Alzheimer's disease

Abstract

Alzheimer's disease is a chronic illness with long preclinical and prodromal phases (20 years) and an average clinical duration of 8–10 years. The disease has an estimated prevalence of 10–30% in the population >65 years of age with an incidence of 1–3%. Most patients with Alzheimer's disease (>95%) have the sporadic form, which is characterized by a late onset (80–90 years of age), and is the consequence of the failure to clear the amyloid-β (Aβ) peptide from the interstices of the brain. A large number of genetic risk factors for sporadic disease have been identified. A small proportion of patients (<1%) have inherited mutations in genes that affect processing of Aβ and develop the disease at a much younger age (mean age of 45 years). Detection of the accumulation of Aβ is now possible in preclinical and prodromal phases using cerebrospinal fluid biomarkers and PET. Several approved drugs ameliorate some of the symptoms of Alzheimer's disease, but no current interventions can modify the underlying disease mechanisms. Management is focused on the support of the social networks surrounding the patient and the treatment of any co-morbid illnesses, such as cerebrovascular disease.

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Figure 1: The pathological evolution of Alzheimer's disease.
Figure 2: The incidence of Alzheimer's disease.
Figure 3: Co-morbidities with Alzheimer's disease in advanced ages.
Figure 4: Pathways leading to plaques and tangles form the basis of the amyloid-β theory of Alzheimer's disease.
Figure 5: Amyloid-β PET imaging.
Figure 6: Schematic representation of changes in cognitive, metabolic, structural and molecular pathogenetic parameters in relation to estimated years to symptomatic onset of dominantly inherited Alzheimer's disease.
Figure 7: Quality of life of patients with Alzheimer's disease.
Figure 8: Potential strategies to manipulate amyloid-β in Alzheimer's disease.

References

  1. 1

    Bachman, D. L. et al. Incidence of dementia and probable Alzheimer's disease in a general population: the Framingham Study. Neurology 43, 515–519 (1993).

    Article  CAS  PubMed  Google Scholar 

  2. 2

    Hebert, L. E. et al. Age-specific incidence of Alzheimer's disease in a community population. JAMA 273, 1354–1359 (1995).

    Article  CAS  PubMed  Google Scholar 

  3. 3

    Evans, D. A. et al. Incidence of Alzheimer disease in a biracial urban community: relation to apolipoprotein E allele status. Arch. Neurol. 60, 185–189 (2003).

    Article  PubMed  Google Scholar 

  4. 4

    Kawas, C., Gray, S., Brookmeyer, R., Fozard, J. & Zonderman, A. Age-specific incidence rates of Alzheimer's disease: the Baltimore Longitudinal Study of Aging. Neurology 54, 2072–2077 (2000). The Baltimore longitudinal study has a good chance of determining the true incidence of Alzheimer's disease.

    Article  CAS  PubMed  Google Scholar 

  5. 5

    Nelson, P. T. et al. Hippocampal sclerosis in advanced age: clinical and pathological features. Brain 134, 1506–1518 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  6. 6

    Duncan, G. W. et al. The incidence of Parkinson's disease in the north-east of England. Age Ageing 43, 257–263 (2014).

    Article  PubMed  Google Scholar 

  7. 7

    Caslake, R. et al. Age-, gender-, and socioeconomic status-specific incidence of Parkinson's disease and parkinsonism in northeast Scotland: the PINE study. Parkinsonism Relat. Disord. 19, 515–521 (2013).

    Article  PubMed  Google Scholar 

  8. 8

    Savica, R., Grossardt, B. R., Bower, J. H., Ahlskog, J. E. & Rocca, W. A. Incidence and pathology of synucleinopathies and tauopathies related to parkinsonism. JAMA Neurol. 70, 859–866 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  9. 9

    Australian Bureau of Statistics. Causes of death, Australia, 2013. ABS[online], (2015).

  10. 10

    Ossenkoppele, R. et al. Prevalence of amyloid PET positivity in dementia syndromes: a meta-analysis. JAMA 313, 1939–1949 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  11. 11

    Jansen, W. J. et al. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA 313, 1924–1938 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  12. 12

    Prince, M. et al. World Alzheimer Report 2015. Alzheimer's Disease International[online], (2015).

  13. 13

    Norton, S., Matthews, F. E., Barnes, D. E., Yaffe, K. & Brayne, C. Potential for primary prevention of Alzheimer's disease: an analysis of population-based data. Lancet Neurol. 13, 788–794 (2014).

    Article  PubMed  Google Scholar 

  14. 14

    Ngandu, T. et al. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet 385, 2255–2263 (2015).

    Article  PubMed  Google Scholar 

  15. 15

    Prince, M., Albanese, E., Guerchet, M. & Prina, M. World Alzheimer Report 2014. Alzheimer's Disease International[online], (2014). An excellent overview of the current evidence of environmental influences on dementia and Alzheimer's disease.

  16. 16

    Golde, T. E., Eckman, C. B. & Younkin, S. G. Biochemical detection of Aβ isoforms: implications for pathogenesis, diagnosis, and treatment of Alzheimer's disease. Biochim. Biophys. Acta 1502, 172–187 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. 17

    Selkoe, D. J. Alzheimer's disease: genes, proteins, and therapy. Physiol. Rev. 81, 741–766 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. 18

    Portelius, E. et al. Mass spectrometric characterization of brain amyloid beta isoform signatures in familial and sporadic Alzheimer's disease. Acta Neuropathol. 120, 185–193 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Holtzman, D. M., Bales, K. R., Paul, S. M. & DeMattos, R. B. Aβ immunization and anti-Aβ antibodies: potential therapies for the prevention and treatment of Alzheimer's disease. Adv. Drug Deliv. Rev. 54, 1603–1613 (2002).

