Brain aging, Alzheimer's disease, and mitochondria.

The relationship between brain aging and Alzheimer's disease (AD) is contentious. One view holds AD results when brain aging surpasses a threshold. The other view postulates AD is not a consequence of brain aging. This review discusses this conundrum from the perspective of different investigative lines that have tried to address it, as well as from the perspective of the mitochondrion, an organelle that appears to play a role in both AD and brain aging. Specific issues addressed include the question of whether AD and brain aging should be conceptually lumped or split, the extent to which AD and brain aging potentially share common molecular mechanisms, whether beta amyloid should be primarily considered a marker of AD or simply brain aging, and the definition of AD itself.

[1]  M. Folstein,et al.  Clinical diagnosis of Alzheimer's disease , 1984, Neurology.

[2]  M. Albert,et al.  Prevalence of Alzheimer's disease in a community population of older persons. Higher than previously reported. , 1989, JAMA.

[3]  L. Fried,et al.  Clinical correlates of white matter findings on cranial magnetic resonance imaging of 3301 elderly people. The Cardiovascular Health Study. , 1996, Stroke.

[4]  T. Salthouse.  Memory Aging From 18 to 80 , 2003, Alzheimer disease and associated disorders.

[5]  S. Folstein,et al.  Functional expressions of the aging brain. , 2010, Nutrition reviews.

[6]  Paul Maruff,et al.  β-amyloid imaging and memory in non-demented individuals: evidence for preclinical Alzheimer's disease , 2007 .

[7]  Robert B. Petersen,et al.  Mitochondrial abnormalities in Alzheimer disease , 2000, Neurobiology of Aging.

[8]  R. Petersen,et al.  Mild cognitive impairment , 2006, The Lancet.

[9]  Pierre J Magistretti,et al.  Food for Thought: Challenging the Dogmas , 2003, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[10]  Ian G. McKeith,et al.  Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales , 2001, The Lancet.

[11]  J. Price,et al.  Mild cognitive impairment represents early-stage Alzheimer disease. , 2001, Archives of neurology.

[12]  J. Parks,et al.  Cytochrome C Oxidase in Alzheimer's Disease Brain , 1995, Neurology.

[13]  J. Blass,et al.  Abnormalities of mitochondrial enzymes in Alzheimer disease , 1998, Journal of Neural Transmission.

[14]  M. Esiri,et al.  Mitochondrial enzyme expression in the hippocampus in relation to Alzheimer-type pathology , 1999, Acta Neuropathologica.

[15]  Keith A. Johnson,et al.  Neuropathology of Cognitively Normal Elderly , 2003, Journal of neuropathology and experimental neurology.

[16]  P. Mecocci,et al.  Oxidative damage to mitochondrial DNA shows marked age‐dependent increases in human brain , 1993, Annals of neurology.

[17]  P. Magistretti,et al.  Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[18]  Nick C Fox,et al.  Revising the definition of Alzheimer's disease: a new lexicon , 2010, The Lancet Neurology.

[19]  S. Resnick,et al.  Longitudinal Magnetic Resonance Imaging Studies of Older Adults: A Shrinking Brain , 2003, The Journal of Neuroscience.

[20]  T. Ozawa,et al.  Genetic and functional changes in mitochondria associated with aging. , 1997, Physiological reviews.

[21]  T. Mizutani,et al.  Neuropathological background of twenty-seven centenarian brains , 1992, Journal of the Neurological Sciences.

[22]  D. Marcus,et al.  White matter lesions are prevalent but differentially related with cognition in aging and early Alzheimer disease. , 2005, Archives of neurology.

[23]  W. Rocca,et al.  Origin of the distinction between Alzheimer's disease and senile dementia , 1986, Neurology.

[24]  S. Zierz,et al.  Cytochrome c oxidase in Alzheimer's disease , 1995, Neurology.

[25]  M. Trabucchi,et al.  Oxidative metabolism in cultured fibroblasts derived from sporadic Alzheimer's disease (AD) patients , 1997, Neuroscience Letters.

