Therapeutic Approach to Alzheimer’s Disease: Current Treatments and New Perspectives

Ci a ion: Pa do-Mo eno, T.; González-Acedo, A.; Ri as-Domínguez, A.; Ga cía-Mo ales, V.; Ga cía-Coza , F.J.; Ramos-Rod íguez, J.J.; Melguizo-Rod íguez, L. The apeu ic App oach o Alzheime ’s Disease: Cu en T ea men s and New Pe spec i es. Pha maceu ics 2022,14, 1117. h ps://doi.o g/10.3390/ pha maceu ics14061117 Academic Edi o s: Anna S asiak and Do o a Ła˙ zewska Recei ed: 27 Ap il 2022 Accep ed: 20 May 2022 Published: 24 May 2022 Publishe ’s No e: MDPI s ays neu al wi h ega d o ju isdic ional claims in published maps and ins i u ional a il- ia ions. Copy igh : © 2022 by he au ho s. Licensee MDPI, Basel, Swi ze land. This a icle is an open access a icle dis ibu ed unde he e ms and condi ions o he C ea i e Commons A ibu ion (CC BY) license (h ps:// c ea i ecommons.o g/licenses/by/ 4.0/). pha maceu ics Re iew The apeu ic App oach o Alzheime ’s Disease: Cu en T ea men s and New Pe spec i es Te esa Pa do-Mo eno 1,†, Anabel González-Acedo 2,†, An onio Ri as-Domínguez 3, Vic o ia Ga cía-Mo ales 4,* , F ancisco Jose Ga cía-Coza 5,6 , Juan Jose Ramos-Rod íguez 7,‡ and Lucía Melguizo-Rod íguez 8,9,‡ 1Ins i u o Nacional de Ges ión Sani a ia (INGESA), P ima y Heal h Ca e, 51003 Ceu a, Spain; e epa do@co eo.ug .es 2Biomedical G oup (BIO277), Depa men o Nu sing, Facul y o Heal h Sciences (Melilla), Uni e si y o G anada, 52005 G anada, Spain; [email p o ec ed].es 3Depa men o Celula Biology, Uni e si y o Se ille, 41009 Se ille, Spain; [email p o ec ed] 4Depa men o Biomedicine, Bio echnology and Public Heal h, Physiology A ea, Facul y o Medicine, Uni e si y o Cádiz, Pl. Falla, 9, 11003 Cádiz, Spain 5Depa men o Biomedicine, Bio echnology and Public Heal h, Immunology A ea, Uni e si y o Cádiz Pl. Falla, 9, 11003 Cádiz, Spain; cu o.ga [email p o ec ed] 6Ins i u e o Biomedical Resea ch Cádiz (INIBICA), Hospi al Uni e si a io Pue o del Ma , No ena Plan a In es igación A da. Ana de Viya, 21, 11009 Cádiz, Spain 7Depa men o Physiology, Facul y o Heal h Sciences (Ceu a), Uni e si y o G anada, 51001 Ceu a, Spain; [email p o ec ed].es 8Biomedical G oup (BIO277), Depa men o Nu sing, Facul y o Heal h Sciences, Uni e si y o G anada, 18016 G anada, Spain; luciam @ug .es 9Ins i u o de In es igación Biosani a ia, Ibs G anada, A . de Mad id, 15, 18012 G anada, Spain *Co espondence: ic o ia.ga [email p o ec ed] † These au ho s con ibu ed equally o his wo k. ‡ These au ho s con ibu ed equally o his wo k. Abs ac : Alzheime ’s disease (AD) is he mos common cause o demen ia. The pa hophysiology o his disease is cha ac e ized by he accumula ion o amyloid- β , leading o he o ma ion o senile plaques, and by he in acellula p esence o neu o ib illa y angles based on hype phospho yla ed au p o ein. In he he apeu ic app oach o AD, we can iden i y h ee impo an on s: he app o ed d ugs cu en ly a ailable o he ea men o he disease, which include aducanumab, donepezil, galan amine, i as igmine, meman ine, and a combina ion o meman ine and donepezil; he apies unde in es iga ion ha wo k mainly on A β pa hology and au pa hology, and which include γ-sec e a se inhibi o s, β -sec e ase inhibi o s, α -sec e ase modula o s, agg ega ion inhibi o s, me al in e e ing d ugs, d ugs ha enhance A β clea ance, inhibi o s o au p o ein hype phospho yla ion, au p o ein agg ega ion inhibi o s, and d ugs ha p omo e he clea ance o au, and inally, o he al e na i e he apies designed