    Article  CAS  PubMed  Google Scholar 

  20. 20

    Potter, R. E. et al. Amyloid-beta 42:40 metabolism is altered in autosomal dominant Alzheimer's disease (ADAD). Ann. Neurol. 70, S88–S89 (2011).

    Google Scholar 

  21. 21

    Scheuner, D. et al. Secreted amyloid β-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nat. Med. 2, 864–870 (1996).

    Article  CAS  PubMed  Google Scholar 

  22. 22

    Hecimovic, S. et al. Mutations in APP have independent effects on Aβ and CTFγ generation. Neurobiol. Dis. 17, 205–218 (2004).

    Article  CAS  PubMed  Google Scholar 

  23. 23

    Kumar-Singh, S. et al. Mean age-of-onset of familial Alzheimer disease caused by presenilin mutations correlates with both increased Aβ42 and decreased Aβ40. Hum. Mutat. 27, 686–695 (2006).

    Article  CAS  Google Scholar 

  24. 24

    Bateman, R. J. et al. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N. Engl. J. Med. 367, 795–804 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Ryman, D. C. et al. Symptom onset in autosomal dominant Alzheimer disease: a systematic review and meta-analysis. Neurology 83, 253–260 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Jankowsky, J. L. et al. Mutant presenilins specifically elevate the levels of the 42 residue β-amyloid peptide in vivo: evidence for augmentation of a 42-specific γ secretase. Hum. Mol. Genet. 13, 159–170 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. 27

    Borchelt, D. R. et al. Familial Alzheimer's disease-linked presenilin 1 variants elevate Aβ1–42/1–40 ratio in vitro and in vivo. Neuron 17, 1005–1013 (1996).

    Article  CAS  PubMed  Google Scholar 

  28. 28

    Gomez-Isla, T. et al. The impact of different presenilin 1 and presenilin 2 mutations on amyloid deposition, neurofibrillary changes and neuronal loss in the familial Alzheimer's disease brain — evidence for other phenotype-modifying factors. Brain 122, 1709–1719 (1999).

    Article  PubMed  Google Scholar 

  29. 29

    Wisniewski, K. E., Wisniewski, H. M. & Wen, G. Y. Occurrence of neuropathological changes and dementia of Alzheimers-disease in Down syndrome. Ann. Neurol. 17, 278–282 (1985).

    Article  CAS  PubMed  Google Scholar 

  30. 30

    Jonsson, T. et al. A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature 488, 96–99 (2012).

    Article  CAS  Google Scholar 

  31. 31

    Bateman, R. J. et al. Human amyloid-β synthesis and clearance rates as measured in cerebrospinal fluid in vivo. Nat. Med. 12, 856–861 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Mawuenyega, K. G. et al. Decreased clearance of CNS β-amyloid in Alzheimer's disease. Science 330, 1774–1774 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Bateman, R. J. et al. A γ-secretase inhibitor decreases amyloid-β production in the central nervous system. Ann. Neurol. 66, 48–54 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Namba, Y., Tomonaga, M., Kawasaki, H., Otomo, E. & Ikeda, K. Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimers disease and kuru plaque amyloid in Creutzfeldt–Jakob disease. Brain Res. 541, 163–166 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Artiga, M. J. et al. Allelic polymorphisms in the transcriptional regulatory region of apolipoprotein E gene. FEBS Lett. 421, 105–108 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Saunders, A. M. et al. Association of apolipoprotein E allele ε4 with late-onset familial and sporadic Alzheimers disease. Neurology 43, 1467–1472 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Huang, Y. D., Weisgraber, K. H., Mucke, L. & Mahley, R. W. Apolipoprotein E: diversity of cellular origins, structural and biophysical properties, and effects in Alzheimer's disease. J. Mol. Neurosci. 23, 189–204 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Fernández-Miranda, C. et al. Changes in phenotypes of apolipoprotein E and apolipoprotein(a) in liver transplant recipients. Clin. Transplant. 11, 325–327 (1997).

    PubMed  PubMed Central  Google Scholar 

  39. 39

    Farrer, L. A. et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease — a meta-analysis. JAMA 278, 1349–1356 (1997).

    Article  CAS  Google Scholar 

  40. 40

    Corder, E. H. et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimers-disease in late-onset families. Science 261, 921–923 (1993). The first identification of the main genetic risk factor in sporadic and late-onset familial Alzheimer's disease.

    Article  CAS  Google Scholar 

  41. 41

    Khachaturian, A. S. et al. Apolipoprotein E ε4 count affects age at onset of Alzheimer disease, but not lifetime susceptibility: the Cache County Study. Arch. Gen. Psychiatry 61, 518–524 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Corder, E. H. et al. Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat. Genet. 7, 180–184 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Serrano-Pozo, A., Qian, J., Monsell, S. E., Betensky, R. A. & Hyman, B. T. APOEε2 is associated with milder clinical and pathological Alzheimer disease. Ann. Neurol. 77, 917–929 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Ashford, J. W. APOE genotype effects on Alzheimer's disease onset and epidemiology. J. Mol. Neurosci. 23, 157–165 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Holtzman, D. M. In vivo effects of ApoE and clusterin on amyloid-β metabolism and neuropathology. J. Mol. Neurosci. 23, 247–254 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Holtzman, D. M. et al. Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease. Proc. Natl Acad. Sci. USA 97, 2892–2897 (2000).

    Article  CAS  Google Scholar 

  47. 47

    Holtzman, D. M. et al. Expression of human apolipoprotein E reduces amyloid-β deposition in a mouse model of Alzheimer's disease. J. Clin. Invest. 103, R15–R21 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    DeMattos, R. B. et al. ApoE and clusterin cooperatively suppress Aβ levels and deposition: evidence that ApoE regulates extracellular Aβ metabolism in vivo. Neuron 41, 193–202 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Strittmatter, W. J. et al. Apolipoprotein E: high-avidity binding to β-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc. Natl Acad. Sci. USA 90, 1977–1981 (1993).

    Article  CAS  Google Scholar 

  50. 50

    Holtzman, D. M. Role of apoE/Aβ interactions in the pathogenesis of Alzheimer's disease and cerebral amyloid angiopathy. J. Mol. Neurosci. 17, 147–155 (2001).

    Article  CAS  PubMed  Google Scholar 

  51. 51

    Bales, K. R. et al. Apolipoprotein E is essential for amyloid deposition in the APPV717F transgenic mouse model of Alzheimer's disease. Proc. Natl Acad. Sci. USA 96, 15233–15238 (1999).

    Article  CAS  PubMed  Google Scholar 

  52. 52

    Shibata, M. et al. Clearance of Alzheimer's amyloid-β1–40 peptide from brain by LDL receptor-related protein-1 at the blood–brain barrier. J. Clin. Invest. 106, 1489–1499 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Huang, Y. D. et al. Apolipoprotein E fragments present in Alzheimer's disease brains induce neurofibrillary tangle-like intracellular inclusions in neurons. Proc. Natl Acad. Sci. USA 98, 8838–8843 (2001).

    Article  CAS  PubMed  Google Scholar 

  54. 54

    Nathan, B. P. et al. Differential effects of apolipoproteins E3 and E4 on neuronal growth in vitro. Science 264, 850–852 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Nathan, B. P. et al. The inhibitory effect of apolipoprotein E4 on neurite outgrowth is associated with microtubule depolymerization. J. Biol. Chem. 270, 19791–19799 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Bellosta, S. et al. Stable expression and secretion of apolipoproteins E3 and E4 in mouse neuroblastoma cells produces differential effects on neurite outgrowth. J. Biol. Chem. 270, 27063–27071 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Deane, R. et al. ApoE isoform-specific disruption of amyloid β peptide clearance from mouse brain. J. Clin. Invest. 118, 4002–4013 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Wisniewski, T., Ghiso, J. & Frangione, B. Biology of Aβ amyloid in Alzheimer's disease. Neurobiol. Dis. 4, 313–328 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Fagan, A. M. et al. Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Aβ42 in humans. Ann. Neurol. 59, 512–519 (2006).

    Article  CAS  Google Scholar 

  60. 60

    Knopman, D. S. et al. Practice parameter: diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 56, 1143–1153 (2001).

    Article  CAS  PubMed  Google Scholar 

  61. 61

    Salloway, S. et al. Two Phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease. N. Engl. J. Med. 370, 322–333 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Mathis, C. A. et al. A lipophilic thioflavin-T derivative for positron emission tomography (PET) imaging of amyloid in brain. Bioorg. Med. Chem. Lett. 12, 295–298 (2002). This study is the beginning of the molecular PET imaging revolution for Alzheimer's disease.

    Article  CAS  PubMed  Google Scholar 

  63. 63

    Klunk, W. E. et al. Imaging brain amyloid in Alzheimer's disease with Pittsburgh compound-B. Ann. Neurol. 55, 306–319 (2004). This landmark paper by William Klunk (co-developer of PiB with his colleague Chet Mathis at the University of Pittsburg, Pennsylvania, USA) marked the beginning of Aβ PET imaging in humans. The paper included the method and showed the distribution of Aβ plaques in patients with Alzheimer's disease from a global 3D brain perspective.

    Article  CAS  Google Scholar 

  64. 64

    Mintun, M. A. et al. [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease. Neurology 67, 446–452 (2006).

    Article  CAS  PubMed  Google Scholar 

  65. 65

    Rowe, C. C. et al. Imaging β-amyloid burden in aging and dementia. Neurology 68, 1718–1725 (2007).

    Article  CAS  PubMed  Google Scholar 

  66. 66

    Morris, J. C. et al. Pittsburgh compound B imaging and prediction of progression from cognitive normality to symptomatic Alzheimer disease. Arch. Neurol. 66, 1469–1475 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  67. 67

    Knopman, D. S. et al. Short-term clinical outcomes for stages of NIA-AA preclinical Alzheimer disease. Neurology 78, 1576–1582 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Rowe, C. C. et al. Predicting Alzheimer disease with β-amyloid imaging: results from the Australian Imaging, Biomarkers, and Lifestyle Study of Ageing. Ann. Neurol. 74, 905–913 (2013).

    Article  CAS  PubMed  Google Scholar 

  69. 69

    Villemagne, V. L. et al. Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: a prospective cohort study. Lancet Neurol. 12, 357–367 (2013). Using longitudinal imaging with 11C -PiB PET, the authors demonstrated the rate of Aβ accummulation, establishing that it takes up to 30 years to reach the level found on average in patients with mild Alzheimer's disease. It also demonstrated that Aβ PET scans showed abnormalities a decade or more before measures of hippocampal volume and cognition became abnormal. This work supported the concept of preclinical Alzheimer's disease and identified a wide time window for early intervention to potentially prevent dementia in those developing Alzheimer's disease.

    Article  CAS  PubMed  Google Scholar 

  70. 70

    Jack, C. R. Jr et al. Brain β-amyloid load approaches a plateau. Neurology 80, 890–896 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Lim, Y. Y. et al. APOE and BDNF polymorphisms moderate amyloid beta-related cognitive decline in preclinical Alzheimer's disease. Mol. Psychiatry http://dx.doi.org/10.1038/mp.2014.123 (2015). The interaction of gene polymorphisms and Alzheimer's disease-related pathology on the progression rates for clinical and cognitive decline is an emerging area that will have implications for individual prognosis and therapy trial design. This prospective observational study confirmed earlier reports of stable memory function in older healthy people with negative Aβ PET scans compared with a slow but significant decline in those who had positive Aβ PET scans; this decline was much faster in APOE4 carriers and even worse in those who also carried the brain-derived neurotrophic factor (BDNF)Val/Met allele.

  72. 72

    Nordberg, A. et al. A European multicentre PET study of fibrillar amyloid in Alzheimer's disease. Eur. J. Nucl. Med. Mol. Imaging 40, 104–114 (2013).

    Article  CAS  PubMed  Google Scholar 

  73. 73

    Ong, K. T. et al. Aβ imaging with 18F-florbetaben in prodromal Alzheimer's disease: a prospective outcome study. J. Neurol. Neurosurg. Psychiatry 86, 431–436 (2014).

    Article  PubMed  Google Scholar 

  74. 74

    Sperling, R. A. et al. The A4 study: stopping AD before symptoms begin? Sci. Transl. Med. 6, 228fs13 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Sperling, R. A. et al. Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging–Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 7, 280–292 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  76. 76

    Albert, M. S. et al. The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging–Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 7, 270–279 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  77. 77

    Dubois, B. et al. Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria. Lancet Neurol. 13, 614–629 (2014). An important review of the evolving diagnostic criteria for Alzheimer's disease.

    Article  PubMed  Google Scholar 

  78. 78

    Fagan, A. M. et al. Cerebrospinal fluid tau/β-amyloid42 ratio as a prediction of cognitive decline in nondemented older adults. Arch. Neurol. 64, 343–349 (2007).

    Article  PubMed  Google Scholar 

  79. 79

    Toledo, J. B., Xie, S. X., Trojanowski, J. Q. & Shaw, L. M. Longitudinal change in CSF tau and Aβ biomarkers for up to 48 months in ADNI. Acta Neuropathol. 126, 659–670 (2013).

    Article  CAS  PubMed  Google Scholar 

  80. 80

    Palmqvist, S. et al. Accuracy of brain amyloid detection in clinical practice using cerebrospinal fluid β-amyloid 42: a cross-validation study against amyloid positron emission tomography. JAMA Neurol. 71, 1282–1289 (2014).

    Article  Google Scholar 

  81. 81

    Mattsson, N. et al. Independent information from cerebrospinal fluid amyloid-β and florbetapir imaging in Alzheimer's disease. Brain 138, 772–783 (2015).

    Article  PubMed  Google Scholar 

  82. 82

    Rowe, C. C. et al. Imaging of amyloid β in Alzheimer's disease with 18F-BAY94-9172, a novel PET tracer: proof of mechanism. Lancet Neurol. 7, 129–135 (2008).

    Article  CAS  PubMed  Google Scholar 

  83. 83

    Clark, C. M. et al. Cerebral PET with florbetapir compared with neuropathology at autopsy for detection of neuritic amyloid-β plaques: a prospective cohort study. Lancet Neurol. 11, 669–678 (2012).

    Article  CAS  PubMed  Google Scholar 

  84. 84

    Curtis, C. et al. Phase 3 trial of flutemetamol labeled with radioactive fluorine 18 imaging and neuritic plaque density. JAMA Neurol. 72, 287–294 (2015).

    Article  PubMed  Google Scholar 

  85. 85

    Sabri, O., Seibyl, J., Rowe, C. & Barthel, H. Beta-amyloid imaging with florbetaben. Clin. Transl. Imaging 3, 13–26 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  86. 86

    Villemagne, V. L., Fodero-Tavoletti, M. T., Masters, C. L. & Rowe, C. C. Tau imaging: early progress and future directions. Lancet Neurol. 14, 114–124 (2015).

    Article  PubMed  Google Scholar 

  87. 87

    Ellis, K. A. et al. The Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging: methodology and baseline characteristics of 1112 individuals recruited for a longitudinal study of Alzheimer's disease. Int. Psychogeriatr. 21, 672–687 (2009).

    Article  PubMed  Google Scholar 

  88. 88

    Blennow, K., Hampel, H., Weiner, M. & Zetterberg, H. Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat. Rev. Neurol. 6, 131–144 (2010).

    Article  CAS  PubMed  Google Scholar 

  89. 89

    Strozyk, D., Blennow, K., White, L. R. & Launer, L. J. CSF Aβ42 levels correlate with amyloid-neuropathology in a population-based autopsy study. Neurology 60, 652–656 (2003).

    Article  CAS  PubMed  Google Scholar 

  90. 90

    Mattsson, N. et al. Diagnostic accuracy of CSF Ab42 and florbetapir PET for Alzheimer's disease. Ann. Clin. Transl. Neurol. 1, 534–543 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    Wallin, A. K. et al. CSF biomarkers predict a more malignant outcome in Alzheimer disease. Neurology 74, 1531–1537 (2010).

    Article  CAS  PubMed  Google Scholar 

  92. 92

    Riemenschneider, M. et al. Phospho-tau/total tau ratio in cerebrospinal fluid discriminates Creutzfeldt–Jakob disease from other dementias. Mol. Psychiatry 8, 343–347 (2003).

    Article  CAS  PubMed  Google Scholar 

  93. 93

    Lee, J. M. et al. The brain injury biomarker VLP-1 is increased in the cerebrospinal fluid of Alzheimer disease patients. Clin. Chem. 54, 1617–1623 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Skillback, T. et al. CSF neurofilament light differs in neurodegenerative diseases and predicts severity and survival. Neurology 83, 1945–1953 (2014).

    Article  CAS  PubMed  Google Scholar 

  95. 95

    Saman, S. et al. Exosome-associated tau is secreted in tauopathy models and is selectively phosphorylated in cerebrospinal fluid in early Alzheimer disease. J. Biol. Chem. 287, 3842–3849 (2012).

    Article  CAS  PubMed  Google Scholar 

  96. 96

    Maia, L. F. et al. Changes in amyloid-β and tau in the cerebrospinal fluid of transgenic mice overexpressing amyloid precursor protein. Sci. Transl. Med. 5, 194re2 (2013).

    Article  CAS  PubMed  Google Scholar 

  97. 97

    Buerger, K. et al. CSF phosphorylated tau protein correlates with neocortical neurofibrillary pathology in Alzheimer's disease. Brain 129, 3035–3041 (2006).

    Article  PubMed  Google Scholar 

  98. 98

    Hampel, H. et al. Measurement of phosphorylated tau epitopes in the differential diagnosis of Alzheimer disease: a comparative cerebrospinal fluid study. Arch. Gen. Psychiatry 61, 95–102 (2004).

    Article  CAS  PubMed  Google Scholar 

  99. 99

    Blom, E. S. et al. Rapid progression from mild cognitive impairment to Alzheimer's disease in subjects with elevated levels of tau in cerebrospinal fluid and the APOE ε4/ε4 genotype. Dement. Geriatr. Cogn. Disord. 27, 458–464 (2009).

    Article  CAS  PubMed  Google Scholar 

  100. 100

    Maddalena, A. et al. Biochemical diagnosis of Alzheimer disease by measuring the cerebrospinal fluid ratio of phosphorylated tau protein to β-amyloid peptide42. Arch. Neurol. 60, 1202–1206 (2003).

    Article  PubMed  Google Scholar 

  101. 101

    Mattsson, N. et al. CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA 302, 385–393 (2009).

    Article  CAS  PubMed  Google Scholar 

  102. 102

    Blennow, K. et al. Tau protein in cerebrospinal fluid: a biochemical marker for axonal degeneration in Alzheimer disease? Mol. Chem. Neuropathol. 26, 231–245 (1995).

    Article  CAS  PubMed  Google Scholar 

  103. 103

    Koopman, K. et al. Improved discrimination of autopsy-confirmed Alzheimer's disease (AD) from non-AD dementias using CSF P-tau181P . Neurochem. Int. 55, 214–218 (2009).

    Article  CAS  PubMed  Google Scholar 

  104. 104

    Buchhave, P. et al. Cerebrospinal fluid levels of β-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 (2012).

    Article  CAS  PubMed  Google Scholar 

  105. 105

    van Rossum, I. A. et al. Injury markers predict time to dementia in subjects with MCI and amyloid pathology. Neurology 79, 1809–1816 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. 106

    Roe, C. M. et al. Amyloid imaging and CSF biomarkers in predicting cognitive impairment up to 7.5 years later. Neurology 80, 1784–1791 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. 107

    Skoog, I. et al. Cerebrospinal fluid β-amyloid 42 is reduced before the onset of sporadic dementia: a population-based study in 85-year-olds. Dement. Geriatr. Cogn. Disord. 15, 169–176 (2003).

    Article  CAS  PubMed  Google Scholar 

  108. 108

    Skoog, I. et al. A population-based study of tau protein and ubiquitin in cerebrospinal fluid in 85-year-olds: relation to severity of dementia and cerebral atrophy, but not to the apolipoprotein E4 allele. Neurodegeneration 4, 433–442 (1995).

    Article  CAS  PubMed  Google Scholar 

  109. 109

    Gustafson, D. R., Skoog, I., Rosengren, L., Zetterberg, H. & Blennow, K. Cerebrospinal fluid β-amyloid 1–42 concentration may predict cognitive decline in older women. J. Neurol. Neurosurg. Psychiatry 78, 461–464 (2007).

    Article  PubMed  Google Scholar 

  110. 110

    Stomrud, E., Hansson, O., Blennow, K., Minthon, L. & Londos, E. Cerebrospinal fluid biomarkers predict decline in subjective cognitive function over 3 years in healthy elderly. Dement. Geriatr. Cogn. Disord. 24, 118–124 (2007).

    Article  CAS  PubMed  Google Scholar 

  111. 111

    van Harten, A. C. et al. Cerebrospinal fluid Aβ42 is the best predictor of clinical progression in patients with subjective complaints. Alzheimers Dement. 9, 481–487 (2013).

    Article  PubMed  Google Scholar 

  112. 112

    Ringman, J. M. et al. Biochemical markers in persons with preclinical familial Alzheimer disease. Neurology 71, 85–92 (2008).

    Article  CAS  PubMed  Google Scholar 

  113. 113

    Ringman, J. M. et al. Cerebrospinal fluid biomarkers and proximity to diagnosis in preclinical familial Alzheimer's disease. Dement. Geriatr. Cogn. Disord. 33, 1–5 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. 114

    Petersen, R. C. et al. Alzheimer's Disease Neuroimaging Initiative (ADNI) clinical characterization. Neurology 74, 201–209 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  115. 115

    Jack, C. R. Jr et al. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol. 9, 119–128 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. 116

    Kovacs, G. G. et al. Non-Alzheimer neurodegenerative pathologies and their combinations are more frequent than commonly believed in the elderly brain: a community-based autopsy series. Acta Neuropathol. 126, 365–384 (2013).

    Article  CAS  PubMed  Google Scholar 

  117. 117

    Zimmer, E. R., Leuzy, A., Gauthier, S. & Rosa-Neto, P. Developments in tau PET imaging. Can. J. Neurol. Sci. 41, 547–553 (2014).

    Article  PubMed  Google Scholar 

  118. 118

    Brinkmalm, A. et al. SNAP-25 is a promising novel cerebrospinal fluid biomarker for synapse degeneration in Alzheimer's disease. Mol. Neurodegener. 9, 53 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. 119

    Kvartsberg, H. et al. Cerebrospinal fluid levels of the synaptic protein neurogranin correlates with cognitive decline in prodromal Alzheimer's disease. Alzheimers Dement. http://dx.doi.org/10.1016/j.jalz.2014.10.009 (2014).

  120. 120

    Hampel, H. et al. Biomarkers for Alzheimer's disease: academic, industry and regulatory perspectives. Nat. Rev. Drug Discov. 9, 560–574 (2010).

    Article  CAS  PubMed  Google Scholar 

  121. 121

    May, P. C. et al. Robust central reduction of amyloid-β in humans with an orally available, non-peptidic β-secretase inhibitor. J. Neurosci. 31, 16507–16516 (2011).

    Article  CAS  PubMed  Google Scholar 

  122. 122

    Blennow, K., Hampel, H. & Zetterberg, H. Biomarkers in amyloid-β immunotherapy trials in Alzheimer's disease. Neuropsychopharmacology 39, 189–201 (2014).

    Article  CAS  PubMed  Google Scholar 

  123. 123

    Blennow, K. et al. Effect of immunotherapy with bapineuzumab on cerebrospinal fluid biomarker levels in patients with mild to moderate Alzheimer disease. Arch. Neurol. 69, 1002–1010 (2012).

    Article  PubMed  Google Scholar 

  124. 124

    Henriksen, K. et al. The future of blood-based biomarkers for Alzheimer's disease. Alzheimers Dement. 10, 115–131 (2014).

    Article  PubMed  Google Scholar 

  125. 125

    Mehta, P. D. et al. Plasma and cerebrospinal fluid levels of amyloid β proteins 1–40 and 1–42 in Alzheimer disease. Arch. Neurol. 57, 100–105 (2000).

    Article  CAS  PubMed  Google Scholar 

  126. 126

    Reiman, E. M. et al. Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer's disease in the presenilin 1 E280A kindred: a case–control study. Lancet Neurol. 11, 1048–1056 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. 127

    Sperling, R. A., Jack, C. R. Jr & Aisen, P. S. Testing the right target and right drug at the right stage. Sci. Transl. Med. 3, 111cm33 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  128. 128

    Doody, R. S. et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease. N. Engl. J. Med. 370, 311–321 (2014). One of many ‘failed’ Phase III studies that contains evidence of some efficacy, which requires further study in biomarker-defined Alzheimer's disease.

    Article  CAS  PubMed  Google Scholar 

  129. 129

    Hoffmann-La Roche. A study of gantenerumab in patients with mild Alzheimer disease. ClinicalTrials.gov[online], (2014).

  130. 130

    Genentech, Inc. A study of crenezumab in patients with mild to moderate Alzheimer disease (AD). ClinicalTrials.gov[online], (2015).

  131. 131

    Donohue, M. C. et al. The preclinical Alzheimer cognitive composite: measuring amyloid-related decline. JAMA Neurol. 71, 961–970 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  132. 132

    Amariglio, R. E. et al. Tracking early decline in cognitive function in older individuals at risk for Alzheimer disease dementia: The Alzheimer's Disease Cooperative Study Cognitive Function Instrument. JAMA Neurol. 72, 446–454 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  133. 133

    Moulder, K. L. et al. Dominantly Inherited Alzheimer Network: facilitating research and clinical trials. Alzheimers Res. Ther. 5, 48 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  134. 134

    Langbaum, J. B. et al. Ushering in the study and treatment of preclinical Alzheimer disease. Nat. Rev. Neurol. 9, 371–381 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. 135

    Roses, A. D. et al. New applications of disease genetics and pharmacogenetics to drug development. Curr. Opin. Pharmacol. 14, 81–89 (2014).

    Article  CAS  PubMed  Google Scholar 

  136. 136

    Mormino, E. C. et al. Synergistic effect of β-amyloid and neurodegeneration on cognitive decline in clinically normal individuals. JAMA Neurol. 71, 1379–1385 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  137. 137

    Noetzli, M. & Eap, C. B. Pharmacodynamic, pharmacokinetic and pharmacogenetic aspects of drugs used in the treatment of Alzheimer's disease. Clin. Pharmacokinet. 52, 225–241 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. 138

    Parsons, C. G., Danysz, W., Dekundy, A. & Pulte, I. Memantine and cholinesterase inhibitors: complementary mechanisms in the treatment of Alzheimer's disease. Neurotox. Res. 24, 358–369 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. 139

    Tariot, P. N. et al. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA 291, 317–324 (2004).

    Article  CAS  PubMed  Google Scholar 

  140. 140

    Rountree, S. D., Atri, A., Lopez, O. L. & Doody, R. S. Effectiveness of antidementia drugs in delaying Alzheimer's disease progression. Alzheimers Dement. 9, 338–345 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  141. 141

    Takeda, A. et al. A systematic review of the clinical effectiveness of donepezil, rivastigmine and galantamine on cognition, quality of life and adverse events in Alzheimer's disease. Int. J. Geriatr. Psychiatry 21, 17–28 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. 142

    Di Santo, S. G., Prinelli, F., Adorni, F., Caltagirone, C. & Musicco, M. A meta-analysis of the efficacy of donepezil, rivastigmine, galantamine, and memantine in relation to severity of Alzheimer's disease. J. Alzheimers Dis. 35, 349–361 (2013).

    Article  CAS  PubMed  Google Scholar 

  143. 143

    Thaipisuttikul, P. & Galvin, J. E. Use of medical foods and nutritional approaches in the treatment of Alzheimer's disease. Clin. Pract. (Lond.) 9, 199–209 (2012).

    Article  CAS  Google Scholar 

  144. 144

    U.S. Food and Drug Administration. Draft Guidance for Industry: frequently asked questions about medical foods. FDA[online], (2013).

  145. 145

    Sun, Y., Lu, C. J., Chien, K. L., Chen, S. T. & Chen, R. C. Efficacy of multivitamin supplementation containing vitamins B6 and B12 and folic acid as adjunctive treatment with a cholinesterase inhibitor in Alzheimer's disease: a 26-week, randomized, double-blind, placebo-controlled study in Taiwanese patients. Clin. Ther. 29, 2204–2214 (2007).

    Article  CAS  PubMed  Google Scholar 

  146. 146

    Dysken, M. W. et al. Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial. JAMA 311, 33–44 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  147. 147

    Petersen, R. C. et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N. Engl. J. Med. 352, 2379–2388 (2005).

    Article  CAS  PubMed  Google Scholar 

  148. 148

    Lonn, E. et al. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA 293, 1338–1347 (2005).

    Article  PubMed  Google Scholar 

  149. 149

    Shah, R. The role of nutrition and diet in Alzheimer disease: a systematic review. J. Am. Med. Dir. Assoc. 14, 398–402 (2013).

    Article  PubMed  Google Scholar 

  150. 150

    Echavarri, C. et al. Neuropsychiatric symptoms in Alzheimer's disease and vascular dementia. J. Alzheimers Dis. 33, 715–721 (2013).

    Article  PubMed  Google Scholar 

  151. 151

    Brodaty, H., Connors, M. H., Xu, J., Woodward, M. & Ames, D. Predictors of institutionalization in dementia: a three year longitudinal study. J. Alzheimers Dis. 40, 221–226 (2014).

    Article  PubMed  Google Scholar 

  152. 152

    Rog, L. A. et al. The independent contributions of cognitive impairment and neuropsychiatric symptoms to everyday function in older adults. Clin. Neuropsychol. 28, 215–236 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  153. 153

    Salzman, C. et al. Elderly patients with dementia-related symptoms of severe agitation and aggression: consensus statement on treatment options, clinical trials methodology, and policy. J. Clin. Psychiatry 69, 889–898 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  154. 154

    Black, B. S. et al. Quality of life of community-residing persons with dementia based on self-rated and caregiver-rated measures. Qual. Life Res. 21, 1379–1389 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  155. 155

    Thinnes, A. & Padilla, R. Effect of educational and supportive strategies on the ability of caregivers of people with dementia to maintain participation in that role. Am. J. Occup. Ther. 65, 541–549 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  156. 156

    Lussier, D., Bruneau, M. A. & Villalpando, J. M. Management of end-stage dementia. Prim. Care 38, 247–264 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  157. 157

    Bhattacharya, S., Vogel, A., Hansen, M. L., Waldorff, F. B. & Waldemar, G. Generic and disease-specific measures of quality of life in patients with mild Alzheimer's disease. Dement. Geriatr. Cogn. Disord. 30, 327–333 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  158. 158

    Gomez-Gallego, M., Gomez-Amor, J. & Gomez-Garcia, J. Determinants of quality of life in Alzheimer's disease: perspective of patients, informal caregivers, and professional caregivers. Int. Psychogeriatr. 24, 1805–1815 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  159. 159

    Bosboom, P. R., Alfonso, H., Eaton, J. & Almeida, O. P. Quality of life in Alzheimer's disease: different factors associated with complementary ratings by patients and family carers. Int. Psychogeriatr. 24, 708–721 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  160. 160

    Ready, R. E., Ott, B. R. & Grace, J. Patient versus informant perspectives of quality of life in mild cognitive impairment and Alzheimer's disease. Int. J. Geriatr. Psychiatry 19, 256–265 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  161. 161

    Zucchella, C., Bartolo, M., Bernini, S., Picascia, M. & Sinforiani, E. Quality of life in Alzheimer disease: a comparison of patients' and caregivers' points of view. Alzheimer Dis. Assoc. Disord. 29, 50–54 (2014).

    Article  CAS  Google Scholar 

  162. 162

    Abdollahpour, I., Nedjat, S., Salimi, Y., Noroozian, M. & Majdzadeh, R. Which variable is the strongest adjusted predictor of quality of life in caregivers of patients with dementia? Psychogeriatrics 15, 51–57 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  163. 163

    Sousa, M. F. et al. Awareness of disease is different for cognitive and functional aspects in mild Alzheimer's disease: a one-year observation study. J. Alzheimers Dis. 43, 905–913 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  164. 164

    Santos, R. L. et al. Caregivers' quality of life in mild and moderate dementia. Arq. Neuropsiquiatr. 72, 931–937 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  165. 165

    Logsdon, R. G., Gibbons, L. E., McCurry, S. M. & Teri, L. Assessing quality of life in older adults with cognitive impairment. Psychosom. Med. 64, 510–519 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  166. 166

    Mohs, R. C. et al. A 1-year, placebo-controlled preservation of function survival study of donepezil in AD patients. Neurology 57, 481–488 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. 167

    Street, J. S. et al. Olanzapine treatment of psychotic and behavioral symptoms in patients with Alzheimer disease in nursing care facilities: a double-blind, randomized, placebo-controlled trial. The HGEU Study Group. Arch. Gen. Psychiatry 57, 968–976 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. 168

    Mittelman, M. S., Ferris, S. H., Shulman, E., Steinberg, G. & Levin, B. A family intervention to delay nursing home placement of patients with Alzheimer disease. A randomized controlled trial. JAMA 276, 1725–1731 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. 169

    Green, R. C. et al. Disclosure of APOE genotype for risk of Alzheimer's disease. N. Engl. J. Med. 361, 245–254 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. 170

    Shulman, M. B., Harkins, K., Green, R. C. & Karlawish, J. Using AD biomarker research results for clinical care: a survey of ADNI investigators. Neurology 81, 1114–1121 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. 171

    Doody, R. S. et al. A Phase 3 trial of semagacestat for treatment of Alzheimer's disease. N. Engl. J. Med. 369, 341–350 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. 172

    Spielmeyer, W. Histopathologie des Nervensystems (Julius Springer, 1922).

    Google Scholar 

  173. 173

    Braak, H. & Braak, E. Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol. Aging 18, 351–357 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. 174

    Thathiah, A. & De Strooper, B. The role of G protein-coupled receptors in the pathology of Alzheimer's disease. Nat. Rev. Neurosci. 12, 73–87 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. 175

    Scheltens, P. et al. Efficacy of souvenaid in mild Alzheimer's disease: results from a randomized, controlled trial. J. Alzheimers Dis. 31, 225–236 (2012).

    Article  CAS  PubMed  Google Scholar 

  176. 176

    Schneider, L. S., Dagerman, K. & Insel, P. S. Efficacy and adverse effects of atypical antipsychotics for dementia: meta-analysis of randomized, placebo-controlled trials. Am. J. Geriatr. Psychiatry 14, 191–210 (2006).

    Article  PubMed  Google Scholar 

  177. 177

    Cummings, J. et al. Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet 383, 533–540 (2014).

    Article  CAS  PubMed  Google Scholar 

  178. 178

    Porsteinsson, A. P. et al. Effect of citalopram on agitation in Alzheimer disease: the CitAD randomized clinical trial. JAMA 311, 682–691 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. 179

    Rosenberg, P. B. et al. Sertraline for the treatment of depression in Alzheimer disease. Am. J. Geriatr. Psychiatry 18, 136–145 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  180. 180

    Lanctot, K. L. et al. Effect of methylphenidate on attention in apathetic AD patients in a randomized, placebo-controlled trial. Int. Psychogeriatr. 26, 239–246 (2014).

    Article  PubMed  Google Scholar 

  181. 181

    McCleery, J., Cohen, D. A. & Sharpley, A. L. Pharmacotherapies for sleep disturbances in Alzheimer's disease. Cochrane Database Syst. Rev. 3, CD009178 (2014).

    Google Scholar 

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Contributions

Introduction (C.L.M.); Epidemiology (C.L.M.); Mechanisms/pathophysiology (R.B.); Diagnosis, screening and prevention (K.B., C.C.R. and R.A.S.); Management (J.L.C.); Quality of life (J.L.C.); Outlook (C.L.M.); Overview of the Primer (C.L.M.).

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Correspondence to Colin L. Masters.

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Competing interests

C.L.M. has provided consultation to Eli Lilly, Actinogen and Prana Biotechnology. He has stock ownership in Prana Biotechnology. R.B. has provided consultation to FORUM, Merck, Roche, Sanofi, Boehringer Ingelheim and Eli Lilly. He currently consults and owns stock in C2N Diagnostics, which he co-founded. He also receives research support from Eli Lilly, Roche, Merck and the Dominantly Inherited Alzheimer Network (DIAN) Pharma Consortium (comprising Amgen, Biogen Idec, Eisai, FORUM, Genentech, Janssen, Lilly, Roche and Sanofi). K.B. has served on advisory boards for Amgen, Eli Lilly, IBL International, Novartis, Roche Diagnostics and Sanofi-Aventis. C.C.R. has received research grants from GE Healthcare, Avid Radiopharmaceuticals, Primal, AstraZeneca and Navidea in the past 2 years. R.A.S. has served as a consultant for Janssen, Genentech, ISIS Pharmaceuticals and Roche. She receives research support from Eli Lilly and Janssen. J.L.C. has provided consultation to AbbVie, Acadia, Actinogen, ADAMAS, Alzheon, Anavex, Avanir, Biogen Idec, Biotie, Boehinger Ingelheim, Chase, Eisai, FORUM, Genentech, Grifols, Intracellular Therapies, Eli Lilly, Lundbeck, Merck, Neurotrope, Novartis, Nutricia, Otsuka, Pfizer, Resverlogix, Roche, Roivant, Suven, Takeda and Toyoma companies.

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Masters, C., Bateman, R., Blennow, K. et al. Alzheimer's disease. Nat Rev Dis Primers 1, 15056 (2015). https://doi.org/10.1038/nrdp.2015.56

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