Preventing Alzheimer's disease and cognitive decline.

OBJECTIVES To assess whether previous research on purported risk or protective factors for Alzheimer's disease (AD) and cognitive decline is of sufficient strength to warrant specific recommendations for behavioral, lifestyle, or pharmaceutical interventions/modifications targeted to these endpoints. DATA SOURCES MEDLINE and the Cochrane Database of Systematic Reviews. Additional studies were identified from reference lists and technical experts. REVIEW METHODS A group of experts in the field developed the list of factors to be evaluated in preparation for an upcoming National Institutes of Health (NIH) Office of Medical Applications of Research (OMAR) State-of-the-Science Conference addressing the prevention of AD and cognitive decline. We grouped the factors into the following categories: nutritional factors, medical conditions and prescription and non-prescription medications, social/economic/behavioral factors, toxic environmental factors, and genetics. Outcomes of interest were the development of AD or cognitive decline. Both observational and intervention studies were evaluated. Studies were evaluated for eligibility and quality, and data were abstracted on study design, demographics, intervention or predictor factor, and cognitive outcomes. RESULTS A total of 25 systematic reviews and 250 primary research studies were included. Only a few factors showed a consistent association with AD or cognitive decline across multiple studies, including both observational studies and randomized controlled trials (when available). Such factors associated with increased risk of AD and cognitive decline were: diabetes, epsilon 4 allele of the apolipoprotein E gene (APOE e4), smoking, and depression. Factors showing a fairly consistent association with decreased risk of AD and cognitive decline were: cognitive engagement and physical activities. A consistent association does not imply that findings were robust, as the data were often limited, and the quality of evidence was typically low. In addition, the modification of risk for reported associations was typically small to moderate for AD, and small for cognitive decline. Some of the factors that did not show an association with AD or cognitive decline in this review may still play an influential role in late-life cognition, but there was not sufficient evidence to draw this conclusion. Many of the factors evaluated are not amenable to randomization, so rigorous observational studies are required to assess their effect on AD and cognitive decline. CONCLUSIONS The current research on the list of putative risk or protective factors is largely inadequate to confidently assess their association with AD or cognitive decline. Further research that addresses the limitations of existing studies is needed prior to be able to make recommendations on interventions.

[1]  M. Albert,et al.  Cognitive Profiles of Normal Human Aging , 1999 .

[2]  D. Butterfield,et al.  Redox proteomics identification of oxidatively modified brain proteins in Alzheimer's disease and mild cognitive impairment: insights into the progression of this dementing disorder. , 2007 .

[3]  C. Lyketsos,et al.  Mild behavioral impairment and risk of dementia: a prospective cohort study of 358 patients. , 2009, The Journal of clinical psychiatry.

[4]  Kristine Yaffe,et al.  Obesity in middle age and future risk of dementia: a 27 year longitudinal population based study , 2005, BMJ : British Medical Journal.

[5]  Robert F Schoeni,et al.  Recent trends in disability and functioning among older adults in the United States: a systematic review. , 2002, JAMA.

[6]  L. Thal,et al.  Conjugated equine estrogens and global cognitive function in postmenopausal women: Women's Health Initiative Memory Study , 2004, JAMA.

[7]  A. Dale,et al.  High consistency of regional cortical thinning in aging across multiple samples. , 2009, Cerebral cortex.

[8]  T. Montine,et al.  Chronic dietary α-lipoic acid reduces deficits in hippocampal memory of aged Tg2576 mice , 2007, Neurobiology of Aging.

[9]  I. Deary,et al.  Childhood mental ability and dementia , 2000, Neurology.

[10]  E. Teng,et al.  Donepezil delays progression to AD in MCI subjects with depressive symptoms , 2009, Neurology.

[11]  Mary Sano,et al.  Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer's disease: a randomised, double-blind, placebo-controlled study , 2008, The Lancet.

[12]  David A Bennett,et al.  Frailty is Associated With Incident Alzheimer’s Disease and Cognitive Decline in the Elderly , 2007, Psychosomatic medicine.

[13]  L S Honig,et al.  Aggregation of vascular risk factors and risk of incident Alzheimer disease , 2005, Neurology.

[14]  Jennifer L. Etnier,et al.  A meta-regression to examine the relationship between aerobic fitness and cognitive performance , 2006, Brain Research Reviews.

[15]  M. Hamer,et al.  Physical activity and risk of neurodegenerative disease: a systematic review of prospective evidence , 2008, Psychological Medicine.

[16]  Henry Brodaty,et al.  Lifespan Mental Activity Predicts Diminished Rate of Hippocampal Atrophy , 2008, Alzheimer's & Dementia.

[17]  H C Liu,et al.  Prevalence and Subtypes of Dementia in a Rural Chinese Population , 1998, Alzheimer disease and associated disorders.

[18]  Laura Fratiglioni,et al.  Late-life engagement in social and leisure activities is associated with a decreased risk of dementia: a longitudinal study from the Kungsholmen project. , 2002, American journal of epidemiology.

[19]  R. Mayeux,et al.  Depressed mood and the incidence of Alzheimer's disease in the elderly living in the community. , 1996, Archives of general psychiatry.

[20]  Yaakov Stern,et al.  Mediterranean diet and risk for Alzheimer's disease , 2006, Annals of neurology.

[21]  R. Whitmer.  Type 2 diabetes and risk of cognitive impairment and dementia , 2007, Current neurology and neuroscience reports.

[22]  T. Arbuckle,et al.  The role of psychosocial context, age, and intelligence in memory performance of older men. , 1992, Psychology and aging.

[23]  S. Zeger,et al.  Cognition 6 years after surgical or medical therapy for coronary artery disease , 2008, Annals of neurology.

[24]  Jeannie-Marie S. Leoutsakos,et al.  Neuropsychiatric symptoms in MCI subtypes: the importance of executive dysfunction , 2011, International journal of geriatric psychiatry.

[25]  P. Reddy,et al.  Neuronal protection by sirtuins in Alzheimer's disease , 2006, Journal of neurochemistry.

[26]  David A Bennett,et al.  The apolipoprotein E epsilon 4 allele and decline in different cognitive systems during a 6-year period. , 2002, Archives of neurology.

[27]  Andrew J. Saykin,et al.  Neuropsychological Assessment of Neuropsychiatric Disorders , 1988 .

[28]  G. Guyatt,et al.  GRADE: an emerging consensus on rating quality of evidence and strength of recommendations , 2008, BMJ : British Medical Journal.

[29]  J. Morrison,et al.  Circuit-Specific Alterations in Hippocampal Synaptophysin Immunoreactivity Predict Spatial Learning Impairment in Aged Rats , 2000, The Journal of Neuroscience.

[30]  J. Rusted,et al.  Vitamin E for Alzheimer's dementia and mild cognitive impairment. , 2012, The Cochrane database of systematic reviews.

[31]  J. Schneider,et al.  Education modifies the relation of AD pathology to level of cognitive function in older persons , 2003, Neurology.