[26]  J. Morris,et al.  Evidence That Age-Associated Memory Impairment Is Not a Normal Variant of Aging , 2001, Alzheimer disease and associated disorders.

[27]  Nick C Fox,et al.  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 , 2011 .

[28]  P. Francis,et al.  The effects of perturbed energy metabolism on the processing of amyloid precursor protein in PC12 cells , 1998, Journal of Neural Transmission.

[29]  A. Navarro,et al.  Brain mitochondrial dysfunction in aging , 2008, IUBMB life.

[30]  Charles Duyckaerts,et al.  Beta A4 deposits are constant in the brain of the oldest old: an immunocytochemical study of 20 French centenarians. , 1993, Neurobiology of aging.

[31]  Mark J West,et al.  Hippocampal neurons in pre-clinical Alzheimer’s disease , 2004, Neurobiology of Aging.

[32]  M. Beal,et al.  High aggregate burden of somatic mtDNA point mutations in aging and Alzheimer's disease brain. , 2002, Human molecular genetics.

[33]  P. Matsudaira,et al.  Inhibition of energy metabolism alters the processing of amyloid precursor protein and induces a potentially amyloidogenic derivative. , 1994, The Journal of biological chemistry.

[34]  J. Morris,et al.  Current concepts in mild cognitive impairment. , 2001, Archives of neurology.

[35]  C. Jack,et al.  Mild cognitive impairment – beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment , 2004, Journal of internal medicine.

[36]  Stavros J. Baloyannis,et al.  Mitochondrial alterations in Alzheimer's disease. , 2006, Journal of Alzheimer's disease : JAD.

[37]  Roberta F. White,et al.  The preclinical phase of alzheimer disease: A 22-year prospective study of the Framingham Cohort. , 2000, Archives of neurology.

[38]  G. Binetti,et al.  Effect of energy shortage and oxidative stress on amyloid precursor protein metabolism in COS cells , 1997, Neuroscience Letters.

[39]  L. Chin,et al.  Telomere dysfunction induces metabolic and mitochondrial compromise , 2011, Nature.

[40]  G. Ratcliff,et al.  Preclinical Alzheimer disease , 2004, Neurology.

[41]  T. Ozawa,et al.  Hypothesis. Mitochondrial DNA mutations as an important contributor to ageing and degenerative diseases , 1989 .

[42]  T. Grabowski.  Preclinical Alzheimer Disease: Neuropsychological Test Performance 1.5 to 8 Years Prior to Onset , 2006 .

[43]  J. Hardy,et al.  Alzheimer's disease: the amyloid cascade hypothesis. , 1992, Science.

[44]  R. Swerdlow.  Mitochondria and cell bioenergetics: increasingly recognized components and a possible etiologic cause of Alzheimer's disease. , 2012, Antioxidants & redox signaling.

[45]  P. Hof,et al.  The neuropathological changes associated with normal brain aging. , 1996, Histology and histopathology.

[46]  J. Troncoso,et al.  Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer's disease , 1994, The Lancet.

[47]  B. Winblad,et al.  The course of cognitive impairment in preclinical Alzheimer disease: three- and 6-year follow-up of a population-based sample. , 2000, Archives of neurology.

[48]  R. Katzman.,et al.  Clinical, pathological, and neurochemical changes in dementia: A subgroup with preserved mental status and numerous neocortical plaques , 1988, Annals of neurology.

[49]  David A. Bennett,et al.  Mixed brain pathologies account for most dementia cases in community-dwelling older persons , 2007, Neurology.

[50]  T. Fritsch,et al.  Worker functions and traits associated with occupations and the development of AD , 2004, Neurology.

[51]  John Breitner,et al.  Prevalence and classification of mild cognitive impairment in the Cardiovascular Health Study Cognition Study: part 1. , 2003, Archives of neurology.

