Assises régionales PMND – ARS – 18 décembre 2019

Les cibles thérapeutiques dans la maladie d’Alzheimer

Dr Vincent Planche

Centre Mémoire Ressources Recherche, Pôle des Neurosciences Cliniques, CHU de BordeauxInstitut des Maladies Neurodégénératives, Université de Bordeaux, CNRS, UMR 5293

Introduction Les cibles thérapeutiques dans la maladie d’Alzheimer

La prévention

Les thérapies non-médicamenteuses

Les thérapies médicamenteuses:

- Approche étiologique/curative- Approche symptomatique

Introduction Physiopathologie de la maladie d’Alzheimer

Sperling et al., Alzheimers Dementia, 2011

Figure 1. Commonalities among age-related neurodegenerative diseasesThe deposited proteins adopt an amyloid conformation and show prion-like self-propagationand spreading in experimental settings, consistent with the progressive appearance of thelesions in the human diseases. a, AŚ deposits (senile plaques) in the neocortex of a patientwith Alzheimer’s disease. b, Tau inclusion as a neurofibrillary tangle in a neocortical neuronof a patient with Alzheimer’s disease. c, ř-Synuclein inclusion (Lewy body) in a neocorticalneuron from a patient with Parkinson’s disease/Lewy body dementia. d, TDP-43 inclusionin a motoneuron of the spinal cord from a patient with amyotrophic lateral sclerosis. Scalebars are 50 µm in a and 20 µm in b–d. e–h, Characteristic progression of specificproteinaceous lesions in neurodegenerative diseases over time (t, black arrows), inferredfrom post-mortem analyses of brains. AŚ deposits and tau inclusions in brains of patientswith Alzheimer’s disease (e and f), ř-synuclein inclusions in brains of patients withParkinson’s disease (g), and TDP-43 inclusions in brains of patients with amyotrophiclateral sclerosis (h). Three stages are shown for each disease, with white arrows indicatingthe putative spread of the lesions (for details see refs 5–8). Panels e and f are reproduced,with permission, from ref. 61.

Jucker and Walker Page 13

Nature. Author manuscript; available in PMC 2014 March 24.

NIH

-PA Author Manuscript

NIH

-PA Author Manuscript

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-PA Author Manuscript

Tau

Jucker & Walker, Nature 2013

Introduction Physiopathologie de la maladie d’Alzheimer

__PERSPECTIVE

Alzheimer's disease causes dementia inmany elderly people and in some individu-als with Down syndrome who survive to age50. Alzheimer's is characterized by variouspathological markers in the brain-largenumbers of amyloid plaques surrounded byneurons containing neurofibrillary tangles(1), vascular damage from extensive plaquedeposition (2), and neuronal cell loss (1).Because it is not known if the amyloidplaques or the neurofibrillary tangles are theearliest lesion in the disease process, therole of these markers in the etiology of thedisease is controversial.

Our hypothesis is that deposition ofamyloid fi protein (A3P), the main com-ponent of the (3) plaques, is the causativeagent of Alzheimer's pathology and that theneurofibrillary tangles, cell loss, vasculardamage, and dementia follow as a directresult of this deposition. APP is a peptideproduct of the larger amyloid precursorprotein (APP) (4). Because Down syn-drome is caused by trisomy of the region ofchromosome 21 that contains the APPgene, deposition of APP is likely to be anearly event in the disease (5). The AIPmolecule is a 39- to 42-amino acid peptide(4, 6), part of which forms the hydrophobictransmembrane domain in the COOH-ter-minal portion of APP (Fig. 1). AI3P is oneof a diverse group of "amyloid" (starch-like)proteins that forms insoluble extracellulardeposits. The APP gene undergoes alterna-tive RNA splicing to produce several pro-tein isoforms; the predominant variant inbrain lacks a serine protease inhibitor do-main that is present in APP molecules inother tissues (7).

We now know something about howAPP proteolysis leads to APP deposition.APP is inserted into the cytoplasmic mem-brane and then cleaved at residues 15 to 17within the APP sequence by the APP"secretase" (8) (Fig. 1). This cleavageevent therefore produces fragments that donot contain intact APP and so cannotresult in amyloid deposition. These frag-ments include secreted NH2-terminal de-rivatives that can be detected in brain and

J. A. Hardy, Department of Biochemistry, St. Mary'sHospital Medical School, London W2 1 PG, U.K., andDepartment of Psychiatry, University of South Florida,Tampa, FL 33612.G. A. Higgins, Molecular Neurobiology, Laboratory ofBiological Chemistry, National Institute on Aging, Na-tional Institutes of Health, Baltimore, MD 21224.

184

cerebrospinal fluid (9). The APP secretasethat cuts within the APP region has anextraordinarily broad sequence specificityand recognizes the secondary structure ofAPP, cleaving at a defined distance from themembrane (10). Several recent studies sug-gest that APP can also be processed by theendosomal-lysosomal pathway, after recy-cling of membrane-bound APP and possiblyvia an intracellular metabolic route (11-13).Carboxyl-terminal fragments containing theentire AMPP sequence can be derived fromthis alternate normal processing of APP (12,14) and may eventually lead to amyloiddeposition (12, 14) (Fig. 1).

Fig. 1. The amyloid cas-cade hypothesis. Pro-cessing of APP can oc-cur via two pathways: (i)Cleavage within APP bythe secretase, whichgenerates peptide prod-ucts that do not precipi-tate to form amyloid and(ii) cleavage in the endo-somal-lysosomal com-partment, resulting in in-tact AI3P that precipi-tates to form amyloidand, in turn, causesneurofibrillary tanglesand cell death, the hall-marks of Alzheimer'sdisease.

