 association with dementia in a population-based study: the Framingham study. Neurology 46:673–677

    PubMed  CAS  Google Scholar 

  145. Nagy Z, Hindley NJ, Braak H et al (1999) The progression of Alzheimer’s disease from limbic regions to the neocortex: clinical, radiological and pathological relationships. Dement Geriatr Cogn Disord 10:115–120

    Article  PubMed  CAS  Google Scholar 

  146. Nelson PT, Abner EL, Scheff SW et al (2009) Alzheimer’s-type neuropathology in the precuneus is not increased relative to other areas of neocortex across a range of cognitive impairment. Neurosci Lett 450:336–339

    Article  PubMed  CAS  Google Scholar 

  147. Nelson PT, Abner EL, Schmitt FA et al (2009) Brains with medial temporal lobe neurofibrillary tangles but no neuritic amyloid plaques are a diagnostic dilemma but may have pathogenetic aspects distinct from Alzheimer disease. J Neuropathol Exp Neurol 68:774–784

    Article  PubMed  Google Scholar 

  148. Nelson PT, Abner EL, Schmitt FA et al (2010) Modeling the association between 43 different clinical and pathological variables and the severity of cognitive impairment in a large autopsy cohort of elderly persons. Brain Pathol 20:66–79

    Article  PubMed  Google Scholar 

  149. Nelson PT, Braak H, Markesbery WR (2009) Neuropathology and cognitive impairment in Alzheimer disease: a complex but coherent relationship. J Neuropathol Exp Neurol 68:1–14

    Article  PubMed  CAS  Google Scholar 

  150. Nelson PT, Jicha GA, Schmitt FA et al (2007) Clinicopathologic correlations in a large Alzheimer disease center autopsy cohort: neuritic plaques and neurofibrillary tangles “do count” when staging disease severity. J Neuropathol Exp Neurol 66:1136–1146

    Article  PubMed  Google Scholar 

  151. Nelson PT, Kukull WA, Frosch MP (2010) Thinking outside the box: Alzheimer-type neuropathology that does not map directly onto current consensus recommendations. J Neuropathol Exp Neurol 69:449–454

    Article  PubMed  Google Scholar 

  152. Nelson PT, Schmitt FA, Lin Y et al (2010) Hippocampal sclerosis in advanced age: clinical and pathological features in 106 cases. Brain

  153. Nelson PT, Smith CD, Abner EA et al (2009) Human cerebral neuropathology of type 2 diabetes mellitus. Biochim Biophys Acta 1792:454–469

    PubMed  CAS  Google Scholar 

  154. Newman AB, Glynn NW, Taylor CA et al (2011) Health and function of participants in the Long Life Family Study: a comparison with other cohorts. Aging (Albany NY)

  155. Nicoll JA, Barton E, Boche D et al (2006) Abeta species removal after abeta42 immunization. J Neuropathol Exp Neurol 65:1040–1048

    Article  PubMed  CAS  Google Scholar 

  156. Noda K, Sasaki K, Fujimi K et al (2006) Quantitative analysis of neurofibrillary pathology in a general population to reappraise neuropathological criteria for senile dementia of the neurofibrillary tangle type (tangle-only dementia): the Hisayama Study. Neuropathology 26:508–518

    Article  PubMed  Google Scholar 

  157. Nunomura A, Castellani RJ, Zhu X et al (2006) Involvement of oxidative stress in Alzheimer disease. J Neuropathol Exp Neurol 65:631–641

    Article  PubMed  CAS  Google Scholar 

  158. O’Brien RJ, Resnick SM, Zonderman AB et al (2009) Neuropathologic studies of the Baltimore Longitudinal Study of Aging (BLSA). J Alzheimers Dis 18:665–675

    PubMed  Google Scholar 

  159. Okereke OI, Kang JH, Cook NR et al (2008) Type 2 diabetes mellitus and cognitive decline in two large cohorts of community-dwelling older adults. J Am Geriatr Soc 56:1028–1036