o imp o e li es yle, hus con ibu ing o he p e en ion o he disease. The e o e, he aim o his e iew was o analyze and desc ibe cu en ea men s and possible u u e al e na i es in he he apeu ic app oach o AD. Keywo ds: Alzheime ’s disease; demen ia; Aβpa hology; au pa hology; pha macology; d ugs 1. In oduc ion 1.1. Epidemiology o Alzheime ’s Disease Cu en ly, app oxima ely 35.6 million people wo ldwide su e om demen ia, and 7.7 million new cases a e diagnosed each yea . Recen s udies ha e con i med his end, p edic ing an 87% inc ease in Eu ope be ween 2010 and 2050 [ 1 ]. Alzheime ’s disease (AD), which is he mos common cause o demen ia, accoun s o 60–75% o all cases [ 2 ] Mo eo e , while dea hs caused by o he heal h p oblems, such as hea disease, ha e dec eased in ecen yea s, hose a ibu ed o AD ha e inc eased by 68% in he las decade alone [ 3 ]. The Pha maceu ics 2022,14, 1117. h ps://doi.o g/10.3390/pha maceu ics14061117 h ps://www.mdpi.com/jou nal/pha maceu ics Pha maceu ics 2022,14, 1117 2 o 20 main isk ac o in he e iopa hogenesis o AD is age, and as li e expec ancy p og essi ely inc eases, so does he numbe o people a ec ed. S udies ha ha e e alua ed AD show ha he annual p e alence in people aged 45–64 yea s is app oxima ely 24.2/100,000, and he incidence is 6.3/100,000 [ 4 ]. Howe e , he disease is mo e common in people o e 65 yea s o age, and he likelihood o de eloping AD inc eases exponen ially wi h age, doubling e e y 5 yea s he ea e . 1.2. Physiopa hology o Alzheime ’s Disease AD is cha ac e ized by a p edominan impai men o episodic memo y. This symp om is o en accompanied by a mul i ude o cogni i e impai men s in a eas such as execu i e unc ion, language, isuospa ial abili y, and decision making [ 2 ]. Thus, AD appea s as a p og essi e de e io a ion o highe b ain unc ions, also a ec ing decision-making abili y. Alzheime ’s pa ien s su i e an a e age o 7–10 yea s a e diagnosis [ 3 ]. Mo eo e , his disease cu en ly has no unequi ocal p emo em diagnosis, and can only be diagnosed his ologically pos mo em by he p esence o senile plaques (SP), neu o ib illa y angles, and neu onal and synap ic loss [ 5 ], which makes ea ly iden i ica ion and ea men e en mo e di icul . 1.2.1. Amyloid-βPa hology SP a e a classic neu opa hological ea u e in AD-a ec ed b ains and emain a easible o igin o synap ic and neu onal loss. SP a e he esul o a p og essi e accumula ion o pa enchymal amyloid- β (A β ) [ 5 ]. A β is a 39–43 amino acid pep ide de i ed om he p og essi e p ocessing o A β p ecu so p o ein (APP) by β - and γ -sec e ase complexes ollowing an amyloidogenic pa hway. The amyloidogenic pa hway is enhanced in AD, and mu a ions in he APP pep ide o in he β -sec e ase enzyme may p omo e o accele a e he onse o he pa hology. While APP and β -sec e ase mu a ions a e esponsible o mos known cases o AD, li le is ye known abou he causes o demen ia, as he as majo i y o cases (~95%) a e spo adic, and hese pa ien s accumula e A β wi hou known mu a ions. The e o e, i has been p oposed ha al e a ions in A β deg ada ion o clea ance may also play a key ole in he pa hogenesis o AD [ 6 ]. The oxic e ec s o A β desc ibed, bo h in humans and in expe imen al models, ange om ee oligome s o compac SP, and di e en A β species ha e been associa ed wi h synap ic loss and he de elopmen o neu i ic dys ophies [ 7 ]. Fu he mo e, some s udies ha e sugges ed ha he accumula ion o A β , like SP, may also con ibu e o he loss o dend i ic