Alzheimer's disease. These mutations all oc-cur at codon 717 of the protein (15, 16) andchange the native valine, located three resi-dues from the COOH-terminal end of ASP,to isoleucine, phenylalanine, or glycine (Fig.1). It is unclear how these mutations causeamyloid deposition, but they may inhibit thebreakdown of a COOH-terminal fragment ofAPP that contains A,3P (15), alter the an-choring of APP in the cell membrane, orstabilize APP-containing amyloidogenic frag-ments within lysosomes (12, 15).

Our cascade hypothesis states that A3PPitself, or APP cleavage products containingAPP, are neurotoxic and lead to neu-rofibrillary tangle formation and cell death.Thus, two successive events are needed toproduce Alzheimer's pathology. First, APPmust be generated as an intact entity, eitherby accumulation of AI3P or as an APP-containing fragment of APP. Second, thismolecule must facilitate or cause neuronaldeath and neurofibrillary tangle formation.Neve and her colleagues have reported that

693APP I717

Lysosomes Secretase

1 1 1* I

| Amyloid|

tCaf /

tau-PO4

Neurofibrilarytang

Mutations in the COOH-terminal por-tion of APP cause hereditary, early onsetAlzheimer's disease (15, 16) and hereditarycerebral hemorrhage with amyloidosis(Dutch-type) (17). The APP mutation thatcauses massive A3P deposition in theDutch amyloidopathy is a glutamic acid toglutamine substitution at codon 693 [withreference to the longest form of APP, APP-770 (7)1 (Fig. 1), located only six residuesaway from the cleavage site within the ASPsequence (17). It has been speculated thatthis mutation might cause APP depositionby inhibiting secretase cleavage of APP,although this now seems less likely becauseof the apparent lack of sequence specificityof the enzyme (10).

Three mutations have been describedwithin the APP gene that cause familial

SCIENCE * VOL. 256 * 10 APRIL 1992

death

the Af3P-containing COOH-terminal frag-ment is toxic to cultured neurons (18), andKowall and co-workers (19) have suggestedthat APP alone exerts toxic effects onneurons, an effect possibly mediatedthrough the serpin receptor (20). Otherinvestigators, however, have reported thatAPP itself is not neurotoxic, but that itrenders neurons more sensitive to excito-toxic damage (21 ). Although it is not clearexactly how APP causes neuronal loss andtangle formation, the peptide is known todisrupt calcium homeostasis and increaseintraneuronal calcium concentrations (Fig.1). This observation could explain howneurofibrillary tangles form. The tangles arelargely composed of paired helical filamentsformed from a hyperphosphorylated form ofthe microtubule associated protein, tau (6),

Alzheimer's Disease: The AmyloidCascade Hypothesis

John A. Hardy and Gerald A. Higgins

on July 3, 2018

http://science.sciencemag.org/

Dow

nloaded from

__PERSPECTIVE

Alzheimer's disease causes dementia inmany elderly people and in some individu-als with Down syndrome who survive to age50. Alzheimer's is characterized by variouspathological markers in the brain-largenumbers of amyloid plaques surrounded byneurons containing neurofibrillary tangles(1), vascular damage from extensive plaquedeposition (2), and neuronal cell loss (1).Because it is not known if the amyloidplaques or the neurofibrillary tangles are theearliest lesion in the disease process, therole of these markers in the etiology of thedisease is controversial.

Our hypothesis is that deposition ofamyloid fi protein (A3P), the main com-ponent of the (3) plaques, is the causativeagent of Alzheimer's pathology and that theneurofibrillary tangles, cell loss, vasculardamage, and dementia follow as a directresult of this deposition. APP is a peptideproduct of the larger amyloid precursorprotein (APP) (4). Because Down syn-drome is caused by trisomy of the region ofchromosome 21 that contains the APPgene, deposition of APP is likely to be anearly event in the disease (5). The AIPmolecule is a 39- to 42-amino acid peptide(4, 6), part of which forms the hydrophobictransmembrane domain in the COOH-ter-minal portion of APP (Fig. 1). AI3P is oneof a diverse group of "amyloid" (starch-like)proteins that forms insoluble extracellulardeposits. The APP gene undergoes alterna-tive RNA splicing to produce several pro-tein isoforms; the predominant variant inbrain lacks a serine protease inhibitor do-main that is present in APP molecules inother tissues (7).

We now know something about howAPP proteolysis leads to APP deposition.APP is inserted into the cytoplasmic mem-brane and then cleaved at residues 15 to 17within the APP sequence by the APP"secretase" (8) (Fig. 1). This cleavageevent therefore produces fragments that donot contain intact APP and so cannotresult in amyloid deposition. These frag-ments include secreted NH2-terminal de-rivatives that can be detected in brain and

J. A. Hardy, Department of Biochemistry, St. Mary'sHospital Medical School, London W2 1 PG, U.K., andDepartment of Psychiatry, University of South Florida,Tampa, FL 33612.G. A. Higgins, Molecular Neurobiology, Laboratory ofBiological Chemistry, National Institute on Aging, Na-tional Institutes of Health, Baltimore, MD 21224.

184

cerebrospinal fluid (9). The APP secretasethat cuts within the APP region has anextraordinarily broad sequence specificityand recognizes the secondary structure ofAPP, cleaving at a defined distance from themembrane (10). Several recent studies sug-gest that APP can also be processed by theendosomal-lysosomal pathway, after recy-cling of membrane-bound APP and possiblyvia an intracellular metabolic route (11-13).Carboxyl-terminal fragments containing theentire AMPP sequence can be derived fromthis alternate normal processing of APP (12,14) and may eventually lead to amyloiddeposition (12, 14) (Fig. 1).