[32]  Joel S Perlmutter,et al.  Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline. , 2002, Archives of neurology.

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

[34]  L. Honig,et al.  Depressive symptoms, vascular risk factors, and Alzheimer's disease , 2008, International journal of geriatric psychiatry.

[35]  T. Manolio,et al.  Lacunar infarcts defined by magnetic resonance imaging of 3660 elderly people: the Cardiovascular Health Study. , 1998, Archives of neurology.

[36]  M. Glymour,et al.  Lifecourse Social Conditions and Racial and Ethnic Patterns of Cognitive Aging , 2008, Neuropsychology Review.

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

[38]  G. Münch,et al.  α-Lipoic acid as a new treatment option for Alzheimer’s disease — a 48 months follow-up analysis , 2007 .

[39]  L. Fratiglioni,et al.  Prevention of common neurodegenerative disorders in the elderly , 2009, Experimental Gerontology.

[40]  C. Barnes,et al.  Neural plasticity in the ageing brain , 2006, Nature Reviews Neuroscience.

[41]  M. Mintun,et al.  Alzheimer disease and cognitive reserve: variation of education effect with carbon 11-labeled Pittsburgh Compound B uptake. , 2008, Archives of neurology.

[42]  J. Schneider,et al.  Dietary folate and vitamin B12 intake and cognitive decline among community-dwelling older persons. , 2005, Archives of neurology.

[43]  R. Mayeux,et al.  Caloric intake and the risk of Alzheimer disease. , 2002, Archives of neurology.

[44]  Owen Carmichael,et al.  Regional pattern of white matter microstructural changes in normal aging, MCI, and AD , 2009, Neurology.

[45]  R. Mayeux,et al.  Hypertension and the risk of mild cognitive impairment. , 2007, Archives of neurology.

[46]  D. Bennett,et al.  Chronic Psychological Distress and Risk of Alzheimer’s Disease in Old Age , 2006, Neuroepidemiology.

[47]  R. Havlik,et al.  Midlife blood pressure and dementia: the Honolulu–Asia aging study☆ , 2000, Neurobiology of Aging.

[48]  M. Rice,et al.  Prevalence of dementia and its subtypes in the Japanese American population of King County, Washington state. The Kame Project. , 1996, American journal of epidemiology.

[49]  Suzanne Craft,et al.  The role of metabolic disorders in Alzheimer disease and vascular dementia: two roads converged. , 2009, Archives of neurology.

[50]  E. Cochran,et al.  Loss of nucleus basalis neurons containing trkA immunoreactivity in individuals with mild cognitive impairment and early Alzheimer's disease , 2000, The Journal of comparative neurology.

[51]  K. Welsh-Bohmer,et al.  Longitudinal magnetic resonance imaging vascular changes, apolipoprotein E genotype, and development of dementia in the neurocognitive outcomes of depression in the elderly study. , 2007, The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry.

[52]  S. Leurgans,et al.  The neuropathology of probable Alzheimer disease and mild cognitive impairment , 2009, Annals of neurology.

[53]  F. Craik,et al.  Executive control in a modified antisaccade task: Effects of aging and bilingualism. , 2006, Journal of experimental psychology. Learning, memory, and cognition.

[54]  Denis A. Evans,et al.  Physical activity, cognitive activity, and cognitive decline in a biracial community population. , 2005, Archives of neurology.

[55]  B. Lernfelt,et al.  15-year longitudinal study of blood pressure and dementia , 1996, The Lancet.

[56]  W. Markesbery,et al.  AD brain pathology: Vascular origins? Results from the HAAS autopsy study , 2008, Neurobiology of Aging.

[57]  K. Schaie,et al.  Individual differences in cross-sectional and 3-year longitudinal memory performance across the adult life span. , 1993, Psychology and aging.

[58]  R. Petersen,et al.  Mild Cognitive Impairment Should Be Considered for DSM-V , 2006, Journal of geriatric psychiatry and neurology.

[59]  A. Hofman,et al.  Diet and risk of dementia: Does fat matter? , 2002, Neurology.

[60]  J. Manson,et al.  Physical activity, including walking, and cognitive function in older women. , 2004, JAMA.

[61]  Dominic M. Walsh,et al.  Deciphering the Molecular Basis of Memory Failure in Alzheimer's Disease , 2004, Neuron.

[62]  D. Blacker,et al.  Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database , 2007, Nature Genetics.

[63]  G. Small,et al.  Depression and anxiety symptoms are associated with cerebral FDDNP-PET binding in middle-aged and older nondemented adults. , 2009, The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry.

[64]  K Yaffe,et al.  A prospective study of physical activity and cognitive decline in elderly women: women who walk. , 2001, Archives of internal medicine.

[65]  Anthony F Jorm.  History of Depression as a Risk Factor for Dementia: An Updated Review , 2001, The Australian and New Zealand journal of psychiatry.

[66]  D. Selkoe,et al.  Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity , 1999, Nature.

[67]  H. Beydoun,et al.  Obesity and central obesity as risk factors for incident dementia and its subtypes: a systematic review and meta‐analysis , 2008, Obesity reviews : an official journal of the International Association for the Study of Obesity.

[68]  G. Dai,et al.  Coenzyme Q10 Reduces β-Amyloid Plaque in an APP/PS1 Transgenic Mouse Model of Alzheimer’s Disease , 2010, Journal of Molecular Neuroscience.

[69]  S Rabe-Hesketh,et al.  Head injury as a risk factor for Alzheimer’s disease: the evidence 10 years on; a partial replication , 2003, Journal of neurology, neurosurgery, and psychiatry.

[70]  K. Sink,et al.  Ginkgo biloba for preventing cognitive decline in older adults: a randomized trial. , 2009, JAMA.

[71]  C. DeCarli,et al.  Inflammatory biomarkers are associated with total brain volume , 2007, Neurology.

[72]  C. Steele,et al.  Stereotype threat and the intellectual test performance of African Americans. , 1995, Journal of personality and social psychology.

[73]  P Pietrini,et al.  Association of premorbid intellectual function with cerebral metabolism in Alzheimer's disease: implications for the cognitive reserve hypothesis. , 1997, The American journal of psychiatry.

[74]  S. Goodman,et al.  Nonsteroidal Anti-Inflammatory Drugs for the Prevention of Alzheimer’s Disease: A Systematic Review , 2004, Neuroepidemiology.

[75]  K Yaffe,et al.  Midlife cardiovascular risk factors and risk of dementia in late life , 2005, Neurology.

[76]  P. Aisen,et al.  Recent developments in Alzheimer's disease therapeutics , 2009, BMC medicine.

[77]  N. Schuff,et al.  Longitudinal volumetric MRI change and rate of cognitive decline , 2005, Neurology.

[78]  M. Mattson,et al.  Prophylactic treatment with paroxetine ameliorates behavioral deficits and retards the development of amyloid and tau pathologies in 3xTgAD mice , 2007, Experimental Neurology.