spines [ 8 ]. In addi ion, senile compac plaques ha e also been associa ed wi h he abno mal cu a u e o nea by neu i es and may al e co ical synap ic in eg a ion [ 7 ]. I has been sugges ed ha A β pe se can e en p omo e neu onal dea h in he hippocampus and en o hinal co ex in AD de elopmen [ 9 ]. Mo eo e , hese a eas a e pa icula ly ele an in lea ning and memo y, and he e o e, a e e y ulne able in his disease. A β deposi ion also occu s a he ascula le el as ce eb al amyloid angiopa hy (CAA), which is p esen in mos AD pa ien s, causing damage o impai men o he blood-b ain ba ie (BBB), a ec ing i s unc ionali y [ 10 ]. Howe e , CAA can also occu in he absence o AD [ 11 ], emaining a possible exponen o ascula demen ia (VaD). 1.2.2. Tau Pa hology A β pa hology p ecedes he o he majo neu opa hological ea u e o AD, he hy- pe phospho yla ion and agg ega ion o au p o ein in o neu o ib illa y angles. Tau is a mic o ubule-associa ed p o ein ha is abundan ly exp essed in he b ain, binding o ubulin o p omo e mic o ubule assembly. I suppo s o he cy oskele al s uc u es and egula es se e al majo unc ions in he neu ons [ 12 ]. Tau p o ein plays an impo an ole in he pa hogenesis o AD, as when i is abno mally phospho yla ed, i can be ound as an in a- neu onal deposi , o ming ilamen ous agg ega es in he soma and p oximal dend i es [ 13 ]. Neu o ib illa y angles cons i u e masses o a gy ophilic ibe s ha can s ain in ensely wi h hio la in-S. I appea s ha au p o ein deposi ion in Alzheime ’s pa ien s inc eases Pha maceu ics 2022,14, 1117 3 o 20 p opo ionally wi h he du a ion and se e i y o he disease. Fu he mo e, i is gene ally accep ed ha au dys unc ion is one o he main p oximal causes o neu onal loss in AD, al hough neu o ib illa y angles appea o be downs eam pa hological p ocesses [5]. 1.2.3. Neu oin lamma ion and Neu onal Loss Neu onal loss is he his ological ea u e ha bes co ela es wi h he se e i y and du a ion o demen ia [ 5 ]. I is also he main cause o co ical a ophy obse ed in AD. The dis ibu ion o neu onal loss co ela es wi h he loca ion o neu o ib illa y angles, al hough he p esence o neu o ib illa y angles is no su icien o explain he eno mous neu onal loss obse ed in AD pa ien s [ 14 ]. In addi ion o SP and au hype phospho yla ion, neu oin lamma ion and oxida i e s ess also play an impo an ole in neu odegene a ion. In lamma ion is a wo-sided mechanism. On he one hand, i p omo es he sec e ion o p oin lamma o y ac o s, such as cy okines, which lead o inc eased ce eb al blood low o he a ec ed a ea and he emo al o damaged issue by mic oglial cells [ 15 , 16 ]. In his ega d, mic oglial cells play a key ole in he i s line o immune de ense. They a e in ol ed in phagocy ic p ocesses and play a c ucial ole in he a emp o elimina e oxic p oduc s and elease cy o oxic ac o s, and can also ac as an igen-p esen ing cells. On he o he hand, an excessi e in lamma o y esponse can cause issue damage, p omo e ch onic in lamma ion, and e en ually lead o neu onal dea h [ 5 ]. In addi ion, he inc eased p oduc ion o eac i e oxygen species can damage he BBB. Oxida i e s ess plays a de imen al ole in he pa hogenesis o neu onal dea h in AD by damaging di e en cellula elemen s, such as p o eins, lipids, o nucleic acids, which accumula e as oxidized/damaged mac omolecules and a e no e icien ly emo ed and enewed by an ioxidan enzymes [ 17 ]. Following his idea, a educ ion in, o he loss o unc ion o an ioxidan enzymes in AD has been epo ed as a possible con ibu o o neu onal dea h [18]. 