[52]  C. Filley,et al.  Cytochrome oxidase deficiency in Alzheimer's disease , 1990, Neurology.

[53]  Sangkot Marzuki,et al.  MITOCHONDRIAL DNA MUTATIONS AS AN IMPORTANT CONTRIBUTOR TO AGEING AND DEGENERATIVE DISEASES , 1989, The Lancet.

[54]  G. Linazasoro,et al.  IMAGING β-AMYLOID BURDEN IN AGING AND DEMENTIA , 2008, Neurology.

[55]  R. Swerdlow,et al.  Pathogenesis of Alzheimer’s disease , 2007, Clinical interventions in aging.

[56]  Howard T. Jacobs,et al.  Premature ageing in mice expressing defective mitochondrial DNA polymerase , 2004, Nature.

[57]  John X. Morris,et al.  Spatial correlation between brain aerobic glycolysis and amyloid-β (Aβ) deposition , 2010, Proceedings of the National Academy of Sciences.

[58]  C. Rowe,et al.  Amyloid imaging results from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging , 2010, Neurobiology of Aging.

[59]  A. Fagan,et al.  Pittsburgh compound B imaging and prediction of progression from cognitive normality to symptomatic Alzheimer disease. , 2009, Archives of neurology.

[60]  S. Kish,et al.  Mitochondria in Alzheimer's disease. , 2002, International review of neurobiology.

[61]  T. Kunkel,et al.  DNA replication fidelity with 8-oxodeoxyguanosine triphosphate. , 1994, Biochemistry.

[62]  J. Nobrega,et al.  Brain Cytochrome Oxidase in Alzheimer's Disease , 1992, Journal of neurochemistry.

[63]  A. Navarro,et al.  The mitochondrial energy transduction system and the aging process. , 2007, American journal of physiology. Cell physiology.

[64]  Russell H. Swerdlow,et al.  The Alzheimer's disease mitochondrial cascade hypothesis: An update , 2009, Experimental Neurology.

[65]  D. Bennett,et al.  Alzheimer disease in the US population: prevalence estimates using the 2000 census. , 2003, Archives of neurology.

[66]  H. Haug,et al.  Morphometry of the human cortex cerebri and corpus striatum during aging , 1991, Neurobiology of Aging.

[67]  J. Touchon,et al.  Cognitive decline in ageing: are AAMI and AACD distinct entities? , 1999, International journal of geriatric psychiatry.

[68]  John X. Morris,et al.  Increased risk of dementia in mothers of Alzheimer's disease cases , 1996, Neurology.

[69]  K. Blennow,et al.  Prediction and longitudinal study of CSF biomarkers in mild cognitive impairment , 2009, Neurobiology of Aging.

[70]  D. Wallace.  Mitochondrial genetics: a paradigm for aging and degenerative diseases? , 1992, Science.

[71]  M. Beal,et al.  Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age , 1992, Nature Genetics.

[72]  C. Jack,et al.  Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade , 2010, The Lancet Neurology.

[73]  B. Reisberg,et al.  Longitudinal CSF and MRI biomarkers improve the diagnosis of mild cognitive impairment , 2006, Neurobiology of Aging.

[74]  P. Magistretti,et al.  Cellular mechanisms of brain energy metabolism and their relevance to functional brain imaging. , 1999, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[75]  R. Swerdlow,et al.  The Alzheimer's disease mitochondrial cascade hypothesis. , 2010, Journal of Alzheimer's disease : JAD.

[76]  J. Morris,et al.  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 , 2011, Alzheimer's & Dementia.

[77]  W. M. van der Flier,et al.  Heterogeneity of White Matter Hyperintensities in Alzheimer's Disease: Post-Mortem Quantitative MRI and Neuropathology , 2008, Brain : a journal of neurology.

[78]  F. Barkhof,et al.  Histopathologic correlates of white matter changes on MRI in Alzheimer's disease and normal aging , 1995, Neurology.