Fig. 1. The amyloid cas-cade hypothesis. Pro-cessing of APP can oc-cur via two pathways: (i)Cleavage within APP bythe secretase, whichgenerates peptide prod-ucts that do not precipi-tate to form amyloid and(ii) cleavage in the endo-somal-lysosomal com-partment, resulting in in-tact AI3P that precipi-tates to form amyloidand, in turn, causesneurofibrillary tanglesand cell death, the hall-marks of Alzheimer'sdisease.

Alzheimer's disease. These mutations all oc-cur at codon 717 of the protein (15, 16) andchange the native valine, located three resi-dues from the COOH-terminal end of ASP,to isoleucine, phenylalanine, or glycine (Fig.1). It is unclear how these mutations causeamyloid deposition, but they may inhibit thebreakdown of a COOH-terminal fragment ofAPP that contains A,3P (15), alter the an-choring of APP in the cell membrane, orstabilize APP-containing amyloidogenic frag-ments within lysosomes (12, 15).

Our cascade hypothesis states that A3PPitself, or APP cleavage products containingAPP, are neurotoxic and lead to neu-rofibrillary tangle formation and cell death.Thus, two successive events are needed toproduce Alzheimer's pathology. First, APPmust be generated as an intact entity, eitherby accumulation of AI3P or as an APP-containing fragment of APP. Second, thismolecule must facilitate or cause neuronaldeath and neurofibrillary tangle formation.Neve and her colleagues have reported that

693APP I717

Lysosomes Secretase

1 1 1* I

| Amyloid|

tCaf /

tau-PO4

Neurofibrilarytang

Mutations in the COOH-terminal por-tion of APP cause hereditary, early onsetAlzheimer's disease (15, 16) and hereditarycerebral hemorrhage with amyloidosis(Dutch-type) (17). The APP mutation thatcauses massive A3P deposition in theDutch amyloidopathy is a glutamic acid toglutamine substitution at codon 693 [withreference to the longest form of APP, APP-770 (7)1 (Fig. 1), located only six residuesaway from the cleavage site within the ASPsequence (17). It has been speculated thatthis mutation might cause APP depositionby inhibiting secretase cleavage of APP,although this now seems less likely becauseof the apparent lack of sequence specificityof the enzyme (10).

Three mutations have been describedwithin the APP gene that cause familial

SCIENCE * VOL. 256 * 10 APRIL 1992

death

the Af3P-containing COOH-terminal frag-ment is toxic to cultured neurons (18), andKowall and co-workers (19) have suggestedthat APP alone exerts toxic effects onneurons, an effect possibly mediatedthrough the serpin receptor (20). Otherinvestigators, however, have reported thatAPP itself is not neurotoxic, but that itrenders neurons more sensitive to excito-toxic damage (21 ). Although it is not clearexactly how APP causes neuronal loss andtangle formation, the peptide is known todisrupt calcium homeostasis and increaseintraneuronal calcium concentrations (Fig.1). This observation could explain howneurofibrillary tangles form. The tangles arelargely composed of paired helical filamentsformed from a hyperphosphorylated form ofthe microtubule associated protein, tau (6),

Alzheimer's Disease: The AmyloidCascade Hypothesis

John A. Hardy and Gerald A. Higgins

on July 3, 2018

http://science.sciencemag.org/

Downloaded from

tau pathology above a critical threshold for ‘tau positi-vity’, used to distinguish patients with AD from both patients with non- AD neurodegenerative disorders and cognitively normal individuals) is more often observed in A!- positive cognitively normal persons than in A!- negative cognitively normal individuals5,26,27,34,41. These findings have led to the hypothesis that AD is an A!- facilitated tauopathy51 in which"the presence of A! triggers the spread of tau beyond the medial temporal lobe, which in turn leads to tau- mediated neurodegeneration (FIG.!2d). Although this hypothesis does not address how or why tau pathology initially occurs in the temporal lobe, it suggests that a poorly understood interaction between A! and tau facilitates the spread of tau pathology to the neocortex in patients with AD, possibly via connected white matter tracts such as the hippocampal cingu-lum bundle52. An alternative explanation is that shared upstream processes simultaneously drive both tau and A! pathology independently in the neocortex, which is known as the dual- cascade hypothesis53 (FIG.!1c).

Although the idea that A! drives tau pathology in AD has been the major framework for understanding this disease and for the development of targeted therapeutic agents, the emerging preclinical work discussed later in this Review is inconsistent with this idea, and instead supports the notion that the biological pathways associ-ated with sporadic AD, including cholesterol metabolism, endocytic trafficking and microglial immune activation, as well as specific proteins such as apolipoprotein E (ApoE) and the !- secretase C- terminal fragment of APP (!CTF; also known as C99), drive tau pathology in an A!- independent manner. These pathways and proteins are addressed in more detail in the next sections.

