Official reprint from UpToDate®
www.uptodate.com ©2015 UpToDate®

Clinical features and diagnosis of Alzheimer disease

David A Wolk, MD
Bradford C Dickerson, MD
Section Editor
Steven T DeKosky, MD, FAAN, FACP, FANA
Deputy Editor
April F Eichler, MD, MPH


Alzheimer disease (AD) is a neurodegenerative disorder of uncertain cause and pathogenesis that primarily affects older adults and is the most common cause of dementia [1]. The most essential and often earliest clinical manifestation of AD is selective memory impairment, although there are exceptions. While treatments are available that can ameliorate some symptoms of the illness, there is no cure or disease-modifying therapy (treatment that slows the course of the illness) currently available, and the disease inevitably progresses in all patients.

This topic reviews the clinical manifestations and diagnosis of AD. Other topics review the risk factors and treatment of AD and the clinical manifestations of other causes of dementia and cognitive impairment. (See "Epidemiology, pathology, and pathogenesis of Alzheimer disease" and "Treatment of dementia" and "Cholinesterase inhibitors in the treatment of dementia" and "Mild cognitive impairment: Epidemiology, pathology, and clinical assessment" and "Clinical features and diagnosis of dementia with Lewy bodies" and "Frontotemporal dementia: Clinical features and diagnosis" and "Etiology, clinical manifestations, and diagnosis of vascular dementia".)


Age of onset — Alzheimer disease (AD) is characteristically a disease of older age [2]. It is exceptional for AD to occur before age 60. The incidence and prevalence of AD increase exponentially with age, essentially doubling in prevalence every 5 years after the age of 65 years. (See "Epidemiology, pathology, and pathogenesis of Alzheimer disease", section on 'Incidence and prevalence'.)

Early-onset AD (onset of symptoms before 65 years of age) is unusual, and many of these patients present for evaluation due to occupation-related difficulties. Many of these patients have no clear familial pattern and thus would be considered sporadic, although some exhibit familial clustering.

There are rare inherited forms of AD that routinely present before 65 years of age, and frequently in the fifth decade or earlier. These account for less than one percent of all cases of AD. They typically exhibit an autosomal dominant inheritance pattern related to mutations in genes that alter beta-amyloid (Aβ) protein production or metabolism, including amyloid precursor protein (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2). In a meta-analysis with individual-level data on 1307 patients with autosomal dominant AD, the mean age of symptom onset was 46 years and was highly correlated with parental age of onset and mutation type [3]. Patients with PSEN1 mutations had the earliest median age of onset (43 years) (figure 1). The range of symptom onset across all mutation types is nonetheless fairly broad, with some presentations in the fourth decade and some mutations not manifesting symptoms until the seventh decade. There are active longitudinal observational studies as well as clinical trials of amyloid-modulating therapies in progress in symptomatic patients and asymptomatic family members in these families. (See "Genetics of Alzheimer disease", section on 'Early-onset Alzheimer Disease'.)


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Oct 2015. | This topic last updated: Sep 14, 2015.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2015 UpToDate, Inc.
  1. Ballard C, Gauthier S, Corbett A, et al. Alzheimer's disease. Lancet 2011; 377:1019.
  2. Braak H, Braak E. Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging 1997; 18:351.
  3. Ryman DC, Acosta-Baena N, Aisen PS, et al. Symptom onset in autosomal dominant Alzheimer disease: a systematic review and meta-analysis. Neurology 2014; 83:253.
  4. Schupf N, Kapell D, Nightingale B, et al. Earlier onset of Alzheimer's disease in men with Down syndrome. Neurology 1998; 50:991.
  5. McKhann GM, Knopman DS, Chertkow H, 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. Alzheimers Dement 2011; 7:263.
  6. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), American Psychiatric Association, Arlington, VA 2013.
  7. Markowitsch HJ, Staniloiu A. Amnesic disorders. Lancet 2012; 380:1429.
  8. SCOVILLE WB, MILNER B. Loss of recent memory after bilateral hippocampal lesions. J Neurol Neurosurg Psychiatry 1957; 20:11.
  9. Zola-Morgan S, Squire LR, Amaral DG. Human amnesia and the medial temporal region: enduring memory impairment following a bilateral lesion limited to field CA1 of the hippocampus. J Neurosci 1986; 6:2950.
  10. Peters F, Collette F, Degueldre C, et al. The neural correlates of verbal short-term memory in Alzheimer's disease: an fMRI study. Brain 2009; 132:1833.