[79]  R. Sulkava,et al.  Incidence of Dementia in Very Elderly Individuals: A Clinical, Neuropathological and Molecular Genetic Study , 2006, Neuroepidemiology.

[80]  T. Ozawa.  Mitochondrial DNA Mutations and Age , 1998, Annals of the New York Academy of Sciences.

[81]  H. Amièva,et al.  Prodromal Alzheimer's disease: Successive emergence of the clinical symptoms , 2008, Annals of neurology.

[82]  E. Tangalos,et al.  Mild Cognitive Impairment Clinical Characterization and Outcome , 1999 .

[83]  J. Kramer,et al.  Mild cognitive impairment, dementia, and their subtypes in oldest old women. , 2011, Archives of neurology.

[84]  J. Hardy,et al.  Amyloid deposition as the central event in the aetiology of Alzheimer's disease. , 1991, Trends in pharmacological sciences.

[85]  Henrik Zetterberg,et al.  Longitudinal Study of CSF Biomarkers in Patients with Alzheimer's Disease , 2009, PloS one.

[86]  Bradley T. Hyman,et al.  Distribution of Alzheimer‐type pathologic changes in nondemented elderly individuals matches the pattern in Alzheimer's disease , 1992, Neurology.

[87]  E. Mandelkow,et al.  Tau in Alzheimer's disease. , 1998, Trends in cell biology.

[88]  S. Borson.  Cognition, aging, and disabilities: conceptual issues. , 2010, Physical medicine and rehabilitation clinics of North America.

[89]  R. Swerdlow.  Is aging part of Alzheimer's disease, or is Alzheimer's disease part of aging? , 2007, Neurobiology of Aging.

[90]  M. L. Genova,et al.  Mitochondrial bioenergetics in aging. , 2000, Biochimica et biophysica acta.

[91]  S. Leurgans,et al.  Cognitive decline in prodromal Alzheimer disease and mild cognitive impairment. , 2011, Archives of neurology.

[92]  K. Marder,et al.  Neuropsychological detection and characterization of preclinical Alzheimer's disease , 1995, Neurology.

[93]  A. Gatherer,et al.  Sarcoma of the Larynx , 1958, The Journal of Laryngology & Otology.

[94]  C. Duyckaerts,et al.  Prevalence, Incidence and Duration of Braak’s Stages in the General Population: Can We Know? , 1997, Neurobiology of Aging.

[95]  H. Braak,et al.  Staging of alzheimer's disease-related neurofibrillary changes , 1995, Neurobiology of Aging.

[96]  Andrei G. Vlassenko,et al.  Regional aerobic glycolysis in the human brain , 2010, Proceedings of the National Academy of Sciences.

[97]  P. Scheltens,et al.  Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS–ADRDA criteria , 2007, The Lancet Neurology.

[98]  C. Brayne,et al.  Neuropathological Findings in the Very Old: Results from the First 101 Brains of a Population‐based Longitudinal Study of Dementing Disorders , 2000, Annals of the New York Academy of Sciences.

[99]  M. D. de Leon,et al.  Reduced mitochondria cytochrome oxidase activity in adult children of mothers with Alzheimer's disease. , 2011, Journal of Alzheimer's disease : JAD.

[100]  F. Boller,et al.  History of dementia and dementia in history: An overview , 1998, Journal of the Neurological Sciences.

[101]  M. Sjögren,et al.  Prodromal cognitive signs of dementia in 85-year-olds using four sources of information , 2005, Neurology.

[102]  G. Perry,et al.  Oxidative Stress Increases Expression and Activity of BACE in NT2 Neurons , 2002, Neurobiology of Disease.

[103]  R Brookmeyer,et al.  Prevalence of dementia after age 90 , 2008, Neurology.

[104]  W. Parker,et al.  Secondary inhibition of 2‐ketoglutarate dehydrogenase complex by MPTP , 1998, Neuroreport.