2. Resul s 2.1. App o ed T ea men o Alzheime ’s Disease Despi e he inc ease in he numbe o cases in ecen yea s and he associa ed socio- economic cos s, he e is s ill no e ec i e ea men o e e se o slow he p og ession o AD. So a , only six d ugs ha e been app o ed by he US Food and D ug Adminis a ion (FDA): aducanumab, donepezil, galan amine, i as igmine, meman ine, and a manu ac- u ed combina ion o meman ine and donepezil (Figu e 1). O hese, aducanumab is he only one used o he clea ing o A β plaques, while he emaining i e a e ocused on symp oma ological ea men ac ing a wo le els: h ough agonism o he choline gic sys em o as an agonis s o he N-me hyl-D-aspa a e ecep o (NMDA- ecep o ). Pha maceu ics 2022, 13, x FOR PEER REVIEW 3 o 21 in ensely wi h hio la in-S. I appea s ha au p o ein deposi ion in Alzheime ’s pa ien s inc eases p opo ionally wi h he du a ion and se e i y o he disease. Fu he mo e, i is gene ally accep ed ha au dys unc ion is one o he main p oximal causes o neu onal loss in AD, al hough neu o ib illa y angles appea o be downs eam pa hological p o- cesses [5]. 1.2.3. Neu oin lamma ion and Neu onal Loss Neu onal loss is he his ological ea u e ha bes co ela es wi h he se e i y and du- a ion o demen ia [5]. I is also he main cause o co ical a ophy obse ed in AD. The dis ibu ion o neu onal loss co ela es wi h he loca ion o neu o ib illa y angles, al - hough he p esence o neu o ib illa y angles is no su icien o explain he eno mous neu onal loss obse ed in AD pa ien s [14]. In addi ion o SP and au hype phospho yla- ion, neu oin lamma ion and oxida i e s ess also play an impo an ole in neu odegen- e a ion. In lamma ion is a wo-sided mechanism. On he one hand, i p omo es he sec e- ion o p oin lamma o y ac o s, such as cy okines, which lead o inc eased ce eb al blood low o he a ec ed a ea and he emo al o damaged issue by mic oglial cells [15,16]. In his ega d, mic oglial cells play a key ole in he i s line o immune de ense. They a e in ol ed in phagocy ic p ocesses and play a c ucial ole in he a emp o elimina e oxic p oduc s and elease cy o oxic ac o s, and can also ac as an igen-p esen ing cells. On he o he hand, an excessi e in lamma o y esponse can cause issue damage, p omo e ch onic in lamma ion, and e en ually lead o neu onal dea h [5]. In addi ion, he in- c eased p oduc ion o eac i e oxygen species can damage he BBB. Oxida i e s ess plays a de imen al ole in he pa hogenesis o neu onal dea h in AD by damaging di e en cellula elemen s, such as p o eins, lipids, o nucleic acids, which accumula e as oxi- dized/damaged mac omolecules and a e no e icien ly emo ed and enewed by an iox- idan enzymes [17]. Following his idea, a educ ion in, o he loss o unc ion o an ioxi- dan enzymes in AD has been epo ed as a possible con ibu o o neu onal dea h [18]. 2. Resul s 2.1. App o ed T ea men o Alzheime ’s Disease Despi e he inc ease in he numbe o cases in ecen yea s and he associa ed socio- economic cos s, he e is s ill no e ec i e ea men o e e se o slow he p og ession o AD. So a , only six d ugs ha e been app o ed by he US Food and D ug Adminis a ion (FDA): aducanumab, donepezil, galan amine, i as igmine, meman ine, and a manu ac- u ed combina ion o meman ine and donepezil (Figu e 1). O hese, aducanumab is he only one used o he clea ing o Aβ plaques, while he emaining i e a e ocused on symp oma ological ea men ac ing a wo le els: h ough agonism o he choline gic sys- em o as an agonis s o he N-me hyl-D-aspa a e ecep o (NMDA- ecep o ). Figu e 1. D ugs app o ed o he ea men o Alzheime ’s disease: mechanisms o ac ion, weigh , and molecula s uc u e. Pha maceu ics 2022,14, 1117 4 o 20 2.1.1. Aducanumab Aducanumab is a monoclonal an ibody speci ic o soluble b-amyloid p o ein ib ils and oligome s whose applica ion is aimed a he clea ance o A β plaques. The ecom- mended dose o aducanumab is 10 mg/kg, adminis e ed by IV o e one hou e e y 4 weeks, and a leas 21 days apa [ 19 ]. This d ug was ecen ly app o ed in Ap il 2021 by he FDA, as i is conside ed o be able o ac on SP, slowing he p og ession o AD. This app o al was based on he esul s o h ee clinical ials ha p o ide s ong e idence o he e ec i eness o his ea men . The i s , PRIME (NCT01677572), a mul icen e , andomized, 12-mon h, double-blind, placebo-con olled, mul iple-dose s udy, en olled 165 indi iduals who we e adminis e ed mon hly in a enous (IV) pull doses o aducanumab (1, 3, 6, o 10 mg kg−1) o one yea . This s udy showed a dose- ime-dependen educ ion in A β plaques and an imp o emen in clinical mani es a ions o AD, as assessed by he Clinical Demen ia Ra ing- Sum o Boxes (CDR-SB) and Mini Men al S a e Examina ion (MMSE) sco es o he highes dose [ 20 ]. The o he wo s udies, EMERGE (NCT02484547) and ENGAGE (NCT02477800), 2 double-blind, placebo-con olled, pa allel-g oup, phase 3 andomized clinical ials wi h 1643 and 1653 pa icipan s espec i ely, showed con adic o y esul s. While he EMERGE s udy showed a 22% dec ease in CDR-SB sco es, and a signi ican imp o emen in ques ion- nai es such as he MMSE, he Alzheime ’s Disease Assessmen Scale-Cogni i e Subscale (13 I ems) (ADAS-Cog 13), and he Alzheime ’s Disease Coope a i e S udy-Ac i i ies o Daily Li ing In en o y (Mild Cogni i e Impai men Ve sion) (ADCS-ADL-MCI) a e adminis a ion o Aducanumab, 10 mg/kg IV mon hly, he ENGAGED s udy did no ep oduce hese esul s, p obably due o di e ences be ween he s udies, in he cou se o he disease, and in he esponse acco ding o he numbe o ea men s ecei ed. Howe e , addi ional pha macome ic analyses showed an associa ion be ween aducanumab admin- is a ion and esponse o he a o emen ioned ques ionnai es obse ed in he wo phase 3 s udies. These s udies also showed, in a subg oup analysis o pa icipan s, signi ican educ ions in amyloid deposi ion in bo h subg oup s udies o high-dose aducanumab ea men s (10 mg/kg) e sus placebo, bu signi ican educ ions in ce eb ospinal luid (CSF) au p o eins we e only obse ed o he EMERGE s udy [ 21 , 22 ]. On he o he hand, he main ad e se e ec was amyloid- ela ed imaging abno mali ies—mani es ing as edema o hemoside in deposi ion—which was epo ed in 41% o pa ien s e sus 10% o hose aking he placebo. Mos cases we e symp om- ee, and ad e se e ec s esol ed in mos pa ien s [23]. Howe e , he Eu opean Medicines Agency has wi hd awn he ma ke ing au ho iza- ion o his p oduc o he ea men o Alzheime ’s disease due o in e ac ions wi h he CHMP, indica ing ha he da a p o ided hus a would no be su icien o suppo a posi i e opinion on he e ec i eness o he p oduc . Thus, ollowing FDA amendmen , his ea men is limi ed o cases o mild Alzheime ’s disease o mild cogni i e impai men due o Alzheime ’s disease, as epo ed in he ials. In his case, pa ien s mus ha e a b ain MRI be o e s a ing ea men . These MRI scans should be epea ed a 7 and 12 mon hs o assess he p esence o b ain edema, mic ohemo hages, and supe icial side osis [19]. 