C. L. Masters, R. Bateman, K. Blennow, C. C. Rowe, R. A. Sperling et al., Alzheimer's disease, Nat Rev Dis Primers, vol.1, p.15056, 2015.
URL : https://hal.archives-ouvertes.fr/inserm-01723790

P. Scheltens, K. Blennow, M. M. Breteler, B. De-strooper, G. B. Frisoni et al., Alzheimer's disease, Lancet, vol.388, pp.505-522, 2016.
URL : https://hal.archives-ouvertes.fr/inserm-01723790

D. J. Selkoe and J. Hardy, The amyloid hypothesis of Alzheimer's disease at 25 years, EMBO Mol Med, vol.8, issue.6, pp.595-608, 2016.

R. Yan and R. Vassar, Targeting the beta secretase BACE1 for Alzheimer's disease therapy, Lancet Neurol, vol.13, issue.3, pp.319-348, 2014.

V. Coric, C. H. Van-dyck, S. Salloway, N. Andreasen, M. Brody et al., Safety and tolerability of the gamma-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease, Arch Neurol, vol.69, issue.11, pp.1430-1470, 2012.

R. S. Doody, R. Raman, M. Farlow, T. Iwatsubo, B. Vellas et al., A phase 3 trial of semagacestat for treatment of Alzheimer's disease, N Engl J Med, vol.369, issue.4, pp.341-50, 2013.

R. S. Doody, R. G. Thomas, M. Farlow, T. Iwatsubo, B. Vellas et al., Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease, N Engl J Med, vol.370, issue.4, pp.311-332, 2014.

S. Salloway, R. Sperling, N. C. Fox, K. Blennow, W. Klunk et al., Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease, N Engl J Med, vol.370, issue.4, pp.322-355, 2014.

J. Sevigny, P. Chiao, T. Bussiere, P. H. Weinreb, L. Williams et al., The antibody aducanumab reduces A? plaques in Alzheimer's disease, Nature, vol.537, issue.7618, pp.50-56, 2016.

R. Vassar, P. H. Kuhn, C. Haass, M. E. Kennedy, L. Rajendran et al., Function, therapeutic potential and cell biology of BACE proteases: current status and future prospects, J Neurochem, vol.130, issue.1, pp.4-28, 2014.

S. Barao, D. Moechars, S. F. Lichtenthaler, D. Strooper, and B. , BACE1 physiological functions may limit its use as therapeutic target for Alzheimer's disease, Trends Neurosci, vol.39, issue.3, pp.158-69, 2016.

J. D. Scott, S. W. Li, A. P. Brunskill, X. Chen, K. Cox et al., Discovery of the 3-imino-1,2,4-thiadiazinane 1,1-dioxide derivative verubecestat (MK-8931)-a beta-site amyloid precursor protein cleaving enzyme 1 inhibitor for the treatment of Alzheimer's disease, J Med Chem, vol.59, issue.23, pp.10435-50, 2016.

M. E. Kennedy, A. W. Stamford, X. Chen, K. Cox, J. N. Cumming et al., The BACE1 inhibitor verubecestat (MK-8931) reduces CNS betaamyloid in animal models and in Alzheimer's disease patients, Sci Transl Med, vol.8, issue.363, pp.363-150, 2016.

M. F. Egan, J. Kost, P. N. Tariot, P. S. Aisen, J. L. Cummings et al., Randomized trial of verubecestat for mild-to-moderate Alzheimer's disease, N Engl J Med, vol.378, issue.18, pp.1691-703, 2018.

C. Sur, J. Kost, D. Scott, K. Adamczuk, N. C. Fox et al., BACE inhibition by verubecestat produces a rapid, non-progressive reduction in brain and hippocampal volume in Alzheimer's disease, J Prev Alzheimers Disease, vol.5, issue.4, pp.18-27, 2018.

G. Mckhann, D. Drachman, M. Folstein, R. Katzman, D. Price et al., Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's disease, Neurology, vol.34, issue.7, pp.939-983, 1984.

, Diagnostic and statistical manual of mental disorders, 2000.

M. F. Folstein, S. E. Folstein, and P. R. Mchugh, Mini-mental state". A practical method for grading the cognitive state of patients for the clinician, J Psychiatr Res, vol.12, issue.3, pp.189-98, 1975.

K. Posner, G. K. Brown, B. Stanley, D. A. Brent, K. V. Yershova et al., The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults, Am J Psychiatry, vol.168, issue.12, pp.1266-77, 2011.

J. L. Cummings, M. Mega, K. Gray, S. Rosenberg-thompson, D. A. Carusi et al., The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia, Neurology, vol.44, issue.12, pp.2308-2322, 1994.

