Biomarkers for preclinical alzheimer's disease

Journal of Alzheimer's Disease

Volumn 42, Issue 4, 2014, Pages 1051-1069

  Tan, Chen Chen ^a   Yu, Jin Tai ^a,b,c   Tan, Lan ^a,b,c  

^a QINGDAO MUNICIPAL HOSPITAL   (China)

^b OCEAN UNIVERSITY OF CHINA   (China)

^c NANJING MEDICAL UNIVERSITY   (China)

Author keywords

Biomarker; blood; cerebrospinal fluid biomarkers; clinical biomarkers; genetic biomarkers; neuroimaging; preclinical Alzheimer's disease

Indexed keywords

BIOLOGICAL MARKER; FLUORODEOXYGLUCOSE; PITTSBURGH COMPOUND B;

ALZHEIMER DISEASE; BLOOD; CEREBROSPINAL FLUID; COGNITIVE DEFECT; DIAGNOSTIC PROCEDURE; DISEASE COURSE; FUNCTIONAL MAGNETIC RESONANCE IMAGING; GENETIC MARKER; HUMAN; NEUROCHEMISTRY; NEUROIMAGING; NUCLEAR MAGNETIC RESONANCE IMAGING; POSITRON EMISSION TOMOGRAPHY; REVIEW; SLEEP DISORDER; ANIMAL; BRAIN; EARLY DIAGNOSIS; GENETICS; METABOLISM; PATHOLOGY; PRODROMAL SYMPTOM;

ALZHEIMER DISEASE; ANIMALS; BIOLOGICAL MARKERS; BRAIN; EARLY DIAGNOSIS; HUMANS; PRODROMAL SYMPTOMS;

EID: 84907962441     PISSN: 13872877     EISSN: 18758908     Source Type: Journal    
DOI: 10.3233/JAD-140843     Document Type: Review

References (167)