A!- independent regulators of tau in ADCholesterol metabolismLipids, particularly cholesterol, are heavily implicated in the pathogenesis of AD54 (FIG.!3). A number of prev-alent polymorphisms associated with the risk of devel-oping sporadic AD occur in genes associated with

the regulation of lipid metabolism, including APOE (which encodes ApoE, the major lipid transporter in the brain55), CLU (encoding clusterin, also known as ApoJ), ABCA7 (encoding ATP- binding cassette sub-family A member 7), SORL1 (encoding sortilin- related receptor A (SORLA))56–58 and possibly TREM2 (which encodes triggering receptor expressed on myeloid cells 2 (TREM2))59. In addition, cholesteryl esters, the storage product of excess cholesterol, abnormally accumulate in the AD brain60 and drive amyloidogenic processing of APP to A!61–64 in a manner dependent on a lipid- binding domain in the C terminus of APP64,65 (FIG.!3a). Cholesteryl esters also enhance the accumulation of phosphorylated tau (p- tau)64,66 by inhibiting its proteasomal degradation64 (FIG.!3a). Importantly, this effect of cholesteryl esters on p- tau is independent of both APP and A!, as reduc-ing cholesteryl ester levels also reduces p- tau levels in human induced pluripotent stem cell (hiPSC)-derived APP null neurons64 (BOX!2). Additional evidence for a direct relationship between cholesteryl esters and tau comes from the observation that inhibition of cholesterol synthesis reduces tau pathology in tau transgenic mice67. These mice develop tau pathology despite the absence of overt A! pathology, and cholesterol- targeting drugs that reduce the tau pathology load in these mice are there-fore likely to act in an A!- independent manner. Readers should note, however, that although these mice lack A! pathology, APP is endogenously expressed, and thus a role of APP cannot be completely excluded. However, in combination with the results of experiments in APPnull hiPSC- derived neurons, these data strongly indicate that cholesteryl esters regulate both A! and tau through correlated but independent pathways (FIG.!3d).

The notion that alterations in lipid metabolism can drive A! and tau pathology through shared but independ-ent mechanisms has been corroborated by the results of a combined tau PET and A! PET study in cognitively nor-mal individuals68. In this study, distinct as well as shared genetic pathways underlying spatiotemporal propaga-tion of A! and tau through the brain were investigated

a Familial ADMutations

APP, PSEN1, PSEN2

A!

Tau pathology

Neurodegeneration

b Sporadic ADRisk polymorphisms

A!

Tau pathology

Neurodegeneration

Lipid metabolismImmunity Endocytosis

c Sporadic ADRisk polymorphisms

A! Tau pathology

Neurodegeneration

Lipid metabolismImmunity Endocytosis

Amyloid-cascade hypothesis Dual-cascade hypothesis

Fig. 1 | The amyloid- cascade hypothesis and the dual- cascade hypothesis of AD. a | Mutations in (or duplications of) APP, PSEN1 or PSEN2, which respectively encode amyloid- ! (A!) precursor protein (APP) and the APP- processing enzymes presenilin 1 and 2, alter amyloidogenic processing of APP and cause familial Alzheimer disease (AD). These findings led VQ|VJG�CO[NQKF��ECUECFG�J[RQVJGUKU��YJKEJ�RTGFKEVU�VJCV�KPKVKCN�EJCPIGU�KP�#! drive downstream tau pathology and tau-mediated neurodegeneration. b | Although mutations in APP or its processing enzymes are absent in patients with sporadic AD, the neuropathology of sporadic AD closely mirrors that of familial AD. Therefore, the amyloid- cascade hypothesis is suggested to also be applicable to sporadic AD. Polymorphisms in genes that regulate microglial immune activation, lipid metabolism and endocytosis are risk factors for sporadic AD. c | The dual- cascade hypothesis offers an alternative model to explain the pathogenesis of sporadic AD. This hypothesis predicts that the polymorphisms associated with the risk of sporadic AD contribute to A! and tau pathology through correlated but independent cellular pathways.

Positron emission tomography(PET). Functional imaging technique that measures gamma rays emitted by radioactively labelled tracers and is used to track biological processes in!vivo. Several PET tracers for amyloid- ! and tau have been developed that can measure Alzheimer disease pathology in living individuals.

A! plaquesAggregates of amyloid- ! (A!) protein that accumulate extracellularly in individuals with Alzheimer disease. A! plaques (also known as neuritic or senile plaques) develop early in the course of Alzheimer disease but do not correlate well with cognitive decline or local neurodegeneration.

Primary age- related tauopathy(PART). A neuropathological condition characterized by neurofibrillary tangles, restricted mostly to the temporal lobe in the absence of amyloid- !; evident in the brains of approximately 20% of cognitively normal elderly individuals.

!- secretase C- terminal fragment of APP(!CTF). Direct precursor of amyloid- ! (A!) that is generated by !- secretase cleavage of full- length amyloid precursor protein, prior to its #- secretase cleavage to A!. A! and !CTF are therefore generated at equimolar concentration. !CTF drives the accumulation of phosphorylated tau in neurons from patients with familial Alzheimer disease.

PolymorphismsGenetic variants that occur in at least 1% of the population; rare variants occur at frequencies below 1%.

Proteasomal degradationThe process by which cells recycle unneeded or damaged cytosolic proteins. Such proteins are first ubiquitylated, which targets them for degradation by the proteasome (a proteolytic multisubunit protein complex).

NATURE REVIEWS | NEUROSCIENCE

REV IEWS

Van der Kant et al, Nat Rev Neurosci 2019

Introduction Physiopathologie de la maladie d’Alzheimer

Cible thérapeutique n°1: l’amyloidopathie

Panza et al, Nat Rev Neurol 2019

of tau protein29. These findings conflict with the idea that elevated CSF tau levels in people with AD arise primar-ily from dead and dying neurons. Neuritic A! plaques trigger the formation of a specific type of tau aggregate, which in turn fuels the formation and spreading of NFTs and neuropil threads30. High tau and low A!1-42 levels in the CSF are associated with progression to mild cognitive impairment (MCI) in cognitively healthy individuals16 and progression to AD in patients with MCI31.

In view of the fact that A! and tau aggregates show different spatial and temporal patterns of progression within vulnerable brain regions32, three distinct tempo-ral phases in AD have been proposed. First, in clinically unaffected individuals, tau- associated network disruption occurs in specific brain regions. Second, this disruption can trigger A!- associated compensatory brain network changes. Last, A! deposition marks the saturation of func-tional compensation and heralds acceleration of the inciting phenotype- specific, tau- associated network failure33.

Putative disease- modifying therapiesFIGURE"2 summarizes the stage of clinical development of current and abandoned anti- A! drugs for AD. In this section, we review the anti- A! drugs that are in phase"III

trials at present and have the potential to modify AD progression. These drugs include anti- A! immuno-therapies, which stimulate A! clearance, and BACE inhibitors, which decrease A! production.

Active anti- amyloid-! immunotherapiesActive immunization involves administration of an A! antigen that can elicit an immunological response against A!. Elan Pharmaceuticals pursued this approach in 2002 by administering pre- aggregated A!1–42 with the immunological adjuvant QS-21. This vaccine, known as AN-1792, significantly reduced A! deposits in the brains of patients with AD but produced no cognitive or clinical benefits34. In addition, AN-1792 elicited a T cell- mediated immunological response; thus, ~6% of the treated patients developed meningoencephalitis35. Safer A! antigens and adjuvants were later developed but did not produce clinical benefits (TABLE"1). Vanutide is a conjugate of multiple short A! fragments linked to a carrier of inactivated diphtheria toxin and was designed to avoid the safety concerns associated with AN-1792. Vanutide, with or without QS-21 adjuvant, was tested in ascending doses in two placebo- controlled phase IIa studies involving 245 patients with mild to moderate

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AD36. The drug was well tolerated, but no differences in cognitive measures, brain volumes or CSF biomarkers were observed between the vanutide and placebo groups.

Only one active anti- A! vaccine, CAD106, is cur-rently in phase III trials. CAD106 is an A! antigen that consists of multiple copies of the A!1–6 fragment, coupled to an adjuvant carrier (Q! virus- like particle). In two APP transgenic mouse lines, CAD106 reduced brain amyloid accumulation without evidence of increased microhaemorrhages or inflammatory reac-tions37. Antibodies elicited by CAD106 reacted with A! monomers and oligomers and blocked A! toxicity in cell cultures38. However, no studies are available on the behavioural or cognitive effects of CAD106 in animal models of AD.

A 1-year, double- blind, placebo- controlled phase I trial of two subcutaneous doses of CAD106 in 58 peo-ple with mild to moderate AD found dose- related A! antibody titre responses but no significant changes on cognitive or clinical scales38. In a 66-week open- label extension study and a phase II study, prolonged increases in A!- specific antibody titres were observed, and no unexpected adverse events were reported39.

A 90-week, double- blind, placebo- controlled phase"IIb study assessed the safety, tolerability and immunogenicity of CAD106 in 121 patients with mild AD40. Patients received up to seven doses of CAD106 (150 #g or 450 #g) or placebo, with or without alum adju-vant, over 60 weeks. Serious adverse events (SAEs) were reported in 7% of the placebo- treated patients and in 25% of the CAD106-treated patients. Amyloid- related imaging abnormalities (ARIAs) occurred in six patients treated with CAD106. The drug induced strong anti-body responses in 55% of patients on the 150 #g dose and in 81% of patients on the 450 #g dose. Serum A!– immunoglobulin G (IgG) titres correlated with the reduction in brain amyloid burden, as assessed by PET, from baseline to week 78. Unexpectedly, cognitive

decline over 78 weeks, measured on the Mini- Mental State Examination (MMSE) scale, was greater in CAD106-treated patients who had a strong serologi-cal response than in the control group, although the difference failed to reach statistical significance40.

CAD106 is being evaluated in a preventive paradigm in a 5-year, double- blind, placebo- controlled phase II/III study (Generation S1) involving 1,340 homozygous APOE*!4 carriers who are cognitively healthy. Half of the participants will be randomly assigned to receive intramuscular CAD106 or a matching placebo, whereas the other half will be randomly assigned to receive oral CNP520 (a BACE inhibitor) or a matching placebo. The trial will measure the ability of the treatment to delay diagnosis to MCI or AD dementia and will also assess the change in the Alzheimer’s Prevention Initiative Composite Cognitive (APCC) test score41. The study is expected to be completed by May 2024.

Passive anti- amyloid-! immunotherapiesPassive anti- A! immunotherapies consist of monoclo-nal or polyclonal humanized anti- A! antibodies. Several such antibodies were found to be ineffective in patients mild to moderate or mild AD (TABLE"1). Five antibod-ies — solanezumab, gantenerumab, crenezumab, adu-canumab and BAN2401 — are now being developed in patients with early AD, people at a preclinical stage of familial AD and asymptomatic individuals at high risk of AD.

Solanezumab. Solanezumab is a humanized IgG1 mon-oclonal antibody that targets the central region of A! (A!13–28). Studies in transgenic mice and humans indi-rectly suggest that solanezumab recognizes soluble mon-omeric A! because it causes a substantial rise in total plasma A! levels. However, in vitro studies in human brain tissue indicate that this antibody also binds to A! plaques42. A single injection of m266, the mouse version

ABvac 40UB 311ACI-24LY3002813BAN2401PQ912CT1812AcitretinThalidomide

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SolanezumabAducanumabCrenezumabImmunoglobulin + albuminGantenerumabCAD106ElenbecestatCNP520Sodium oligo-mannurarate

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(KI��� | Stage of clinical development of anti- A! drugs to treat Alzheimer disease. The figure does not include drugs that indirectly interfere with amyloid- ! (A!) or do not have fully proven anti- A!�OGEJCPKUOU�QH�CEVKQP��6TKCNU�QH�FTWIU�UJQYP�KP�TGF�JCXG�DGGP�FKUEQPVKPWGF�QT�CTG�KPCEVKXG��$#%'��!��UGETGVCUG�

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Panza et al, Nat Rev Neurol 2019

Cible thérapeutique n°1: l’amyloidopathieL’Aducanumab

23

ITT population. aDifference vs placebo at Week 78. Negative percentage means less progression in the treated arm.ADAS-Cog 13, Alzheimer’s Disease Assessment Scale–Cognitive Subscale (13-item); ADCS-ADL-MCI, Alzheimer’s Disease Cooperative Study–Activities of Daily Living Inventory (mild cognitive impairment version); CDR-SB, Clinical Dementia Rating–Sum of Boxes; ITT, intent to treat; MCI, mild cognitive impairment; MMSE, Mini-Mental State Examination.

EMERGE: Primary and secondary endpoints from final data set at Week 78

Placebo decline(n=548)

Difference vs. placebo (%)a

p-valueLow dose(n=543)

High dose(n=547)

CDR-SB 1.74-0.26 (-15%)

0.0901-0.39 (-22%)

0.0120

MMSE -3.3-0.1 (3%) 0.7578

0.6 (-18%)0.0493

ADAS-Cog 13 5.162-0.701 (-14%)

0.1962-1.400 (-27%)

0.0097

ADCS-ADL-MCI -4.30.7 (-16%)

0.15151.7 (-40%)

0.0006

CTAD, San Diego, Dec. 2019

Formes « prodromales » à légère de maladie d’Alzheimer

Cible thérapeutique n°1: l’amyloidopathieL’Aducanumab

28

-0.35

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***

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***

EMERGE: Longitudinal change from baseline in amyloidPET SUVR

18F-florbetapir amyloid PET analysis population. ***p<0.0001 compared with placebo (nominal). Values at each time point were based on an MMRM model, with change from baseline in MMSE as the dependent variable and with fixed effects of treatment group, categorical visit, treatment-by-visit interaction, baseline SUVR, baseline SUVR by visit interaction, baseline MMSE, Alzheimer’s disease symptomatic medication use at baseline, region, and laboratory ApoE ε4 status. ApoE, apolipoprotein E; MMRM, mixed model for repeated measure; MMSE, Mini Mental State Examination; PET, positron emission tomography; SE, standard error; SUVR, standardized uptake value ratio.

Placebo n=157 128 74Low dose aducanumab n=157 125 79High dose aducanumab n=171 136 87

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ENGAGE: CSF biomarkers of tau pathology and neurodegeneration

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CSF modified analysis population (patients with both baseline and post-baseline CSF assessments). **p<0.01 compared with placebo (nominal). Values were based on an ANCOVA model at Week 78, fitted with change from baseline as the dependent variable, and with categorical treatment, baseline biomarker value, baseline age, and laboratory ApoE ε4 status (carrier and non-carrier) as the independent variables. ANCOVA, analysis of covariance; ApoE, apolipoprotein E; CSF, cerebrospinal fluid; SE, standard error.Formes « prodromales » à légère de maladie d’Alzheimer

Cible thérapeutique n°2: la tauopathie

Neurons containing tangles also have fewer synapses and reduced levels of synaptophysin mRNA compared with tangle-free neurons52,53. However, the mature fil-aments are unlikely to be the primary toxic species: current evidence suggests that small soluble species are more detrimental to cells (reviewed previously54,55). Indeed, larger aggregates might exert beneficial effects by sequestering misfolded monomers and soluble aggregates. This phenomenon could account for the seemingly paradoxical findings regarding tau levels in the cerebrospinal fluid (CSF) of patients with AD. Although CSF tau levels are higher in AD than in controls, the levels decrease as the disease progresses, despite the accrual of NFTs56. These observations might be explained by decreased tau secretion and/or release, possibly resulting from assembly of tau into larger, more stable filaments within the neurons as well as from loss of synapses and neurons. CSF tau levels are not increased in non-AD tauopathies57–60, suggesting that extracellular tau is not a primary target in these conditions. These well-established findings should be taken into account in biomarker and therapeutic studies. For example, the documented decrease in CSF tau with pathology progression in patients with AD might impede the detection of drug-induced reduc-tions in CSF tau. It also raises concerns about the

validity of targeting extracellular tau in the later stages of the disease. Furthermore, detailed information on tau fragments obtained by mass spectroscopy could provide additional insight into therapy-related changes in CSF tau levels that are not detected with current enzyme-linked immunosorbent assays. This infor-mation will also guide which epitopes can be targeted extracellularly.

Oligomeric tau has emerged as the probable candi-date for the most toxic species in tauopathies and is present in the brain at early stages of mild cognitive impairment (MCI) and AD54,55,61. Tau oligomers pro-mote toxicity in cell models to a greater extent than fil-amentous tau and are linked to neurodegeneration and cognitive phenotypes in!vivo54,55 Soluble tau aggregates might also affect the integrity of membranes62,63. In addition, tau oligomers are implicated in the spreading of tau pathology. For example, in cell models, soluble oligomeric tau can induce seeding of native tau54,64, and small tau aggregates isolated from patients or animals with AD can induce tau pathology in mice54,64,65. Thus, compounds that prevent or reverse tau aggregation have the potential to improve cell health and prevent the spread of tau pathology to other brain regions.