[105]  R. Swerdlow,et al.  Alzheimer's disease cybrids replicate β‐amyloid abnormalities through cell death pathways , 2000 .

[106]  Charles D. Smith,et al.  Alzheimer's-type neuropathology in the precuneus is not increased relative to other areas of neocortex across a range of cognitive impairment , 2009, Neuroscience Letters.

[107]  D. Berlau,et al.  APOE ε2 is associated with intact cognition but increased Alzheimer pathology in the oldest old , 2009, Neurology.

[108]  C. Kawas,et al.  Synaptic proteins, neuropathology and cognitive status in the oldest-old , 2009, Neurobiology of Aging.

[109]  Nick C Fox,et al.  The clinical use of structural MRI in Alzheimer disease , 2010, Nature Reviews Neurology.

[110]  C. J. Rivara,et al.  Morphological substrates of cognitive decline in nonagenarians and centenarians: A new paradigm? , 2007, Journal of the Neurological Sciences.

[111]  R. Swerdlow,et al.  A "mitochondrial cascade hypothesis" for sporadic Alzheimer's disease. , 2004, Medical hypotheses.

[112]  Seiji Nishino,et al.  Amyloid-β Dynamics Are Regulated by Orexin and the Sleep-Wake Cycle , 2009, Science.

[113]  J. Hardy,et al.  Prevalence of Alzheimer’s disease in very elderly people , 2001, Neurology.

[114]  Jeffrey A. James,et al.  Frequent amyloid deposition without significant cognitive impairment among the elderly. , 2008, Archives of neurology.

[115]  David A. Snowdon,et al.  Healthy Aging and Dementia: Findings from the Nun Study , 2003, Annals of Internal Medicine.

[116]  V. Pesce,et al.  Aging and mitochondria. , 1998, Biochimie.

[117]  Y. Ihara,et al.  Effect of Apolipoprotein E Allele ε4 on the Initial Phase of Amyloid β-Protein Accumulation in the Human Brain , 2000 .

[118]  T. D. Pugh,et al.  Mitochondrial DNA Mutations, Oxidative Stress, and Apoptosis in Mammalian Aging , 2005, Science.

[119]  Gina N. LaRossa,et al.  [11C]PIB in a nondemented population , 2006, Neurology.

[120]  J. Ashford,et al.  “Preclinical” AD revisited , 2000, Neurology.

[121]  Lars Bäckman,et al.  Cognitive impairment in preclinical Alzheimer's disease: a meta-analysis. , 2005, Neuropsychology.

[122]  F. Schmitt,et al.  Alzheimer neuropathologic alterations in aged cognitively normal subjects. , 1999, Journal of neuropathology and experimental neurology.

[123]  David L. Brody,et al.  Amyloid-β Dynamics Correlate with Neurological Status in the Injured Human Brain , 2008, Science.

[124]  E. Reiman,et al.  Reduced posterior cingulate mitochondrial activity in expired young adult carriers of the APOE ε4 allele, the major late-onset Alzheimer's susceptibility gene. , 2010, Journal of Alzheimer's disease : JAD.

[125]  D. Selkoe,et al.  Aβ Oligomers – a decade of discovery , 2007, Journal of neurochemistry.

[126]  Ron Brookmeyer,et al.  Dementia incidence continues to increase with age in the oldest old: The 90+ study , 2010, Annals of neurology.

[127]  J. Molinuevo,et al.  Cerebrospinal fluid biomarkers and memory present distinct associations along the continuum from healthy subjects to AD patients. , 2011, Journal of Alzheimer's disease : JAD.

[128]  T. Crook,et al.  Age-associated memory impairment: diagnostic criteria and treatment strategies. , 1987, International journal of neurology.

[129]  D. Holtzman,et al.  Amyloid-beta dynamics in the injured human brain , 2009, Alzheimer's & Dementia.

[130]  J. Wands,et al.  Mitochondrial DNA Damage as a Mechanism of Cell Loss in Alzheimer's Disease , 2000, Laboratory Investigation.