    Article  PubMed  Google Scholar 

  160. Olovnikov AM (2007) Hypothesis: lifespan is regulated by chronomere DNA of the hypothalamus. J Alzheimers Dis 11:241–252

    PubMed  CAS  Google Scholar 

  161. Pakkenberg B, Gundersen HJ (1997) Neocortical neuron number in humans: effect of sex and age. J Comp Neurol 384:312–320

    Article  PubMed  CAS  Google Scholar 

  162. Pakkenberg B, Pelvig D, Marner L et al (2003) Aging and the human neocortex. Exp Gerontol 38:95–99

    Article  PubMed  Google Scholar 

  163. Pallas M, Casadesus G, Smith MA et al (2009) Resveratrol and neurodegenerative diseases: activation of SIRT1 as the potential pathway towards neuroprotection. Curr Neurovasc Res 6:70–81

    Article  PubMed  CAS  Google Scholar 

  164. Pallas M, Verdaguer E, Tajes M, Gutierrez-Cuesta J, Camins A (2008) Modulation of sirtuins: new targets for antiageing. Recent Pat CNS Drug Discov 3:61–69

    Article  PubMed  CAS  Google Scholar 

  165. Pao WC, Dickson DW, Crook JE et al (2011) Hippocampal sclerosis in the elderly: genetic and pathologic findings, some mimicking Alzheimer disease clinically. Alzheimer Dis Assoc Disord [Epub ahead of print]

  166. Peila R, Rodriguez BL, Launer LJ (2002) Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: the Honolulu-Asia Aging Study. Diabetes 51:1256–1262

    Article  PubMed  CAS  Google Scholar 

  167. Perry G, Nunomura A, Hirai K et al (2002) Is oxidative damage the fundamental pathogenic mechanism of Alzheimer’s and other neurodegenerative diseases? Free Radic Biol Med 33:1475–1479

    Article  PubMed  CAS  Google Scholar 

  168. Perry JJ, Fan L, Tainer JA (2007) Developing master keys to brain pathology, cancer and aging from the structural biology of proteins controlling reactive oxygen species and DNA repair. Neuroscience 145:1280–1299

    Article  PubMed  CAS  Google Scholar 

  169. Pertovaara M, Lehtimaki T, Rontu R et al (2004) Presence of apolipoprotein E epsilon4 allele predisposes to early onset of primary Sjogren’s syndrome. Rheumatology (Oxford) 43:1484–1487

    Article  CAS  Google Scholar 

  170. Petrovitch H, Ross GW, He Q et al (2007) Characterization of Japanese–American men with a single neocortical AD lesion type. Neurobiol Aging [Epub ahead of print]

  171. Petrovitch H, Ross GW, Steinhorn SC et al (2005) AD lesions and infarcts in demented and non-demented Japanese–American men. Ann Neurol 57:98–103

    Article  PubMed  Google Scholar 

  172. Polvikoski TM, van Straaten EC, Barkhof F et al (2010) Frontal lobe white matter hyperintensities and neurofibrillary pathology in the oldest old. Neurology 75:2071–2078

    Article  PubMed  CAS  Google Scholar 

  173. Poon LW, Clayton GM, Martin P et al (1992) The Georgia Centenarian Study. Int J Aging Hum Dev 34:1–17

    Article  PubMed  CAS  Google Scholar 

  174. D.o.E.a.S.A (2002) Population Division, United Nations Secretariat, World Population Ageing 1950–2050. United Nations, New York

  175. Price JL, McKeel DW Jr, Buckles VD et al (2009) Neuropathology of nondemented aging: presumptive evidence for preclinical Alzheimer disease. Neurobiol Aging 30:1026–1036

    Article  PubMed  Google Scholar 

  176. Prohovnik I, Perl DP, Davis KL et al (2006) Dissociation of neuropathology from severity of dementia in late-onset Alzheimer disease. Neurology 66:49–55

    Article  PubMed  CAS  Google Scholar 

  177. Prolla TA (2005) Multiple roads to the aging phenotype: insights from the molecular dissection of progerias through DNA microarray analysis. Mech Ageing Dev 126:461–465

    Article  PubMed  CAS  Google Scholar 

  178. Puzianowska-Kuznicka M, Kuznicki J (2005) Genetic alterations in accelerated ageing syndromes. Do they play a role in natural ageing? Int J Biochem Cell Biol 37:947–960

    Article  PubMed  CAS  Google Scholar 

  179. Rauramaa T, Pikkarainen M, Englund E et al (2011) TAR-DNA binding protein-43 and alterations in the hippocampus. J Neural Transm [Epub ahead of print]

  180. Rebeck GW, Cho HS, Grabowski TJ, Greenberg SM (2001) The effects of AbetaPP mutations and APOE polymorphisms on cerebral amyloid angiopathy. Amyloid 8(Suppl 1):43–47

    PubMed  CAS  Google Scholar 

  181. Regan C, Katona C, Walker Z et al (2006) Relationship of vascular risk to the progression of Alzheimer disease. Neurology 67:1357–1362

    Article  PubMed  CAS  Google Scholar 

  182. Reiman EM, Caselli RJ, Yun LS et al (1996) Preclinical evidence of Alzheimer’s disease in persons homozygous for the epsilon 4 allele for apolipoprotein E. N Engl J Med 334:752–758

    Article  PubMed  CAS  Google Scholar 

  183. Reitz C, Brayne C, Mayeux R (2011) Epidemiology of Alzheimer disease. Nat Rev Neurol

  184. Riley KP, Snowdon DA, Markesbery WR (2002) Alzheimer’s neurofibrillary pathology and the spectrum of cognitive function: findings from the Nun Study. Ann Neurol 51:567–577

    Article  PubMed  Google Scholar 

  185. Rocca WA, Cha RH, Waring SC, Kokmen E (1998) Incidence of dementia and Alzheimer’s disease: a reanalysis of data from Rochester, Minnesota, 1975–1984. Am J Epidemiol 148:51–62

    PubMed  CAS  Google Scholar 

  186. Rocca WA, Petersen RC, Knopman DS et al (2011) Trends in the incidence and prevalence of Alzheimer’s disease, dementia, and cognitive impairment in the United States. Alzheimers Dement 7:80–93

    Article  PubMed  Google Scholar 

  187. Rosvall L, Rizzuto D, Wang HX et al (2009) APOE-related mortality: effect of dementia, cardiovascular disease and gender. Neurobiol Aging 30:1545–1551

    Article  PubMed  CAS  Google Scholar 

  188. Roth M, Tomlinson BE, Blessed G (1966) Correlation between scores for dementia and counts of ‘senile plaques’ in cerebral grey matter of elderly subjects. Nature 209:109–110

    Article  PubMed  CAS  Google Scholar 

  189. Roulson J, Benbow EW, Hasleton PS (2005) Discrepancies between clinical and autopsy diagnosis and the value of post mortem histology; a meta-analysis and review. Histopathology 47:551–559

    Article  PubMed  CAS  Google Scholar 

  190. Rubin EH, Kinscherf DA, Grant EA, Storandt M (1991) The influence of major depression on clinical and psychometric assessment of senile dementia of the Alzheimer type. Am J Psychiatry 148:1164–1171

    PubMed  CAS  Google Scholar 

  191. Salloway S, Sperling R, Gilman S et al (2009) A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology 73:2061–2070

    Article  PubMed  CAS  Google Scholar 

  192. Sarkar D, Fisher PB (2006) Molecular mechanisms of aging-associated inflammation. Cancer Lett 236:13–23

    Article  PubMed  CAS  Google Scholar 

  193. Savva GM, Wharton SB, Ince PG et al (2009) Age, neuropathology, and dementia. N Engl J Med 360:2302–2309

    Article  PubMed  CAS  Google Scholar 

  194. Scarmeas N, Habeck CG, Hilton J et al (2005) APOE related alterations in cerebral activation even at college age. J Neurol Neurosurg Psychiatry 76:1440–1444