Protein degradation pathway impairmentIn addition to changes to the tau protein itself, other factors can promote the development of tau pathol-ogy (FIG.!2). Impairment of protein degradation path-ways, including autophagy (reviewed previously66–68), is found in a host of neurodegenerative diseases. In MCI and AD, the pattern of kinase activation in the mechanistic target of rapamycin (mTOR) pathway is altered69–71 and expression of other key autophagy-related proteins is reduced72 in the brain. Disruption of autophagic flux and a failure of auto-phagosomes to fuse with lysosomes leads to a build-up of vesicles, which can be seen in dystrophic neurites and cell bodies in AD, CBD and PSP as well as in tauopathy models73–76. Impaired flux also directly contributes to AD pathology. Autophagosomes contain APP, preseni-lin and "-secretase, and disruption of autophagosome processing in neurons can lead to increased produc-tion of A#77, which can in turn further inhibit protein digestion78,79. As tau is a target of autophagy80, any defi-ciencies in processing could lead to increased levels of intracellular tau, including misfolded, damaged or aggregated protein.

The ubiquitin–proteasome system is also dysfunc-tional in AD, leading to a build-up of ubiquitylated proteins including tau81,82. Alterations in proteasome efficiency also affect learning and memory via the CREB pathway. Digestion of the regulatory subunit of cAMP-dependent protein kinase A (PKA) in the protea-some results in increased PKA activity and phosphoryla-tion of CREB83. Tau pathology and cognitive deficits can be either exacerbated84 or reduced85,86 in model animals through the use of inhibitors or enhancers of proteasome function. Interestingly, as with autophagic degradation, tau inhibits proteasome activity87, suggesting that tau pathology can become self-perpetuating once aggregates are present in neurons.

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Fig. 2 | Tau-related therapeutic targets. Drugs in preclinical or clinical development include active and passive immunotherapies; inhibitors of O-deglycosylation, aggregation, kinases, acetylation, caspases or tau expression; phosphatase activators; microtubule stabilizers; and modulators of autophagy or proteasomal degradation. Ac, acetyl group; Gly , glycosyl group; OGA , O-GlcNAcase; P, phosphate. Figure adapted from REF.266, Macmillan Publishers Limited.

© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

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levels of tau in the interstitial space and soluble A!1–40 in the brain.

Four clinical trials of BMS-986168 have been regis-tered. A phase I trial in healthy individuals248 and patients with PSP249 has been completed. This trial used a single ascending dose methodology and was designed to assess tolerability, with effects on CSF tau as a second-ary outcome. A second phase I trial in patients with PSP, involving a multiple ascending dose paradigm, is under way at several centres in the USA249, with follow-up studies planned for those who participated in the ear-lier trial250. A phase II trial aiming to study the clinical efficacy of BMS-986168 in 400 patients with PSP began recruiting in March 2017. In April 2017, BMS-986168 was licensed by Biogen, with plans to proceed with phase II testing251.

C2N-8E12. C2N-8E12 recognizes amino acids 25–30 of the tau protein and, similar to BMS-986168, it was inten-ded to work extracellularly. In cell culture, C2N-8E12 prevented pathological tau seeding caused by exoge-nous tau aggregates212. Infusion of this antibody into the brain in a transgenic mouse model of tauopathy reduced the levels of aggregated and hyperphosphorylated tau and improved cognition213. Similar results were seen when a higher dose was delivered systemically239. No adverse immune reactions were seen; in fact, microglial activation was reduced in the treated animals213,239.

Phase I testing of C2N-8E12 in patients with PSP did not show any major adverse effects or safety issues compared with placebo252. In 2016, two phase II trials were initiated, one in 330 patients with PSP253 and the other in 400 patients with early-stage AD254. The studies are expected to run until 2019 and 2020, respectively, with patients being assessed on multiple cognitive and behavioural measures. The trial descriptions do not indicate whether CSF analysis and/or brain imaging will be included. The FDA has granted fast-track status to C2N-8E12 in view of its potential utility in PSP.

RO 7105705. The epitope of RO 7105705 has not been disclosed, but this antibody probably targets pSer409 on the tau protein222. Phase I safety assessments of RO 7105705 are being conducted in healthy individ-uals and in patients with AD255. The participants will receive either a single dose or multiple doses of the antibody to assess tolerability, and the antibody con-centration in serum will be measured to determine the pharmacokinetics. In addition, patients with AD will be assessed using the Clinical Dementia Rating scale. As an early-stage trial, the number of participants is insufficient for efficacy assessment. Early reports from the Alzheimer’s Association International Conference in 2017 showed that the antibody was well tolerated in patients at doses up to 16.8 g, and the antibody was detectable in the CSF256.

LY3303560. Eli Lilly initiated two phase I trials to study the safety and pharmacokinetics of the anti-tau antibody LY3303560, one in healthy individuals and patients with AD257 and the other in patients with MCI or AD258. LY3303560 possibly targets a conformational epitope, although this information has not been officially disclosed259. In the first trial, individuals will be given a single dose of LY3303560, and the concentrations of the antibody in serum and CSF will be monitored. In the second trial, patients with MCI or AD will receive multiple doses of LY3303560, and levels of the antibody in serum and CSF will be assessed, as will the uptake ratio of the A!-binding compound 18F-florbetapir in the brain. These studies are expected to end in 2017 and 2020, respectively.

Future prospectsNewly initiated and forthcoming trials. Recently, it was announced that two new antibodies were entering human testing. Janssen Pharmaceuticals has begun a phase I clinical trial of passive immunization with JNJ-63733657 (REF.260). The trial is recruiting healthy individuals and patients with AD to assess the safety, tolerability and pharmacological profile of this anti-tau antibody. We are not aware of any preclinical data on this antibody, but it seems to bind to the middle region of tau and has been designed to prevent tau seeding and spreading261. Also advancing into human trials is UCB0107, a tau antibody developed by UCB Biopharma262. Preclinical testing showed that this antibody binds to amino acids 235–246 in the proline-rich region of tau, and that the antibody was effective in preventing seeding and spreading of pathological tau261. The trial is currently recruiting healthy individuals.