1. Wortmann M (2013) Overcoming the stigma of dementia. Alzheimers Dement 9, P547.
2. Tan CC, Yu JT, Wang HF, Tan MS, Meng XF, Wang C, Jiang T, Zhu XC, Tan L (2014) Efficacy and safety of donepezil, galantamine, rivastigmine, and memantine for the treatment of Alzheimer's disease: A systematic review and meta-analysis. J Alzheimers Dis 41, 615-631.
3. Knopman DS, Jack CR Jr, Wiste HJ, Weigand SD, Vemuri P, Lowe V, Kantarci K, Gunter JL, Senjem ML, Ivnik RJ, Roberts RO, Boeve BF, Petersen RC (2012) Short-term clinical outcomes for stages of NIA-AA preclinical Alzheimer disease. Neurology 78, 1576-1582.
4. Price JL, Morris JC (1999) Tangles and plaques in nonde-mented aging and "preclinical" Alzheimer's disease. Ann Neurol 45, 358-368.
5. Hulette CM, Welsh-Bohmer KA, Murray MG, Saunders AM, Mash DC, McIntyre LM (1998) Neuropathological and neuropsychological changes in "normal" aging: Evidence for preclinical Alzheimer diseaseincognitively normal individuals. J Neuropathol Exp Neurol 57, 1168-1174.
6. Jiang T, Yu JT, Tian Y, Tan L (2013) Epidemiology and etiology of Alzheimer's disease: From genetic to non-genetic factors. Curr Alzheimer Res 10, 852-867.
7. Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, Iwatsubo T, Jack CR Jr, Kaye J, Montine TJ, Park DC, Reiman EM, Rowe CC, Siemers E, Stern Y, Yaffe K, Carrillo MC, Thies B, Morrison-Bogorad M, Wagster MV, Phelps CH (2011) 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 7, 280-292.
8. Jack CR Jr, Knopman DS, Weigand SD, Wiste HJ, Vemuri P, Lowe V, Kantarci K, Gunter JL, Senjem ML, Ivnik RJ, Roberts RO, Rocca WA, Boeve BF, Petersen RC (2012) An operational approach to National Institute on Aging-Alzheimer's Association criteria for preclinical Alzheimer disease. Ann Neurol 71, 765-775.
9. Amariglio RE, Becker JA, Carmasin J, Wadsworth LP, Lorius N, Sullivan C, Maye JE, Gidicsin C, Pepin LC, Sperling RA, Johnson KA, Rentz DM (2012) Subjective cognitive complaints and amyloid burdenin cognitively normal older individuals. Neuropsychologia 50, 2880-2886.
10. Salmon DP (2012) Neuropsychological features of mild cognitive impairment and preclinical Alzheimer's disease. Curr Top Behav Neurosci 10, 187-212.
11. Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, Fox NC, Marcus DS, Cairns NJ, Xie X, Blazey TM, Holtzman DM, Santacruz A, Buckles V, Oliver A, Moulder K, Aisen PS, Ghetti B, Klunk WE, McDade E, Martins RN, Masters CL, Mayeux R, Ringman JM, Rossor MN, Schofield PR, Sperling RA, Salloway S, Morris JC, Dominantly Inherited Alzheimer N (2012) Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N Engl J Med 367, 795-804.
12. Lim YY, Pietrzak RH, Ellis KA, Jaeger J, Harrington K, Ashwood T, Szoeke C, Martins RN, Bush AI, Masters CL, Rowe CC, Villemagne VL, Ames D, Darby D, Maruff P (2013) Rapid decline in episodic memory in healthy older adults with high amyloid-beta. J Alzheimers Dis 33, 675-679.
13. Rentz DM, Amariglio RE, Becker JA, Frey M, Olson LE, Frishe K, Carmasin J, Maye JE, Johnson KA, Sperling RA (2011) Face-name associative memory performance is relatedto amyloid burdenin normal elderly. Neuropsycholo-gia 49, 2776-2783.
14. Wolk DA, Mancuso L, Kliot D, Arnold SE, Dickerson BC (2013) Familiarity-based memory as an early cognitive marker of preclinical and prodromal AD. Neuropsychologia 51, 1094-1102.
15. van Harten AC, Smits LL, Teunissen CE, Visser PJ, Koene T, Blankenstein MA, Scheltens P, van der Flier WM (2013) Preclinical AD predicts decline in memory and executive functions in subjective complaints. Neurology 81, 1409-1416.
16. Stonnington CM, Chen K, Lee W, Locke DE, Dueck AC, Liu X, Roontiva A, Fleisher AS, Caselli RJ, Reiman EM (2014) Fibrillar amyloid correlates of preclinical cognitive decline. Alzheimers Dement 10, e1-e8.
17. Clark LR, Schiehser DM, Weissberger GH, Salmon DP, Delis DC, Bondi MW (2012) Specific measures of executive function predict cognitive decline in older adults. J Int Neuropsychol Soc 18, 118-127.
18. Harrington MG, Chiang J, Pogoda JM, Gomez M, Thomas K, Marion SD, Miller KJ, Siddarth P, Yi X, Zhou F, Lee S, Arakaki X, Cowan RP, Tran T, Charleswell C, Ross BD, Fonteh AN (2013) Executive function changes before memory in preclinical Alzheimer's pathology: A prospective, cross-sectional, case control study. PLoS One 8, e79378.
19. Hayden KM, Kuchibhatla M, Romero HR, Plassman BL, Burke JR, Browndyke JN, Welsh-Bohmer KA (2013) Pre-clinical cognitive phenotypes for Alzheimer disease: A latent profile approach. Am J Geriatr Psychiatry, doi:10.1016/j.jagp.2013.07.008.
20. Roh JH, Huang Y, Bero AW, Kasten T, Stewart FR, Bate-man RJ, Holtzman DM (2012) Disruption of the sleep-wake cycle and diurnal fluctuation of beta-amyloid in mice with Alzheimer's disease pathology. Sci Transl Med 4, 150ra122.
21. Potvin O, Lorrain D, Forget H, Dube M, Grenier S, Preville M, Hudon C (2012) Sleep quality and 1-year incident cognitive impairment in community-dwelling older adults. Sleep 35, 491-499.
22. Ju YE, McLeland JS, Toedebusch CD, Xiong C, Fagan AM, Duntley SP, Morris JC, Holtzman DM (2013) Sleep quality and preclinical Alzheimer disease. JAMA Neurol 70, 587-593.
23. Sterniczuk R, Theou O, Rusak B, Rockwood K (2013) Sleep disturbance is associated with incident dementia and mortality. Curr Alzheimer Res 10, 767-775.
24. Moghekar A, Li S, Lu Y, Li M, Wang MC, Albert M, O'Brien R, Team BR (2013) CSF biomarker changes precede symptom onset of mild cognitive impairment. Neurology 81, 1753-1758.
25. Sunderland T, Linker G, Mirza N, Putnam KT, Friedman DL, Kimmel LH, Bergeson J, Manetti GJ, Zimmermann M, Tang B, Bartko JJ, Cohen RM (2003) Decreased beta-amyloid1-42 and increased tau levels in cerebrospinal fluid of patients with Alzheimer disease. JAMA 289, 2094-2103.
26. Roe CM, Fagan AM, Grant EA, Hassenstab J, Moulder KL, Maue Dreyfus D, Sutphen CL, Benzinger TL, Mintun MA, Holtzman DM, Morris JC (2013) Amyloid imaging and CSF biomarkers in predicting cognitive impairment up to 7.5 years later. Neurology 80, 1784-1791.
27. Hedden T, Oh H, Younger AP, Patel TA (2013) Meta-analysis of amyloid-cognition relations in cognitively normal older adults. Neurology 80, 1341-1348.
28. Schmand B, Huizenga HM, van Gool WA (2010) Meta-analysis of CSF and MRI biomarkers for detecting preclinical Alzheimer's disease. Psychol Med 40, 135-145.
29. Fagan AM, Head D, Shah AR, Marcus D, Mintun M, Morris JC, Holtzman DM (2009) Decreased cerebrospinal fluid Abeta (42) correlates with brain atrophy in cognitively normal elderly. Ann Neurol 65, 176-183.
30. Stomrud E, Hansson O, Blennow K, Minthon L, Londos E (2007) Cerebrospinal fluid biomarkers predict decline in subjective cognitive function over 3 years in healthy elderly. Dement Geriatr Cogn Disord 24, 118-124.
31. Ringman JM, Coppola G, Elashoff D, Rodriguez-Agudelo Y, Medina LD, Gylys K, Cummings JL, Cole GM (2012) Cerebrospinal fluid biomarkers and proximity to diagnosis in preclinical familial Alzheimer's disease. Dement Geriatr Cogn Disord 33, 1-5.
32. de Souza LC, Chupin M, Lamari F, Jardel C, Leclercq D, Colliot O, Lehericy S, Dubois B, Sarazin M (2012) CSF tau markers are correlated with hippocampal volume in Alzheimer's disease. Neurobiol Aging 33, 1253-1257.
33. Fagan AM, Mintun MA, Shah AR, Aldea P, Roe CM, Mach RH, Marcus D, Morris JC, Holtzman DM (2009) Cerebrospinal fluid tau and ptau (181) increase with cortical amyloid deposition in cognitively normal individuals: Implications for future clinical trials of Alzheimer's disease. EMBO Mol Med 1, 371-380.
34. Buerger K, Zinkowski R, Teipel SJ, Tapiola T, Arai H, Blennow K, Andreasen N, Hofmann-Kiefer K, DeBernardis J, Kerkman D, McCulloch C, Kohnken R, Padberg F, Pirttila T, Schapiro MB, Rapoport SI, Moller HJ, Davies P, Hampel H (2002) Differential diagnosis of Alzheimer disease with cerebrospinal fluid levels of tau protein phosphorylated at threonine 231. Arch Neurol 59, 1267-1272.
35. Hampel H, Buerger K, Zinkowski R, Teipel SJ, Goernitz A, Andreasen N, Sjoegren M, DeBernardis J, Kerkman D, Ishiguro K, Ohno H, Vanmechelen E, Vanderstichele H, McCulloch C, Moller HJ, Davies P, Blennow K (2004) Measurement of phosphorylated tau epitopes in the differential diagnosis of Alzheimer disease: A comparative cerebrospinal fluid study. Arch Gen Psychiatry 61, 95-102.
36. Hu YY, He SS, Wang X, Duan QH, Grundke-Iqbal I, Iqbal K, Wang J (2002) Levels of nonphosphorylated and phosphorylated tauincerebrospinalfluidofAlzheimer's disease patients: An ultrasensitive bienzyme-substrate-recycle enzyme-linked immunosorbent assay. Am J Pathol 160, 1269-1278.
37. Seppala TT, Koivisto AM, Hartikainen P, Helisalmi S, Soininen H, Herukka SK (2011) Longitudinal changes of CSF biomarkers in Alzheimer's disease. J Alzheimers Dis 25, 583-594.
38. Buchhave P, Minthon L, Zetterberg H, Wallin AK, Blennow K, Hansson O (2012) Cerebrospinal fluid levels of beta-amyloid 1-42, but not of tau, are fully changed already 5 to 10 years before the onset of Alzheimer dementia. Arch Gen Psychiatry 69, 98-106.
39. Jones DT, Machulda MM, Vemuri P, McDade EM, Zeng G, Senjem ML, Gunter JL, Przybelski SA, Avula RT, Knopman DS, Boeve BF, Petersen RC, Jack CR Jr (2011) Age-related changes in the default mode network are more advanced in Alzheimer disease. Neurology 77, 1524-1531.
40. Wang L, Brier MR, Snyder AZ, Thomas JB, Fagan AM, Xiong C, Benzinger TL, Holtzman DM, Morris JC, Ances BM (2013) Cerebrospinal fluid Abeta42, phosphorylated Tau181, and resting-state functional connectivity. JAMA Neurol 70, 1242-1248.
41. Paternico D, Galluzzi S, Drago V, Bocchio-Chiavetto L, Zanardini R, Pedrini L, Baronio M, Amicucci G, Frisoni GB (2012) Cerebrospinal fluid markers for Alzheimer's disease in a cognitively healthy cohort of young and old adults. Alzheimers Dement 8, 520-527.
42. Irwin DJ, Trojanowski JQ, Grossman M (2013) Cere-brospinal fluid biomarkers for differentiation of frontotem-poral lobar degeneration from Alzheimer's disease. Front Aging Neurosci 5, 6.
43. Fagan AM, Shaw LM, Xiong C, Vanderstichele H, Mintun MA, Trojanowski JQ, Coart E, Morris JC, Holtzman DM (2011) Comparison ofanalytical platforms for cerebrospinal fluid measures of beta-amyloid 1-42, total tau, and p-tau181 for identifying Alzheimer disease amyloid plaque pathology. Arch Neurol 68, 1137-1144.
44. Swerdlow RH, Burns JM, Khan SM (2010) The Alzheimer's disease mitochondrial cascade hypothesis. J Alzheimers Dis 20 (Suppl 2), S265-S279.
45. Coskun P, Wyrembak J, Schriner SE, Chen HW, Marciniack C, Laferla F, Wallace DC (2012) A mitochondrial etiology of Alzheimer and Parkinson disease. Biochim Biophys Acta 1820, 553-564.
46. Podlesniy P, Figueiro-Silva J, Llado A, Antonell A, Sanchez-Valle R, Alcolea D, Lleo A, Molinuevo JL, Serra N, Trullas R (2013) Low cerebrospinal fluid concentration of mitochon-drial DNA in preclinical Alzheimer disease. Ann Neurol 74, 655-668.
47. Mrak RE, Griffin WS (2005) Potential inflammatory biomarkers in Alzheimer's disease. J Alzheimers Dis 8, 369-375.
48. Cuello AC, Ferretti MT, Iulita MF (2012) Preplaque ('pre-clinical') Abeta-induced inflammation and nerve growth factor deregulation in transgenic models of Alzheimer's disease-like amyloid pathology. Neurodegener Dis 10, 104-107.
49. Ferretti MT, Cuello AC (2011) Does a pro-inflammatory process precede Alzheimer's disease and mild cognitive impairment? Curr Alzheimer Res 8, 164-174.
50. Koyama A, Okereke OI, Yang T, Blacker D, Selkoe DJ, Grodstein F (2012) Plasma amyloid-beta as a predictor of dementia and cognitive decline: A systematic review and meta-analysis. Arch Neurol 69, 824-831.
51. Ringman JM, Younkin SG, Pratico D, Seltzer W, Cole GM, Geschwind DH, Rodriguez-Agudelo Y, Schaffer B, Fein J, Sokolow S, Rosario ER, Gylys KH, Varpetian A, Medina LD, Cummings JL (2008) Biochemical markers in persons with preclinical familial Alzheimer disease. Neurology 71, 85-92.
52. Hansson O, Zetterberg H, Vanmechelen E, Vanderstichele H, Andreasson U, Londos E, Wallin A, Minthon L, Blennow K (2010) Evaluation of plasma Abeta (40) and Abeta (42) as predictors of conversion to Alzheimer's disease in patients with mild cognitive impairment. Neurobiol Aging 31, 357-367.
53. Lewczuk P, Kornhuber J, Vanmechelen E, Peters O, Heuser I, Maier W, Jessen F, Burger K, Hampel H, Frolich L, Henn F, Falkai P, Ruther E, Jahn H, Luckhaus C, Perneczky R, Schmidtke K, Schroder J, Kessler H, Pantel J, Gertz HJ, Vanderstichele H, de Meyer G, Shapiro F, Wolf S, Bibl M, Wiltfang J (2010) Amyloid beta peptides in plasma in early diagnosis of Alzheimer's disease: A multicenter study with multiplexing. Exp Neurol 223, 366-370.
54. Cosentino SA, Stern Y, Sokolov E, Scarmeas N, Manly JJ, Tang MX, Schupf N, Mayeux RP (2010) Plasma ss-amyloid and cognitive decline. Arch Neurol 67, 1485-1490.
55. Laske C, Sopova K, Gkotsis C, Eschweiler GW, Straten G, Gawaz M, Leyhe T, Stellos K (2010) Amyloid-beta peptides in plasma and cognitive decline after 1 year follow-up in Alzheimer's disease patients. J Alzheimers Dis 21, 1263-1269.
56. Lui JK, Laws SM, Li QX, Villemagne VL, Ames D, Brown B, Bush AI, De Ruyck K, Dromey J, Ellis KA, Faux NG, Foster J, Fowler C, Gupta V, Hudson P, Laughton K, Masters CL, Pertile K, Rembach A, Rimajova M, Rodrigues M, Rowe CC, Rumble R, Szoeke C, Taddei K, Taddei T, Trounson B, Ward V, Martins RN, Group AR (2010) Plasma amyloid-beta as a biomarker in Alzheimer's disease: The AIBL study of aging. J Alzheimers Dis 20, 1233-1242.
57. Rembach A, Faux NG, Watt AD, Pertile KK, Rumble RL, Trounson BO, Fowler CJ, Roberts BR, Perez KA, Li QX, Laws SM, Taddei K, Rainey-Smith S, Robertson JS, Vandi-jck M, Vanderstichele H, Barnham KJ, Ellis KA, Szoeke C, Macaulay L, Rowe CC, Villemagne VL, Ames D, Martins RN, Bush AI, Masters CL (2014) Changes in plasma amyloid beta in a longitudinal study of aging and Alzheimer's disease. Alzheimers Dement 10, 53-61.
58. Burnham SC, Faux NG, Wilson W, Laws SM, Ames D, Bedo J, Bush AI, Doecke JD, Ellis KA, Head R, Jones G, Kiiveri H, Martins RN, Rembach A, Rowe CC, Salvado O, Macaulay SL, Masters CL, Villemagne VL (2014) A blood-based predictor for neocortical Abeta burden in Alzheimer's disease: Results from the AIBL study. Mol Psychiatry 19, 519-526.
59. Tan L, Yu JT, Hu N (2013) Non-codingRNAs in Alzheimer's disease. Mol Neurobiol 47, 382-393.
60. Tan L, Yu JT, Liu QY, Tan MS, Zhang W, Hu N, Wang YL, Sun L, Jiang T (2014) Circulating miR-125b as a biomarker of Alzheimer's disease. J Neurol Sci 336, 52-56.
61. Tan L, Yu JT, Tan MS, Liu QY, Wang HF, Zhang W, Jiang T (2014) Genome-wide serum microRNA expression profiling identifies serum biomarkers for Alzheimer's disease. J Alzheimers Dis 40, 1017-1027.