2.1.2. Ace ylcholines e ase Inhibi o s (AChE) 1. Tac ine Tac ine was he i s d ug in his g oup o be app o ed by he FDA in Sep embe 1993. I is an ac idine-de i ed choline gic ha wo ks as a cen al inhibi o o ace ylcholines e ase, inc easing ace ylcholine le els in a ious b ain egions [ 24 ]. I s ac ion in inhibi ing pseu- docholines e ase is mo e po en han ace ylcholines e ase i sel . Tac ine was i s es ed in AD by D . Williams Summe in 1989. I s main ad an ages a e i s abili y o be adminis e ed o ally and enously and i s abili y o c oss he BBB. Howe e , as i s use became mo e widesp ead, i s e ec i eness began o be ques ioned due o con lic ing esul s in clinical ials [ 25 – 28 ]. Thus, i was concluded ha ac ine had a pallia i e e ec in he ea men o pa ien s wi h mild o mode a e demen ia, bu did no al e he cou se o he unde lying neu odegene a ion [ 29 ]. I s use was discon inued in 2013 due o a la ge numbe o ad e se Pha maceu ics 2022,14, 1117 5 o 20 e ec s such as nausea, omi ing, loss o appe i e, dia hea, and clumsiness, as well as hepa ic cy o oxici y ha has been epo ed as a consequence o i s adminis a ion [30,31]. 2. Donepezil Donepezil is a pipe idine-de i ed choline gic d ug, a cen al e e sible, non-compe i i e inhibi o o ace ylcholines e ase, he enzyme esponsible o he hyd olysis o ace ylcholine. Mo eo e , donepezil also ac s a he molecula and cellula le el in he pa hogenesis o AD, causing inhibi ion o a ious aspec s o glu ama e-induced exci o oxici y, educ ion o ea ly exp ession o in lamma o y cy okines, induc ion o a neu op o ec i e iso o m o AChE, and educ ion o oxida i e s ess-induced e ec s. [ 32 ]. I was app o ed in 1996 o he he apeu ic managemen o mild o mode a e cases o AD [ 33 ]. Donepezil can be adminis e ed o ally in able , liquid, o jelly o m, o ansde mally. In mild o mode a e demen ia, i is ecommended o s a ea men wi h 5 mg/day, inc easing o 10 mg/day o ou o six weeks. Fo pa ien s wi h mode a e o se e e demen ia, he dose could be inc eased o 23 mg/day, as long as he pa ien has been on he 10 mg/day dose o a leas 3 mon hs [ 33 ]. Donepezil adminis a ion a a dose o 10 mg/day has been shown o imp o e cogni i e unc ion, basic ac i i ies o daily li ing, and clinician- a ed global imp ession sco es, wi h no imp o emen in beha io o quali y o li e [ 34 – 37 ]. In addi ion, he e ec i eness o doses up o 23 mg/day has been s udied, and no signi ican di e ences ha e been ound compa ed o a dose o 10 mg/day [ 38 , 39 ]. Howe e , none o he doses s udied has been able o in e up he p og ession o AD [ 40 ]. On he o he hand, his d ug is cha ac e ized by good pa ien ole ance and mild ad e se e ec s, especially on he gas oin es inal ac o he ne ous sys em [41]. 3. Galan amine Galan amine is a selec i e e ia y isoquinoline alkaloid ha ac s as a selec i e, com- pe i i e, and e e sible ace ylcholines e ase inhibi o . In addi ion, i s imula es he in insic ac ion o ace ylcholine on nico inic ecep o s [42]. This d ug was app o ed by he FDA in 2001 [ 43 ]. The ou e o adminis a ion is o al, wi h doses o 4, 8, 12, 16, and 24 mg, ei he as a quick- elease solu ion ( wice a day), o as ex ended- elease capsules (once a day). The ini ial dose p oposed o ea men is 8 mg/day wi h an inc ease, as a main enance dose, up o 16 mg/day wice a day a e 4–8 weeks [ 44 ]. In e ms o i s applica ion in AD, wha is eally in e es ing abou galan amine is i s abili y o ac a he le el o he cen al ne ous sys em, wi h li le ac i