[79]  A. Hofman,et al.  Silent brain infarcts and the risk of dementia and cognitive decline. , 2003, The New England journal of medicine.

[80]  E. Barrett-Connor,et al.  Central obesity and increased risk of dementia more than three decades later , 2008, Neurology.

[81]  D. Levy,et al.  Lifetime risk of coronary heart disease by cholesterol levels at selected ages. , 2003, Archives of internal medicine.

[82]  D. Amaral,et al.  Evidence for task-dependent memory dysfunction in the aged monkey , 1989, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[83]  Nancy Cook,et al.  A randomized trial of vitamin E supplementation and cognitive function in women. , 2006, Archives of internal medicine.

[84]  H. Buschke,et al.  Leisure activities and the risk of amnestic mild cognitive impairment in the elderly , 2006, Neurology.

[85]  J. Schneider,et al.  The effect of social networks on the relation between Alzheimer's disease pathology and level of cognitive function in old people: a longitudinal cohort study , 2006, The Lancet Neurology.

[86]  C. Lyketsos,et al.  Cognitive response to pharmacological treatment for depression in Alzheimer disease: secondary outcomes from the depression in Alzheimer's disease study (DIADS). , 2004, The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry.

[87]  H. Kuo,et al.  Diabetes and the Risk of Multi-System Aging Phenotypes: A Systematic Review and Meta-Analysis , 2009, PloS one.

[88]  L. Thal,et al.  Idebenone treatment fails to slow cognitive decline in Alzheimer’s disease , 2003, Neurology.

[89]  Kristine Yaffe,et al.  A Cognitive Training Program Based on Principles of Brain Plasticity: Results from the Improvement in Memory with Plasticity‐based Adaptive Cognitive Training (IMPACT) Study , 2009, Journal of the American Geriatrics Society.

[90]  J. C. Flores,et al.  Risk factors for dementia in the epidemiological study of Munguialde County (Basque Country-Spain) , 2008 .

[91]  Sudha Seshadri,et al.  Association of plasma leptin levels with incident Alzheimer disease and MRI measures of brain aging. , 2009, JAMA.

[92]  J. Treanor,et al.  Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. , 1999, Science.

[93]  Y. Ben-Shlomo,et al.  A life course approach to chronic disease epidemiology: conceptual models, empirical challenges and interdisciplinary perspectives. , 2002, International journal of epidemiology.

[94]  P. Modrego,et al.  Depression in patients with mild cognitive impairment increases the risk of developing dementia of Alzheimer type: a prospective cohort study. , 2004, Archives of neurology.

[95]  G. Perry,et al.  Chronic antioxidant therapy reduces oxidative stress in a mouse model of Alzheimer's disease , 2009, Free radical research.

[96]  Li Wang,et al.  Exercise Is Associated with Reduced Risk for Incident Dementia among Persons 65 Years of Age and Older , 2006, Annals of Internal Medicine.

[97]  B. Winblad,et al.  Predictors of progression from mild cognitive impairment to Alzheimer disease , 2007, Neurology.

[98]  H. Fillit,et al.  Cardiovascular risk factors and dementia. , 2008, The American journal of geriatric pharmacotherapy.

[99]  R Brookmeyer,et al.  Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset. , 1998, American journal of public health.

[100]  R. Stackman,et al.  Prevention of age-related spatial memory deficits in a transgenic mouse model of Alzheimer's disease by chronic Ginkgo biloba treatment , 2003, Experimental Neurology.

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

[102]  A. Hofman,et al.  Prevalence of dementia and major subtypes in Europe: A collaborative study of population-based cohorts. Neurologic Diseases in the Elderly Research Group. , 2000, Neurology.

[103]  G. Ratcliff,et al.  Relation of education to brain size in normal aging , 1999, Neurology.

[104]  Elizabeth Head,et al.  The canine (dog) model of human aging and disease: dietary, environmental and immunotherapy approaches. , 2008, Journal of Alzheimer's disease : JAD.

[105]  J. Jolles,et al.  Affective symptoms as predictors of Alzheimer's disease in subjects with mild cognitive impairment: a 10-year follow-up study , 2009, Psychological Medicine.

[106]  E. Tangalos,et al.  Neuropathologic features of amnestic mild cognitive impairment. , 2006, Archives of neurology.

[107]  R. Moreau,et al.  Alpha-lipoic acid as a dietary supplement: molecular mechanisms and therapeutic potential. , 2009, Biochimica et biophysica acta.

[108]  David A Bennett,et al.  Physical Frailty Is Associated with Incident Mild Cognitive Impairment in Community‐Based Older Persons , 2010, Journal of the American Geriatrics Society.

[109]  Paige E. Scalf,et al.  Cardiovascular fitness, cortical plasticity, and aging. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[110]  J. Schneider,et al.  Cognitive activity and incident AD in a population-based sample of older persons , 2002, Neurology.

[111]  Alistair Burns,et al.  Observations on the brains of demented old people. B.E. Tomlinson, G. Blessed and M. Roth, Journal of the Neurological Sciences (1970) 11, 205–242; (1968) 7, 331–356 , 1997 .

[112]  J. Mortimer,et al.  Early-Life Risk Factors for Alzheimer Disease , 2006, Alzheimer disease and associated disorders.

[113]  C. Lyketsos,et al.  Rates of Depression in Individuals With Pathologic But Not Clinical Alzheimer Disease are Lower Than Those in Individuals Without the Disease: Findings From the Baltimore Longitudinal Study on Aging (BLSA) , 2007, Alzheimer Disease and Associated Disorders.

[114]  Barry E. Levin,et al.  Neurobiology of Exercise , 2006 .

[115]  A. Mann,et al.  Risk factors for Alzheimer's disease and dementia , 1994, Neurology.

[116]  R. Rupprecht,et al.  Differential effects of single versus combined cognitive and physical training with older adults: the SimA study in a 5-year perspective , 2006, European journal of ageing.

[117]  M. Gallagher,et al.  The use of animal models to study the effects of aging on cognition. , 1997, Annual review of psychology.

[118]  C. Jack,et al.  Mild cognitive impairment: ten years later. , 2009, Archives of neurology.

[119]  D. Drachman.  Rethinking Alzheimer’s disease: The role of age-related changes , 2007, Current neurology and neuroscience reports.

[120]  M. Naveh-Benjamin,et al.  The associative memory deficit of older adults: the role of strategy utilization. , 2007, Psychology and aging.

[121]  Charles D. Smith,et al.  Neuropathologic substrate of mild cognitive impairment. , 2006, Archives of neurology.

[122]  K. Hawton,et al.  Dementia and suicidal behavior: a review of the literature , 2009, International Psychogeriatrics.

[123]  Lewis H Kuller,et al.  Midlife and late-life obesity and the risk of dementia: cardiovascular health study. , 2009, Archives of neurology.

[124]  Bruce G. Link,et al.  Relationship between lifetime occupation and parietal flow , 1995, Neurology.