[131]  T. Kunkel,et al.  The fidelity of the human leading and lagging strand DNA replication apparatus with 8-oxodeoxyguanosine triphosphate. , 1994, Nucleic acids research.

[132]  R. Lévy,et al.  Aging-Associated Cognitive Decline , 1994, International Psychogeriatrics.

[133]  J. Morris,et al.  Tangles and plaques in nondemented aging and “preclinical” Alzheimer's disease , 1999, Annals of neurology.

[134]  J. Hardy,et al.  The Amyloid Hypothesis of Alzheimer ’ s Disease : Progress and Problems on the Road to Therapeutics , 2009 .

[135]  Tracy L. Niedzielko,et al.  Impaired platelet mitochondrial activity in Alzheimer's disease and mild cognitive impairment. , 2006, Mitochondrion.

[136]  Carol Brayne,et al.  Age, neuropathology, and dementia. , 2009, The New England journal of medicine.

[137]  G. G. Stokes.  "J." , 1890, The New Yale Book of Quotations.

[138]  P. Scheltens,et al.  White matter lesions on magnetic resonance imaging in clinically diagnosed Alzheimer's disease. Evidence for heterogeneity. , 1992, Brain : a journal of neurology.

[139]  B. Anderton,et al.  The Ageing Brain , 2003 .

[140]  Y. Ihara,et al.  Effect of apolipoprotein E allele epsilon4 on the initial phase of amyloid beta-protein accumulation in the human brain. , 2000, The American journal of pathology.

[141]  Simon A. Moss,et al.  b -amyloid imaging and memory in non-demented individuals: evidence for preclinical Alzheimer’s disease , 2007 .

[142]  Denise C. Park,et al.  Toward defining the preclinical stages of Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease , 2011, Alzheimer's & Dementia.

[143]  J. Barrio,et al.  Correlation of brain amyloid with “aerobic glycolysis”: A question of assumptions? , 2010, Proceedings of the National Academy of Sciences.

[144]  C. Enzinger,et al.  Progression of cerebral white matter lesions — Clinical and radiological considerations , 2007, Journal of the Neurological Sciences.

[145]  J. Gabrieli,et al.  Insights into the ageing mind: a view from cognitive neuroscience , 2004, Nature Reviews Neuroscience.

[146]  X. Estivill,et al.  Reduced steady-state levels of mitochondrial RNA and increased mitochondrial DNA amount in human brain with aging. , 1997, Brain research. Molecular brain research.

[147]  D R Wekstein,et al.  Linguistic ability in early life and cognitive function and Alzheimer's disease in late life. Findings from the Nun Study. , 1996, JAMA.

[148]  Alex Kiss,et al.  Neuropsychological tests accurately predict incident Alzheimer disease after 5 and 10 years , 2005, Neurology.

[149]  Age , 2000, BMJ : British Medical Journal.

[150]  Neuropsychological prediction of dementia and the absence of dementia in healthy elderly persons , 1995 .

[151]  R. Swerdlow.  Mitochondria in cybrids containing mtDNA from persons with mitochondriopathies , 2007, Journal of neuroscience research.

[152]  C. Jack,et al.  Serial PIB and MRI in normal, mild cognitive impairment and Alzheimer's disease: implications for sequence of pathological events in Alzheimer's disease , 2009, Brain : a journal of neurology.

[153]  M. Gado,et al.  Periventricular white matter lucencies in senile dementia of the Alzheimer type and in normal aging , 1987, Neurology.

[154]  Robert S. Balaban,et al.  Mitochondria, Oxidants, and Aging , 2005, Cell.

[155]  G. Holstege,et al.  No disease in the brain of a 115-year-old woman , 2007, Neurobiology of Aging.

[156]  G. B. Frisoni,et al.  The dynamics of Alzheimer's disease biomarkers in the Alzheimer's Disease Neuroimaging Initiative cohort , 2010, Neurobiology of Aging.