    Article  PubMed  CAS  Google Scholar 

  195. Scheff SW, Price DA (2006) Alzheimer’s disease-related alterations in synaptic density: neocortex and hippocampus. J Alzheimers Dis 9:101–115

    PubMed  Google Scholar 

  196. Scheff SW, Price DA, Sparks DL (2001) Quantitative assessment of possible age-related change in synaptic numbers in the human frontal cortex. Neurobiol Aging 22:355–365

    Article  PubMed  CAS  Google Scholar 

  197. Schmitt FA, Davis DG, Wekstein DR et al (2000) “Preclinical” AD revisited: neuropathology of cognitively normal older adults. Neurology 55:370–376

    PubMed  CAS  Google Scholar 

  198. Schneider JA, Aggarwal NT, Barnes L, Boyle P, Bennett DA (2009) The neuropathology of older persons with and without dementia from community versus clinic cohorts. J Alzheimers Dis 18:691–701

    PubMed  Google Scholar 

  199. Schneider JA, Boyle PA, Arvanitakis Z, Bienias JL, Bennett DA (2007) Subcortical infarcts, Alzheimer’s disease pathology, and memory function in older persons. Ann Neurol 62:59–66

    Article  PubMed  Google Scholar 

  200. Schneider JA, Wilson RS, Bienias JL, Evans DA, Bennett DA (2004) Cerebral infarctions and the likelihood of dementia from Alzheimer disease pathology. Neurology 62:1148–1155

    PubMed  CAS  Google Scholar 

  201. Sedel F, Tourbah A, Fontaine B et al (2008) Leukoencephalopathies associated with inborn errors of metabolism in adults. J Inherit Metab Dis 31:295–307

    Article  PubMed  CAS  Google Scholar 

  202. Serrano-Pozo A, William CM, Ferrer I et al (2010) Beneficial effect of human anti-amyloid-beta active immunization on neurite morphology and tau pathology. Brain 133:1312–1327

    Article  PubMed  Google Scholar 

  203. Seshadri S, Beiser A, Au R et al (2011) Operationalizing diagnostic criteria for Alzheimer’s disease and other age-related cognitive impairment—part 2. Alzheimers Dement 7:35–52

    Article  PubMed  Google Scholar 

  204. Seshadri S, Fitzpatrick AL, Ikram MA et al (2010) Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA 303:1832–1840

    Article  PubMed  CAS  Google Scholar 

  205. Sharma S, Shin JS, Grimshaw M, Clarke RA, Lee CS (2010) The senescence pathway in prostatic carcinogenesis. Pathology 42:507–511

    Article  PubMed  Google Scholar 

  206. Shojania KG, Burton EC, McDonald KM, Goldman L (2005) Overestimation of clinical diagnostic performance caused by low necropsy rates. Qual Saf Health Care 14:408–413

    Article  PubMed  CAS  Google Scholar 

  207. Sleegers K, Brouwers N, Gijselinck I et al (2006) APP duplication is sufficient to cause early onset Alzheimer’s dementia with cerebral amyloid angiopathy. Brain 129:2977–2983

    Article  PubMed  Google Scholar 

  208. Small BJ, Mobly JL, Laukka EJ, Jones S, Backman L (2003) Cognitive deficits in preclinical Alzheimer’s disease. Acta Neurol Scand Suppl 179:29–33

    Article  PubMed  Google Scholar 

  209. Snowdon DA, Greiner LH, Mortimer JA et al (1997) Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA 277:813–817

    Article  PubMed  CAS  Google Scholar 

  210. Sonnen JA, Larson EB, Brickell K et al (2009) Different patterns of cerebral injury in dementia with or without diabetes. Arch Neurol 66:315–322