  11. Wagner M, Wolf S, Reischies FM, et al. Biomarker validation of a cued recall memory deficit in prodromal Alzheimer disease. Neurology 2012; 78:379.
  12. Ahmed S, Mitchell J, Arnold R, et al. Memory complaints in mild cognitive impairment, worried well, and semantic dementia patients. Alzheimer Dis Assoc Disord 2008; 22:227.
  13. Stokholm J, Vogel A, Gade A, Waldemar G. Heterogeneity in executive impairment in patients with very mild Alzheimer's disease. Dement Geriatr Cogn Disord 2006; 22:54.
  14. Harwood DG, Sultzer DL, Feil D, et al. Frontal lobe hypometabolism and impaired insight in Alzheimer disease. Am J Geriatr Psychiatry 2005; 13:934.
  15. Barrett AM, Eslinger PJ, Ballentine NH, Heilman KM. Unawareness of cognitive deficit (cognitive anosognosia) in probable AD and control subjects. Neurology 2005; 64:693.
  16. McDaniel KD, Edland SD, Heyman A. Relationship between level of insight and severity of dementia in Alzheimer disease. CERAD Clinical Investigators. Consortium to Establish a Registry for Alzheimer's Disease. Alzheimer Dis Assoc Disord 1995; 9:101.
  17. Harwood DG, Sultzer DL, Wheatley MV. Impaired insight in Alzheimer disease: association with cognitive deficits, psychiatric symptoms, and behavioral disturbances. Neuropsychiatry Neuropsychol Behav Neurol 2000; 13:83.
  18. Mizrahi R, Starkstein SE, Jorge R, Robinson RG. Phenomenology and clinical correlates of delusions in Alzheimer disease. Am J Geriatr Psychiatry 2006; 14:573.
  19. Parakh R, Roy E, Koo E, Black S. Pantomime and imitation of limb gestures in relation to the severity of Alzheimer's disease. Brain Cogn 2004; 55:272.
  20. Kato M, Meguro K, Sato M, et al. Ideomotor apraxia in patients with Alzheimer disease: why do they use their body parts as objects? Neuropsychiatry Neuropsychol Behav Neurol 2001; 14:45.
  21. Giannakopoulos P, Duc M, Gold G, et al. Pathologic correlates of apraxia in Alzheimer disease. Arch Neurol 1998; 55:689.
  22. Sarazin M, Stern Y, Berr C, et al. Neuropsychological predictors of dependency in patients with Alzheimer disease. Neurology 2005; 64:1027.
  23. Rahayel S, Frasnelli J, Joubert S. The effect of Alzheimer's disease and Parkinson's disease on olfaction: a meta-analysis. Behav Brain Res 2012; 231:60.
  24. Sun GH, Raji CA, Maceachern MP, Burke JF. Olfactory identification testing as a predictor of the development of Alzheimer's dementia: a systematic review. Laryngoscope 2012; 122:1455.
  25. Bahar-Fuchs A, Moss S, Rowe C, Savage G. Olfactory performance in AD, aMCI, and healthy ageing: a unirhinal approach. Chem Senses 2010; 35:855.
  26. Stamps JJ, Bartoshuk LM, Heilman KM. A brief olfactory test for Alzheimer's disease. J Neurol Sci 2013; 333:19.
  27. Ju YE, Lucey BP, Holtzman DM. Sleep and Alzheimer disease pathology--a bidirectional relationship. Nat Rev Neurol 2014; 10:115.
  28. Ju YE, McLeland JS, Toedebusch CD, et al. Sleep quality and preclinical Alzheimer disease. JAMA Neurol 2013; 70:587.
  29. Spira AP, Gamaldo AA, An Y, et al. Self-reported sleep and β-amyloid deposition in community-dwelling older adults. JAMA Neurol 2013; 70:1537.
  30. Hauser WA, Morris ML, Heston LL, Anderson VE. Seizures and myoclonus in patients with Alzheimer's disease. Neurology 1986; 36:1226.
  31. McAreavey MJ, Ballinger BR, Fenton GW. Epileptic seizures in elderly patients with dementia. Epilepsia 1992; 33:657.
  32. Romanelli MF, Morris JC, Ashkin K, Coben LA. Advanced Alzheimer's disease is a risk factor for late-onset seizures. Arch Neurol 1990; 47:847.
  33. Scarmeas N, Honig LS, Choi H, et al. Seizures in Alzheimer disease: who, when, and how common? Arch Neurol 2009; 66:992.
  34. Irizarry MC, Jin S, He F, et al. Incidence of new-onset seizures in mild to moderate Alzheimer disease. Arch Neurol 2012; 69:368.
  35. Portet F, Scarmeas N, Cosentino S, et al. Extrapyramidal signs before and after diagnosis of incident Alzheimer disease in a prospective population study. Arch Neurol 2009; 66:1120.
  36. McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 1984; 34:939.
  37. Galton CJ, Patterson K, Xuereb JH, Hodges JR. Atypical and typical presentations of Alzheimer's disease: a clinical, neuropsychological, neuroimaging and pathological study of 13 cases. Brain 2000; 123 Pt 3:484.
  38. Alladi S, Xuereb J, Bak T, et al. Focal cortical presentations of Alzheimer's disease. Brain 2007; 130:2636.
  39. Harasty JA, Halliday GM, Xuereb J, et al. Cortical degeneration associated with phonologic and semantic language impairments in AD. Neurology 2001; 56:944.
  40. Ng SY, Villemagne VL, Masters CL, Rowe CC. Evaluating atypical dementia syndromes using positron emission tomography with carbon 11 labeled Pittsburgh Compound B. Arch Neurol 2007; 64:1140.
  41. Bokde AL, Pietrini P, Ibáñez V, et al. The effect of brain atrophy on cerebral hypometabolism in the visual variant of Alzheimer disease. Arch Neurol 2001; 58:480.
  42. Whitwell JL, Dickson DW, Murray ME, et al. Neuroimaging correlates of pathologically defined subtypes of Alzheimer's disease: a case-control study. Lancet Neurol 2012; 11:868.
  43. Ridgway GR, Lehmann M, Barnes J, et al. Early-onset Alzheimer disease clinical variants: multivariate analyses of cortical thickness. Neurology 2012; 79:80.
  44. Balasa M, Gelpi E, Antonell A, et al. Clinical features and APOE genotype of pathologically proven early-onset Alzheimer disease. Neurology 2011; 76:1720.
  45. van der Flier WM, Pijnenburg YA, Fox NC, Scheltens P. Early-onset versus late-onset Alzheimer's disease: the case of the missing APOE ɛ4 allele. Lancet Neurol 2011; 10:280.
  46. Mendez MF, Mendez MA, Martin R, et al. Complex visual disturbances in Alzheimer's disease. Neurology 1990; 40:439.
  47. Cogan DG. Visual disturbances with focal progressive dementing disease. Am J Ophthalmol 1985; 100:68.
  48. Hof PR, Bouras C, Constantinidis J, Morrison JH. Selective disconnection of specific visual association pathways in cases of Alzheimer's disease presenting with Balint's syndrome. J Neuropathol Exp Neurol 1990; 49:168.
  49. Levine DN, Lee JM, Fisher CM. The visual variant of Alzheimer's disease: a clinicopathologic case study. Neurology 1993; 43:305.
  50. Renner JA, Burns JM, Hou CE, et al. Progressive posterior cortical dysfunction: a clinicopathologic series. Neurology 2004; 63:1175.
  51. Andrade K, Kas A, Valabrègue R, et al. Visuospatial deficits in posterior cortical atrophy: structural and functional correlates. J Neurol Neurosurg Psychiatry 2012; 83:860.
  52. Pelak VS, Smyth SF, Boyer PJ, Filley CM. Computerized visual field defects in posterior cortical atrophy. Neurology 2011; 77:2119.
  53. Migliaccio R, Agosta F, Rascovsky K, et al. Clinical syndromes associated with posterior atrophy: early age at onset AD spectrum. Neurology 2009; 73:1571.
  54. Tang-Wai DF, Graff-Radford NR, Boeve BF, et al. Clinical, genetic, and neuropathologic characteristics of posterior cortical atrophy. Neurology 2004; 63:1168.
  55. Crutch SJ, Lehmann M, Schott JM, et al. Posterior cortical atrophy. Lancet Neurol 2012; 11:170.
  56. Whitwell JL, Jack CR Jr, Kantarci K, et al. Imaging correlates of posterior cortical atrophy. Neurobiol Aging 2007; 28:1051.
  57. Rosenbloom MH, Alkalay A, Agarwal N, et al. Distinct clinical and metabolic deficits in PCA and AD are not related to amyloid distribution. Neurology 2011; 76:1789.
  58. Caroppo P, Belin C, Grabli D, et al. Posterior cortical atrophy as an extreme phenotype of GRN mutations. JAMA Neurol 2015; 72:224.
  59. Josephs KA, Whitwell JL, Duffy JR, et al. Progressive aphasia secondary to Alzheimer disease vs FTLD pathology. Neurology 2008; 70:25.
  60. Knibb JA, Xuereb JH, Patterson K, Hodges JR. Clinical and pathological characterization of progressive aphasia. Ann Neurol 2006; 59:156.
  61. Mesulam M, Wicklund A, Johnson N, et al. Alzheimer and frontotemporal pathology in subsets of primary progressive aphasia. Ann Neurol 2008; 63:709.
  62. Gorno-Tempini ML, Dronkers NF, Rankin KP, et al. Cognition and anatomy in three variants of primary progressive aphasia. Ann Neurol 2004; 55:335.
  63. Rabinovici GD, Jagust WJ, Furst AJ, et al. Abeta amyloid and glucose metabolism in three variants of primary progressive aphasia. Ann Neurol 2008; 64:388.
  64. Deramecourt V, Lebert F, Debachy B, et al. Prediction of pathology in primary progressive language and speech disorders. Neurology 2010; 74:42.
  65. Hu WT, McMillan C, Libon D, et al. Multimodal predictors for Alzheimer disease in nonfluent primary progressive aphasia. Neurology 2010; 75:595.
  66. Gorno-Tempini ML, Hillis AE, Weintraub S, et al. Classification of primary progressive aphasia and its variants. Neurology 2011; 76:1006.
  67. Dickerson BC, Wolk DA, Alzheimer's Disease Neuroimaging Initiative. Dysexecutive versus amnesic phenotypes of very mild Alzheimer's disease are associated with distinct clinical, genetic and cortical thinning characteristics. J Neurol Neurosurg Psychiatry 2011; 82:45.
  68. Blennerhassett R, Lillo P, Halliday GM, et al. Distribution of pathology in frontal variant Alzheimer's disease. J Alzheimers Dis 2014; 39:63.
  69. Ross SJ, Graham N, Stuart-Green L, et al. Progressive biparietal atrophy: an atypical presentation of Alzheimer's disease. J Neurol Neurosurg Psychiatry 1996; 61:388.
  70. Galasko D, Hansen LA, Katzman R, et al. Clinical-neuropathological correlations in Alzheimer's disease and related dementias. Arch Neurol 1994; 51:888.
  71. Connor DJ, Salmon DP, Sandy TJ, et al. Cognitive profiles of autopsy-confirmed Lewy body variant vs pure Alzheimer disease. Arch Neurol 1998; 55:994.
  72. Weiner MF, Hynan LS, Parikh B, et al. Can alzheimer's disease and dementias with Lewy bodies be distinguished clinically? J Geriatr Psychiatry Neurol 2003; 16:245.
  73. Merdes AR, Hansen LA, Jeste DV, et al. Influence of Alzheimer pathology on clinical diagnostic accuracy in dementia with Lewy bodies. Neurology 2003; 60:1586.
  74. Clark CM, Sheppard L, Fillenbaum GG, et al. Variability in annual Mini-Mental State Examination score in patients with probable Alzheimer disease: a clinical perspective of data from the Consortium to Establish a Registry for Alzheimer's Disease. Arch Neurol 1999; 56:857.
  75. Adak S, Illouz K, Gorman W, et al. Predicting the rate of cognitive decline in aging and early Alzheimer disease. Neurology 2004; 63:108.
  76. Nourhashémi F, Ousset PJ, Gillette-Guyonnet S, et al. A 2-year follow-up of 233 very mild (CDR 0.5) Alzheimer's disease patients (REAL.FR cohort). Int J Geriatr Psychiatry 2008; 23:460.
  77. Han L, Cole M, Bellavance F, et al. Tracking cognitive decline in Alzheimer's disease using the mini-mental state examination: a meta-analysis. Int Psychogeriatr 2000; 12:231.
  78. Schmidt C, Wolff M, Weitz M, et al. Rapidly progressive Alzheimer disease. Arch Neurol 2011; 68:1124.
  79. Bernick C, Cummings J, Raman R, et al. Age and rate of cognitive decline in Alzheimer disease: implications for clinical trials. Arch Neurol 2012; 69:901.
  80. Peters ME, Schwartz S, Han D, et al. Neuropsychiatric symptoms as predictors of progression to severe Alzheimer's dementia and death: the Cache County Dementia Progression Study. Am J Psychiatry 2015; 172:460.
  81. Helzner EP, Scarmeas N, Cosentino S, et al. Survival in Alzheimer disease: a multiethnic, population-based study of incident cases. Neurology 2008; 71:1489.