[125]  G. Alexander,et al.  Inverse relationship between education and parietotemporal perfusion deficit in Alzheimer's disease , 1992, Annals of neurology.

[126]  D. Harvey,et al.  Extent and distribution of white matter hyperintensities in normal aging, MCI, and AD , 2006, Neurology.

[127]  C. Cotman,et al.  Three weeks of running wheel exposure improves cognitive performance in the aged Tg2576 mouse , 2007, Behavioural Brain Research.

[128]  C. Jack,et al.  Alzheimer's Disease Neuroimaging Initiative , 2008 .

[129]  C. Hong,et al.  Conversion to Dementia From Questionable Dementia in an Ethnic Chinese Population , 2007, Journal of geriatric psychiatry and neurology.

[130]  L. Launer,et al.  Apolipoprotein E epsilon4 allele genotype and the effect of depressive symptoms on the risk of dementia in men: the Honolulu-Asia Aging Study. , 2008, Archives of general psychiatry.

[131]  R. Petersen,et al.  Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects , 2009, Annals of neurology.

[132]  D. Kaufer,et al.  The Concentration and Persistence of Health Care Expenditures and Prescription Drug Expenditures in Medicare Beneficiaries With Alzheimer Disease and Related Dementias , 2009, Medical care.

[133]  J. Kaye,et al.  A randomized placebo-controlled trial of Ginkgo biloba for the prevention of cognitive decline , 2008, Neurology.

[134]  J. Morris,et al.  Predictors of preclinical Alzheimer disease and dementia: a clinicopathologic study. , 2005, Archives of neurology.

[135]  A. Alzheimer.  Uber eine eigenartige Erkrankung der Hirnrinde , 1907 .

[136]  B. Winblad,et al.  Leisure-time physical activity at midlife and the risk of dementia and Alzheimer's disease , 2005, The Lancet Neurology.

[137]  A. Kramer,et al.  Fitness Effects on the Cognitive Function of Older Adults , 2003, Psychological science.

[138]  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.

[139]  K. Yaffe,et al.  Metabolic Syndrome and Cognitive Decline in Elderly Latinos: Findings from the Sacramento Area Latino Study of Aging Study , 2007, Journal of the American Geriatrics Society.

[140]  Paige E. Scalf,et al.  Aerobic exercise training increases brain volume in aging humans. , 2006, The journals of gerontology. Series A, Biological sciences and medical sciences.

[141]  C. Masters,et al.  Treatment with a Copper-Zinc Chelator Markedly and Rapidly Inhibits β-Amyloid Accumulation in Alzheimer's Disease Transgenic Mice , 2001, Neuron.

[142]  Y. Stern,et al.  Cognitive test performance among nondemented elderly African Americans and whites , 1998, Neurology.

[143]  H. Braak,et al.  Frequency of Stages of Alzheimer-Related Lesions in Different Age Categories , 1997, Neurobiology of Aging.

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

[145]  C. Jack,et al.  Alzheimer's Disease Neuroimaging Initiative (ADNI) , 2010, Neurology.

[146]  K. Ball,et al.  Long-term effects of cognitive training on everyday functional outcomes in older adults. , 2006, JAMA.

[147]  D. Leys,et al.  Treatment of vascular risk factors is associated with slower decline in Alzheimer disease , 2009, Neurology.

[148]  D J Foley,et al.  Prevalence of dementia in older Japanese-American men in Hawaii: The Honolulu-Asia Aging Study. , 1996, JAMA.

[149]  A. Fagan,et al.  Multimodal techniques for diagnosis and prognosis of Alzheimer's disease , 2009, Nature.

[150]  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.

[151]  Ronald C Petersen,et al.  Alzheimer's disease: progress in prediction , 2010, The Lancet Neurology.

[152]  S. Leurgans,et al.  Association of muscle strength with the risk of Alzheimer disease and the rate of cognitive decline in community-dwelling older persons. , 2009, Archives of neurology.

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

[154]  D A Bennett,et al.  Relation of cognitive activity to risk of developing Alzheimer disease , 2007, Neurology.

[155]  K. Langa,et al.  Prevalence of Dementia in the United States: The Aging, Demographics, and Memory Study , 2007, Neuroepidemiology.

[156]  D. Bennett,et al.  The APOE ε4 Allele Is Associated with Incident Mild Cognitive Impairment among Community-Dwelling Older Persons , 2009, Neuroepidemiology.

[157]  H. Tuokko,et al.  Neuropsychiatric Impairments as Predictors of Mild Cognitive Impairment, Dementia, and Alzheimer's Disease , 2008, American journal of Alzheimer's disease and other dementias.

[158]  Kazuomi Kario,et al.  Hypertension and dementia. , 2010, American journal of hypertension.

[159]  David A. Bennett,et al.  Decision Rules Guiding the Clinical Diagnosis of Alzheimer’s Disease in Two Community-Based Cohort Studies Compared to Standard Practice in a Clinic-Based Cohort Study , 2006, Neuroepidemiology.

[160]  Laura Mickes,et al.  Cognitive and physiologic correlates of subclinical structural brain disease in elderly healthy control subjects. , 2002, Archives of neurology.

[161]  Xudong Huang,et al.  Pilot study of the reducing effect on amyloidosis in vivo by three FDA pre-approved drugs via the Alzheimer's APP 5' untranslated region. , 2005, Current Alzheimer research.

[162]  F. Gunning-Dixon,et al.  The cognitive correlates of white matter abnormalities in normal aging: a quantitative review. , 2000, Neuropsychology.

[163]  Race and Schooling in the South, 1880-1950: An Economic History , 1990 .

[164]  L. Wolfson,et al.  Clinico‐pathologic studies in dementia , 1988, Neurology.

[165]  Anders M. Dale,et al.  Consistent neuroanatomical age-related volume differences across multiple samples , 2011, Neurobiology of Aging.

[166]  Carl W. Cotman,et al.  Exercise builds brain health: key roles of growth factor cascades and inflammation , 2007, Trends in Neurosciences.

[167]  L. Whalley,et al.  A life-course approach to the aetiology of late-onset dementias , 2006, The Lancet Neurology.

[168]  S. Lovestone,et al.  Midlife Neuroticism and the age of onset of Alzheimer's disease , 2008, Psychological Medicine.

[169]  K. Markides,et al.  Predictors of decline in MMSE scores among older Mexican Americans. , 2002, The journals of gerontology. Series A, Biological sciences and medical sciences.

[170]  N. Raz,et al.  Aging white matter and cognition: Differential effects of regional variations in diffusion properties on memory, executive functions, and speed , 2009, Neuropsychologia.

[171]  R. Killiany,et al.  Executive system dysfunction occurs as early as middle-age in the rhesus monkey , 2006, Neurobiology of Aging.

[172]  K. Hall,et al.  Low education and childhood rural residence , 2000, Neurology.

[173]  K. Yaffe,et al.  Glycosylated hemoglobin level and development of mild cognitive impairment or dementia in older women. , 2006, The journal of nutrition, health & aging.