    Article  PubMed  Google Scholar 

  211. Sonnen JA, Larson EB, Crane PK et al (2007) Pathological correlates of dementia in a longitudinal, population-based sample of aging. Ann Neurol 62:406–413

    Article  PubMed  Google Scholar 

  212. Stanta G, Campagner L, Cavallieri F, Giarelli L (1997) Cancer of the oldest old. What we have learned from autopsy studies. Clin Geriatr Med 13:55–68

    PubMed  CAS  Google Scholar 

  213. Strittmatter WJ, Saunders AM, Schmechel D et al (1993) Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci USA 90:1977–1981

    Article  PubMed  CAS  Google Scholar 

  214. Struble RG, Ala T, Patrylo PR, Brewer GJ, Yan XX (2010) Is brain amyloid production a cause or a result of dementia of the Alzheimer’s type? J Alzheimers Dis 22:393–399

    PubMed  CAS  Google Scholar 

  215. 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

    Article  PubMed  CAS  Google Scholar 

  216. Sultana R, Butterfield DA (2010) Role of oxidative stress in the progression of Alzheimer’s disease. J Alzheimers Dis 19:341–353

    PubMed  Google Scholar 

  217. Thal DR, Del Tredici K, Braak H (2004) Neurodegeneration in normal brain aging and disease. Sci Aging Knowledge Environ pe26

  218. Theuns J, Brouwers N, Engelborghs S et al (2006) Promoter mutations that increase amyloid precursor-protein expression are associated with Alzheimer disease. Am J Hum Genet 78:936–946

    Article  PubMed  CAS  Google Scholar 

  219. Tomlinson BE, Blessed G, Roth M (1970) Observations on the brains of demented old people. J Neurol Sci 11:205–242

    Article  PubMed  CAS  Google Scholar 

  220. Tractenberg RE, Singer CM, Kaye JA (2006) Characterizing sleep problems in persons with Alzheimer’s disease and normal elderly. J Sleep Res 15:97–103

    Article  PubMed  Google Scholar 

  221. Vaillancourt DE, Newell KM (2002) Changing complexity in human behavior and physiology through aging and disease. Neurobiol Aging 23:1–11

    Article  PubMed  Google Scholar 

  222. von Gunten A, Ebbing K, Imhof A, Giannakopoulos P, Kovari E (2010) Brain aging in the oldest-old. Curr Gerontol Geriatr Res

  223. Watson GS, Craft S (2006) Insulin resistance, inflammation, and cognition in Alzheimer’s disease: lessons for multiple sclerosis. J Neurol Sci 245:21–33

    Article  PubMed  CAS  Google Scholar 

  224. White L, Petrovitch H, Hardman J et al (2002) Cerebrovascular pathology and dementia in autopsied Honolulu-Asia Aging Study participants. Ann N Y Acad Sci 977:9–23

    Article  PubMed  Google Scholar 

  225. White L, Small BJ, Petrovitch H et al (2005) Recent clinical–pathologic research on the causes of dementia in late life: update from the Honolulu-Asia Aging Study. J Geriatr Psychiatry Neurol 18:224–227

    Article  PubMed  Google Scholar 

  226. Williams LR, Hutchinson CE, Jackson A et al (2010) Clinical correlates of cerebral white matter hyperintensities in cognitively normal older adults. Arch Gerontol Geriatr 50:127–131

    Article  PubMed  CAS  Google Scholar 

  227. Wilson RS, Barnes LL, Mendes de Leon CF et al (2002) Depressive symptoms, cognitive decline, and risk of AD in older persons. Neurology 59:364–370

    PubMed  Google Scholar 

  228. Wilson RS, Leurgans SE, Boyle PA, Schneider JA, Bennett DA (2010) Neurodegenerative basis of age-related cognitive decline. Neurology 75:1070–1078

