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).
Hebert, L. E. et al. Age-specific incidence of Alzheimer's disease in a community population. JAMA 273, 1354–1359 (1995).
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).
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.
Nelson, P. T. et al. Hippocampal sclerosis in advanced age: clinical and pathological features. Brain 134, 1506–1518 (2011).
Duncan, G. W. et al. The incidence of Parkinson's disease in the north-east of England. Age Ageing 43, 257–263 (2014).
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).
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).
Australian Bureau of Statistics. Causes of death, Australia, 2013. ABS [online], (2015).
Ossenkoppele, R. et al. Prevalence of amyloid PET positivity in dementia syndromes: a meta-analysis. JAMA 313, 1939–1949 (2015).
Jansen, W. J. et al. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA 313, 1924–1938 (2015).
Prince, M. et al. World Alzheimer Report 2015. Alzheimer's Disease International [online], (2015).
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).
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).
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.
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).
Selkoe, D. J. Alzheimer's disease: genes, proteins, and therapy. Physiol. Rev. 81, 741–766 (2001).
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).
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).
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).
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).
Hecimovic, S. et al. Mutations in APP have independent effects on Aβ and CTFγ generation. Neurobiol. Dis. 17, 205–218 (2004).
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).
Bateman, R. J. et al. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N. Engl. J. Med. 367, 795–804 (2012).
Ryman, D. C. et al. Symptom onset in autosomal dominant Alzheimer disease: a systematic review and meta-analysis. Neurology 83, 253–260 (2014).
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).
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).
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).
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).
Jonsson, T. et al. A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature 488, 96–99 (2012).
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).
Mawuenyega, K. G. et al. Decreased clearance of CNS β-amyloid in Alzheimer's disease. Science 330, 1774–1774 (2010).
Bateman, R. J. et al. A γ-secretase inhibitor decreases amyloid-β production in the central nervous system. Ann. Neurol. 66, 48–54 (2009).
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).
Artiga, M. J. et al. Allelic polymorphisms in the transcriptional regulatory region of apolipoprotein E gene. FEBS Lett. 421, 105–108 (1998).
Saunders, A. M. et al. Association of apolipoprotein E allele ε4 with late-onset familial and sporadic Alzheimers disease. Neurology 43, 1467–1472 (1993).
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).
Fernández-Miranda, C. et al. Changes in phenotypes of apolipoprotein E and apolipoprotein(a) in liver transplant recipients. Clin. Transplant. 11, 325–327 (1997).
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).
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.
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).
Corder, E. H. et al. Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat. Genet. 7, 180–184 (1994).
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).
Ashford, J. W. APOE genotype effects on Alzheimer's disease onset and epidemiology. J. Mol. Neurosci. 23, 157–165 (2004).
Holtzman, D. M. In vivo effects of ApoE and clusterin on amyloid-β metabolism and neuropathology. J. Mol. Neurosci. 23, 247–254 (2004).
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).
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).
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).
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).
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).
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).
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).
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).
Nathan, B. P. et al. Differential effects of apolipoproteins E3 and E4 on neuronal growth in vitro. Science 264, 850–852 (1994).
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).
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).
Deane, R. et al. ApoE isoform-specific disruption of amyloid β peptide clearance from mouse brain. J. Clin. Invest. 118, 4002–4013 (2008).
Wisniewski, T., Ghiso, J. & Frangione, B. Biology of Aβ amyloid in Alzheimer's disease. Neurobiol. Dis. 4, 313–328 (1997).
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).
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).
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).
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.
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.
Mintun, M. A. et al. [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease. Neurology 67, 446–452 (2006).
Rowe, C. C. et al. Imaging β-amyloid burden in aging and dementia. Neurology 68, 1718–1725 (2007).
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).
Knopman, D. S. et al. Short-term clinical outcomes for stages of NIA-AA preclinical Alzheimer disease. Neurology 78, 1576–1582 (2012).
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).
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.
Jack, C. R. Jr et al. Brain β-amyloid load approaches a plateau. Neurology 80, 890–896 (2013).
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.
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).
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).
Sperling, R. A. et al. The A4 study: stopping AD before symptoms begin? Sci. Transl. Med. 6, 228fs13 (2014).
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).
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).
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.
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).
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).
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).
Mattsson, N. et al. Independent information from cerebrospinal fluid amyloid-β and florbetapir imaging in Alzheimer's disease. Brain 138, 772–783 (2015).
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).
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).
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).
Sabri, O., Seibyl, J., Rowe, C. & Barthel, H. Beta-amyloid imaging with florbetaben. Clin. Transl. Imaging 3, 13–26 (2015).
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).
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).
Blennow, K., Hampel, H., Weiner, M. & Zetterberg, H. Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat. Rev. Neurol. 6, 131–144 (2010).
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).
Mattsson, N. et al. Diagnostic accuracy of CSF Ab42 and florbetapir PET for Alzheimer's disease. Ann. Clin. Transl. Neurol. 1, 534–543 (2014).
Wallin, A. K. et al. CSF biomarkers predict a more malignant outcome in Alzheimer disease. Neurology 74, 1531–1537 (2010).
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).
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).
Skillback, T. et al. CSF neurofilament light differs in neurodegenerative diseases and predicts severity and survival. Neurology 83, 1945–1953 (2014).
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).
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).
Buerger, K. et al. CSF phosphorylated tau protein correlates with neocortical neurofibrillary pathology in Alzheimer's disease. Brain 129, 3035–3041 (2006).
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).
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).
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).
Mattsson, N. et al. CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA 302, 385–393 (2009).
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).
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).
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).
van Rossum, I. A. et al. Injury markers predict time to dementia in subjects with MCI and amyloid pathology. Neurology 79, 1809–1816 (2012).
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).
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).
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).
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).
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).
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).
Ringman, J. M. et al. Biochemical markers in persons with preclinical familial Alzheimer disease. Neurology 71, 85–92 (2008).
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).
Petersen, R. C. et al. Alzheimer's Disease Neuroimaging Initiative (ADNI) clinical characterization. Neurology 74, 201–209 (2010).
Jack, C. R. Jr et al. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol. 9, 119–128 (2010).
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).
Zimmer, E. R., Leuzy, A., Gauthier, S. & Rosa-Neto, P. Developments in tau PET imaging. Can. J. Neurol. Sci. 41, 547–553 (2014).
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).
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).
Hampel, H. et al. Biomarkers for Alzheimer's disease: academic, industry and regulatory perspectives. Nat. Rev. Drug Discov. 9, 560–574 (2010).
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).
Blennow, K., Hampel, H. & Zetterberg, H. Biomarkers in amyloid-β immunotherapy trials in Alzheimer's disease. Neuropsychopharmacology 39, 189–201 (2014).
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).
Henriksen, K. et al. The future of blood-based biomarkers for Alzheimer's disease. Alzheimers Dement. 10, 115–131 (2014).
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).
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).
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).
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.
Hoffmann-La Roche. A study of gantenerumab in patients with mild Alzheimer disease. ClinicalTrials.gov [online], (2014).
Genentech, Inc. A study of crenezumab in patients with mild to moderate Alzheimer disease (AD). ClinicalTrials.gov [online], (2015).
Donohue, M. C. et al. The preclinical Alzheimer cognitive composite: measuring amyloid-related decline. JAMA Neurol. 71, 961–970 (2014).
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).
Moulder, K. L. et al. Dominantly Inherited Alzheimer Network: facilitating research and clinical trials. Alzheimers Res. Ther. 5, 48 (2013).
Langbaum, J. B. et al. Ushering in the study and treatment of preclinical Alzheimer disease. Nat. Rev. Neurol. 9, 371–381 (2013).
Roses, A. D. et al. New applications of disease genetics and pharmacogenetics to drug development. Curr. Opin. Pharmacol. 14, 81–89 (2014).
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).
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).
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).
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).
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).
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).
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).
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).
U.S. Food and Drug Administration. Draft Guidance for Industry: frequently asked questions about medical foods. FDA [online], (2013).
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).
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).
Petersen, R. C. et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N. Engl. J. Med. 352, 2379–2388 (2005).
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).
Shah, R. The role of nutrition and diet in Alzheimer disease: a systematic review. J. Am. Med. Dir. Assoc. 14, 398–402 (2013).
Echavarri, C. et al. Neuropsychiatric symptoms in Alzheimer's disease and vascular dementia. J. Alzheimers Dis. 33, 715–721 (2013).
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).
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).
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).
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).
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).
Lussier, D., Bruneau, M. A. & Villalpando, J. M. Management of end-stage dementia. Prim. Care 38, 247–264 (2011).
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).
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).
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).
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).
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).
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).
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).
Santos, R. L. et al. Caregivers' quality of life in mild and moderate dementia. Arq. Neuropsiquiatr. 72, 931–937 (2014).
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).
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).
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).
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).
Green, R. C. et al. Disclosure of APOE genotype for risk of Alzheimer's disease. N. Engl. J. Med. 361, 245–254 (2009).
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).
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).
Spielmeyer, W. Histopathologie des Nervensystems (Julius Springer, 1922).
Braak, H. & Braak, E. Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol. Aging 18, 351–357 (1997).
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).
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).
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).
Cummings, J. et al. Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet 383, 533–540 (2014).
Porsteinsson, A. P. et al. Effect of citalopram on agitation in Alzheimer disease: the CitAD randomized clinical trial. JAMA 311, 682–691 (2014).
Rosenberg, P. B. et al. Sertraline for the treatment of depression in Alzheimer disease. Am. J. Geriatr. Psychiatry 18, 136–145 (2010).
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).
McCleery, J., Cohen, D. A. & Sharpley, A. L. Pharmacotherapies for sleep disturbances in Alzheimer's disease. Cochrane Database Syst. Rev. 3, CD009178 (2014).