J. M. Guirguis-blake, Y. L. Michael, L. A. Perdue, E. L. Coppola, and T. L. Beil, Interventions to prevent falls in older adults: updated evidence report and systematic review for the US Preventive Services Task Force, JAMA, vol.319, issue.16, pp.1705-1721, 2018.

E. Fernando, M. Fraser, J. Hendriksen, C. H. Kim, . Muir-hunter et al., Risk factors associated with falls in older adults with dementia: a systematic review, Physiother Can, vol.69, issue.2, pp.161-70, 2017.

J. C. Woolcott, K. J. Richardson, M. O. Wiens, B. Patel, J. Marin et al., Meta-analysis of the impact of 9 medication classes on falls in elderly persons, Arch Intern Med, vol.169, issue.21, pp.1952-60, 2009.

L. J. Seppala, A. Wermelink, M. De-vries, K. J. Ploegmakers, E. Van-de-glind et al., Fall-risk-increasing drugs: a systematic review and metaanalysis: II. Psychotropics, J Am Med Dir Assoc, vol.19, issue.4, pp.371-382, 2018.

I. Conejero, S. Navucet, J. Keller, E. Olie, P. Courtet et al., A complex relationship between suicide, dementia, and amyloid: a narrative review, Front Neurosci, vol.12, p.371, 2018.
URL : https://hal.archives-ouvertes.fr/hal-02320316

, Suicidal ideation and behavior: prospective assessment of occurrence in clinical trials, 2019.

, BACE inhibitor BI 1181181 voluntarily put on temporary clinical hold for safety evaluation, BACE-Inhibitor-BI-1181181-Voluntarily-Put-on-Temporary-Clinical-Hold-for-Safety-Evaluation.html. Accessed 4, 2015.

D. R. Shimshek, L. H. Jacobson, C. Kolly, N. Zamurovic, K. K. Balavenkatraman et al., Pharmacological BACE1 and BACE2inhibition induces hair depigmentation by inhibiting PMEL17 processing in mice, Sci Rep, vol.6, p.21917, 2016.

L. Rochin, I. Hurbain, L. Serneels, C. Fort, B. Watt et al., BACE2 processes PMEL to form the melanosome amyloid matrix in pigment cells, Proc Natl Acad Sci, vol.110, issue.26, pp.10658-63, 2013.
URL : https://hal.archives-ouvertes.fr/hal-02328958

P. C. May, B. A. Willis, S. L. Lowe, R. A. Dean, S. A. Monk et al., The potent BACE1 inhibitor LY2886721 elicits robust central A? pharmacodynamic responses in mice, dogs, and humans, J Neurosci, vol.35, issue.3, pp.1199-210, 2015.

J. Global, Update on Janssen's BACE Inhibitor Program, 2019.

R. Sperling, S. Salloway, D. J. Brooks, D. Tampieri, J. Barakos et al., Amyloid-related imaging abnormalities in patients with Alzheimer's disease treated with bapineuzumab: a retrospective analysis, Lancet Neurol, vol.11, issue.3, pp.241-250, 2012.

C. Sur, J. Kost, D. Scott, K. Adamczuk, N. C. Fox et al., BACE inhibition by verubecestat produces a rapid non-progressive reduction in brain and hippocampal volume in Alzheimer's disease, JPAD, vol.5, p.19, 2018.

N. C. Fox, R. S. Black, S. Gilman, M. N. Rossor, S. G. Griffith et al., Effects of A? immunization (AN1792) on MRI measures of cerebral volume in Alzheimer disease, Neurology, vol.64, issue.9, pp.1563-72, 2005.

G. Novak, N. Fox, S. Clegg, C. Nielsen, S. Einstein et al., Changes in brain volume with bapineuzumab in mild to moderate Alzheimer's disease, J Alzheimers Dis, vol.49, issue.4, pp.1123-1157, 2016.

M. F. Egan, J. Kost, T. Voss, Y. Mukai, P. S. Aisen et al., Randomized trial of verubecestat for prodromal Alzheimer's disease, N Engl J Med, vol.380, issue.15, pp.1408-1428, 2019.

D. Henley, N. Raghavan, R. Sperling, P. Aisen, R. Raman et al., Preliminary results of a trial of atabecestat in preclinical Alzheimer's disease, N Engl J Med, vol.380, issue.15, pp.1483-1488, 2019.

D. S. Knopman, Lowering of amyloid-beta by ?-secretase inhibitors -some informative failures, N Engl J Med, vol.380, issue.15, pp.1476-1484, 2019.

, Publisher's Note

, Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations