Vulnerability and resilience to Alzheimer’s disease: early life conditions modulate neuropathology and determine cognitive reserve

1.

Selkoe DJ, Schenk D. Alzheimer’s disease: molecular understanding predicts amyloid-based therapeutics. Annu Rev Pharmacol Toxicol. 2003;43:545–84. https://doi.org/10.1146/annurev.pharmtox.43.100901.140248.CrossRefPubMed

2.

Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, et al. Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991;30:572–80. https://doi.org/10.1002/ana.410300410.CrossRefPubMed

3.

Querfurth HW, LaFerla FM. Alzheimer’s disease. N Engl J Med. 2010;362:329–44. https://doi.org/10.1056/NEJMra0909142.CrossRefPubMed

4.

Scheltens P, Blennow K, Breteler MMB, de Strooper B, Frisoni GB, Salloway S, et al. Alzheimer’s disease. Lancet. 2016;388:505–17.CrossRefPubMed

5.

Campion D, Dumanchin C, Hannequin D, Dubois B, Belliard S, Puel M, et al. Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999;65:664–70.CrossRefPubMedCentralPubMed

6.

Matthews FE, Arthur A, Barnes LE, Bond J, Jagger C, Robinson L, et al. A two-decade comparison of prevalence of dementia in individuals aged 65 years and older from three geographical areas of England: results of the Cognitive Function and Ageing Study I and II. Lancet. 2013;382:1405–12.CrossRefPubMedCentralPubMed

7.

Baumgart M, Snyder HM, Carrillo MC, Fazio S, Kim H, Johns H. Summary of the evidence on modifiable risk factors for cognitive decline and dementia: a population-based perspective. Alzheimers Dement. 2015;11:718–26. https://doi.org/10.1016/j.jalz.2015.05.016.CrossRefPubMed

8.

Xu W, Tan L, Wang H-F, Jiang T, Tan M-S, Tan L, et al. Meta-analysis of modifiable risk factors for Alzheimer’s disease. Cogn Neurol. 2015;86:1299–306. https://doi.org/10.1136/jnnp-2015-310548.

9.

Abbott RD, White LR, Ross GW, Masaki KH, Curb JD, Petrovitch H. Walking and dementia in physically capable elderly men. JAMA. 2004;292:1447. https://doi.org/10.1001/jama.292.12.1447.CrossRefPubMed

10.

Barnard ND, Bush AI, Ceccarelli A, Cooper J, de Jager CA, Erickson KI, et al. Dietary and lifestyle guidelines for the prevention of Alzheimer’s disease. Neurobiol Aging. 2014;35:S74–8. https://doi.org/10.1016/J.NEUROBIOLAGING.2014.03.033.CrossRefPubMed

11.

Daffner KR. Promoting successful cognitive aging: a comprehensive review. J Alzheimers Dis. 2010;19:1101–22. https://doi.org/10.3233/JAD-2010-1306.CrossRefPubMedPubMedCentral

12.

Fratiglioni L, Qiu C. Prevention of common neurodegenerative disorders in the elderly. Exp Gerontol. 2009;44:46–50.CrossRefPubMed

13.

Friedland RP, Fritsch T, Smyth KA, Koss E, Lerner AJ, Chen CH, et al. Patients with Alzheimer’s disease have reduced activities in midlife compared with healthy control-group members. Proc Natl Acad Sci U S A. 2001;98:3440–5. https://doi.org/10.1073/pnas.061002998.CrossRefPubMedPubMedCentral

14.

Gates N, Valenzuela M. Cognitive exercise and its role in cognitive function in older adults. Curr Psychiatry Rep. 2010;12:20–7. https://doi.org/10.1007/s11920-009-0085-y.CrossRefPubMed

15.

Papp KV, Walsh SJ, Snyder PJ. Immediate and delayed effects of cognitive interventions in healthy elderly: a review of current literature and future directions. Alzheimers Dement. 2009;5:50–60. https://doi.org/10.1016/j.jalz.2008.10.008.CrossRefPubMed

16.

Riley KP, Snowdon DA, Desrosiers MF, Markesbery WR. Early life linguistic ability, late life cognitive function, and neuropathology: findings from the Nun Study. Neurobiol Aging. 2005;26:341–7. https://doi.org/10.1016/j.neurobiolaging.2004.06.019.CrossRefPubMed

17.

Stern Y. Cognitive reserve. Neuropsychologia. 2009;47:2015–28. https://doi.org/10.1016/j.neuropsychologia.2009.03.004.CrossRefPubMedPubMedCentral

18.

Tyas SL, Snowdon DA, Desrosiers MF, Riley KP, Markesbery WR. Healthy ageing in the Nun Study: definition and neuropathologic correlates. Age Ageing. 2007;36:650–5. https://doi.org/10.1093/ageing/afm120.CrossRefPubMed

19.

Mejía S, Giraldo M, Pineda D, Ardila A, Lopera F. Nongenetic factors as modifiers of the age of onset of familial Alzheimer’s disease. Int Psychogeriatr. 2003;15:337–49. https://doi.org/10.1017/S1041610203009591.CrossRefPubMed

20.

Arsenault-Lapierre G, Chertkow H, Lupien S. Seasonal effects on cortisol secretion in normal aging, mild cognitive impairment and Alzheimer’s disease. Neurobiol Aging. 2010;31:1051–4.CrossRefPubMed

21.

Herbert J, Lucassen P. Depression as a risk factor for Alzheimer’s disease: genes, steroids, cytokines and neurogenesis—what do we need to know? Neuroendocrinology. 2016;41:153–71.CrossRef

22.

Csernansky JG, Dong H, Fagan AM, Wang L, Xiong C, Holtzman DM, et al. Plasma cortisol and progression of dementia in subjects with Alzheimer-type dementia. Am J Psychiatry. 2006;163:2164–9. https://doi.org/10.1176/appi.ajp.163.12.2164.CrossRefPubMedPubMedCentral

23.

Hoogendijk WJG, Meynen G, Endert E, Hofman MA, Swaab DF. Increased cerebrospinal fluid cortisol level in Alzheimer’s disease is not related to depression. Neurobiol Aging. 2006;27:780.e1–2.CrossRef

24.

Rasmuson S, Näsman B, Carlström K, Olsson T. Increased levels of adrenocortical and gonadal hormones in mild to moderate Alzheimer’s disease. Dement Geriatr Cogn Disord. 2002;13:74–9. http://www.scopus.com/inward/record.url?eid=2-s2.0-0036177775&partnerID=40&md5=b1702d2ed86d643dd7f8df8e2c0f9491 CrossRefPubMed

25.

Näsman B, Olsson T, Viitanen M, Carlström K. A subtle disturbance in the feedback regulation hypothalamic-pituitary-adrenal axis in the early phase of Alzheimer’s disease. Psychoneuroendocrinology. 1995;20:211–20.CrossRefPubMed

26.

Elgh E, Lindqvist Astot A, Fagerlund M, Eriksson S, Olsson T, Näsman B. Cognitive dysfunction, hippocampal atrophy and glucocorticoid feedback in Alzheimer’s disease. Biol Psychiatry. 2006;59:155–61. https://doi.org/10.1016/j.biopsych.2005.06.017.CrossRefPubMed

27.

Raadsheer FC, Van Heerikhuize JJ, Lucassen PJ, Hoogendijk WJG, Tilders FJH, Swaab DF. Corticotropin-releasing hormone mRNA levels in the paraventricular nucleus of patients with Alzheimer’s disease and depression. Am J Psychiatry. 1995;152:1372–6.CrossRefPubMed

28.

Wang H-X, MacDonald SWS, Dekhtyar S, Fratiglioni L, Mante M, Saitoh T. Association of lifelong exposure to cognitive reserve-enhancing factors with dementia risk: a community-based cohort study. PLoS Med. 2017;14:e1002251. https://doi.org/10.1371/journal.pmed.1002251.CrossRefPubMedPubMedCentral

29.

Andersen SL, Teicher MH. Stress, sensitive periods and maturational events in adolescent depression. Trends Neurosci. 2008;31:183–91. https://doi.org/10.1016/J.TINS.2008.01.004.CrossRefPubMed

30.

Cirulli F, Berry A, Alleva E. Early disruption of the mother–infant relationship: effects on brain plasticity and implications for psychopathology. Neurosci Biobehav Rev. 2003;27:73–82. https://doi.org/10.1016/S0149-7634(03)00010-1.CrossRefPubMed

31.

Davidson RJ, McEwen BS. Social influences on neuroplasticity: stress and interventions to promote well-being. Nat Neurosci. 2012;15:689–95. https://doi.org/10.1038/nn.3093.CrossRefPubMedPubMedCentral

32.

Fox SE, Levitt P, Nelson CA III. How the timing and quality of early experiences influence the development of brain architecture. Child Dev. 2010;81:28–40. https://doi.org/10.1111/j.1467-8624.2009.01380.x.CrossRefPubMedPubMedCentral

33.

Knudsen EI. Sensitive periods in the development of the brain and behavior. J Cogn Neurosci. 2004;16:1412–25. https://doi.org/10.1162/0898929042304796.CrossRefPubMed

34.

Liu D, Diorio J, Day JC, Francis DD, Meaney MJ. Maternal care, hippocampal synaptogenesis and cognitive development in rats. Nat Neurosci. 2000;3:799–806. https://doi.org/10.1038/77702.CrossRefPubMed

35.

Roth TL, Sweatt JD. Annual Research Review: Epigenetic mechanisms and environmental shaping of the brain during sensitive periods of development. J Child Psychol Psychiatry. 2011;52:398–408. https://doi.org/10.1111/j.1469-7610.2010.02282.x.CrossRefPubMedPubMedCentral

36.

Teicher MH, Samson JA, Anderson CM, Ohashi K. The effects of childhood maltreatment on brain structure, function and connectivity. Nat Rev Neurosci. 2016;17:652–66. https://doi.org/10.1038/nrn.2016.111.CrossRefPubMed

37.

Bale TL, Baram TZ, Brown AS, Goldstein JM, Insel TR, McCarthy MM, et al. Early life programming and neurodevelopmental disorders. Biol Psychiatry. 2010;68:314–9. https://doi.org/10.1016/j.biopsych.2010.05.028.CrossRefPubMedPubMedCentral

38.

Heim C, Binder EB. Current research trends in early life stress and depression: review of human studies on sensitive periods, gene–environment interactions, and epigenetics. Exp Neurol. 2012;233:102–11. https://doi.org/10.1016/J.EXPNEUROL.2011.10.032.CrossRefPubMed

39.

McEwen BS. Central effects of stress hormones in health and disease: understanding the protective and damaging effects of stress and stress mediators. Eur J Pharmacol. 2008;583:174–85. https://doi.org/10.1016/j.ejphar.2007.11.071.CrossRefPubMedPubMedCentral

40.

Raineki C, Szawka RE, Gomes CM, Lucion MK, Barp J, Belló-Klein A, et al. Effects of neonatal handling on central noradrenergic and nitric oxidergic systems and reproductive parameters in female rats. Neuroendocrinology. 2008;87:151–9. https://doi.org/10.1159/000112230.CrossRefPubMed

41.

Lesuis SL, van Hoek BACE, Lucassen PJ, Krugers HJ. Early postnatal handling reduces hippocampal amyloid plaque formation and enhances cognitive performance in APPswe/PS1dE9 mice at middle age. Neurobiol Learn Mem. 2017;144:27–35. https://doi.org/10.1016/J.NLM.2017.05.016.CrossRefPubMed

42.

Sierksma ASR, Prickaerts J, Chouliaras L, Rostamian S, Delbroek L, Rutten BPF, et al. Behavioral and neurobiological effects of prenatal stress exposure in male and female APPswe/PS1dE9 mice. Neurobiol Aging. 2013;34:319–37. https://doi.org/10.1016/j.neurobiolaging.2012.05.012.CrossRefPubMed

43.

Hui J, Feng G, Zheng C, Jin H, Jia N. Maternal separation exacerbates Alzheimer’s disease-like behavioral and pathological changes in adult APPswe/PS1dE9 mice. Behav Brain Res. 2017;318:18–23. https://doi.org/10.1016/j.bbr.2016.10.030.CrossRefPubMed

44.

Lesuis SL, Weggen S, Baches S, Lucassen PJ, Krugers HJ. Early life stress accelerates amyloid pathology and cognitive decline in APPswe/PS1dE9 mice; rescue by briefly blocking GRs at middle age. Transl Psychiatry. 2018;8(1):53.

45.

Hoeijmakers L, Ruigrok SR, Amelianchik A, Ivan D, van Dam A-M, Lucassen PJ, et al. Early-life stress lastingly alters the neuroinflammatory response to amyloid pathology in an Alzheimer’s disease mouse model. Brain Behav Immun. 2016;63:160-75.CrossRefPubMed

46.

Lesuis SL, Maurin H, Borghgraef P, Lucassen PJ, Van Leuven F, Krugers HJ. Positive and negative early life experiences differentially modulate long term survival and amyloid protein levels in a mouse model of Alzheimer’s disease. Oncotarget. 2016;7(26):39118-35.

47.

Martisova E, Aisa B, Guerenu G, Ramirez M. Effects of early maternal separation on biobehavioral and neuropathological markers of Alzheimer’s disease in adult male rats. Curr Alzheimer Res. 2013;10:420–32.CrossRefPubMed

48.

Cordner ZA, Tamashiro KLK. Effects of chronic variable stress on cognition and Bace1 expression among wild-type mice. Transl Psychiatry. 2016;6:e854. https://doi.org/10.1038/tp.2016.127.CrossRefPubMedPubMedCentral

49.

Fujio J, Hosono H, Ishiguro K, Ikegami S, Fujita SC. Tau phosphorylation in the mouse brain during aversive conditioning. Neurochem Int. 2007;51:200–8. https://doi.org/10.1016/j.neuint.2007.04.024.CrossRefPubMed

50.

Sotiropoulos I, Catania C, Pinto LG, Silva R, Pollerberg GE, Takashima A, et al. Stress acts cumulatively to precipitate Alzheimer’s disease-like tau pathology and cognitive deficits. J Neurosci. 2011;31:7840–7. https://doi.org/10.1523/JNEUROSCI.0730-11.2011.CrossRefPubMedPubMedCentral

51.

Yang C, Guo X, Wang GH, Wang HL, Liu ZC, Liu H, et al. Changes in tau phosphorylation levels in the hippocampus and frontal cortex following chronic stress. Brazilian J Med Biol Res = Rev Bras Pesqui medicas e Biol. 2014;47:237–44. https://doi.org/10.1590/1414-431X20133275.CrossRef

52.

Nogueira ML, Hamraz M, Abolhassani M, Bigan E, Lafitte O, Steyaert J-M, et al. Mechanical stress increases brain amyloid β, tau, and α-synuclein concentrations in wild-type mice. Alzheimers Dement. 2017;14(4):444-53. https://doi.org/10.1016/j.jalz.2017.11.003.CrossRef

53.

Lopes S, Vaz-Silva J, Pinto V, Dalla C, Kokras N, Bedenk B, et al. Tau protein is essential for stress-induced brain pathology. Proc Natl Acad Sci U S A. 2016;113:E3755–63. https://doi.org/10.1073/pnas.1600953113.CrossRefPubMedPubMedCentral

54.

Cañete T, Blázquez G, Tobeña A, Giménez-Llort L, Fernández-Teruel A. Cognitive and emotional alterations in young Alzheimer’s disease (3xTgAD) mice: effects of neonatal handling stimulation and sexual dimorphism. Behav Brain Res. 2015;281:156–71. https://doi.org/10.1016/j.bbr.2014.11.004.CrossRefPubMed

55.

Wang Y-J, Zhou H-D, Zhou X-F. Clearance of amyloid-beta in Alzheimer’s disease: progress, problems and perspectives. Drug Discov Today. 2006;11:931–8. https://doi.org/10.1016/J.DRUDIS.2006.08.004.CrossRefPubMed

56.

de Kloet E, Joëls M, Holsboer F. Stress and the brain: from adaptation to disease. Nat Rev Neurosci. 2005;6:463–75. https://doi.org/10.1038/nrn1683.CrossRefPubMed

57.

Davis KL, Davis BM, Greenwald BS, Mohs RC, Mathé AA, Johns CA, et al. Cortisol and Alzheimer’s disease. I: basal studies. Am J Psychiatry. 1986;143:300–5.CrossRefPubMed

58.

Masugi F, Ogihara T, Sakaguchi K, Otsuka A, Tsuchiya Y, Morimoto S, et al. High plasma levels of cortisol in patients with senile dementia of the Alzheimer’s type. Methods Find Exp Clin Pharmacol. 1989;11:707–10. http://www.ncbi.nlm.nih.gov/pubmed/2560104. Accessed 21 Feb 2016PubMed

59.

Olsson T, Näsman B, Rasmuson S, Ahrén B. Dual relation between leptin and cortisol in humans is disturbed in Alzheimer’s disease. Biol Psychiatry. 1998;44:374–6. http://www.ncbi.nlm.nih.gov/pubmed/9755363. Accessed 22 Apr 2017CrossRefPubMed

60.

Näsman B, Olsson T, Fagerlund M, Eriksson S, Viitanen M, Carlström K. Blunted adrenocorticotropin and increased adrenal steroid response to human corticotropin-releasing hormone in Alzheimer’s disease. Biol Psychiatry. 1996;39:311–8.CrossRefPubMed

61.

Greenwald BS, Mathé AA, Mohs RC, Levy M, Johns CA, Davis KL. Cortisol and Alzheimer’s disease, II: dexamethasone suppression, dementia severity, and affective symptoms. Am J Psychiatry. 1986;143:442–6.CrossRefPubMed

62.

Popp J, Wolfsgruber S, Heuser I, Peters O, Hüll M, Schröder J, et al. Cerebrospinal fluid cortisol and clinical disease progression in MCI and dementia of Alzheimer’s type. Neurobiol Aging. 2015;36:601–7. https://doi.org/10.1016/j.neurobiolaging.2014.10.031.CrossRefPubMed

63.

Swanwick GRJ, Kirby M, Bruce I, Buggy F, Coen RF, Coakley D, et al. Hypothalamic-pituitary-adrenal axis dysfunction in Alzheimer’s disease: lack of association between longitudinal and cross-sectional findings. Am J Psychiatry. 1998;155:286–9.CrossRefPubMed

64.

Swaab DF, Bao A-M, Lucassen PJ. The stress system in the human brain in depression and neurodegeneration. Ageing Res Rev. 2005;4:141–94.CrossRefPubMed

65.

Green K, Billings L, Roozendaal B, McGaugh J, LaFerla F. Glucocorticoids increase amyloid-β and tau pathology in a mouse model of Alzheimer’s disease. J Neurosci. 2006;26:9047–56. https://doi.org/10.1523/JNEUROSCI.2797-06.2006.CrossRefPubMedPubMedCentral

66.

Catania C, Sotiropoulos I, Silva R, Onofri C, Breen KC, Sousa N, et al. The amyloidogenic potential and behavioral correlates of stress. Mol Psychiatry. 2009;14:95–105.CrossRefPubMed

67.

Vallée M, Mayo W, Dellu F, Le Moal M, Simon H, Maccari S. Prenatal stress induces high anxiety and postnatal handling induces low anxiety in adult offspring: correlation with stress-induced corticosterone secretion. J Neurosci. 1997;17:2626–36. http://www.ncbi.nlm.nih.gov/pubmed/9065522. Accessed 9 Dec 2017CrossRefPubMedCentralPubMed

68.

Ivy AS, Rex CS, Chen Y, Maras PM, Grigoriadis DE, Gall CM, et al. Hippocampal dysfunction and cognitive impairments provoked by chronic early-life stress involve excessive activation of CRH receptors. J Neurosci. 2010;30:13005–15.CrossRefPubMed

69.

Lucassen PJ, Mü MB, Holsboer F, Bauer J, Holtrop A, Wouda J, et al. Hippocampal apoptosis in major depression is a minor event and absent from subareas at risk for glucocorticoid overexposure. Am J Pathol. 2001;158:453–68. https://doi.org/10.1016/S0002-9440(10)63988-0.CrossRefPubMedPubMedCentral

70.

Müller MB, Lucassen PJ, Yassouridis A, Hoogendijk WJ, Holsboer F, Swaab DF. Neither major depression nor glucocorticoid treatment affects the cellular integrity of the human hippocampus. Eur J Neurosci. 2001;14:1603–12. http://www.ncbi.nlm.nih.gov/pubmed/11860455. Accessed 5 Feb 2018CrossRefPubMed

71.

Solas M, Aisa B, Tordera RM, Mugueta MC, Ramírez MJ. Stress contributes to the development of central insulin resistance during aging: implications for Alzheimer’s disease. Biochim Biophys Acta. 1832;2013:2332–9. https://doi.org/10.1016/j.bbadis.2013.09.013.CrossRef

72.

Solas M, Aisa B, Mugueta MC, Del Río J, Tordera RM, Ramírez MJ. Interactions between age, stress and insulin on cognition: implications for Alzheimer’s disease. Neuropsychopharmacology. 2010;35:1664–73. https://doi.org/10.1038/npp.2010.13.CrossRefPubMedPubMedCentral

73.

Sambamurti K, Kinsey R, Maloney B, Ge Y, Lahiri D. Gene structure and organization of the human β-secretase (BACE) promoter. FASEB J. 2004;18:1034–6. https://doi.org/10.1096/fj.03-1378fje.CrossRefPubMed

74.

Baglietto-Vargas D, Medeiros R, Martinez-Coria H, Laferla FM, Green KN. Mifepristone alters amyloid precursor protein processing to preclude amyloid beta and also reduces tau pathology. Biol Psychiatry. 2013;74:357–66. https://doi.org/10.1016/j.biopsych.2012.12.003.CrossRefPubMedPubMedCentral

75.

Martisova E, Solas M, Gerenu G, Milagro FI, Campion J, Ramirez MJ. Mechanisms involved in BACE upregulation associated to stress. Curr Alzheimer Res. 2012;9:822–9. http://www.ncbi.nlm.nih.gov/pubmed/22631614. Accessed 14 Dec 2017CrossRefPubMed

76.

De Souza EB, Whitehouse PJ, Price DL, Vale WW. Abnormalities in corticotropin-releasing hormone (CRH) in Alzheimer’s disease and other human disorders. Ann N Y Acad Sci. 1987;512:237–47. http://www.ncbi.nlm.nih.gov/pubmed/3502064. Accessed 30 Dec 2017CrossRefPubMed

77.

May C, Rapoport SI, Tomai TP, Chrousos GP, Gold PW. Cerebrospinal fluid concentrations of corticotropin-releasing hormone (CRH) and corticotropin (ACTH) are reduced in patients with Alzheimer’s disease. Neurology. 1987;37:535–8. http://www.ncbi.nlm.nih.gov/pubmed/3029628. Accessed 30 Dec 2017CrossRefPubMed

78.

Pedersen WA, McCullers D, Culmsee C, Haughey NJ, Herman JP, Mattson MP. Corticotropin-releasing hormone protects neurons against insults relevant to the pathogenesis of Alzheimer’s disease. Neurobiol Dis. 2001;8:492–503. https://doi.org/10.1006/nbdi.2001.0395.CrossRefPubMed

79.

Lezoualc’h F, Engert S, Berning B, Behl C. Corticotropin-releasing hormone-mediated neuroprotection against oxidative stress is associated with the increased release of non-amyloidogenic amyloid beta precursor protein and with the suppression of nuclear factor-kappaB. Mol Endocrinol. 2000;14:147–59. https://doi.org/10.1210/mend.14.1.0403.CrossRefPubMed

80.

Bayatti N, Behl C. The neuroprotective actions of corticotropin releasing hormone. Ageing Res Rev. 2005;4:258–70. https://doi.org/10.1016/j.arr.2005.02.004.CrossRefPubMed

81.

Baglietto-Vargas D, Chen Y, Suh D, Ager RR, Rodriguez-Ortiz CJ, Medeiros R, et al. Short-term modern life-like stress exacerbates Aβ-pathology and synapse loss in 3xTg-AD mice. J Neurochem. 2015;134:915–26. https://doi.org/10.1111/jnc.13195.CrossRefPubMedPubMedCentral

82.

Dong H, Murphy KM, Meng L, Montalvo-Ortiz J, Zeng Z, Kolber BJ, et al. Corticotrophin releasing factor accelerates neuropathology and cognitive decline in a mouse model of Alzheimer’s disease. J Alzheimers Dis. 2012;28:579–92. https://doi.org/10.3233/JAD-2011-111328.CrossRefPubMedPubMedCentral

83.

Aisa B, Gil-Bea FJ, Marcos B, Tordera R, Lasheras B, Del Río J, et al. Neonatal stress affects vulnerability of cholinergic neurons and cognition in the rat: involvement of the HPA axis. Psychoneuroendocrinology. 2009;34:1495–505. https://doi.org/10.1016/j.psyneuen.2009.05.003.CrossRefPubMed

84.

Hebda-Bauer EK, Simmons TA, Sugg A, Ural E, Stewart JA, Beals JL, et al. 3xTg-AD mice exhibit an activated central stress axis during early-stage pathology. J Alzheimers Dis. 2013;33:407–22. https://doi.org/10.3233/JAD-2012-121438.CrossRefPubMedPubMedCentral

85.

Roberts KF, Elbert DL, Kasten TP, Patterson BW, Sigurdson WC, Connors RE, et al. Amyloid-β efflux from the central nervous system into the plasma. Ann Neurol. 2014;76:837–44. https://doi.org/10.1002/ana.24270.CrossRefPubMedPubMedCentral

86.

Kanekiyo T, Cirrito JR, Liu C-C, Shinohara M, Li J, Schuler DR, et al. Neuronal clearance of Amyloid-β by endocytic receptor LRP1. J Neurosci. 2013;33:19276–83. https://doi.org/10.1523/JNEUROSCI.3487-13.2013.CrossRefPubMedPubMedCentral

87.

Deane R, Du Yan S, Submamaryan RK, LaRue B, Jovanovic S, Hogg E, et al. RAGE mediates amyloid-β peptide transport across the blood-brain barrier and accumulation in brain. Nat Med. 2003;9:907–13. https://doi.org/10.1038/nm890.CrossRefPubMed

88.

Montagne A, Barnes SR, Sweeney MD, Halliday MR, Sagare AP, Zhao Z, et al. Blood-brain barrier breakdown in the aging human hippocampus. Neuron. 2015;85:296–302. https://doi.org/10.1016/j.neuron.2014.12.032.CrossRefPubMedPubMedCentral

89.

Menard C, Pfau ML, Hodes GE, Kana V, Wang VX, Bouchard S, et al. Social stress induces neurovascular pathology promoting depression. Nat Neurosci. 2017;20:1752–60. https://doi.org/10.1038/s41593-017-0010-3.CrossRefPubMedPubMedCentral

90.

Sántha P, Veszelka S, Hoyk Z, Mészáros M, Walter FR, Tóth AE, et al. Restraint stress-induced morphological changes at the blood-brain barrier in adult rats. Front Mol Neurosci. 2016;8:88. https://doi.org/10.3389/fnmol.2015.00088.CrossRefPubMedPubMedCentral

91.

Lee CYD, Landreth GE. The role of microglia in amyloid clearance from the AD brain. J Neural Transm. 2010;117:949–60. https://doi.org/10.1007/s00702-010-0433-4.CrossRefPubMed

92.

Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP, et al. Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci U S A. 2003;100:4162–7. https://doi.org/10.1073/pnas.0230450100.CrossRefPubMedPubMedCentral

93.

Harada S, Smith R, Hu D, Jarett L. Dexamethasone inhibits insulin binding to insulin-degrading enzyme and cytosolic insulin-binding protein p82. Biochem Biophys Res Commun. 1996;218:154–8.CrossRefPubMed

94.

Osborn LM, Kamphuis W, Wadman WJ, Hol EM. Astrogliosis: an integral player in the pathogenesis of Alzheimer’s disease. Prog Neurobiol. 2016;144:121–41.CrossRefPubMed

95.

ElAli A, Rivest S. Microglia in Alzheimer’s disease: a multifaceted relationship. Brain Behav Immun. 2016;55:138–50. https://doi.org/10.1016/j.bbi.2015.07.021.CrossRefPubMed

96.

Pekny M, Pekna M, Messing A, Steinhäuser C, Lee J-M, Parpura V, et al. Astrocytes: a central element in neurological diseases. Acta Neuropathol. 2016;131:323–45. https://doi.org/10.1007/s00401-015-1513-1.CrossRefPubMed

97.

Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015;14:388–405. https://doi.org/10.1016/S1474-4422(15)70016-5.CrossRefPubMedPubMedCentral

98.

Hoeijmakers L, Lucassen PJ, Korosi A. The interplay of early-life stress, nutrition, and immune activation programs adult hippocampal structure and function. Front Mol Neurosci. 2015;7:103. https://doi.org/10.3389/fnmol.2014.00103.CrossRefPubMedPubMedCentral

99.

Hoeijmakers L, Heinen Y, van Dam A-M, Lucassen PJ, Korosi A. Microglial priming and Alzheimer’s disease: a possible role for (early) immune challenges and epigenetics? Front Hum Neurosci. 2016;10:398. https://doi.org/10.3389/fnhum.2016.00398.CrossRefPubMedPubMedCentral

100.

Johnson FK, Kaffman A. Early life stress perturbs the function of microglia in the developing rodent brain: new insights and future challenges. Brain Behav Immun. 2017;69:18-27. https://doi.org/10.1016/j.bbi.2017.06.008.CrossRefPubMed

101.

Li Q, Barres BA. Microglia and macrophages in brain homeostasis and disease. Nat Rev Immunol. 2018;18(4):225-42. https://doi.org/10.1038/nri.2017.125.CrossRefPubMed

102.

Füger P, Hefendehl JK, Veeraraghavalu K, Wendeln A-C, Schlosser C, Obermüller U, et al. Microglia turnover with aging and in an Alzheimer’s model via long-term in vivo single-cell imaging. Nat Neurosci. 2017;20:1371–6. https://doi.org/10.1038/nn.4631.CrossRefPubMed

103.

Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017;541:481–7. https://doi.org/10.1038/nature21029.CrossRefPubMedPubMedCentral

104.

Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016;352:712–6. https://doi.org/10.1126/science.aad8373.CrossRefPubMedPubMedCentral

105.

Schwarz JM, Hutchinson MR, Bilbo SD. Early-life experience decreases drug-induced reinstatement of morphine CPP in adulthood via microglial-specific epigenetic programming of anti-inflammatory IL-10 expression. J Neurosci. 2011;31:17835–47. https://doi.org/10.1523/JNEUROSCI.3297-11.2011.CrossRefPubMedPubMedCentral

106.

Swaab DF. Brain aging and Alzheimer’s disease, “wear and tear” versus “use it or lose it”. Neurobiol Aging. 12:317–24. http://www.ncbi.nlm.nih.gov/pubmed/1755879. Accessed 11 Feb 2018CrossRefPubMed

107.

Ince G. Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales. Lancet. 2001;357:169–75. https://doi.org/10.1016/S0140-6736(00)03589-3.CrossRef

108.

Stern Y, Gurland B, Tatemichi TK, Tang MX, Wilder D, Mayeux R. Influence of education and occupation on the incidence of Alzheimer’s disease. JAMA J Am Med Assoc. 1994;271:1004. https://doi.org/10.1001/jama.1994.03510370056032.CrossRef

109.

Bennett DA, Wilson RS, Schneider JA, Evans DA, Mendes de Leon CF, Arnold SE, et al. Education modifies the relation of AD pathology to level of cognitive function in older persons. Neurology. 2003;60:1909–15. http://www.ncbi.nlm.nih.gov/pubmed/12821732. Accessed 18 Apr 2017CrossRefPubMed

110.

Dekhtyar S, Wang H-X, Scott K, Goodman A, Koupil I, Herlitz A. A life-course study of cognitive reserve in dementia-from childhood to old age. Am J Geriatr Psychiatry. 2015;23:885–96. https://doi.org/10.1016/j.jagp.2015.02.002.CrossRefPubMed

111.

Scarmeas N, Levy G, Tang MX, Manly J, Stern Y. Influence of leisure activity on the incidence of Alzheimer’s disease. Neurology. 2001;57:2236–42. http://www.ncbi.nlm.nih.gov/pubmed/11756603. Accessed 20 Dec 2017CrossRefPubMed

112.

Bartolotti N, Lazarov O. Lifestyle and Alzheimer’s disease. In: Genes, environment and Alzheimer’s disease. London: Elsevier; 2016. p. 197–237. https://doi.org/10.1016/B978-0-12-802851-3.00007-3.CrossRef

113.

Ravona-Springer R, Beeri MS, Goldbourt U. Younger age at crisis following parental death in male children and adolescents is associated with higher risk for dementia at old age. Alzheimer Dis Assoc Disord. 2012;26:68–73. https://doi.org/10.1097/WAD.0b013e3182191f86.CrossRefPubMedPubMedCentral

114.

Bloss EB, Janssen WG, Ohm DT, Yuk FJ, Wadsworth S, Saardi KM, et al. Evidence for reduced experience-dependent dendritic spine plasticity in the aging prefrontal cortex. J Neurosci. 2011;31:7831–9. https://doi.org/10.1523/JNEUROSCI.0839-11.2011.CrossRefPubMedPubMedCentral

115.

Wagner AP, Schmoll H, Badan I, Platt D, Kessler C. Brain plasticity: to what extent do aged animals retain the capacity to coordinate gene activity in response to acute challenges. Exp Gerontol. 2000;35:1211–27. http://ac.els-cdn.com/S0531556500001546/1-s2.0-S0531556500001546-main.pdf?_tid=cf065e9a-2447-11e7-8237-00000aacb35e&acdnat=1492527829_6ae9053199753dcba936a1a713cb3b78. Accessed 18 Apr 2017CrossRefPubMed

116.

Stern Y, Albert S, Tang MX, Tsai WY. Rate of memory decline in AD is related to education and occupation: cognitive reserve? Neurology. 1999;53:1942–7. https://doi.org/10.1212/WNL.53.9.1942.CrossRefPubMed

117.

Scarmeas N, Albert SM, Manly JJ, Stern Y. Education and rates of cognitive decline in incident Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 2006;77:308–16. https://doi.org/10.1136/jnnp.2005.072306.CrossRefPubMedPubMedCentral

118.

Barulli D, Stern Y. Efficiency, capacity, compensation, maintenance, plasticity: emerging concepts in cognitive reserve. Trends Cogn Sci. 2013;17:502–9. https://doi.org/10.1016/j.tics.2013.08.012.CrossRefPubMed

119.

Granger MW, Franko B, Taylor MW, Messier C, George-Hyslop PS, Bennett SAL. A TgCRND8 mouse model of Alzheimer’s disease exhibits sexual dimorphisms in behavioral indices of cognitive reserve. J Alzheimers Dis. 2016;51:757–73. https://doi.org/10.3233/JAD-150587.CrossRefPubMed

120.

Vogel S, Klumpers F, Kroes MCW, Oplaat KT, Krugers HJ, Oitzl MS, et al. A stress-induced shift from trace to delay conditioning depends on the mineralocorticoid receptor. Biol Psychiatry. 2015;78:830–9. https://doi.org/10.1016/j.biopsych.2015.02.014.CrossRefPubMed

121.

Schwabe L, Dalm S, Schächinger H, Oitzl MS. Chronic stress modulates the use of spatial and stimulus-response learning strategies in mice and man. Neurobiol Learn Mem. 2008;90:495–503. https://doi.org/10.1016/j.nlm.2008.07.015.CrossRefPubMed

122.

Schwabe L, Tegenthoff M, Höffken O, Wolf OT. Mineralocorticoid receptor blockade prevents stress-induced modulation of multiple memory systems in the human brain. Biol Psychiatry. 2013;74:801–8. https://doi.org/10.1016/j.biopsych.2013.06.001.CrossRefPubMed

123.

Schwabe L, Wolf OT. Stress and multiple memory systems: from “thinking” to “doing”. Trends Cogn Sci. 2013;17:60–8. https://doi.org/10.1016/j.tics.2012.12.001.CrossRefPubMed

124.

Schwabe L, Schächinger H, de Kloet ER, Oitzl MS. Stress impairs spatial but not early stimulus–response learning. Behav Brain Res. 2010;213:50–5. https://doi.org/10.1016/j.bbr.2010.04.029.CrossRefPubMed

125.

Schwabe L, Schächinger H, de Kloet ER, Oitzl MS. Corticosteroids operate as a switch between memory systems. J Cogn Neurosci. 2010;22:1362–72. https://doi.org/10.1162/jocn.2009.21278.CrossRefPubMed

126.

Sutherland RJ, McDonald RJ, Savage DD. Prenatal exposure to moderate levels of ethanol can have long-lasting effects on hippocampal synaptic plasticity in adult offspring. Hippocampus. 1997;7:232–8. https://doi.org/10.1002/(SICI)1098-1063(1997)7:2<232::AID-HIPO9>3.0.CO;2-O.CrossRefPubMed

127.

Schwabe L, Bohbot VD, Wolf OT. Prenatal stress changes learning strategies in adulthood. Hippocampus. 2012;22:2136–43. https://doi.org/10.1002/hipo.22034.CrossRefPubMed

128.

Grissom EM, Hawley WR, Bromley-Dulfano SS, Marino SE, Stathopoulos NG, Dohanich GP. Learning strategy is influenced by trait anxiety and early rearing conditions in prepubertal male, but not prepubertal female rats. Neurobiol Learn Mem. 2012;98:174–81. https://doi.org/10.1016/j.nlm.2012.06.001.CrossRefPubMed

129.

Bock J, Gruss M, Becker S, Braun K. Experience-induced changes of dendritic spine densities in the prefrontal and sensory cortex: correlation with developmental time windows. Cereb Cortex. 2005;15:802–8. https://doi.org/10.1093/cercor/bhh181.CrossRefPubMed

130.

Bock J, Murmu MS, Biala Y, Weinstock M, Braun K. Prenatal stress and neonatal handling induce sex-specific changes in dendritic complexity and dendritic spine density in hippocampal subregions of prepubertal rats. Neuroscience. 2011;193:34–43. https://doi.org/10.1016/j.neuroscience.2011.07.048.CrossRefPubMed

131.

Murmu MS, Salomon S, Biala Y, Weinstock M, Braun K, Bock J. Changes of spine density and dendritic complexity in the prefrontal cortex in offspring of mothers exposed to stress during pregnancy. Eur J Neurosci. 2006;24:1477–87. https://doi.org/10.1111/j.1460-9568.2006.05024.x.CrossRefPubMed

132.

Kolb B, Mychasiuk R, Muhammad A, Li Y, Frost DO, Gibb R. Experience and the developing prefrontal cortex. Proc Natl Acad Sci U S A. 2012;109(Suppl 2):17186–93. https://doi.org/10.1073/pnas.1121251109.CrossRefPubMedPubMedCentral

133.

McEwen BS, Eiland L, Hunter RG, Miller MM. Stress and anxiety: structural plasticity and epigenetic regulation as a consequence of stress. Neuropharmacology. 2012;62:3–12. https://doi.org/10.1016/j.neuropharm.2011.07.014.CrossRefPubMed

134.

Brunson KL, Kramár E, Lin B, Chen Y, Colgin LL, Yanagihara TK, et al. Mechanisms of late-onset cognitive decline after early-life stress. J Neurosci. 2005;25:9328–38. https://doi.org/10.1523/JNEUROSCI.2281-05.2005.CrossRefPubMedPubMedCentral

135.

Wang X-D, Rammes G, Kraev I, Wolf M, Liebl C, Scharf SH, et al. Forebrain CRF₁ modulates early-life stress-programmed cognitive deficits. J Neurosci. 2011;31:13625–34. https://doi.org/10.1523/JNEUROSCI.2259-11.2011.CrossRefPubMedPubMedCentral

136.

Yang X, Liao X, Uribe-Mariño A, Liu R, Xie X, Jia J, et al. Stress during a critical postnatal period induces region-specific structural abnormalities and dysfunction of the prefrontal cortex via CRF1. Neuropsychopharmacology. 2015;40(5):1203–15. https://doi.org/10.1038/npp.2014.304.CrossRefPubMedCentral

137.

Guadagno A, Wong TP, Walker C-D. Morphological and functional changes in the preweaning basolateral amygdala induced by early chronic stress associate with anxiety and fear behavior in adult male, but not female rats. Prog Neuro-Psychopharmacology Biol Psychiatry. 2018;81:25–37. https://doi.org/10.1016/j.pnpbp.2017.09.025.CrossRef

138.

Bagot R, van Hasselt F, Champagne D, Meaney M, Krugers H, Joëls M. Maternal care determines rapid effects of stress mediators on synaptic plasticity in adult rat hippocampal dentate gyrus. Neurobiol Learn Mem. 2009;92:292–300. https://doi.org/10.1016/j.nlm.2009.03.004.CrossRefPubMed

139.

Champagne D, Bagot R, van Hasselt F, Ramakers G, Meaney M, de Kloet E, et al. Maternal care and hippocampal plasticity: evidence for experience-dependent structural plasticity, altered synaptic functioning, and differential responsiveness to glucocorticoids and stress. J Neurosci. 2008;28:6037–45. https://doi.org/10.1523/JNEUROSCI.0526-08.2008.CrossRefPubMedPubMedCentral

140.

Chocyk A, Bobula B, Dudys D, Przyborowska A, Majcher-Maślanka I, Hess G, et al. Early-life stress affects the structural and functional plasticity of the medial prefrontal cortex in adolescent rats. Eur J Neurosci. 2013;38:2089–107. https://doi.org/10.1111/ejn.12208.CrossRefPubMed

141.

Oomen CA, Soeters H, Audureau N, Vermunt L, Van Hasselt FN, Manders EMM, et al. Early maternal deprivation affects dentate gyrus structure and emotional learning in adult female rats. Psychopharmacology. 2011;214:249–60.CrossRefPubMed

142.

Oomen CA, Soeters H, Audureau N, Vermunt L, van Hasselt FN, Manders EMM, et al. Severe early life stress hampers spatial learning and neurogenesis, but improves hippocampal synaptic plasticity and emotional learning under high-stress conditions in adulthood. J Neurosci. 2010;30:6635–45. https://doi.org/10.1523/JNEUROSCI.0247-10.2010.CrossRefPubMedPubMedCentral

143.

Krugers HJ, Oomen CA, Gumbs M, Li M, Velzing EH, Joels M, et al. Maternal deprivation and dendritic complexity in the basolateral amygdala. Neuropharmacology. 2012;62:534–7. https://doi.org/10.1016/j.neuropharm.2011.09.022.CrossRefPubMed

144.

Harris JA, Devidze N, Verret L, Ho K, Halabisky B, Thwin MT, et al. Transsynaptic progression of amyloid-β-induced neuronal dysfunction within the entorhinal-hippocampal network. Neuron. 2010;68:428–41. https://doi.org/10.1016/j.neuron.2010.10.020.CrossRefPubMedPubMedCentral

145.

Reinders NR, Pao Y, Renner MC, da Silva-Matos CM, Lodder TR, Malinow R, et al. Amyloid-β effects on synapses and memory require AMPA receptor subunit GluA3. Proc Natl Acad Sci U S A. 2016;113:6526–34. https://doi.org/10.1073/pnas.1614249113.CrossRef

146.

Nimmrich V, Ebert U. Is Alzheimer’s disease a result of presynaptic failure? Synaptic dysfunctions induced by oligomeric β-amyloid. Rev Neurosci. 2009;20:1–12. https://doi.org/10.1515/REVNEURO.2009.20.1.1.CrossRefPubMed

147.

Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, et al. Diffusible, nonfibrillar ligands derived from Aβ1–42 are potent central nervous system neurotoxins. Neurobiology. 1998;95:6448–53. http://www.pnas.org/content/95/11/6448.full.pdf. Accessed 1 Jan 2018

148.

Wang H-W, Pasternak JF, Kuo H, Ristic H, Lambert MP, Chromy B, et al. Soluble oligomers of β amyloid (1-42) inhibit long-term potentiation but not long-term depression in rat dentate gyrus. Brain Res. 2002;924:133–40. https://doi.org/10.1016/S0006-8993(01)03058-X.CrossRefPubMed

149.

Lesné S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, et al. A specific amyloid-β protein assembly in the brain impairs memory. Nature. 2006;440:352–7. https://doi.org/10.1038/nature04533.CrossRefPubMed

150.

Shankar GM, Bloodgood BL, Townsend M, Walsh DM, Selkoe DJ, Sabatini BL. Natural oligomers of the Alzheimer amyloid-β protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. Nat Med. 2008;14:837–42. https://doi.org/10.1523/JNEUROSCI.4970-06.2007.CrossRefPubMedPubMedCentral

151.

Barry AE, Klyubin I, Mc Donald JM, Mably AJ, Farrell MA, Scott M, et al. Alzheimer’s disease brain-derived amyloid-β-mediated inhibition of LTP in vivo is prevented by immunotargeting cellular prion protein. J Neurosci. 2011;31:7259–63. https://doi.org/10.1523/JNEUROSCI.6500-10.2011.CrossRefPubMedPubMedCentral

152.

Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, Iwatsubo T, et al. APP processing and synaptic function. Neuron. 2003;37:925–37. https://doi.org/10.1016/S0896-6273(03)00124-7.CrossRefPubMed

153.

Bagot RC, Tse YC, Nguyen H-B, Wong AS, Meaney MJ, Wong TP. Maternal care influences hippocampal N-methyl-D-aspartate receptor function and dynamic regulation by corticosterone in adulthood. Biol Psychiatry. 2012;72:491–8. https://doi.org/10.1016/J.BIOPSYCH.2012.03.016.CrossRefPubMed

154.

Nguyen H-B, Bagot RC, Diorio J, Wong TP, Meaney MJ. Maternal care differentially affects neuronal excitability and synaptic plasticity in the dorsal and ventral hippocampus. Neuropsychopharmacology. 2015;40:1590–9. https://doi.org/10.1038/npp.2015.19.CrossRefPubMedPubMedCentral

155.

Derks NAV, Krugers HJ, Hoogenraad CC, Joëls M, Sarabdjitsingh RA. Effects of early life stress on synaptic plasticity in the developing hippocampus of male and female rats. PLoS One. 2016;11:e0164551. https://doi.org/10.1371/journal.pone.0164551.CrossRefPubMedPubMedCentral

156.

Son GH, Geum D, Chung S, Kim EJ, Jo J-H, Kim C-M, et al. Maternal stress produces learning deficits associated with impairment of NMDA receptor-mediated synaptic plasticity. J Neurosci. 2006;26:3309–18. https://doi.org/10.1523/JNEUROSCI.3850-05.2006.CrossRefPubMedPubMedCentral

157.

Yang J, Hou C, Ma N, Liu J, Zhang Y, Zhou J, et al. Enriched environment treatment restores impaired hippocampal synaptic plasticity and cognitive deficits induced by prenatal chronic stress. Neurobiol Learn Mem. 2007;87:257–63. https://doi.org/10.1016/j.nlm.2006.09.001.CrossRefPubMed

158.

Liu X-B, Murray KD, Jones EG. Switching of NMDA receptor 2A and 2B subunits at thalamic and cortical synapses during early postnatal development. J Neurosci. 2004;24:8885–95. https://doi.org/10.1523/JNEUROSCI.2476-04.2004.CrossRefPubMedPubMedCentral

159.

Rodenas-Ruano A, Chávez AE, Cossio MJ, Castillo PE, Zukin RS. REST-dependent epigenetic remodeling promotes the developmental switch in synaptic NMDA receptors. Nat Neurosci. 2012;15:1382–90. https://doi.org/10.1038/nn.3214.CrossRefPubMedPubMedCentral

160.

Ballas N, Mandel G. The many faces of REST oversee epigenetic programming of neuronal genes. Curr Opin Neurobiol. 2005;15:500–6. https://doi.org/10.1016/j.conb.2005.08.015.CrossRefPubMed

161.

Singh-Taylor A, Molet J, Jiang S, Korosi A, Bolton JL, Noam Y, et al. NRSF-dependent epigenetic mechanisms contribute to programming of stress-sensitive neurons by neonatal experience, promoting resilience. Mol Psychiatry. 2017; https://doi.org/10.1038/mp.2016.240.CrossRefPubMedCentralPubMed

162.

Kessels HW, Nabavi S, Malinow R. Metabotropic NMDA receptor function is required for β-amyloid-induced synaptic depression. Proc Natl Acad Sci U S A. 2013;110:4033–8. https://doi.org/10.1073/pnas.1219605110.CrossRefPubMedPubMedCentral

163.

Lu T, Aron L, Zullo J, Pan Y, Kim H, Chen Y, et al. REST and stress resistance in ageing and Alzheimer’s disease. Nature. 2014;507:448–54. https://doi.org/10.1038/nature13163.CrossRefPubMedPubMedCentral

164.

Steward O, Wallace CS, Lyford GL, Worley PF. Synaptic activation causes the mRNA for the IEG Arc to localize selectively near activated postsynaptic sites on dendrites. Neuron. 1998;21:741–51. http://www.ncbi.nlm.nih.gov/pubmed/9808461. Accessed 30 Dec 2017CrossRefPubMed

165.

Knapska E, Kaczmarek L. A gene for neuronal plasticity in the mammalian brain: Zif268/Egr-1/NGFI-A/Krox-24/TIS8/ZENK? Prog Neurobiol. 2004;74:183–211. https://doi.org/10.1016/j.pneurobio.2004.05.007.CrossRefPubMed

166.

Tzingounis AV, Nicoll RA. Arc/Arg3.1: Linking gene expression to synaptic plasticity and memory. Neuron. 2006;52:403–7. https://doi.org/10.1016/j.neuron.2006.10.016.CrossRefPubMed

167.

Bramham CR, Worley PF, Moore MJ, Guzowski JF. The immediate early gene Arc/Arg3.1: regulation, mechanisms, and function. J Neurosci. 2008;28:11760–7. https://doi.org/10.1523/JNEUROSCI.3864-08.2008.CrossRefPubMedPubMedCentral

168.

Korb E, Finkbeiner S. Arc in synaptic plasticity: from gene to behavior. Trends Neurosci. 2011;34:591–8. https://doi.org/10.1016/j.tins.2011.08.007.CrossRefPubMedPubMedCentral

169.

Veyrac A, Besnard A, Caboche J, Davis S, Laroche S. The transcription factor Zif268/Egr1, brain plasticity, and memory. Prog Mol Biol Transl Sci. 2014. p. 89–129. https://doi.org/10.1016/B978-0-12-420170-5.00004-0.

170.

Jones MW, Errington ML, French PJ, Fine A, Bliss TVP, Garel S, et al. A requirement for the immediate early gene Zif268 in the expression of late LTP and long-term memories. Nat Neurosci. 2001;4:289–96. https://doi.org/10.1038/85138.CrossRefPubMed

171.

Penke Z, Morice E, Veyrac A, Gros A, Chagneau C, LeBlanc P, et al. Zif268/Egr1 gain of function facilitates hippocampal synaptic plasticity and long-term spatial recognition memory. Philos Trans R Soc Lond Ser B Biol Sci. 2014;369:20130159. https://doi.org/10.1098/rstb.2013.0159.CrossRef

172.

Brennan PA, Schellinck HM, Keverne EB. Patterns of expression of the immediate-early gene egr-1 in the accessory olfactory bulb of female mice exposed to pheromonal constituents of male urine. Neuroscience. 1999;90:1463–70. https://doi.org/10.1016/S0306-4522(98)00556-9.CrossRefPubMed

173.

Hall J, Thomas KL, Everitt BJ. Rapid and selective induction of BDNF expression in the hippocampus during contextual learning. Nat Neurosci. 2000;3:533–5. https://doi.org/10.1038/75698.CrossRefPubMed

174.

Besnard A, Serge L, Jocelyne C. Comparative dynamics of MAPK/ERK signalling components and immediate early genes in the hippocampus and amygdala following contextual fear conditioning and retrieval. Brain Struct Funct. 2014;219:415–30. https://doi.org/10.1007/s00429-013-0505-y.CrossRefPubMed

175.

Maddox SA, Monsey MS, Schafe GE. Early growth response gene 1 (Egr-1) is required for new and reactivated fear memories in the lateral amygdala. Learn Mem. 2010;18:24–38. https://doi.org/10.1101/lm.1980211.CrossRefPubMed

176.

Meaney MJ, Diorio J, Francis D, Weaver S, Yau J, Chapman K, et al. Postnatal handling increases the expression of cAMP-inducible transcription factors in the rat hippocampus: the effects of thyroid hormones and serotonin. J Neurosci. 2000;20:3926–35. http://www.ncbi.nlm.nih.gov/pubmed/10804232. Accessed 30 Dec 2017CrossRefPubMedCentralPubMed

177.

Gröger N, Bock J, Goehler D, Blume N, Lisson N, Poeggel G, et al. Stress in utero alters neonatal stress-induced regulation of the synaptic plasticity proteins Arc and Egr1 in a sex-specific manner. Brain Struct Funct. 2016;221:679–85. https://doi.org/10.1007/s00429-014-0889-3.CrossRefPubMed

178.

Revest J-M, Di Blasi F, Kitchener P, Rougé-Pont F, Desmedt A, Turiault M, et al. The MAPK pathway and Egr-1 mediate stress-related behavioral effects of glucocorticoids. Nat Neurosci. 2005;8:664–72. https://doi.org/10.1038/nn1441.CrossRefPubMed

179.

Bossers K, Wirz KTS, Meerhoff GF, Essing AHW, Van Dongen JW, Houba P, et al. Concerted changes in transcripts in the prefrontal cortex precede neuropathology in Alzheimer’s disease. Brain. 2010;133:3699–723. https://doi.org/10.1093/brain/awq258.CrossRefPubMed

180.

Zhu Q-B, Unmehopa U, Bossers K, Hu Y-T, Verwer R, Balesar R, et al. MicroRNA-132 and early growth response-1 in nucleus basalis of Meynert during the course of Alzheimer’s disease. Brain. 2016;139:908–21. https://doi.org/10.1093/brain/awv383.CrossRefPubMed

181.

Dickey CA, Loring JF, Montgomery J, Gordon MN, Eastman PS, Morgan D. Selectively reduced expression of synaptic plasticity-related genes in amyloid precursor protein + presenilin-1 transgenic mice. J Neurosci. 2003;23:5219–26. http://www.jneurosci.org/content/jneuro/23/12/5219.full.pdf. Accessed 30 Dec 2017CrossRefPubMedCentralPubMed

182.

Wirz KTS, Bossers K, Stargardt A, Kamphuis W, Swaab DF, Hol EM, et al. Cortical beta amyloid protein triggers an immune response, but no synaptic changes in the APPswe/PS1dE9 Alzheimer’s disease mouse model. Neurobiol Aging. 2013;34:1328–42. https://doi.org/10.1016/j.neurobiolaging.2012.11.008.CrossRefPubMed

183.

Qin X, Wang Y, Paudel HK. Inhibition of early growth response 1 in the hippocampus alleviates neuropathology and improves cognition in an Alzheimer model with plaques and tangles. Am J Pathol. 2017;187:1828–47. https://doi.org/10.1016/j.ajpath.2017.04.018.CrossRefPubMed

184.

Qin X, Wang Y, Paudel HK. Early growth response 1 (Egr-1) is a transcriptional activator of β-secretase 1 (BACE-1) in the brain. J Biol Chem. 2016;291:22276–87. https://doi.org/10.1074/jbc.M116.738849.CrossRefPubMedPubMedCentral

185.

James AB, Conway A-M, Morris BJ. Genomic profiling of the neuronal target genes of the plasticity-related transcription factor—Zif268. J Neurochem. 2005;95:796–810. https://doi.org/10.1111/j.1471-4159.2005.03400.x.CrossRefPubMed

186.

Li L, Carter J, Gao X, Whitehead J, Tourtellotte WG. The neuroplasticity-associated arc gene is a direct transcriptional target of early growth response (EGR) transcription factors. Mol Cell Biol. 2005;25:10286–300. https://doi.org/10.1128/MCB.25.23.10286-10300.2005.CrossRefPubMedPubMedCentral

187.

Link W, Konietzko U, Kauselmann G, Krugt M, Schwanke B, Frey U, et al. Somatodendritic expression of an immediate early gene is regulated by synaptic activity. Proc Natl Acad Sci U S A. 1995;92:5734–8. http://www.pnas.org/content/92/12/5734.full.pdf. Accessed 30 Dec 2017CrossRefPubMedCentralPubMed

188.

Rodríguez JJ, Davies HA, Silva AT, De Souza IEJ, Peddie CJ, Colyer FM, et al. Long-term potentiation in the rat dentate gyrus is associated with enhanced Arc/Arg3.1 protein expression in spines, dendrites and glia. Eur J Neurosci. 2005;21:2384–96. https://doi.org/10.1111/j.1460-9568.2005.04068.x.CrossRefPubMed

189.

Bloomer WAC, VanDongen HMA, VanDongen AMJ. Activity-regulated cytoskeleton-associated protein Arc/Arg3.1 binds to spectrin and associates with nuclear promyelocytic leukemia (PML) bodies. Brain Res. 2007;1153:20–33. https://doi.org/10.1016/J.BRAINRES.2007.03.079.CrossRefPubMed

190.

Kelly M, Deadwyler S. Acquisition of a novel behavior induces higher levels of Arc mRNA than does overtrained performance. Neuroscience. 2002;110:617–26. https://doi.org/10.1016/S0306-4522(01)00605-4.CrossRefPubMed

191.

Morin J-P, Díaz-Cintra S, Bermúdez-Rattoni F, Delint-Ramírez I. Decreased levels of NMDA but not AMPA receptors in the lipid-raft fraction of 3xTg-AD model of Alzheimer’s disease: relation to Arc/Arg3.1 protein expression. Neurochem Int. 2016;100:159–63. https://doi.org/10.1016/j.neuint.2016.09.013.CrossRefPubMed

192.

Morin J-P, Cerón-Solano G, Velázquez-Campos G, Pacheco-López G, Bermúdez-Rattoni F, Díaz-Cintra S. Spatial memory impairment is associated with intraneural amyloid-β immunoreactivity and dysfunctional Arc expression in the hippocampal-CA3 region of a transgenic mouse model of Alzheimer’s disease. J Alzheimers Dis. 2016;51:69–79. https://doi.org/10.3233/JAD-150975.CrossRefPubMed

193.

Rudinskiy N, Hawkes JM, Betensky RA, Eguchi M, Yamaguchi S, Spires-Jones TL, et al. Orchestrated experience-driven Arc responses are disrupted in a mouse model of Alzheimer’s disease. Nat Neurosci. 2012;15:1422–9. https://doi.org/10.1038/nn.3199.CrossRefPubMedPubMedCentral

194.

Wu J, Petralia RS, Kurushima H, Patel H, Jung M, Volk L, et al. Arc/Arg3.1 regulates an endosomal pathway essential for activity-dependent β-amyloid generation. Cell. 2011;147:615–28. https://doi.org/10.1016/j.cell.2011.09.036.CrossRefPubMedPubMedCentral

195.

Béïque J-C, Na Y, Kuhl D, Worley PF, Huganir RL. Arc-dependent synapse-specific homeostatic plasticity. Proc Natl Acad Sci U S A. 2011;108:816–21. https://doi.org/10.1073/pnas.1017914108.CrossRefPubMed

196.

Rial Verde EM, Lee-Osbourne J, Worley PF, Malinow R, Cline HT. Increased expression of the immediate-early gene arc/arg3.1 reduces AMPA receptor-mediated synaptic transmission. Neuron. 2006;52:461–74. https://doi.org/10.1016/j.neuron.2006.09.031.CrossRefPubMedPubMedCentral

197.

Shi S, Hayashi Y, Esteban JA, Malinow R. Subunit-specific rules governing AMPA receptor trafficking to synapses in hippocampal pyramidal neurons. Cell. 2001;105:331–43. http://www.ncbi.nlm.nih.gov/pubmed/11348590. Accessed 18 Feb 2018CrossRefPubMed

198.

Renner MC, Albers EH, Gutierrez-Castellanos N, Reinders NR, van Huijstee AN, Xiong H, et al. Synaptic plasticity through activation of GluA3-containing AMPA-receptors. elife. 2017;6. https://doi.org/10.7554/eLife.25462.

199.

Makino H, Malinow R. Compartmentalized versus global synaptic plasticity on dendrites controlled by experience. Neuron. 2011;72:1001–11. https://doi.org/10.1016/j.neuron.2011.09.036.CrossRefPubMedPubMedCentral

200.

Molteni R, Chourbaji S, Brandwein C, Racagni G, Gass P, Riva M. Depression-prone mice with reduced glucocorticoid receptor expression display an altered stress-dependent regulation of brain-derived neurotrophic factor and activity-regulated cytoskeleton-associated protein. J Psychopharmacol. 2010;24:595–603. https://doi.org/10.1177/0269881108099815.CrossRefPubMed

201.

Chen A, Kelley LDS, Janušonis S. Effects of prenatal stress and monoaminergic perturbations on the expression of serotonin 5-HT₄ and adrenergic β₂ receptors in the embryonic mouse telencephalon. Brain Res. 2012;1459:27–34. https://doi.org/10.1016/j.brainres.2012.04.019.CrossRefPubMed

202.

Wegenast-Braun BM, Fulgencio Maisch A, Eicke D, Radde R, Herzig MC, Staufenbiel M, et al. Independent effects of intra- and extracellular Aβ on learning-related gene expression. Am J Pathol. 2009;175:271–82. https://doi.org/10.2353/AJPATH.2009.090044.CrossRefPubMedPubMedCentral

203.

Palop JJ, Chin J, Bien-Ly N, Massaro C, Yeung BZ, Yu G-Q, et al. Vulnerability of dentate granule cells to disruption of Arc expression in human amyloid precursor protein transgenic mice. J Neurosci. 2005;25:9686–93. https://doi.org/10.1523/JNEUROSCI.2829-05.2005.CrossRefPubMedPubMedCentral

204.

Palop JJ, Chin J, Roberson ED, Wang J, Thwin MT, Bien-Ly N, et al. Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer’s disease. Neuron. 2007;55:697–711. https://doi.org/10.1016/j.neuron.2007.07.025.CrossRefPubMedPubMedCentral

205.

de Rooij SR, Wouters H, Yonker JE, Painter RC, Roseboom TJ. Prenatal undernutrition and cognitive function in late adulthood. Proc Natl Acad Sci U S A. 2010;107:16881–6. https://doi.org/10.1073/pnas.1009459107.CrossRefPubMedPubMedCentral

206.

de Rooij SR, Caan MWA, Swaab DF, Nederveen AJ, Majoie CB, Schwab M, et al. Prenatal famine exposure has sex-specific effects on brain size. Brain. 2016;139(Pt 8):2136–42. https://doi.org/10.1093/brain/aww132.CrossRefPubMed

207.

Franke K, Gaser C, Roseboom TJ, Schwab M, de Rooij SR. Premature brain aging in humans exposed to maternal nutrient restriction during early gestation. NeuroImage. 2018;173:460–71. https://doi.org/10.1016/j.neuroimage.2017.10.047.CrossRefPubMed

208.

Staufenbiel SM, Penninx BWJH, Spijker AT, Elzinga BM, van Rossum EFC. Hair cortisol, stress exposure, and mental health in humans: a systematic review. Psychoneuroendocrinology. 2013;38:1220–35. https://doi.org/10.1016/j.psyneuen.2012.11.015.CrossRefPubMed

209.

Kulstad JJ, McMillan PJ, Leverenz JB, Cook DG, Green PS, Peskind ER, et al. Effects of chronic glucocorticoid administration on insulin-degrading enzyme and amyloid-β peptide in the aged macaque. J Neuropathol Exp Neurol. 2005;64:139–46. https://doi.org/10.1093/jnen/64.2.139.CrossRefPubMed

210.

Pomara N, Doraiswamy PM, Tun H, Ferris S. Mifepristone (RU 486) for Alzheimer’s disease. Neurology. 2002;58:1436. https://doi.org/10.1212/WNL.58.9.1436.CrossRefPubMed

211.

Lemaire V, Koehl M, Le Moal M, Abrous DN. Prenatal stress produces learning deficits associated with an inhibition of neurogenesis in the hippocampus. Proc Natl Acad Sci U S A. 2000;97:11032–7. http://www.ncbi.nlm.nih.gov/pubmed/11005874. Accessed 5 Feb 2018CrossRefPubMedCentralPubMed

212.

Arenaza-Urquijo EM, Vemuri P. Resistance vs resilience to Alzheimer disease: clarifying terminology for preclinical studies. Neurology. 2018;90:695–703. https://doi.org/10.1212/WNL.0000000000005303.CrossRefPubMedPubMedCentral

213.

Almeida RP, Schultz SA, Austin BP, Boots EA, Dowling NM, Gleason CE, et al. Effect of cognitive reserve on age-related changes in cerebrospinal fluid biomarkers of Alzheimer disease. JAMA Neurol. 2015;72:699. https://doi.org/10.1001/jamaneurol.2015.0098.CrossRefPubMedPubMedCentral

214.

Stern Y. Cognitive reserve in ageing and Alzheimer’s disease. Lancet Neurol. 2012;11:1006–12. https://doi.org/10.1016/S1474-4422(12)70191-6.CrossRefPubMedPubMedCentral

215.

Katzman R. Education and the prevalence of dementia and Alzheimer’s disease. Neurology. 1993;43:13–20. http://www.ncbi.nlm.nih.gov/pubmed/8423876. Accessed 18 Apr 2017CrossRefPubMed

216.

Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, et al. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science. 1996;274:99–102. http://www.ncbi.nlm.nih.gov/pubmed/8810256. Accessed 3 Jan 2018CrossRefPubMed

217.

Jankowsky JL, Slunt HH, Gonzales V, Jenkins NA, Copeland NG, Borchelt DR. APP processing and amyloid deposition in mice haplo-insufficient for presenilin 1. Neurobiol Aging. 2004;25:885–92. https://doi.org/10.1016/j.neurobiolaging.2003.09.008.CrossRefPubMed

218.

Janus C, Flores AY, Xu G, Borchelt DR. Behavioral abnormalities in APPSwe/PS1dE9 mouse model of AD-like pathology: comparative analysis across multiple behavioral domains. Neurobiol Aging. 2015;36:2519–32. https://doi.org/10.1016/j.neurobiolaging.2015.05.010.CrossRefPubMed

219.

Yoshiyama Y, Higuchi M, Zhang B, Huang S-M, Iwata N, Saido TC, et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron. 2007;53:337–51. https://doi.org/10.1016/j.neuron.2007.01.010.CrossRefPubMed

220.

Terwel D, Lasrado R, Snauwaert J, Vandeweert E, Van Haesendonck C, Borghgraef P, et al. Changed conformation of mutant Tau-P301L underlies the moribund tauopathy, absent in progressive, nonlethal axonopathy of tau-4R/2N transgenic mice. J Biol Chem. 2005;280:3963–73. https://doi.org/10.1074/jbc.M409876200.CrossRefPubMed

221.

Lewis J, Dickson DW, Lin WL, Chisholm L, Corral A, Jones G, et al. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science. 2001;293:1487–91. https://doi.org/10.1126/science.1058189.CrossRefPubMed

222.

Terwel D, Muyllaert D, Dewachter I, Borghgraef P, Croes S, Devijver H, et al. Amyloid activates GSK-3β to aggravate neuronal tauopathy in bigenic mice. Am J Pathol. 2008;172:786–98. https://doi.org/10.2353/ajpath.2008.070904.CrossRefPubMedPubMedCentral

223.

Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, et al. Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron. 2003;39:409–21. http://www.ncbi.nlm.nih.gov/pubmed/12895417. Accessed 3 Jan 2018CrossRefPubMed

224.

Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, et al. Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J Neurosci. 2006;26:10129–40. https://doi.org/10.1523/JNEUROSCI.1202-06.2006.CrossRefPubMedPubMedCentral

225.

Saul A, Sprenger F, Bayer TA, Wirths O. Accelerated tau pathology with synaptic and neuronal loss in a novel triple transgenic mouse model of Alzheimer’s disease. Neurobiol Aging. 2013;34:2564–73. https://doi.org/10.1016/j.neurobiolaging.2013.05.003.CrossRefPubMed

226.

Guzmán E, Bouter Y, Richard BC, Lannfelt L, Ingelsson M, Paetau A, et al. Abundance of Aβ5-x like immunoreactivity in transgenic 5XFAD, APP/PS1KI and 3xTG mice, sporadic and familial Alzheimer’s disease. Mol Neurodegener. 2014;9:13. https://doi.org/10.1186/1750-1326-9-13.CrossRefPubMedPubMedCentral

227.

Yin Z, Raj D, Saiepour N, Van Dam D, Brouwer N, Holtman IR, et al. Immune hyperreactivity of Aβ plaque-associated microglia in Alzheimer’s disease. Neurobiol Aging. 2017;55:115–22. https://doi.org/10.1016/j.neurobiolaging.2017.03.021.CrossRefPubMed

228.

Wirths O, Walter S, Kraus I, Klafki HW, Stazi M, Oberstein TJ, et al. N-truncated Aβ4–x peptides in sporadic Alzheimer’s disease cases and transgenic Alzheimer mouse models. Alzheimers Res Ther. 2017;9:80. https://doi.org/10.1186/s13195-017-0309-z.CrossRefPubMedPubMedCentral

229.

Caldji C, Tannenbaum B, Sharma S, Francis D, Plotsky PM, Meaney MJ. Maternal care during infancy regulates the development of neural systems mediating the expression of fearfulness in the rat. Proc Natl Acad Sci U S A. 1998;95:5335–40. http://www.ncbi.nlm.nih.gov/pubmed/9560276. Accessed 8 Dec 2017CrossRefPubMedCentralPubMed

230.

Huot RL, Plotsky PM, Lenox RH, McNamara RK. Neonatal maternal separation reduces hippocampal mossy fiber density in adult Long Evans rats. Brain Res. 2002;950:52–63. https://doi.org/10.1016/S0006-8993(02)02985-2.CrossRefPubMed

231.

Rice CJ, Sandman CA, Lenjavi MR, Baram TZ. A novel mouse model for acute and long-lasting consequences of early life stress. Endocrinology. 2008;149:4892–900. https://doi.org/10.1210/en.2008-0633.CrossRefPubMedPubMedCentral

232.

Avishai-Eliner S, Eghbal-Ahmadi M, Tabachnik E, Brunson KL, Baram TZ. Down-regulation of hypothalamic corticotropin-releasing hormone messenger ribonucleic acid (mRNA) precedes early-life experience-induced changes in hippocampal glucocorticoid receptor mRNA. Endocrinology. 2001;142:89–97.CrossRefPubMed

233.

Meaney M, Aitken D, van Berkel C, Bhatnagar S, Sapolsky R. Effect of neonatal handling on age-related impairments associated with the hippocampus. Science. 1988;239(4841 Pt 1):766–8. http://www.ncbi.nlm.nih.gov/pubmed/3340858. Accessed 27 Jan 2016CrossRefPubMed

234.

Weinberg J, Levine S. Early handling influences on behavioral and physiological responses during active avoidance. Dev Psychobiol. 1977;10:161–9. https://doi.org/10.1002/dev.420100209.CrossRefPubMed

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Vulnerability and resilience to Alzheimer’s disease: early life conditions modulate neuropathology and determine cognitive reserve

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2018

Utility of the Dependence Scale in dementia: validity, meaningfulness, and health economic considerations

Serum neurofilament light levels correlate with severity measures and neurodegeneration markers in autosomal dominant Alzheimer’s disease

Adaptive crossover designs for assessment of symptomatic treatments targeting behaviour in neurodegenerative disease: a phase 2 clinical trial of intranasal oxytocin for frontotemporal dementia (FOXY)

Plasma neurofilament light as a potential biomarker of neurodegeneration in Alzheimer’s disease

MRI predictors of amyloid pathology: results from the EMIF-AD Multimodal Biomarker Discovery study

A two-step immunoassay for the simultaneous assessment of Aβ38, Aβ40 and Aβ42 in human blood plasma supports the Aβ42/Aβ40 ratio as a promising biomarker candidate of Alzheimer’s disease