[174]  B. Winblad,et al.  An active and socially integrated lifestyle in late life might protect against dementia , 2004, The Lancet Neurology.

[175]  Denis A. Evans,et al.  Vitamin E and cognitive decline in older persons. , 2002, Archives of neurology.

[176]  L. Bäckman,et al.  Design your own memory strategies! Self-generated strategy training versus mnemonic training in old age: An 8-month follow-up , 2005, Neuropsychological rehabilitation.

[177]  R L Kane,et al.  Years of life with good and poor mental and physical function in the elderly. , 1989, Journal of clinical epidemiology.

[178]  C. Reynolds,et al.  Imaging Alzheimer Pathology in Late-Life Depression With PET and Pittsburgh Compound-B , 2008, Alzheimer disease and associated disorders.

[179]  J. Quinn,et al.  Evaluation of coenzyme Q as an antioxidant strategy for Alzheimer's disease. , 2008, Journal of Alzheimer's disease : JAD.

[180]  D. Bennett,et al.  Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease. , 2003, Archives of neurology.

[181]  B. Pollock,et al.  Neuropathologic Correlates of Late-Onset Major Depression , 2004, Neuropsychopharmacology.

[182]  R. Mohs,et al.  Consortium to establish a registry for Alzheimer's disease (CERAD) clinical and neuropsychological assessment of Alzheimer's disease. , 2002, Psychopharmacology bulletin.

[183]  C. Jack,et al.  Diet supplement CoQ10 delays brain atrophy in aged transgenic mice with mutations in the amyloid precursor protein: An in vivo volume MRI study , 2008, BioFactors.

[184]  A. Hofman,et al.  Dietary fat intake and the risk of incident dementia in the Rotterdam study , 1997, Annals of neurology.

[185]  Lewis H Kuller,et al.  Physical activity, APOE genotype, and dementia risk: findings from the Cardiovascular Health Cognition Study. , 2005, American journal of epidemiology.

[186]  J. Dickens,et al.  Prevalence of cognitive impairment , 2001, Neurology.

[187]  M. Woodward,et al.  Effects of Blood Pressure Lowering on Cerebral White Matter Hyperintensities in Patients With Stroke: The PROGRESS (Perindopril Protection Against Recurrent Stroke Study) Magnetic Resonance Imaging Substudy , 2005, Circulation.

[188]  W. Honer.  Pathology of presynaptic proteins in Alzheimer’s disease: more than simple loss of terminals , 2003, Neurobiology of Aging.

[189]  C. DeCarli,et al.  Chronic Kidney Disease Is Associated With White Matter Hyperintensity Volume: The Northern Manhattan Study (NOMAS) , 2007, Stroke.

[190]  Robert P. Friedland,et al.  Patients with Alzheimer's disease have reduced activities in midlife compared with healthy control-group members , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[191]  J. Pariente,et al.  Early diagnosis of Alzheimer's disease using cortical thickness: impact of cognitive reserve , 2009, Brain : a journal of neurology.

[192]  John Q. Trojanowski,et al.  Consensus Recommendations for the Postmortem Diagnosis of Alzheimer’s Disease , 1997, Neurobiology of Aging.

[193]  H. Dodge,et al.  Predictors of Nursing Facility Admission: A 12‐Year Epidemiological Study in the United States , 2004, Journal of the American Geriatrics Society.

[194]  Carole Dufouil,et al.  The Association Between Blood Pressure, Hypertension, and Cerebral White Matter Lesions: Cardiovascular Determinants of Dementia Study , 2004, Hypertension.

[195]  W. Kukull,et al.  Lost in translation: epidemiology, risk, and Alzheimer disease. , 2010, Archives of neurology.

[196]  R. Green,et al.  Naproxen and celecoxib do not prevent AD in early results from a randomized controlled trial , 2007, Neurology.

[197]  D. Bennett,et al.  Dietary Intake of Antioxidant Nutrients and the Risk of Incident Alzheimer Disease in a Biracial Community Study , 2022 .

[198]  A Ogunniyi,et al.  Incidence of dementia and Alzheimer disease in 2 communities: Yoruba residing in Ibadan, Nigeria, and African Americans residing in Indianapolis, Indiana. , 2001, JAMA.

[199]  P. Wolf,et al.  Association of matrix metalloproteinases with MRI indices of brain ischemia and aging , 2010, Neurobiology of Aging.

[200]  M. Woodbury,et al.  The prevalence and 3-year incidence of dementia in older Black and White community residents. , 1998, Journal of clinical epidemiology.

[201]  R. D'Agostino,et al.  Association of white matter hyperintensity volume with decreased cognitive functioning: the Framingham Heart Study. , 2006, Archives of neurology.

[202]  P. Aisen.  Alzheimer's disease therapeutic research: the path forward , 2009, Alzheimers Res Ther.

[203]  K. Marder,et al.  Alzheimer's disease after remote head injury: an incidence study. , 1997, Journal of neurology, neurosurgery, and psychiatry.

[204]  K. Yaffe,et al.  Fish consumption, long-chain omega-3 fatty acids and risk of cognitive decline or Alzheimer disease: a complex association , 2009, Nature Clinical Practice Neurology.

[205]  Qi Dai,et al.  Fruit and vegetable juices and Alzheimer's disease: the Kame Project. , 2006, The American journal of medicine.

[206]  L. Nilsson.  Memory function in normal aging , 2003, Acta neurologica Scandinavica. Supplementum.

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

[208]  R. Mayeux,et al.  Antioxidant vitamin intake and risk of Alzheimer disease. , 2003, Archives of neurology.

[209]  Lewis H Kuller,et al.  Ginkgo biloba for prevention of dementia: a randomized controlled trial. , 2008, JAMA.

[210]  Michael A Rapp,et al.  Increased hippocampal plaques and tangles in patients with Alzheimer disease with a lifetime history of major depression. , 2006, Archives of general psychiatry.

[211]  K. Anstey,et al.  Alcohol consumption as a risk factor for dementia and cognitive decline: meta-analysis of prospective studies. , 2009, The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry.

[212]  C. Cotman,et al.  Exercise alters the immune profile in Tg2576 Alzheimer mice toward a response coincident with improved cognitive performance and decreased amyloid , 2008, Journal of Neuroinflammation.

[213]  Charles DeCarli,et al.  Heterogeneity of cognitive trajectories in diverse older persons. , 2010, Psychology and aging.

[214]  R. Mayeux,et al.  Mediterranean diet and mild cognitive impairment. , 2009, Archives of neurology.

[215]  Dan M Mungas,et al.  Composite scores for executive function items: Demographic heterogeneity and relationships with quantitative magnetic resonance imaging , 2008, Journal of the International Neuropsychological Society.

[216]  David A Bennett,et al.  Conscientiousness and the incidence of Alzheimer disease and mild cognitive impairment. , 2007, Archives of general psychiatry.