  82. Larson EB, Shadlen MF, Wang L, et al. Survival after initial diagnosis of Alzheimer disease. Ann Intern Med 2004; 140:501.
  83. Wolfson C, Wolfson DB, Asgharian M, et al. A reevaluation of the duration of survival after the onset of dementia. N Engl J Med 2001; 344:1111.
  84. Nasreddine ZS, Phillips NA, Bédirian V, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 2005; 53:695.
  85. Rossetti HC, Lacritz LH, Cullum CM, Weiner MF. Normative data for the Montreal Cognitive Assessment (MoCA) in a population-based sample. Neurology 2011; 77:1272.
  86. Knopman DS, DeKosky ST, Cummings JL, et al. Practice parameter: diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001; 56:1143.
  87. van de Pol LA, Hensel A, Barkhof F, et al. Hippocampal atrophy in Alzheimer disease: age matters. Neurology 2006; 66:236.
  88. Barkhof F, Polvikoski TM, van Straaten EC, et al. The significance of medial temporal lobe atrophy: a postmortem MRI study in the very old. Neurology 2007; 69:1521.
  89. Whitwell JL, Josephs KA, Murray ME, et al. MRI correlates of neurofibrillary tangle pathology at autopsy: a voxel-based morphometry study. Neurology 2008; 71:743.
  90. Kantarci K, Avula R, Senjem ML, et al. Dementia with Lewy bodies and Alzheimer disease: neurodegenerative patterns characterized by DTI. Neurology 2010; 74:1814.
  91. Raji CA, Lopez OL, Kuller LH, et al. Age, Alzheimer disease, and brain structure. Neurology 2009; 73:1899.
  92. Wahlund LO, Almkvist O, Blennow K, et al. Evidence-based evaluation of magnetic resonance imaging as a diagnostic tool in dementia workup. Top Magn Reson Imaging 2005; 16:427.
  93. Dickerson BC, Wolk DA, Alzheimer's Disease Neuroimaging Initiative. MRI cortical thickness biomarker predicts AD-like CSF and cognitive decline in normal adults. Neurology 2012; 78:84.
  94. McEvoy LK, Holland D, Hagler DJ Jr, et al. Mild cognitive impairment: baseline and longitudinal structural MR imaging measures improve predictive prognosis. Radiology 2011; 259:834.
  95. Minoshima S, Giordani B, Berent S, et al. Metabolic reduction in the posterior cingulate cortex in very early Alzheimer's disease. Ann Neurol 1997; 42:85.
  96. Silverman DH, Small GW, Chang CY, et al. Positron emission tomography in evaluation of dementia: Regional brain metabolism and long-term outcome. JAMA 2001; 286:2120.
  97. Powers WJ, Perlmutter JS, Videen TO, et al. Blinded clinical evaluation of positron emission tomography for diagnosis of probable Alzheimer's disease. Neurology 1992; 42:765.
  98. Duara R, Grady C, Haxby J, et al. Positron emission tomography in Alzheimer's disease. Neurology 1986; 36:879.
  99. O'Brien JL, O'Keefe KM, LaViolette PS, et al. Longitudinal fMRI in elderly reveals loss of hippocampal activation with clinical decline. Neurology 2010; 74:1969.
  100. Hu WT, Wang Z, Lee VM, et al. Distinct cerebral perfusion patterns in FTLD and AD. Neurology 2010; 75:881.
  101. Pickut BA, Saerens J, Mariën P, et al. Discriminative use of SPECT in frontal lobe-type dementia versus (senile) dementia of the Alzheimer's type. J Nucl Med 1997; 38:929.
  102. Ishii K, Sakamoto S, Sasaki M, et al. Cerebral glucose metabolism in patients with frontotemporal dementia. J Nucl Med 1998; 39:1875.
  103. Foster NL, Heidebrink JL, Clark CM, et al. FDG-PET improves accuracy in distinguishing frontotemporal dementia and Alzheimer's disease. Brain 2007; 130:2616.
  104. Rabinovici GD, Rosen HJ, Alkalay A, et al. Amyloid vs FDG-PET in the differential diagnosis of AD and FTLD. Neurology 2011; 77:2034.
  105. Nordberg A. PET imaging of amyloid in Alzheimer's disease. Lancet Neurol 2004; 3:519.
  106. Rabinovici GD, Furst AJ, O'Neil JP, et al. 11C-PIB PET imaging in Alzheimer disease and frontotemporal lobar degeneration. Neurology 2007; 68:1205.