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Fig. 4 | Current status of clinical trials of drugs that target tau pathology. At the time of writing, the most active field is tau immunotherapy , with two active vaccines (AADvac1 and ACI-35) and six antibodies (LY3303560, RO 7105705, BMS-986168, C2N-8E12, JNJ-63733657 and UCB0107) in clinical trials, although most of these therapies are still in the early stages of development. Several of the other compounds in trials have complex or incompletely defined mechanisms of action; in this diagram, these compounds are categorized according to their presumed tau-related mode of action. ‘X’ indicates trials that, to our knowledge, have been halted or terminated, as detailed in the main text, although their current status is difficult to determine. PDE4, phosphodiesterase E4.

© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

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Congdon et al, Nat Rev Neurol 2018

Cible thérapeutique n°3: les traitements symptomatiques

Phase 3 trials included an average of 640 participants andhad a mean duration of 246 weeks (including the recruitmentand the treatment period). Mean treatment exposure periodwas 73 weeks. DMT trials were longer and larger than trialsof symptomatic agents with a mean duration of 297 weeksincluding 112 treatment weeks, and included an average of862 participants. The mean duration of cognitive enhancertrials was 88 weeks (17 treatment weeks), and they includedan average of 333 participants. Trials of agents for behav-ioral symptoms had a mean duration of 187 weeks (15 treat-ment weeks) and included a mean of 311 subjects.

The average duration of treatment exposure for phase 3DMTs is 112 weeks, and themean period from trial initiationto primary completion date (final data collection date for pri-mary outcome measures) is 269 weeks. This indicates that157 weeks, more than the treatment period, is the averageanticipated recruitment time. When examined by trial popu-lation, DMT prevention trials are 405 weeks in duration (192treatment weeks); trials for patients with MCI/prodromal/prodromal-to-mild AD are 263 weeks in duration (98 treat-ment weeks); and trials for patients with mild-to-moderateAD are 264 weeks in duration (57 treatment weeks). Plannedrecruitment periods for these three types of trials are 192,130, and 191 weeks, respectively.

3.3. Phase 2

Phase 2 has a larger array of therapies and mechanismsthat are being assessed than are represented in phase 3. Thereare 74 agents in 83 trials (Figs. 1 and 3, Table 2). Of these,there are 20 symptomatic agents; 14 cognitive enhancers;and six agents targeting behavioral symptoms. There are53 potential disease-modifying agents in phase 2 trials; 16biologics and 37 small molecules. One agent had an undis-closed mechanism. Twelve of the small molecules and eight

of the biologics have amyloid reduction as one of the mech-anisms observed in nonclinical studies (38% of DMTs). Foursmall molecules and six biologics in phase 2 target tau as oneof their mechanisms (19% of DMTs). There are 24 smallmolecules and two biologics with neuroprotection as oneof the mechanisms (49% of DMTs). Other mechanisms rep-resented in phase 2 include anti-inflammatory and metabolicinterventions as the primary or one of a combination of ef-fects documented in animal models. There are six trialsinvolving stem cell therapies. Sixteen of the DMT agentsare repurposed agents approved for use in another indication.

Of the drugs with amyloid targets, there were seven im-munotherapies, one colony-stimulating factor, two BACEinhibitors, and two alpha-secretase modulators. Two agentstargeted synaptic activity, two were anti-aggregation agents,and two agents involved neuroprotection or a metabolicMOA. There were two agents targeting both amyloid andtau reduction. Fig. 3 shows the MOAs of agents in phase 2.

Three of the phase 2 trials were prevention trials; 36 trialsinvolved patients with prodromal or prodromal and mildAD; 38 were trials for mild-to-moderate AD; two trialswere for patients with severe AD; two included patientswith mild, moderate, or severe AD; one included patientswithMCI or healthy volunteers; and one trial was for prodro-mal or mild-to-moderate AD.

Phase 2 trials are shorter in duration and smaller in termsof participant number than phase 3 trials; phase 2 trials had amean duration of 178 weeks, average treatment period of45 weeks, and included an average of 143 subjects in eachtrial.

3.4. Phase 1

Phase 1 has 30 agents in 31 trials (Fig. 1, Table 3).There are two cognitive enhancers being assessed in phase 1.

Fig. 2. Mechanisms of action of agents in phase 3.

J. Cummings et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions 5 (2019) 272-293 275

Cumings et al, Alzheimer Dement. 2018

Traitements symptomatiques

Cible thérapeutique n°3: les traitements symptomatiquesLa Pimavensérine

- Agoniste inverse des recepteurs 5HT2A- Médicament déjà autorisé par la FDA en 2016 dans le traitement de la

psychose parkinsonienne- Essai de phase 3 arrêté prématurément (efficacité) en Septembre 2019 dans

le traitement des hallucinations dans plusieurs types de démences- Pas d’effet indésirable cognitif ou moteur (suivi court)

Cible thérapeutique n°3: les traitements symptomatiquesLe GV-971 (oligomannate) ?

- Polysaccharide dérivé d’une algue- Stades légers, modérés et sévères de la maladie d’Alzheimer: phase 3 positive en Chine

- Approuvé en Chine depuis Novembre 2019: sur le marché au printemps 2020- Essai de phase 3 en Europe aux Etats-Unis débutera en 2020

Alzforum & Shangai Green Valley

Conclusions

Les 3 derniers mois de 2019 ont apporté beaucoup d’espoirs thérapeutiques dans la MA !

(comme jamais depuis les 90’s)