[217]  B. Reed,et al.  Psychometrically matched measures of global cognition, memory, and executive function for assessment of cognitive decline in older persons. , 2003, Neuropsychology.

[218]  M. Glymour,et al.  Is the ‘Stroke Belt' Worn From Childhood?: Risk of First Stroke and State of Residence in Childhood and Adulthood , 2007, Stroke.

[219]  Charles DeCarli,et al.  White matter hyperintensities and cognition: Testing the reserve hypothesis , 2011, Neurobiology of Aging.

[220]  M. Crowe,et al.  Complexity of work and risk of Alzheimer's disease: a population-based study of Swedish twins. , 2005, The journals of gerontology. Series B, Psychological sciences and social sciences.

[221]  W. Rocca,et al.  Prevalence of clinically diagnosed Alzheimer's disease and other dementing disorders , 1990, Neurology.

[222]  R. Katzman.,et al.  The Prevalence and Malignancy of Alzheimer Disease A Major Killer , 2008, Alzheimer's & Dementia.

[223]  H. Brodaty,et al.  ALZHEIMER'S DISEASE INTERNATIONAL , 1997, International journal of geriatric psychiatry.

[224]  W. Perrig,et al.  The effects of resistance training on well-being and memory in elderly volunteers. , 1998, Age and ageing.

[225]  R. Fogel.  Secular Trends in Physiological Capital: Implications for Equity in Health Care , 2003, Perspectives in biology and medicine.

[226]  D. Harvey,et al.  Measures of brain morphology and infarction in the framingham heart study: establishing what is normal , 2005, Neurobiology of Aging.

[227]  Lenore J. Launer,et al.  The NIH Cognitive and Emotional Health Project Report of the Critical Evaluation Study Committee , 2006, Alzheimer's & Dementia.

[228]  Jean-François Dartigues,et al.  Fish, meat, and risk of dementia: cohort study , 2002, BMJ : British Medical Journal.

[229]  J. Schneider,et al.  Olfactory identification and incidence of mild cognitive impairment in older age. , 2007, Archives of general psychiatry.

[230]  Y. Stern,et al.  An association between head circumference and Alzheimer's disease in a population-based study of aging and dementia , 1997, Neurology.

[231]  D. Bennett,et al.  Odor Identification and Decline in Different Cognitive Domains in Old Age , 2006, Neuroepidemiology.

[232]  Fred H. Gage,et al.  An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus , 2007, Proceedings of the National Academy of Sciences.

[233]  H. Wagner,et al.  Persistent mild cognitive impairment in geriatric depression , 2006, International Psychogeriatrics.

[234]  K. Yaffe,et al.  Hormone replacement therapy for cognitive function in postmenopausal women ( Review ) , 2022 .

[235]  D. Bennett,et al.  Early Life Socioeconomic Status and Late Life Risk of Alzheimer’s Disease , 2005, Neuroepidemiology.

[236]  D. Bennett,et al.  Chronic distress and incidence of mild cognitive impairment , 2007, Neurology.

[237]  E. Feskens,et al.  Polyunsaturated fatty acids, antioxidants, and cognitive function in very old men. , 1997, American journal of epidemiology.

[238]  D. Bennett,et al.  Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function. , 2004, Archives of neurology.

[239]  Lewis H Kuller,et al.  Incidence and Prevalence of Dementia in the Cardiovascular Health Study , 2004, Journal of the American Geriatrics Society.

[240]  S. Haneuse,et al.  Pathological correlates of dementia in a longitudinal, population‐based sample of aging , 2007, Annals of neurology.

[241]  K. Blennow,et al.  Safety, efficacy, and biomarker findings of PBT2 in targeting Aβ as a modifying therapy for Alzheimer's disease: a phase IIa, double-blind, randomised, placebo-controlled trial , 2008, The Lancet Neurology.

[242]  Gerd Kempermann,et al.  Additive Effects of Physical Exercise and Environmental Enrichment on Adult Hippocampal Neurogenesis in Mice , 2009, Front. Neurogenesis.

[243]  D. Borchelt,et al.  Environmental Enrichment Exacerbates Amyloid Plaque Formation in a Transgenic Mouse Model of Alzheimer Disease , 2003, Journal of neuropathology and experimental neurology.

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

[245]  S. Lord,et al.  Otago Home‐Based Strength and Balance Retraining Improves Executive Functioning in Older Fallers: A Randomized Controlled Trial , 2008, Journal of the American Geriatrics Society.

[246]  Kaarin J Anstey,et al.  Smoking as a risk factor for dementia and cognitive decline: a meta-analysis of prospective studies. , 2007, American journal of epidemiology.

[247]  Y. Stern,et al.  Reading level attenuates differences in neuropsychological test performance between African American and White elders , 2002, Journal of the International Neuropsychological Society.

[248]  D. Bennett,et al.  Diabetes is related to cerebral infarction but not to AD pathology in older persons , 2006, Neurology.

[249]  A. Korten,et al.  The prevalence of dementia: A quantitative integration of the literature , 1987, Acta psychiatrica Scandinavica.

[250]  J N Morris,et al.  ACTIVE: a cognitive intervention trial to promote independence in older adults. , 2001, Controlled clinical trials.

[251]  V. Pankratz,et al.  The Mayo Clinic Study of Aging: Design and Sampling, Participation, Baseline Measures and Sample Characteristics , 2008, Neuroepidemiology.

[252]  C. Lyketsos,et al.  Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. , 2002, JAMA.

[253]  Y. Stern,et al.  Influence of leisure activity on the incidence of Alzheimer’s Disease , 2001, Neurology.

[254]  Hui-Xin Wang,et al.  Brain reserve hypothesis in dementia. , 2007, Journal of Alzheimer's disease : JAD.

[255]  F. Verhey,et al.  Awareness in dementia: A review of clinical correlates , 2005, Aging & mental health.

[256]  Kristine Yaffe,et al.  Promising strategies for the prevention of dementia. , 2009, Archives of neurology.

[257]  P. Barberger-Gateau,et al.  Dietary patterns and risk of dementia , 2007, Neurology.

[258]  A. Hofman,et al.  History of depression, depressive symptoms, and medial temporal lobe atrophy and the risk of Alzheimer disease , 2008, Neurology.

[259]  C. Ferri,et al.  World Alzheimer Report 2009 , 2009 .

[260]  J. Larson,et al.  Complex environment experience rescues impaired neurogenesis, enhances synaptic plasticity, and attenuates neuropathology in familial Alzheimer's disease‐linked APPswe/PS1ΔE9 mice , 2010, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[261]  D. Bennett,et al.  Loss and atrophy of layer II entorhinal cortex neurons in elderly people with mild cognitive impairment , 2001, Annals of neurology.

[262]  R. Mayeux,et al.  Influence of education and occupation on the incidence of Alzheimer's disease. , 1994, JAMA.

[263]  W. Markesbery,et al.  Oxidative damage in mild cognitive impairment and early Alzheimer's disease , 2007, Journal of neuroscience research.