  107. Edison P, Archer HA, Hinz R, et al. Amyloid, hypometabolism, and cognition in Alzheimer disease: an [11C]PIB and [18F]FDG PET study. Neurology 2007; 68:501.
  108. Jack CR Jr, Lowe VJ, Senjem ML, et al. 11C PiB and structural MRI provide complementary information in imaging of Alzheimer's disease and amnestic mild cognitive impairment. Brain 2008; 131:665.
  109. Rowe CC, Ackerman U, Browne W, et al. Imaging of amyloid beta in Alzheimer's disease with 18F-BAY94-9172, a novel PET tracer: proof of mechanism. Lancet Neurol 2008; 7:129.
  110. Small GW, Bookheimer SY, Thompson PM, et al. Current and future uses of neuroimaging for cognitively impaired patients. Lancet Neurol 2008; 7:161.
  111. Ances BM, Christensen JJ, Teshome M, et al. Cognitively unimpaired HIV-positive subjects do not have increased 11C-PiB: a case-control study. Neurology 2010; 75:111.
  112. Roe CM, Mintun MA, Ghoshal N, et al. Alzheimer disease identification using amyloid imaging and reserve variables: proof of concept. Neurology 2010; 75:42.
  113. Vandenberghe R, Van Laere K, Ivanoiu A, et al. 18F-flutemetamol amyloid imaging in Alzheimer disease and mild cognitive impairment: a phase 2 trial. Ann Neurol 2010; 68:319.
  114. Tolboom N, van der Flier WM, Boverhoff J, et al. Molecular imaging in the diagnosis of Alzheimer's disease: visual assessment of [11C]PIB and [18F]FDDNP PET images. J Neurol Neurosurg Psychiatry 2010; 81:882.
  115. Clark CM, Schneider JA, Bedell BJ, et al. Use of florbetapir-PET for imaging beta-amyloid pathology. JAMA 2011; 305:275.
  116. Barthel H, Gertz HJ, Dresel S, et al. Cerebral amyloid-β PET with florbetaben (18F) in patients with Alzheimer's disease and healthy controls: a multicentre phase 2 diagnostic study. Lancet Neurol 2011; 10:424.
  117. Wolk DA, Grachev ID, Buckley C, et al. Association between in vivo fluorine 18-labeled flutemetamol amyloid positron emission tomography imaging and in vivo cerebral cortical histopathology. Arch Neurol 2011; 68:1398.
  118. Fleisher AS, Chen K, Liu X, et al. Using positron emission tomography and florbetapir F18 to image cortical amyloid in patients with mild cognitive impairment or dementia due to Alzheimer disease. Arch Neurol 2011; 68:1404.
  119. Wolk DA, Zhang Z, Boudhar S, et al. Amyloid imaging in Alzheimer's disease: comparison of florbetapir and Pittsburgh compound-B positron emission tomography. J Neurol Neurosurg Psychiatry 2012; 83:923.
  120. Clark CM, Pontecorvo MJ, Beach TG, et al. Cerebral PET with florbetapir compared with neuropathology at autopsy for detection of neuritic amyloid-β plaques: a prospective cohort study. Lancet Neurol 2012; 11:669.
  121. Doraiswamy PM, Sperling RA, Coleman RE, et al. Amyloid-β assessed by florbetapir F 18 PET and 18-month cognitive decline: a multicenter study. Neurology 2012; 79:1636.
  122. Lim YY, Ellis KA, Pietrzak RH, et al. Stronger effect of amyloid load than APOE genotype on cognitive decline in healthy older adults. Neurology 2012; 79:1645.
  123. Niedowicz DM, Beckett TL, Matveev S, et al. Pittsburgh compound B and the postmortem diagnosis of Alzheimer disease. Ann Neurol 2012; 72:564.
  124. Ikonomovic MD, Klunk WE, Abrahamson EE, et al. Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer's disease. Brain 2008; 131:1630.
  125. Ossenkoppele R, Jansen WJ, Rabinovici GD, et al. Prevalence of amyloid PET positivity in dementia syndromes: a meta-analysis. JAMA 2015; 313:1939.
  126. Jansen WJ, Ossenkoppele R, Knol DL, et al. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA 2015; 313:1924.
  127. Yang L, Rieves D, Ganley C. Brain amyloid imaging--FDA approval of florbetapir F18 injection. N Engl J Med 2012; 367:885.
  128. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.
  129. Johnson KA, Minoshima S, Bohnen NI, et al. Appropriate use criteria for amyloid PET: a report of the Amyloid Imaging Task Force, the Society of Nuclear Medicine and Molecular Imaging, and the Alzheimer's Association. J Nucl Med 2013; 54:476.