62. Wang C, Yu JT, Wang HF, Jiang T, Tan CC, Meng XF, Soares HD, Tan L (2014) Meta-analysis of peripheral blood apolipoprotein E levels in Alzheimer's disease. PLoS One 9, e89041.
63. Ewers M, Sperling RA, Klunk WE, Weiner MW, Hampel H (2011) Neuroimaging markers for the prediction and early diagnosis of Alzheimer's disease dementia. Trends Neurosci 34, 430-442.
64. Du AT, Schuff N, Amend D, Laakso MP, Hsu YY, Jagust WJ, Yaffe K, Kramer JH, Reed B, Norman D, Chui HC, Weiner MW (2001) Magnetic resonance imaging of the entorhi-nal cortex and hippocampus in mild cognitive impairment and Alzheimer's disease. J Neurol Neurosurg Psychiatry 71, 441-447.
65. Morris JC, Csernansky J, Price JL (2002) MRI measures of entorhinal cortex versus hippocampus in preclinical AD. Neurology 59, 1474; author reply 1474-1475.
66. Dickerson BC, Stoub TR, Shah RC, Sperling RA, Killiany RJ, Albert MS, Hyman BT, Blacker D, Detoledo-Morrell L (2011) Alzheimer-signature MRI biomarker predicts AD dementia in cognitively normal adults. Neurology 76, 1395-1402.
67. Berti V, Mosconi L, Glodzik L, Li Y, Murray J, De Santi S, Pupi A, Tsui W, De Leon MJ (2011) Structural brain changes in normal individuals with a maternal history of Alzheimer's. Neurobiol Aging 32, 2325 e2317-2326.
68. Honea RA, Swerdlow RH, Vidoni ED, Burns JM (2011) Progressive regional atrophy in normal adults with a maternal history of Alzheimer disease. Neurology 76, 822-829.
69. Tondelli M, Wilcock GK, Nichelli P, De Jager CA, Jenkinson M, Zamboni G (2012) Structural MRI changes detectable up to ten years before clinical Alzheimer's disease. Neurobiol Aging 33, 825 e825-836.
70. Kantarci K, Weigand SD, Przybelski SA, Preboske GM, Pankratz VS, Vemuri P, Senjem ML, Murphy MC, Gunter JL, Machulda MM, Ivnik RJ, Roberts RO, Boeve BF, Rocca WA, Knopman DS, Petersen RC, Jack CR Jr (2013) MRI and MRS predictors of mild cognitive impairment in a population-based sample. Neurology 81, 126-133.
71. Apostolova LG, Mosconi L, Thompson PM, Green AE, Hwang KS, Ramirez A, Mistur R, Tsui WH, de Leon MJ (2010) Subregional hippocampal atrophy predicts Alzheimer's dementia in the cognitively normal. Neurobiol Aging 31, 1077-1088.
72. Carlson NE, Moore MM, Dame A, Howieson D, Silbert LC, Quinn JF, Kaye JA (2008) Trajectories of brain loss in aging and the development of cognitive impairment. Neurology 70, 828-833.
73. Fennema-Notestine C, Hagler DJ Jr, McEvoy LK, Fleisher AS, Wu EH, Karow DS, Dale AM, Alzheimer's Disease Neuroimaging I (2009) Structural MRI biomarkers for pre-clinical and mild Alzheimer's disease. Hum Brain Mapp 30, 3238-3253.
74. Brickman AM, Provenzano FA, Muraskin J, Manly JJ, Blum S, Apa Z, Stern Y, Brown TR, Luchsinger JA, Mayeux R (2012) Regional white matter hyperintensity volume, not hippocampal atrophy, predicts incident Alzheimer disease in the community. Arch Neurol 69, 1621-1627.
75. Dickerson BC, Wolk DA, Alzheimer's Disease Neuroimag-ing I (2012) MRI cortical thickness biomarker predicts AD-like CSF and cognitive decline in normal adults. Neurology 78, 84-90.
76. Oh H, Mormino EC, Madison C, Hayenga A, Smiljic A, Jagust WJ (2011) beta-Amyloid affects frontal and posterior brain networks in normal aging. Neuroimage 54, 1887-1895.
77. Sheline YI, Raichle ME, Snyder AZ, Morris JC, Head D, Wang S, Mintun MA (2010) Amyloid plaques disrupt resting state default mode network connectivity in cognitively normal elderly. Biol Psychiatry 67, 584-587.
78. Mormino EC, Smiljic A, Hayenga AO, Onami SH, Greicius MD, Rabinovici GD, Janabi M, Baker SL, Yen IV, Madison CM, Miller BL, Jagust WJ (2011) Relationships between beta-amyloid and functional connectivity in different components of the default mode network in aging. Cereb Cortex 21, 2399-2407.
79. Drzezga A, Becker JA, Van Dijk KR, Sreenivasan A, Taluk-dar T, Sullivan C, Schultz AP, Sepulcre J, Putcha D, Greve D, Johnson KA, Sperling RA (2011) Neuronal dysfunction and disconnection ofcortical hubsin non-demented subjects with elevated amyloid burden. Brain 134, 1635-1646.
80. Brier MR, Thomas JB, Fagan AM, Hassenstab J, Holtzman DM, Benzinger TL, Morris JC, Ances BM (2014) Functional connectivity and graph theory in preclinical Alzheimer's disease. Neurobiol Aging 35, 757-768.
81. Chhatwal JP, Sperling RA (2012) Functional MRI of mnemonic networks across the spectrum of normal aging, mild cognitive impairment, and Alzheimer's disease. J Alzheimers Dis 31 (Suppl 3), S155-S167.
82. Sperling R (2011) Potential of functional MRI as a biomarker in early Alzheimer's disease. Neurobiol Aging 32 (Suppl 1), S37-S43.
83. Sheline YI, Morris JC, Snyder AZ, Price JL, Yan Z, D'Angelo G, Liu C, Dixit S, Benzinger T, Fagan A, Goate A, Mintun MA (2010) APOE4 allele disruptsresting statefMRI connectivity in the absence of amyloid plaques or decreased CSF Abeta42. J Neurosci 30, 17035-17040.
84. Suthana NA, Krupa A, Donix M, Burggren A, Ekstrom AD, Jones M, Ercoli LM, Miller KJ, Siddarth P, Small GW, Bookheimer SY (2010) Reduced hippocampal CA2, CA3, and dentate gyrus activity in asymptomatic people at genetic risk for Alzheimer's disease. Neuroimage 53, 1077-1084.
85. Rami L, Sala-Llonch R, Sole-Padulles C, Fortea J, Olives J, Llado A, Pena-Gomez C, Balasa M, Bosch B, Antonell A, Sanchez-Valle R, Bartres-Faz D, Molinuevo JL (2012) Distinct functional activity of the precuneus and posterior cingulate cortex during encoding in the preclinical stage of Alzheimer's disease. J Alzheimers Dis 31, 517-526.
86. Klunk WE (2011) Amyloid imaging as a biomarker for cerebral beta-amyloidosis and risk prediction for Alzheimer dementia. Neurobiol Aging 32 (Suppl 1), S20-S36.
87. Doraiswamy PM, Sperling RA, Coleman RE, Johnson KA, Reiman EM, Davis MD, Grundman M, Sabbagh MN, Sad-owsky CH, Fleisher AS, Carpenter A, Clark CM, Joshi AD, Mintun MA, Skovronsky DM, Pontecorvo MJ, Group AAS (2012) Amyloid-beta assessed by florbetapir F 18 PET and 18-month cognitive decline: Amulticenter study. Neurology 79, 1636-1644.
88. Lim YY, Ellis KA, Pietrzak RH, Ames D, Darby D, Harrington K, Martins RN, Masters CL, Rowe C, Savage G, Szoeke C, Villemagne VL, Maruff P, Group AR (2012) Stronger effect of amyloid load than APOE genotype on cognitive decline in healthy older adults. Neurology 79, 1645-1652.
89. Mormino EC, Kluth JT, Madison CM, Rabinovici GD, Baker SL, Miller BL, Koeppe RA, Mathis CA, Weiner MW, Jagust WJ, Alzheimer's Disease Neuroimaging I (2009) Episodic memory loss is related to hippocampal-mediated beta-amyloid deposition in elderly subjects. Brain 132, 1310-1323.
90. Chetelat G, Villemagne VL, Villain N, Jones G, Ellis KA, Ames D, Martins RN, Masters CL, Rowe CC, Group AR (2012) Accelerated cortical atrophy in cognitively normal elderly with high beta-amyloid deposition. Neurology 78, 477-484.
91. Villemagne VL, Pike KE, Chetelat G, Ellis KA, Mulligan RS, Bourgeat P, Ackermann U, Jones G, Szoeke C, Salvado O, Martins R, O'Keefe G, Mathis CA, Klunk WE, Ames D, Masters CL, Rowe CC (2011) Longitudinal assessment of Abeta and cognition in aging and Alzheimer disease. Ann Neurol 69, 181-192.
92. Rowe CC, Ellis KA, Rimajova M, Bourgeat P, Pike KE, Jones G, Fripp J, Tochon-Danguy H, Morandeau L, O'Keefe G, Price R, Raniga P, Robins P, Acosta O, Lenzo N, Szoeke C, Salvado O, Head R, Martins R, Masters CL, Ames D, Villemagne VL (2010) Amyloid imaging results from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. Neurobiol Aging 31, 1275-1283.
93. Fleisher AS, Chen K, Liu X, Ayutyanont N, Roontiva A, Thiyyagura P, Protas H, Joshi AD, Sabbagh M, Sadowsky CH, Sperling RA, Clark CM, Mintun MA, Pontecorvo MJ, Coleman RE, Doraiswamy PM, Johnson KA, Carpenter AP, Skovronsky DM, Reiman EM (2013) Apolipoprotein E epsilon4 and age effects on florbetapir positron emission tomography in healthy aging and Alzheimer disease. Neurobiol Aging 34, 1-12.
94. Vlassenko AG, Mintun MA, Xiong C, Sheline YI, Goate AM, Benzinger TL, Morris JC (2011) Amyloid-beta plaque growth in cognitively normal adults: Longitudinal [11C]Pittsburgh compound B data. Ann Neurol 70, 857-861.
95. Sperling RA, Johnson KA, Doraiswamy PM, Reiman EM, Fleisher AS, Sabbagh MN, Sadowsky CH, Carpenter A, Davis MD, Lu M, Flitter M, Joshi AD, Clark CM, Grundman M, Mintun MA, Skovronsky DM, Pontecorvo MJ, Group AAS (2013) Amyloid deposition detected with florbetapir F 18 ((18) F-AV-45) is related to lower episodic memory performance in clinically normal older individuals. Neurobiol Aging 34, 822-831.
96. Langbaum JB, Chen K, Lee W, Reschke C, Bandy D, Fleisher AS, Alexander GE, Foster NL, Weiner MW, Koeppe RA, Jagust WJ, Reiman EM, Alzheimer's Disease Neuroimaging I (2009) Categorical and correlational analyses of baseline fluorodeoxyglucose positron emission tomography images from the Alzheimer's Disease Neu-roimaging Initiative (ADNI). Neuroimage 45, 1107-1116.
97. Foster NL, Heidebrink JL, Clark CM, Jagust WJ, Arnold SE, Barbas NR, DeCarli CS, Turner RS, Koeppe RA, Hig-don R, Minoshima S (2007) FDG-PET improves accuracy in distinguishing frontotemporal dementia and Alzheimer's disease. Brain 130, 2616-2635.
98. de Leon MJ, Convit A, Wolf OT, Tarshish CY, DeSanti S, Rusinek H, Tsui W, Kandil E, Scherer AJ, Roche A, Imossi A, Thorn E, Bobinski M, Caraos C, Lesbre P, Schlyer D, Poirier J, Reisberg B, Fowler J (2001) Prediction of cognitive decline in normal elderly subjects with 2-[(18) F]fluoro-2-deoxy-D-glucose/poitron-emission tomography (FDG/PET). Proc Natl Acad Sci USA 98, 10966-10971.
99. Mosconi L, De Santi S, Li J, Tsui WH, Li Y, Boppana M, Laska E, Rusinek H, de Leon MJ (2008) Hippocam-pal hypometabolism predicts cognitive decline from normal aging. Neurobiol Aging 29, 676-692.
100. Langbaum JB, Chen K, Caselli RJ, Lee W, Reschke C, Bandy D, Alexander GE, Burns CM, Kaszniak AW, Reeder SA, Corneveaux JJ, Allen AN, Pruzin J, Huentel-man MJ, Fleisher AS, Reiman EM (2010) Hypometabolism in Alzheimer-affected brain regions in cognitively healthy Latino individuals carrying the apolipoprotein E epsilon4 allele. Arch Neurol 67, 462-468.
101. Ewers M, Brendel M, Rizk-Jackson A, Rominger A, Bartenstein P, Schuff N, Weiner MW, for the Alzheimer's Disease Neuroimaging I (2013) Reduced FDG-PET brain metabolism and executive function predict clinical progression in elderly healthy subjects. Neuroimage Clin 4, 45-52.
102. Lahiri DK, Maloney B, Zawia NH (2009) The LEARn model: An epigenetic explanation for idiopathic neurobi-ological diseases. Mol Psychiatry 14, 992-1003.
103. Lahiri DK, Maloney B (2010) The "LEARn" (Latent Early-life Associated Regulation) model integrates environmental risk factors and the developmental basis of Alzheimer's disease, and proposes remedial steps. Exp Gerontol 45, 291-296.
104. Lahiri DK, Maloney B, Basha MR, Ge YW, Zawia NH (2007) How and when environmental agents and dietary factors affect the course of Alzheimer's disease: The "LEARn" model (latent early-life associated regulation) may explain the triggering of AD. Curr Alzheimer Res 4, 219-228.
105. Basha MR, Wei W, Bakheet SA, Benitez N, Siddiqi HK, Ge YW, Lahiri DK, Zawia NH (2005) The fetal basis of amyloidogenesis: Exposure to lead and latent overexpres-sion of amyloid precursor protein and beta-amyloid in the aging brain. J Neurosci 25, 823-829.
106. Wu J, Basha MR, Brock B, Cox DP, Cardozo-Pelaez F, McPherson CA, Harry J, Rice DC, Maloney B, Chen D, Lahiri DK, Zawia NH (2008) Alzheimer's disease (AD)-like pathology in aged monkeys after infantile exposure to environmental metal lead (Pb): Evidence for a developmental origin and environmental link for AD. J Neurosci 28, 3-9.
107. Coppieters N, Dieriks BV, Lill C, Faull RL, Curtis MA, Dra-gunow M (2014) Global changes in DNA methylation and hydroxymethylation in Alzheimer's disease human brain. Neurobiol Aging 35, 1334-1344.
108. Lopes da Silva S, Vellas B, Elemans S, Luchsinger J, Kam-phuis P, Yaffe K, Sijben J, Groenendijk M, Stijnen T (2013) Plasma nutrient status of patients with Alzheimer's disease: Systematic review and meta-analysis. Alzheimers Dement, doi: 10.1016/j.jalz.2013.05.1771.
109. Douaud G, Refsum H, de Jager CA, Jacoby R, Nichols TE, Smith SM, Smith AD (2013) Preventing Alzheimer's disease-related gray matter atrophy by B-vitamin treatment. Proc Natl Acad Sci USA 110, 9523-9528.
110. Genin E, Hannequin D, Wallon D, Sleegers K, Hiltunen M, Combarros O, Bullido MJ, Engelborghs S, De Deyn P, Berr C, Pasquier F, Dubois B, Tognoni G, Fievet N, Brouw-ers N, Bettens K, Arosio B, Coto E, Del Zompo M, Mateo I, Epelbaum J, Frank-Garcia A, Helisalmi S, Porcellini E, Pilotto A, Forti P, Ferri R, Scarpini E, Siciliano G, Sol-frizzi V, Sorbi S, Spalletta G, Valdivieso F, Vepsalainen S, Alvarez V, Bosco P, Mancuso M, Panza F, Nacmias B, Bossu P, Hanon O, Piccardi P, Annoni G, Seripa D, Galim-berti D, Licastro F, Soininen H, Dartigues JF, Kamboh MI, Van Broeckhoven C, Lambert JC, Amouyel P, Campion D (2011) APOE and Alzheimer disease: A major gene with semi-dominant inheritance. Mol Psychiatry 16, 903-907.
111. Salmon DP, Ferris SH, Thomas RG, Sano M, Cummings JL, Sperling RA, Petersen RC, Aisen PS (2013) Age and apolipoprotein E genotype influence rate of cognitive decline in nondemented elderly. Neuropsychology 27, 391-401.
112. Caselli RJ, Locke DE, Dueck AC, Knopman DS, Woodruff BK, Hoffman-Snyder C, Rademakers R, Fleisher AS, Reiman EM (2014) The neuropsychology of normal aging and preclinical Alzheimer's disease. Alzheimers Dement 10, 84-92.
113. Jorm AF, Mather KA, Butterworth P, Anstey KJ, Chris-tensen H, Easteal S (2007) APOE genotype and cognitive functioning in a large age-stratified population sample. Neu-ropsychology 21, 1-8.
114. Vos SJB, Xiong C, Visser PJ, Jasielec MS, Hassenstab J, Grant EA, Cairns NJ, Morris JC, Holtzman DM, Fagan AM (2013) Preclinical Alzheimer's disease and its outcome: A longitudinal cohort study. Lancet Neurol 12, 957-965.
115. Sperling RA, Karlawish J, Johnson KA (2013) Preclinical Alzheimer disease-the challenges ahead. Nat Rev Neurol 9, 54-58.
116. Yu J-T, Tan L, Hardy J (2014) Apolipoprotein E in Alzheimer's disease: An update. Ann Rev Neurosci, doi: 10.1146/annurev-neuro-071013-014300.
117. Jiang T, Yu JT, Tan MS, Wang HF, Wang YL, Zhu XC, Zhang W, Tan L (2014) Genetic variation in PICALM and Alzheimer's disease risk in Han Chinese. Neurobiol Aging 35, 934 e931-933.
118. Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Williams A, Jones N, Thomas C, Stretton A, Morgan AR, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Morgan K, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Love S, Kehoe PG, Hardy J, Mead S, Fox N, Rossor M, Collinge J, Maier W, Jessen F, Schurmann B, Heun R, van den Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frolich L, Hampel H, Hull M, Rujescu D, Goate AM, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Sleegers K, Bettens K, Engelborghs S, De Deyn PP, Van Broeckhoven C, Livingston G, Bass NJ, Gurl-ing H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Tsolaki M, Singleton AB, Guerreiro R, Muh-leisen TW, Nothen MM, Moebus S, Jockel KH, Klopp N, Wichmann HE, Carrasquillo MM, Pankratz VS, Younkin SG, Holmans PA, O'Donovan M, Owen MJ, Williams J (2009) Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat Genet 41, 1088-1093.
119. Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, Combarros O, Zelenika D, Bullido MJ, Tav-ernier B, Letenneur L, Bettens K, Berr C, Pasquier F, Fievet N, Barberger-Gateau P, Engelborghs S, De Deyn P, Mateo I, Franck A, Helisalmi S, Porcellini E, Hanon O, European Alzheimer's Disease Initiative I, de Pancorbo MM, Lendon C, Dufouil C, Jaillard C, Leveillard T, Alvarez V, Bosco P, Mancuso M, Panza F, Nacmias B, Bossu P, Piccardi P, Annoni G, Seripa D, Galimberti D, Hannequin D, Licastro F, Soininen H, Ritchie K, Blanche H, Dartigues JF, Tzourio C, Gut I, Van Broeckhoven C, Alperovitch A, Lathrop M, Amouyel P (2009) Genome-wide association study identi fies variants at CLU and CR1 associated with Alzheimer's disease. Nat Genet 41, 1094-1099.
120. Seshadri S, Fitzpatrick AL, Ikram MA, De Stefano AL, Gud-nason V, Boada M, Bis JC, Smith AV, Carassquillo MM, Lambert JC, Harold D, Schrijvers EM, Ramirez-Lorca R, Debette S, Longstreth WT Jr, Janssens AC, Pankratz VS, Dartigues JF, Hollingworth P, Aspelund T, Hernandez I, Beiser A, Kuller LH, Koudstaal PJ, Dickson DW, Tzourio C, Abraham R, Antunez C, Du Y, Rotter JI, Aulchenko YS, Harris TB, Petersen RC, Berr C, Owen MJ, Lopez-Arrieta J, Varadarajan BN, Becker JT, Rivadeneira F, Nalls MA, Graff-Radford NR, Campion D, Auerbach S, Rice K, Hof-man A, Jonsson PV, Schmidt H, Lathrop M, Mosley TH, Au R, Psaty BM, Uitterlinden AG, Farrer LA, Lumley T, Ruiz A, Williams J, Amouyel P, Younkin SG, Wolf PA, Launer LJ, Lopez OL, van Duijn CM, Breteler MM, Consortium C, Consortium G, Consortium E (2010) Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA 303, 1832-1840.
121. Hollingworth P, Harold D, Sims R, Gerrish A, Lambert JC, Carrasquillo MM, Abraham R, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Jones N, Stretton A, Thomas C, Richards A, Ivanov D, Widdowson C, Chapman J, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Beaumont H, Warden D, Wilcock G, Love S, Kehoe PG, Hooper NM, Vardy ER, Hardy J, Mead S, Fox NC, Rossor M, Collinge J, Maier W, Jessen F, Ruther E, Schurmann B, Heun R, Kolsch H, van den Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frolich L, Hampel H, Gallacher J, Hull M, Rujescu D, Giegling I, Goate AM, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Sleegers K, Bettens K, Engelborghs S, De Deyn PP, Van Broeckhoven C, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Tsolaki M, Singleton AB, Guerreiro R, Muhleisen TW, Nothen MM, Moebus S, Jockel KH, Klopp N, Wichmann HE, Pankratz VS, Sando SB, Aasly JO, Barcikowska M, Wszolek ZK, Dickson DW, Graff-Radford NR, Petersen RC, Alzheimer's Disease Neuroimaging I, van Duijn CM, Breteler MM, Ikram MA, DeStefano AL, Fitzpatrick AL, Lopez O, Launer LJ, Seshadri S, consortium C, Berr C, Campion D, Epelbaum J, Dartigues JF, Tzourio C, Alper-ovitch A, Lathrop M, consortium E, Feulner TM, Friedrich P, Riehle C, Krawczak M, Schreiber S, Mayhaus M, Nicol-haus S, Wagenpfeil S, Steinberg S, Stefansson H, Stefansson K, Snaedal J, Bjornsson S, Jonsson PV, Chouraki V, Genier-Boley B, Hiltunen M, Soininen H, Combarros O, Zelenika D, Delepine M, Bullido MJ, Pasquier F, Mateo I, Frank-Garcia A, Porcellini E, Hanon O, Coto E, Alvarez V, Bosco P, Siciliano G, Mancuso M, Panza F, Solfrizzi V, Nacmias B, Sorbi S, Bossu P, Piccardi P, Arosio B, Annoni G, Seripa D, Pilotto A, Scarpini E, Galimberti D, Brice A, Hannequin D, Licastro F, Jones L, Holmans PA, Jonsson T, Riemenschnei-der M, Morgan K, Younkin SG, Owen MJ, O'Donovan M, Amouyel P, Williams J (2011) Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat Genet 43, 429-435.
122. Naj AC, Jun G, Beecham GW, Wang LS, Vardarajan BN, Buros J, Gallins PJ, Buxbaum JD, Jarvik GP, Crane PK, Larson EB, Bird TD, Boeve BF, Graff-Radford NR, De Jager PL, Evans D, Schneider JA, Carrasquillo MM, Ertekin-Taner N, Younkin SG, Cruchaga C, Kauwe JS, Nowotny P, Kramer P, Hardy J, Huentelman MJ, Myers AJ, Barmada MM, Demirci FY, Baldwin CT, Green RC, Rogaeva E, St George-Hyslop P, Arnold SE, Barber R, Beach T, Bigio EH, Bowen JD, Boxer A, Burke JR, Cairns NJ, Carlson CS, Carney RM, Carroll SL, Chui HC, Clark DG, Corneveaux J, Cotman CW, Cummings JL, DeCarli C, DeKosky ST, Diaz-Arrastia R, Dick M, Dickson DW, Ellis WG, Faber KM, Fallon KB, Farlow MR, Ferris S, Frosch MP, Galasko DR, Ganguli M, Gearing M, Geschwind DH, Ghetti B, Gilbert JR, Gilman S, Giordani B, Glass JD, Growdon JH, Hamilton RL, Harrell LE, Head E, Honig LS, Hulette CM, Hyman BT, Jicha GA, Jin LW, Johnson N, Karlawish J, Karydas A, Kaye JA, Kim R, Koo EH, Kowall NW, Lah JJ, Levey AI, Lieberman AP, Lopez OL, Mack WJ, Marson DC, Martiniuk F, Mash DC, Masliah E, McCormick WC, McCurry SM, McDavid AN, McKee AC, Mesulam M, Miller BL, Miller CA, Miller JW, Parisi JE, Perl DP, Peskind E, Petersen RC, Poon WW, Quinn JF, Rajbhandary RA, Raskind M, Reisberg B, Ringman JM, Roberson ED, Rosenberg RN, Sano M, Schneider LS, Seeley W, Shelanski ML, Slifer MA, Smith CD, Sonnen JA, Spina S, Stern RA, Tanzi RE, Trojanowski JQ, Troncoso JC, Van Deerlin VM, Vinters HV, Vonsattel JP, Weintraub S, Welsh-Bohmer KA, Williamson J, Woltjer RL, Cantwell LB, Dombroski BA, Beekly D, Lunetta KL, Mar tin ER, Kamboh MI, Saykin AJ, Reiman EM, Bennett DA, Morris JC, Montine TJ, Goate AM, Blacker D, Tsuang DW, Hakonarson H, Kukull WA, Foroud TM, Haines JL, Mayeux R, Pericak-Vance MA, Farrer LA, Schellenberg GD (2011) Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nat Genet 43, 436-441.
123. Hu N, Tan MS, Sun L, Jiang T, Wang YL, Tan L, Zhang W, Yu JT (2014) Decreased expression of CD33 in peripheral mononuclear cells of Alzheimer's disease patients. Neurosci Lett 563, 51-54.
124. Alperovitch A, Boland A, Delepoine M, Dubois B, Duron E, Epelbaum J, Van Cauwenberghe C, Engelborghs S, Vanden-berghe R, De Deyn PP, Ferri R, Romano C, Caltagirone C, Orfei MD, Ciaramella A, Scarpini E, Fenoglio C, Siciliano G, Bonuccelli U, Bagnoli S, Bracco L, Bessi V, Cecchetti R, Bastiani P, Squassina A, Seripa D, Frank-Garcia A, Sastre I, Blesa R, Alcolea D, Suarez-Clavet M, Sanchez-Juan P, Munoz Fernandez C, Aladro Benito Y, Thonberg H, Forshell C, Lilius L, Kinhult-Stahlbom A, Giedraitis V, Kilander L, Brundin RM, Concari L, Helisalmi S, Koivisto AM, Haa-pasalo A, Solfrizzi V, Frisardi V, Ott J, Carney RM, Mash DC, Albert MS, Albin RL, Apostolova LG, Arnold SE, Barmada MM, Barnes LL, Beach TG, Bigio EH, Bird TD, Boeve BF, Bowen JD, Boxer A, Burk JR, Cairns NJ, Cao C, Carlson CS, Carroll SL, Chibnik LB, Chui HC, Clark DG, Corneveaux J, Cribbs DG, DeCarli C, DeKosky ST, Demirci FY, Dick M, Dickson DW, Duara R, Ertekin-Taner N, Fallon KB, Farlow MR, Ferris S, Frosch MP, Galasko DR, Ganguli M, Gearing M, Geschwind DH, Ghetti B, Gilman S, Glass JD, Growdon JH, Hamilton RL, Harrell LE, Head E, Honig LS, Hulette CM, Hyman BT, Jarvik GP, Jicha GA, Jin LW, Karydas A, Kauwe JS, Kaye JA, Kim R, Koo EH, Kowall NW, Kramer JH, Kramer P, LaFerla FM, Lah JJ, Levernez JB, Levey AI, Li G, Lieberman AP, Lyketsos CG, Mack WJ, Marson DC, Martiniuk F, Masliah E, McCormick WC, McCurry SM, McDavid AN, McKee AC, Mesulam M, Miller BL, Miller CA, Miller JW, Morris JC, Murrell JR, Olichney JM, Pankratz VS, Parasi JE, Peskind E, Peterson RC, Pierce A, Poon WW, Potter H, Quinn JF, Raj A, Raskind M, Reiman EM, Reisberg B, Ringman JM, Roberson ED, Rosen HJ, Rosenberg RN, Sano M, Saykin AJ, Schneider JA, Schneider LS, Seeley WW, Smith AG, Sonnen JA, Spina S, Stern RA, Tanzi RE, Trojanowski JQ, Troncoso JC, Van Deerlin VM, Van Eldik LJ, Vinters HV, Vonsattel JP, Wein-traub S, Welsh-Bohmer KA, Williamson J, Woltjer RL, Yu CE, Barber R, Au R, Wolf PA, Beiser A, Debette S, Yang Q, Weinstein G, Johnson AD, Wang J, Uitterlinden AG, Rivadeneira F, Koudstgaal PJ, Longstreth WT Jr, Becker JT, Kuller LH, Lumley T, Rice K, Garcia M, Aspelund T, Marksteiner JJ, Dal-Bianco P, Toglhofer AM, Freuden-berger P, Ransmayr G, Benke T, Toeglhofer AM, Bressler J, Breteler MM, Fornage M, Hernandez I, Rosende Roca M, Ana Mauleon M, Alegrat M, Ramirez-Lorca R, Gonzalez-Perez A, Chapman J, Stretton A, Morgan A, Kehoe PG, Medway C, Lord J, Turton J, Hooper NM, Vardy E, Warren JD, Schott JM, Uphill J, Ryan N, Rossor M, Ben-Shlomo Y, Makrina D, Gkatzima O, Lupton M, Koutroumani M, Avramidou D, Germanou A, Jessen F, Riedel-Heller S, Dichgans M, Heun R, Kolsch H, Schurmann B, Herold C, Lacour A, Drichel D, Hoffman P, Kornhuber J, Gu W, Feulner T, van den Bussche H, Lawlor B, Lynch A, Mann D, Smith AD, Warden D, Wilcock G, Heuser I, Wiltgang J, Frolich L, Hull M, Mayo K, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Singleton AB, Guerreiro R, Jockel KH, Klopp N, Wichmann HE, Graff-Radford NR, Ma L, Bisceglio G, Fisher E, Warner N, Pickering-Brown S (2013) Meta-analysis of 74, 046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet 45, 1452-1458.
125. Cruchaga C, Karch CM, Jin SC, Benitez BA, Cai Y, Guer-reiro R, Harari O, Norton J, Budde J, Bertelsen S, Jeng AT, Cooper B, Skorupa T, Carrell D, Levitch D, Hsu S, Choi J, Ryten M, Hardy J, Trabzuni D, Weale ME, Ramasamy A, Smith C, Sassi C, Bras J, Gibbs JR, Hernandez DG, Lup-ton MK, Powell J, Forabosco P, Ridge PG, Corcoran CD, Tschanz JT, Norton MC, Munger RG, Schmutz C, Leary M, Demirci FY, Bamne MN, Wang X, Lopez OL, Ganguli M, Medway C, Turton J, Lord J, Braae A, Barber I, Brown K, Passmore P, Craig D, Johnston J, McGuinness B, Todd S, Heun R, Kolsch H, Kehoe PG, Hooper NM, Vardy ER, Mann DM, Pickering-Brown S, Kalsheker N, Lowe J, Morgan K, David Smith A, Wilcock G, Warden D, Holmes C, Pastor P, Lorenzo-Betancor O, Brkanac Z, Scott E, Topol E, Rogaeva E, Singleton AB, Kamboh MI, St George-Hyslop P, Cairns N, Morris JC, Kauwe JS, Goate AM (2014) Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease. Nature 505, 550-554.
126. Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, Jun G, Destefano AL, Bis JC, Beecham GW, Grenier-Boley B, Russo G, Thornton-Wells TA, Jones N, Smith AV, Chouraki V, Thomas C, Ikram MA, Zelenika D, Vardarajan BN, Kamatani Y, Lin CF, Gerrish A, Schmidt H, Kunkle B, Dunstan ML, Ruiz A, Bihoreau MT, Choi SH, Reitz C, Pasquier F, Hollingworth P, Ramirez A, Hanon O, Fitzpatrick AL, Buxbaum JD, Campion D, Crane PK, Baldwin C, Becker T, Gudnason V, Cruchaga C, Craig D, Amin N, Berr C, Lopez OL, De Jager PL, Deramecourt V, Johnston JA, Evans D, Lovestone S, Letenneur L, Moron FJ, Rubinsztein DC, Eiriksdottir G, Sleegers K, Goate AM, Fievet N, Huentelman MJ, Gill M, Brown K, Kamboh MI, Keller L, Barberger-Gateau P, McGuinness B, Larson EB, Green R, Myers AJ, Dufouil C, Todd S, Wallon D, Love S, Rogaeva E, Gallacher J, St George-Hyslop P, Clarimon J, Lleo A, Bayer A, Tsuang DW, Yu L, Tsolaki M, Bossu P, Spalletta G, Proitsi P, Collinge J, Sorbi S, Sanchez-Garcia F, Fox NC, Hardy J, Naranjo MC, Bosco P, Clarke R, Brayne C, Galimberti D, Mancuso M, Matthews F, European Alzheimer's Disease I, Genetic, Environmental Risk in Alzheimer's D, Alzheimer's Disease Genetic C, Cohorts for H, Aging Research in Genomic E, Moebus S, Mecocci P, Del Zompo M, Maier W, Hampel H, Pilotto A, Bullido M, Panza F, Caffarra P, Nacmias B, Gilbert JR, Mayhaus M, Lannfelt L, Hakonarson H, Pichler S, Carrasquillo MM, Ingelsson M, Beekly D, Alvarez V, Zou F, Valladares O, Younkin SG, Coto E, Hamilton-Nelson KL, Gu W, Razquin C, Pastor P, Mateo I, Owen MJ, Faber KM, Jonsson PV, Combarros O, O'Donovan MC, Cantwell LB, Soininen H, Blacker D, Mead S, Mosley TH Jr, Bennett DA, Harris TB, Fratiglioni L, Holmes C, de Bruijn RF, Passmore P, Montine TJ, Bettens K, Rotter JI, Brice A, Morgan K, Foroud TM, Kukull WA, Hannequin D, Powell JF, Nalls MA, Ritchie K, Lunetta KL, Kauwe JS, Boerwinkle E, Riemenschneider M, Boada M, Hiltunen M, Martin ER, Schmidt R, Rujescu D, Wang LS, Dartigues JF, Mayeux R, Tzourio C, Hofman A, Nothen MM, Graff C, Psaty BM, Jones L, Haines JL, Holmans PA, Lathrop M, Pericak-Vance MA, Launer LJ, Farrer LA, van Duijn CM, Van Broeckhoven C, Moskvina V, Seshadri S, Williams J, Schellenberg GD, Amouyel P (2013) Meta-analysis of 74, 046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet 45, 1452-1458.
127. Tan L, Yu JT, Zhang W, Wu ZC, Zhang Q, Liu QY, Wang W, Wang HF, Ma XY, Cui WZ (2013) Association of GWAS-linked loci with late-onset Alzheimer's disease in a northern Han Chinese population. Alzheimers Dement 9, 546-553.
128. Barral S, Bird T, Goate A, Farlow MR, Diaz-Arrastia R, Bennett DA, Graff-Radford N, Boeve BF, Sweet RA, Stern Y, Wilson RS, Foroud T, Ott J, Mayeux R, National Institute on Aging Late-Onset Alzheimer's Disease Genetics S (2012) Genotype patterns at PICALM, CR1, BIN1, CLU, and APOE genes are associated with episodic memory. Neurology 78, 1464-1471.
129. Sun L, Tan MS, Hu N, Yu JT, Tan L (2013) Exploring the value of plasma BIN1 as a potential biomarker for Alzheimer's disease. J Alzheimers Dis 37, 291-295.
130. Yu JT, Jiang T, Wang YL, Wang HF, Zhang W, Hu N, Tan L, Sun L, Tan MS, Zhu XC (2014) Triggering receptor expressed on myeloid cells 2 variant is rare in late-onset Alzheimer's disease in Han Chinese individuals. Neurobiol Aging 35, 937 e931-933.
131. Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, Cruchaga C, Sassi C, Kauwe JS, Younkin S, Hazrati L, Collinge J, Pocock J, Lashley T, Williams J, Lambert JC, Amouyel P, Goate A, Rademakers R, Morgan K, Powell J, St George-Hyslop P, Singleton A, Hardy J, Alzheimer Genetic Analysis G (2013) TREM2 variants in Alzheimer's disease. N Engl J Med 368, 117-127.
132. Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jons-son PV, Snaedal J, Bjornsson S, Huttenlocher J, Levey AI, Lah JJ, Rujescu D, Hampel H, Giegling I, Andreassen OA, Engedal K, Ulstein I, Djurovic S, Ibrahim-Verbaas C, Hof-man A, Ikram MA, van Duijn CM, Thorsteinsdottir U, Kong A, Stefansson K (2013) Variant of TREM2 associated with the risk of Alzheimer's disease. N Engl J Med 368, 107-116.
133. Hu N, Tan MS, Yu JT, Sun L, Tan L, Wang YL, Jiang T (2014) Increased expression of TREM2 in peripheral blood of Alzheimer's disease patients. J Alzheimers Dis 38, 497-501.
134. Chen ZY, Patel PD, Sant G, Meng CX, Teng KK, Hempstead BL, Lee FS (2004) Variant brain-derived neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion ofwild-type BDNFin neurose-cretory cells and cortical neurons. J Neurosci 24, 4401-4411.