[264]  B. Winblad,et al.  Influence of social network on occurrence of dementia: a community-based longitudinal study , 2000, The Lancet.

[265]  F. LaFerla,et al.  Chronic copper exposure exacerbates both amyloid and tau pathology and selectively dysregulates cdk5 in a mouse model of AD , 2009, Journal of neurochemistry.

[266]  R. Mayeux,et al.  Hyperinsulinemia and risk of Alzheimer disease , 2004, Neurology.

[267]  D. Gold,et al.  Memory Complaint as a Predictor of Cognitive Decline , 1997, Journal of aging and health.

[268]  K. Kinsella,et al.  An aging world: 2008. , 2009 .

[269]  M. Ganguli,et al.  Modifiable Midlife Risk Factors for Late-Life Cognitive Impairment and Dementia. , 2009, Current psychiatry reviews.

[270]  J. Schneider,et al.  Chronic Distress, Age-Related Neuropathology, and Late-Life Dementia , 2007, Psychosomatic medicine.

[271]  B. Winblad,et al.  Personality and lifestyle in relation to dementia incidence , 2009, Neurology.

[272]  Laura Fratiglioni,et al.  Mental, Physical and Social Components in Leisure Activities Equally Contribute to Decrease Dementia Risk , 2006, Dementia and Geriatric Cognitive Disorders.

[273]  George W Rebok,et al.  Effect of memory impairment on training outcomes in ACTIVE , 2007, Journal of the International Neuropsychological Society.

[274]  D. Amaral,et al.  Hippocampal volume is preserved and fails to predict recognition memory impairment in aged rhesus monkeys (Macaca mulatta) , 2006, Neurobiology of Aging.

[275]  J. Schneider,et al.  Proneness to psychological distress is associated with risk of Alzheimer’s disease , 2003, Neurology.

[276]  Sudha Seshadri,et al.  Lifetime risk of stroke and dementia: current concepts, and estimates from the Framingham Study , 2007, The Lancet Neurology.

[277]  Victoria M Perreau,et al.  Voluntary Exercise Decreases Amyloid Load in a Transgenic Model of Alzheimer's Disease , 2005, The Journal of Neuroscience.

[278]  D. Butterfield,et al.  Roles of amyloid β-peptide-associated oxidative stress and brain protein modifications in the pathogenesis of Alzheimer's disease and mild cognitive impairment , 2007 .

[279]  H. Soininen,et al.  Serum cholesterol changes after midlife and late-life cognition , 2007, Neurology.

[280]  David Loewenstein,et al.  Depression and risk for Alzheimer disease: systematic review, meta-analysis, and metaregression analysis. , 2006, Archives of general psychiatry.

[281]  D. Snowdon,et al.  Age, Education, and Changes in the Mini‐Mental State Exam Scores of Older Women: Findings from the Nun Study , 1996, Journal of the American Geriatrics Society.

[282]  W. Markesbery,et al.  Alzheimer's neurofibrillary pathology and the spectrum of cognitive function: Findings from the Nun Study , 2002, Annals of neurology.

[283]  K Kondo,et al.  A case-control study of Alzheimer's disease in Japan--significance of life-styles. , 1994, Dementia.

[284]  J. Cohen-Mansfield,et al.  Multilingualism and cognitive state in the oldest old. , 2008, Psychology and aging.

[285]  M. Moss.  The longitudinal assessment of recognition memory in aged rhesus monkeys , 1993, Neurobiology of Aging.

[286]  S. Riedel-Heller,et al.  Subclassifications for mild cognitive impairment: prevalence and predictive validity , 2003, Psychological Medicine.

[287]  R L Kane,et al.  Education, survival, and independence in elderly Catholic sisters, 1936-1988. , 1989, American journal of epidemiology.

[288]  Sudha Seshadri,et al.  Residual lifetime risk for developing hypertension in middle-aged women and men: The Framingham Heart Study. , 2002, JAMA.

[289]  B. Mulsant,et al.  The temporal relationship between depressive symptoms and dementia: a community-based prospective study. , 1999, Archives of general psychiatry.

[290]  M. Hutton,et al.  The genetics of frontotemporal lobar degeneration , 2007, Current neurology and neuroscience reports.

[291]  G. Cole,et al.  The Curry Spice Curcumin Reduces Oxidative Damage and Amyloid Pathology in an Alzheimer Transgenic Mouse , 2001, The Journal of Neuroscience.

[292]  L. Berkman,et al.  Cognitive functioning and the incidence of limitations in activities of daily living in an elderly community sample. , 1995, American journal of epidemiology.

[293]  J. Schneider,et al.  Participation in cognitively stimulating activities and risk of incident Alzheimer disease. , 2002, JAMA.

[294]  B. Takkouche,et al.  Education and Dementia: A Meta-Analytic Study , 2006, Neuroepidemiology.

[295]  G. Belle,et al.  Cholinergic dysfunction in diseases with Lewy bodies , 2000, Neurology.

[296]  D. Bennett,et al.  Relation of Blood Pressure to Risk of Incident Alzheimer’s Disease and Change in Global Cognitive Function in Older Persons , 2005, Neuroepidemiology.

[297]  O. Pedraza,et al.  Measurement in Cross-Cultural Neuropsychology , 2008, Neuropsychology Review.

[298]  M. Albert,et al.  Differences in abstraction ability with age. , 1990, Psychology and aging.

[299]  W. Markesbery,et al.  Brain infarction and the clinical expression of Alzheimer disease. , 1997, JAMA.

[300]  J. Adair,et al.  Controlled trial of N-acetylcysteine for patients with probable Alzheimer’s disease , 2001, Neurology.

[301]  E. Chan,et al.  Distribution study of orally administered lipoic acid in rat brain tissues , 2009, Brain Research.

[302]  R. N. Spreng,et al.  Reliable differences in brain activity between young and old adults: A quantitative meta-analysis across multiple cognitive domains , 2010, Neuroscience & Biobehavioral Reviews.

[303]  J. Schneider,et al.  Cerebral infarctions and the likelihood of dementia from Alzheimer disease pathology , 2004, Neurology.

[304]  Charles DeCarli,et al.  Different mechanisms of episodic memory failure in mild cognitive impairment , 2005, Neuropsychologia.

[305]  P. Sachdev,et al.  Brain reserve and dementia: a systematic review , 2005, Psychological Medicine.

[306]  M. Weiner,et al.  Relationships between biomarkers in aging and dementia , 2009, Neurology.

[307]  M. Glymour,et al.  Does childhood schooling affect old age memory or mental status? Using state schooling laws as natural experiments , 2008, Journal of Epidemiology & Community Health.

[308]  J. Trojanowski,et al.  Tau-mediated neurodegeneration in Alzheimer's disease and related disorders , 2007, Nature Reviews Neuroscience.

[309]  H. Soininen,et al.  Fat Intake at Midlife and Risk of Dementia and Alzheimer’s Disease: A Population-Based Study , 2006, Dementia and Geriatric Cognitive Disorders.