    Article  PubMed  CAS  Google Scholar 

  229. Wilson RS, Weir DR, Leurgans SE et al (2011) Sources of variability in estimates of the prevalence of Alzheimer’s disease in the United States. Alzheimers Dement 7:74–79

    Article  PubMed  Google Scholar 

  230. Wong K, Sidransky E, Verma A et al (2004) Neuropathology provides clues to the pathophysiology of Gaucher disease. Mol Genet Metab 82:192–207

    Article  PubMed  CAS  Google Scholar 

  231. Xuereb JH, Brayne C, Dufouil C et al (2000) Neuropathological findings in the very old. Results from the first 101 brains of a population-based longitudinal study of dementing disorders. Ann N Y Acad Sci 903:490–496

    Article  PubMed  CAS  Google Scholar 

  232. Yankner BA, Lu T, Loerch P (2008) The aging brain. Annu Rev Pathol 3:41–66

    Article  PubMed  CAS  Google Scholar 

  233. Zaccai J, Ince P, Brayne C (2006) Population-based neuropathological studies of dementia: design, methods and areas of investigation—a systematic review. BMC Neurol 6:2

    Article  PubMed  Google Scholar 

  234. Zekry D, Duyckaerts C, Moulias R et al (2002) Degenerative and vascular lesions of the brain have synergistic effects in dementia of the elderly. Acta Neuropathol 103:481–487

    Article  PubMed  CAS  Google Scholar 

  235. Zhang L, Bruce-Keller AJ, Dasuri K et al (2009) Diet-induced metabolic disturbances as modulators of brain homeostasis. Biochim Biophys Acta 1792:417–422

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We are deeply grateful to all of the study participants. We also thank Leslie Phillips, MS and Sarah Monsell, MS for help with NACC data. Brain tissue from the DS autopsy case was obtained from NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland, Baltimore, MD, was under contract HHSN275200900011C, reference number N01-HD-9-0011. Corresponding author: Dr. Nelson had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Conflict of interest

This study was supported by NIH grants R01 NS061933, K08 NS050110, P30 AG028383, and U01 AG016976.

Author information

Authors and Affiliations

  1. Department of Pathology, University of Kentucky, Rm 311, Sanders-Brown Building, 800 S. Limestone, Lexington, KY, 40536-0230, USA

    Peter T. Nelson & Janna H. Neltner

  2. Division of Neuropathology, Department of Neurology, University of Kentucky, Lexington, KY, 40536-0230, USA

    Frederick A. Schmitt, Gregory A. Jicha & Charles D. Smith

  3. Department of Statistics, University of Kentucky, Lexington, KY, 40536-0230, USA

    Richard J. Kryscio

  4. Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, 40536-0230, USA

    Peter T. Nelson, Elizabeth Head, Frederick A. Schmitt, Paulina R. Davis, Gregory A. Jicha, Erin L. Abner, Charles D. Smith, Linda J. Van Eldik, Richard J. Kryscio & Stephen W. Scheff

  5. Department of Anatomy and Neurobiology, University of Kentucky, Lexington, KY, 40536-0230, USA

    Elizabeth Head, Paulina R. Davis, Linda J. Van Eldik & Stephen W. Scheff

Authors
  1. Peter T. Nelson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elizabeth Head
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Frederick A. Schmitt
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Paulina R. Davis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Janna H. Neltner
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gregory A. Jicha
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Erin L. Abner
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Charles D. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Linda J. Van Eldik
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Richard J. Kryscio
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Stephen W. Scheff
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter T. Nelson.

Additional information

Dedicated to Kurt Jellinger on occasion of his 80th birthday.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nelson, P.T., Head, E., Schmitt, F.A. et al. Alzheimer’s disease is not “brain aging”: neuropathological, genetic, and epidemiological human studies. Acta Neuropathol 121, 571–587 (2011). https://doi.org/10.1007/s00401-011-0826-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-011-0826-y

Keywords

Search

Navigation