  130. Dubois B, Feldman HH, Jacova C, et al. Revising the definition of Alzheimer's disease: a new lexicon. Lancet Neurol 2010; 9:1118.
  131. Morris JC, Blennow K, Froelich L, et al. Harmonized diagnostic criteria for Alzheimer's disease: recommendations. J Intern Med 2014; 275:204.
  132. Galasko D, Clark C, Chang L, et al. Assessment of CSF levels of tau protein in mildly demented patients with Alzheimer's disease. Neurology 1997; 48:632.
  133. Kahle PJ, Jakowec M, Teipel SJ, et al. Combined assessment of tau and neuronal thread protein in Alzheimer's disease CSF. Neurology 2000; 54:1498.
  134. Sunderland T, Linker G, Mirza N, et al. Decreased beta-amyloid1-42 and increased tau levels in cerebrospinal fluid of patients with Alzheimer disease. JAMA 2003; 289:2094.
  135. Clark CM, Xie S, Chittams J, et al. Cerebrospinal fluid tau and beta-amyloid: how well do these biomarkers reflect autopsy-confirmed dementia diagnoses? Arch Neurol 2003; 60:1696.
  136. Andreasen N, Minthon L, Davidsson P, et al. Evaluation of CSF-tau and CSF-Abeta42 as diagnostic markers for Alzheimer disease in clinical practice. Arch Neurol 2001; 58:373.
  137. Maddalena A, Papassotiropoulos A, Müller-Tillmanns B, et al. Biochemical diagnosis of Alzheimer disease by measuring the cerebrospinal fluid ratio of phosphorylated tau protein to beta-amyloid peptide42. Arch Neurol 2003; 60:1202.
  138. Gómez-Tortosa E, Gonzalo I, Fanjul S, et al. Cerebrospinal fluid markers in dementia with lewy bodies compared with Alzheimer disease. Arch Neurol 2003; 60:1218.
  139. Fagan AM, Roe CM, Xiong C, et al. Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults. Arch Neurol 2007; 64:343.
  140. Graff-Radford NR, Crook JE, Lucas J, et al. Association of low plasma Abeta42/Abeta40 ratios with increased imminent risk for mild cognitive impairment and Alzheimer disease. Arch Neurol 2007; 64:354.
  141. Gustafson DR, Skoog I, Rosengren L, et al. Cerebrospinal fluid beta-amyloid 1-42 concentration may predict cognitive decline in older women. J Neurol Neurosurg Psychiatry 2007; 78:461.
  142. Bian H, Van Swieten JC, Leight S, et al. CSF biomarkers in frontotemporal lobar degeneration with known pathology. Neurology 2008; 70:1827.
  143. Ringman JM, Younkin SG, Pratico D, et al. Biochemical markers in persons with preclinical familial Alzheimer disease. Neurology 2008; 71:85.
  144. Kester MI, van der Vlies AE, Blankenstein MA, et al. CSF biomarkers predict rate of cognitive decline in Alzheimer disease. Neurology 2009; 73:1353.
  145. Wallin AK, Blennow K, Zetterberg H, et al. CSF biomarkers predict a more malignant outcome in Alzheimer disease. Neurology 2010; 74:1531.
  146. De Meyer G, Shapiro F, Vanderstichele H, et al. Diagnosis-independent Alzheimer disease biomarker signature in cognitively normal elderly people. Arch Neurol 2010; 67:949.
  147. Yaffe K, Weston A, Graff-Radford NR, et al. Association of plasma beta-amyloid level and cognitive reserve with subsequent cognitive decline. JAMA 2011; 305:261.
  148. Gupta VB, Laws SM, Villemagne VL, et al. Plasma apolipoprotein E and Alzheimer disease risk: the AIBL study of aging. Neurology 2011; 76:1091.
  149. de Souza LC, Lamari F, Belliard S, et al. Cerebrospinal fluid biomarkers in the differential diagnosis of Alzheimer's disease from other cortical dementias. J Neurol Neurosurg Psychiatry 2011; 82:240.
  150. Tarawneh R, D'Angelo G, Macy E, et al. Visinin-like protein-1: diagnostic and prognostic biomarker in Alzheimer disease. Ann Neurol 2011; 70:274.
  151. Schoonenboom NS, Reesink FE, Verwey NA, et al. Cerebrospinal fluid markers for differential dementia diagnosis in a large memory clinic cohort. Neurology 2012; 78:47.