135. Angelucci F, Spalletta G, di Iulio F, Ciaramella A, Salani F, Colantoni L, Varsi AE, Gianni W, Sancesario G, Caltagirone C, Bossu P (2010) Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI) patients are character ized by increased BDNF serum levels. Curr Alzheimer Res 7, 15-20.
136. Sambataro F, Murty VP, Lemaitre HS, Reed JD, Das S, Goldberg TE, Callicott JH, Weinberger DR, Mattay VS (2010) BDNF modulates normal human hippocampal ageing [corrected]. Mol Psychiatry 15, 116-118.
137. Lim YY, Villemagne VL, Laws SM, Ames D, Pietrzak RH, Ellis KA, Harrington KD, Bourgeat P, Salvado O, Darby D, Snyder PJ, Bush AI, Martins RN, Masters CL, Rowe CC, Nathan PJ, Maruff P, Australian Imaging B, Lifestyle Research G (2013) BDNF Val66Met, Abeta amyloid, and cognitive decline in preclinical Alzheimer's disease. Neuro-biol Aging 34, 2457-2464.
138. Hashimoto R, Hirata Y, Asada T, Yamashita F, Nemoto K, Mori T, Moriguchi Y, Kunugi H, Arima K, Ohnishi T (2009) Effect of the brain-derived neurotrophic factor and the apolipoprotein E polymorphisms on disease progression in preclinical Alzheimer's disease. Genes Brain Behav 8, 43-52.
139. Ferencz B, Karlsson S, Kalpouzos G (2012) Promising genetic biomarkers of preclinical Alzheimer's disease: The influence of APOE and TOMM40 on brain integrity. Int J Alzheimers Dis 2012, 421452.
140. Adamczuk K, De Weer AS, Nelissen N, Chen K, Sleegers K, Bettens K, Van Broeckhoven C, Vandenbulcke M, Thiyyagura P, Dupont P, Van Laere K, Reiman EM, Vandenberghe R (2013) Polymorphism of brain derived neu-rotrophic factor influences beta amyloid load in cognitively intact apolipoprotein E epsilon4 carriers. Neuroimage Clin 2, 512-520.
141. Quiroz YT, Ally BA, Celone K, McKeever J, Ruiz-Rizzo AL, Lopera F, Stern CE, Budson AE (2011) Event-related potential markers of brain changes in preclinical familial Alzheimer disease. Neurology 77, 469-475.
142. Olichney JM, Van Petten C, Paller KA, Salmon DP, Iragui VJ, Kutas M (2000) Word repetition in amnesia. Electro-physiological measures of impaired and spared memory. Brain 123 (Pt 9), 1948-1963.
143. Olichney JM, Pak J, Salmon DP, Yang J-C, Gahagan T, Nowacki R, Hansen L, Galasko D, Kutas M, Iragui-Madoz VJ (2013) Abnormal P600 word repetition effect in elderly persons with preclinical Alzheimer's disease. Cogn Neu-rosci 4, 143-151.
144. Rosenberg RN, Baskin F, Fosmire JA, Risser R, Adams P, Svetlik D, Honig LS, Cullum CM, Weiner MF (1997) Altered amyloid protein processing in platelets of patients with Alzheimer disease. Arch Neurol 54, 139-144.
145. Zainaghi IA, Forlenza OV, Gattaz WF (2007) Abnormal APP processing in platelets of patients with Alzheimer's disease: Correlations with membrane fluidity and cognitive decline. Psychopharmacology (Berl) 192, 547-553.
146. Borroni B, Colciaghi F, Caltagirone C, Rozzini L, Broglio L, Cattabeni F, Di Luca M, Padovani A (2003) Platelet amyloid precursor protein abnormalities in mild cognitive impairment predict conversion to dementia of Alzheimer type: A 2-year follow-up study. Arch Neurol 60, 1740-1744.
147. Jelic V, Hagman G, Yamamoto NG, Teranishi Y, Nishimura T, Winblad B, Pavlov PF (2013) Abnormal platelet amyloid-beta protein precursor (AbetaPP) metabolism in Alzheimer's disease: Identification and characterization of a new AbetaPP isoform as potential biomarker. J Alzheimers Dis 35, 285-295.
148. Wilson RS, Schneider JA, Arnold SE, Tang Y, Boyle PA, Bennett DA (2007) Olfactory identification and incidence of mild cognitive impairmentinolder age. Arch Gen Psychiatry 64, 802-808.
149. Schofield PW, Ebrahimi H, Jones AL, Bateman GA, Murray SR (2012) An olfactory 'stress test' may detect preclinical Alzheimer's disease. BMC Neurol 12, 24.
150. Hakala BE, White C, Recklies AD (1993) Human cartilage gp-39, a major secretory product of articular chondrocytes and synovial cells, is a mammalian member of a chitinase protein family. J Biol Chem 268, 25803-25810.
151. Colton CA, Mott RT, Sharpe H, Xu Q, Van Nostrand WE, Vitek MP (2006) Expression profiles for macrophage alternative activation genes in AD and in mouse models of AD. J Neuroinflammation 3, 27.
152. Craig-Schapiro R, Perrin RJ, Roe CM, Xiong C, Carter D, Cairns NJ, Mintun MA, Peskind ER, Li G, Galasko DR, Clark CM, Quinn JF, D'Angelo G, Malone JP, Townsend RR, Morris JC, Fagan AM, Holtzman DM (2010) YKL-40: A novel prognostic fluid biomarker for preclinical Alzheimer's disease. Biol Psychiatry 68, 903-912.
153. Paquet C, Boissonnot M, Roger F, Dighiero P, Gil R, Hugon J (2007) Abnormal retinal thickness inpatients with mild cognitive impairment and Alzheimer's disease. Neurosci Lett 420, 97-99.
154. Mandal PK, Joshi J, Saharan S (2012) Visuospatial perception: An emerging biomarker for Alzheimer's disease. J Alzheimers Dis 31 (Suppl 3), S117-S135.
155. Cavanagh C, Colby-Milley J, Bouvier D, Farso M, Chabot JG, Quirion R, Krantic S (2013) betaCTF-correlated burst of hippocampal TNFalpha occurs at a very early, pre-plaque stageinthe TgCRND8mouse modelofAlzheimer's disease. J Alzheimers Dis 36, 233-238.
156. Lista S, Garaci FG, Ewers M, Teipel S, Zetterberg H, Blennow K, Hampel H (2013) CSF Abeta1-42 combined with neuroimaging biomarkers in the early detection, diagnosis and prediction of Alzheimer's disease. Alzheimers Dement 10, 381-392.
157. Vemuri P, Wiste HJ, Weigand SD, Shaw LM, Trojanowski JQ, Weiner MW, Knopman DS, Petersen RC, Jack CR Jr, Alzheimer's Disease Neuroimaging I (2009) MRI and CSF biomarkers in normal, MCI, and AD subjects: Predicting future clinical change. Neurology 73, 294-301.
158. Brys M, Glodzik L, Mosconi L, Switalski R, De Santi S, Pir-raglia E, Rich K, Kim BC, Mehta P, Zinkowski R, Pratico D, Wallin A, Zetterberg H, Tsui WH, Rusinek H, Blennow K, de Leon MJ (2009) Magnetic resonance imaging improves cerebrospinal fluid biomarkers in the early detection of Alzheimer's disease. J Alzheimers Dis 16, 351-362.
159. Profenno LA, Porsteinsson AP, Faraone SV (2010) Meta-analysis of Alzheimer's disease risk with obesity, diabetes, and related disorders. Biol Psychiatry 67, 505-512.
160. Girouard H, Iadecola C (2006) Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease. J Appl Physiol (1985) 100, 328-335.
161. Carlsson CM (2010) Type 2 diabetes mellitus, dyslipidemia, and Alzheimer's disease. J Alzheimers Dis 20, 711-722.
162. Cataldo JK, Prochaska JJ, Glantz SA (2010) Cigarette smoking is a risk factor for Alzheimer's disease: An analysis controlling for tobacco industry affiliation. J Alzheimers Dis 19, 465-480.
163. Katzman R (1993) Education andthe prevalenceofdementia and Alzheimer's disease. Neurology 43, 13-20.
164. Mayeux R, Ottman R, Maestre G, Ngai C, Tang MX, Ginsberg H, Chun M, Tycko B, Shelanski M (1995) Synergistic effects of traumatic head injury and apolipoprotein-epsilon 4 in patients with Alzheimer's disease. Neurology 45, 555-557.
165. Tan CC, Yu JT, Tan MS, Jiang T, Zhu XC, Tan L (2014) Autophagy in aging and neurodegenerative diseases: Implications for pathogenesis and therapy. Neurobiol Aging 35, 941-957.
166. Holtzman DM (2011) CSF biomarkers for Alzheimer's disease: Current utility and potential future use. Neurobiol Aging 32 (Suppl 1), S4-S9.
167. Perry G, Castellani RJ, Moreira PI, Lee HG, Zhu X, Smith MA (2008) Pathology's new role: Defining disease process and protective responses. Int J Clin Exp Pathol 1, 1-4.