[310]  Lars Bäckman,et al.  Differential evolution of cognitive impairment in nondemented older persons: results from the Kungsholmen Project. , 2002, The American journal of psychiatry.

[311]  V. Pankratz,et al.  Prevalence of neuropsychiatric symptoms in mild cognitive impairment and normal cognitive aging: population-based study. , 2008, Archives of general psychiatry.

[312]  J. Trojanowski,et al.  The Levels of Soluble versus Insoluble Brain Aβ Distinguish Alzheimer's Disease from Normal and Pathologic Aging , 1999, Experimental Neurology.

[313]  J. Schneider,et al.  Neuropathology of older persons without cognitive impairment from two community-based studies , 2006, Neurology.

[314]  B. Lawlor,et al.  Review: Blood pressure and dementia — a comprehensive review , 2009, Therapeutic advances in neurological disorders.

[315]  D. Borchelt,et al.  Environmental Enrichment Mitigates Cognitive Deficits in a Mouse Model of Alzheimer's Disease , 2005, The Journal of Neuroscience.

[316]  Kristine Yaffe,et al.  Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus. , 2009, JAMA.

[317]  George W Rebok,et al.  Effects of cognitive training interventions with older adults: a randomized controlled trial. , 2002, JAMA.

[318]  W. Markesbery,et al.  AD lesions and infarcts in demented and non‐demented Japanese‐American men , 2005, Annals of neurology.

[319]  F. Tchantchou,et al.  N-acteyl cysteine alleviates oxidative damage to central nervous system of ApoE-deficient mice following folate and vitamin E-deficiency. , 2005, Journal of Alzheimer's disease : JAD.

[320]  P. Barberger‐Gateau,et al.  Association between antioxidant nutritional indicators and the incidence of dementia: results from the PAQUID prospective cohort study , 2003, European Journal of Clinical Nutrition.

[321]  P. Passmore,et al.  The effects of blood pressure lowering on development of cognitive impairment and dementia in patients without apparent prior cerebrovascular disease. , 2006, The Cochrane database of systematic reviews.

[322]  Nilüfer Ertekin-Taner,et al.  Genetics of Alzheimer's disease: a centennial review. , 2007, Neurologic clinics.

[323]  J. Becker,et al.  Patterns of mild cognitive impairment after treatment of depression in the elderly. , 2009, The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry.

[324]  Clyde Hertzman,et al.  Birth weight, childhood socioeconomic environment, and cognitive development in the 1958 British birth cohort study , 2002, BMJ : British Medical Journal.

[325]  Anders M. Dale,et al.  Frontal connections and cognitive changes in normal aging rhesus monkeys: A DTI study , 2007, Neurobiology of Aging.

[326]  A. Mackinnon,et al.  Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. , 2003, Archives of neurology.

[327]  Nicola Vanacore,et al.  Cholinesterase Inhibitors in Mild Cognitive Impairment: A Systematic Review of Randomised Trials , 2007, PLoS medicine.

[328]  I. Shapira.  The Nun Study. , 2008, Journal of the American Dental Association.

[329]  A. Mitchell,et al.  Rate of progression of mild cognitive impairment to dementia – meta‐analysis of 41 robust inception cohort studies , 2009, Acta psychiatrica Scandinavica.

[330]  A. Hofman,et al.  Dietary Intake of Antioxidants and Risk of Alzheimer Disease , 2002 .

[331]  Yaakov Stern,et al.  Association of life activities with cerebral blood flow in Alzheimer disease: implications for the cognitive reserve hypothesis. , 2003, Archives of neurology.

[332]  A. Peters,et al.  The effects of aging on area 46 of the frontal cortex of the rhesus monkey. , 1994, Cerebral cortex.

[333]  Laura Fratiglioni,et al.  Prevalence of chronic diseases and multimorbidity among the elderly population in Sweden. , 2008, American journal of public health.

[334]  P. Mecocci,et al.  Plasma antioxidants are similarly depleted in mild cognitive impairment and in Alzheimer’s disease , 2003, Neurobiology of Aging.

[335]  B. Winblad,et al.  Mentally stimulating activities at work during midlife and dementia risk after age 75: follow-up study from the Kungsholmen Project. , 2009, The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry.

[336]  J. Becker,et al.  Depressed mood is not a risk factor for incident dementia in a community-based cohort. , 2009, The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry.

[337]  H. Dodge,et al.  Cognitive Decline and Mortality in a Community‐Based Cohort: The Monongahela Valley Independent Elders Survey , 2009, Journal of the American Geriatrics Society.

[338]  Arthur F Kramer,et al.  Achieving and maintaining cognitive vitality with aging. , 2002, Mayo Clinic proceedings.

[339]  C. Mathers,et al.  Global prevalence of dementia: a Delphi consensus study , 2005, The Lancet.

[340]  H. Buschke,et al.  Leisure activities and the risk of dementia in the elderly. , 2003, The New England journal of medicine.

[341]  Miia Kivipelto,et al.  Rethinking the Dementia Diagnoses in a Population-Based Study: What Is Alzheimer’s Disease and What Is Vascular Dementia? , 2006, Dementia and Geriatric Cognitive Disorders.

[342]  J. Schneider,et al.  Neurofibrillary tangles mediate the association of amyloid load with clinical Alzheimer disease and level of cognitive function. , 2004, Archives of neurology.

[343]  J. Manson,et al.  Vitamin E, Vitamin C, Beta Carotene, and Cognitive Function Among Women With or at Risk of Cardiovascular Disease: The Women’s Antioxidant and Cardiovascular Study , 2009, Circulation.

[344]  Daniel Levy,et al.  Lifetime risk of developing coronary heart disease , 1999, The Lancet.

[345]  P. Zandi,et al.  Knee height and arm span , 2008, Neurology.

[346]  R. Abbott,et al.  Walking and dementia in physically capable elderly men. , 2004, JAMA.

[347]  A. Geronimus,et al.  The weathering hypothesis and the health of African-American women and infants: evidence and speculations. , 1992, Ethnicity & disease.

[348]  Paul K Crane,et al.  Spanish and English Neuropsychological Assessment Scales (SENAS): further development and psychometric characteristics. , 2004, Psychological assessment.

[349]  Piero Antuono,et al.  Alzheimer's disease and vascular dementia in developing countries: prevalence, management, and risk factors , 2008, The Lancet Neurology.

[350]  K. Hall,et al.  The relationships between age, sex, and the incidence of dementia and Alzheimer disease: a meta-analysis. , 1998, Archives of general psychiatry.

[351]  Constantine G Lyketsos,et al.  Point and 5‐year period prevalence of neuropsychiatric symptoms in dementia: the Cache County Study , 2008, International journal of geriatric psychiatry.

[352]  C. DeCarli,et al.  Inflammatory Biomarkers of Vascular Risk as Correlates of Leukoariosis , 2009, Stroke.