  152. Mattsson N, Rosén E, Hansson O, et al. Age and diagnostic performance of Alzheimer disease CSF biomarkers. Neurology 2012; 78:468.
  153. Watabe-Rudolph M, Song Z, Lausser L, et al. Chitinase enzyme activity in CSF is a powerful biomarker of Alzheimer disease. Neurology 2012; 78:569.
  154. Tarawneh R, Lee JM, Ladenson JH, et al. CSF VILIP-1 predicts rates of cognitive decline in early Alzheimer disease. Neurology 2012; 78:709.
  155. Kas A, Uspenskaya O, Lamari F, et al. Distinct brain perfusion pattern associated with CSF biomarkers profile in primary progressive aphasia. J Neurol Neurosurg Psychiatry 2012; 83:695.
  156. Hu WT, Holtzman DM, Fagan AM, et al. Plasma multianalyte profiling in mild cognitive impairment and Alzheimer disease. Neurology 2012; 79:897.
  157. Irwin DJ, McMillan CT, Toledo JB, et al. Comparison of cerebrospinal fluid levels of tau and Aβ 1-42 in Alzheimer disease and frontotemporal degeneration using 2 analytical platforms. Arch Neurol 2012; 69:1018.
  158. Bateman RJ, Xiong C, Benzinger TL, et al. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N Engl J Med 2012; 367:795.
  159. Soares HD, Potter WZ, Pickering E, et al. Plasma biomarkers associated with the apolipoprotein E genotype and Alzheimer disease. Arch Neurol 2012; 69:1310.
  160. Doecke JD, Laws SM, Faux NG, et al. Blood-based protein biomarkers for diagnosis of Alzheimer disease. Arch Neurol 2012; 69:1318.
  161. Hall S, Öhrfelt A, Constantinescu R, et al. Accuracy of a panel of 5 cerebrospinal fluid biomarkers in the differential diagnosis of patients with dementia and/or parkinsonian disorders. Arch Neurol 2012; 69:1445.
  162. Rasmussen KL, Tybjaerg-Hansen A, Nordestgaard BG, Frikke-Schmidt R. Plasma levels of apolipoprotein E and risk of dementia in the general population. Ann Neurol 2015; 77:301.
  163. Galasko D. Cerebrospinal fluid biomarkers in Alzheimer disease: a fractional improvement? Arch Neurol 2003; 60:1195.
  164. Bateman RJ, Wen G, Morris JC, Holtzman DM. Fluctuations of CSF amyloid-beta levels: implications for a diagnostic and therapeutic biomarker. Neurology 2007; 68:666.
  165. Bouwman FH, van der Flier WM, Schoonenboom NS, et al. Longitudinal changes of CSF biomarkers in memory clinic patients. Neurology 2007; 69:1006.
  166. Sonnen JA, Montine KS, Quinn JF, et al. Biomarkers for cognitive impairment and dementia in elderly people. Lancet Neurol 2008; 7:704.
  167. Mayeux R, Saunders AM, Shea S, et al. Utility of the apolipoprotein E genotype in the diagnosis of Alzheimer's disease. Alzheimer's Disease Centers Consortium on Apolipoprotein E and Alzheimer's Disease. N Engl J Med 1998; 338:506.
  168. Petersen RC, Smith GE, Ivnik RJ, et al. Apolipoprotein E status as a predictor of the development of Alzheimer's disease in memory-impaired individuals. JAMA 1995; 273:1274.
  169. Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 1991; 82:239.
  170. 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 1997; 18:S1.
  171. Khachaturian ZS. Diagnosis of Alzheimer's disease. Arch Neurol 1985; 42:1097.
  172. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), American Psychiatric Association, Arlington, VA 2013.
  173. Phung TK, Andersen BB, Høgh P, et al. Validity of dementia diagnoses in the Danish hospital registers. Dement Geriatr Cogn Disord 2007; 24:220.
  174. Petersen RC, Smith GE, Waring SC, et al. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 1999; 56:303.
  175. Tierney MC, Szalai JP, Snow WG, et al. Prediction of probable Alzheimer's disease in memory-impaired patients: A prospective longitudinal study. Neurology 1996; 46:661.
  176. Albert MS, DeKosky ST, Dickson D, 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. Alzheimers Dement 2011; 7:270.
  177. Vos SJ, Verhey F, Frölich L, et al. Prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage. Brain 2015; 138:1327.
  178. Dubois B, Feldman HH, Jacova C, et al. Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria. Lancet Neurol 2014; 13:614.
  179. Sperling RA, Aisen PS, Beckett LA, 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. Alzheimers Dement 2011; 7:280.