i y in he pe iphe al sys em. In his line, galan amine has been asso- cia ed wi h di e en molecules ha a o i s deli e y in he b ain, such as ce ia-con aining hyd oxyapa i e pa icles, solid lipid nanopa icles, o chi osan [ 45 – 47 ]. The clinical ials de eloped on his pa hology ha e shown ha his ea men is able o educe he beha io al and cogni i e symp oms (agi a ion, anxie y, disinhibi ion, and abe an mo emen s) in pa ien s wi h mild o mode a e AD [ 44 , 48 , 49 ]. A ecen me a-analysis conduc ed by Li e al. showed ha his d ug is no only e ec i e in con olling beha io al symp oms, bu i also imp o es he pe o mance o basic ac i i ies o daily li ing, cogni i e unc ion, and clinicians’ pe cep ions o global s a e, which makes i he d ug o choice o he ea men o AD [ 50 ]. Al hough his d ug has shown good sa e y and ole abili y, i s use is no wi hou ad e se e ec s, such as con ulsions, se e e nausea, s omach c amps, omi ing, i egula b ea hing, con usion, muscle weakness, and wa e ing eyes [51]. 4. Ri as igmine This pha maceu ical agen was in oduced in Swi ze land in 1997 and app o ed by he FDA in 2000; is indica ed o mild and mode a e AD, as well as mild-mode a e Pa kinson’s demen ia. I is a pseudo-i e e sible inhibi o o AChE and bu y ylcholines e ase ha ac s by binding o he anionic and s ea ic si e o AChE [ 52 ]. I is a ailable as able s o d ops, adminis e ed a an ini ial dose o 1.5 mg/12 h, which can be inc eased acco ding o ole abili y up o 6 mg/12 h, a in e als o a leas 2 weeks om he p e ious dose, he mos e ec i e dose being be ween 3–6 mg/12 h. This d ug is also a ailable in ansde mal pa ches, he ini ial dose o which is 4.6 mg/day, al hough, i ole abili y is adequa e, he Pha maceu ics 2022,14, 1117 6 o 20 dosage can be inc eased o 13.3 mg/day [ 53 ]. This ou e also allows con inuous elease o 24 h, a oiding gas oin es inal e ec s due o in es inal and hepa ic me abolism. Simila ly, ansde mal pa ches a e a pa icula ly in e es ing op ion in AD pa ien s, who o en ha e memo y loss and impai ed swallowing, making i di icul o use he o al ou e [ 54 ]. In addi ion, cos -e ec i eness s udies ha e shown ha his me hod o deli e y is he op imal ea men s a egy in economic e ms [ 55 ]. T ials ha ha e e alua ed he use o i as igmine in he managemen o AD ound an imp o emen in cogni i e unc ion as assessed by he ADAS-Cog and MMSE, ac i i ies o daily li ing, as well as an imp o emen in clinician- a ed global imp ession o change a e 26 weeks o ea men , using doses o 6–12 mg daily o ally, o 9.5 mg daily ansde mally [ 56 – 61 ]. Howe e , i should be no ed ha pa ien s aking i as igmine a e no e y adhe en o ea men due o ad e se e ec s, including s omach pain, weigh loss, dia hea, loss o appe i e, nausea, and omi ing. Mo eo e , an o e dose o his d ug may cause nume ous symp oms, including i egula , ( as o slow) b ea hing, ches pain, and slow o i egula hea bea [62]. 2.1.3. N-Me hyl D-Aspa a e (NMDA) An agonis s 1. Meman ine Meman ine is a non-compe i i e, mode a e a ini y, ol age-dependen NMDA ecep- o an agonis . I blocks he e ec s o pa hologically ele a ed glu ama e onic le els ha can lead o neu onal dys unc ion. The mal unc ion o glu ama e-media ed neu o ansmission, pa icula ly a he NMDA ecep o s, con ibu es o bo h symp om exp ession and p og es- sion o AD o neu odegene a i e demen ia [ 63 ]. In 2003, meman ine became he i s d ug app o ed by he US FDA o ea mode a e- o-se e e AD [ 64 ]. I is a ailable as slow- elease capsules o 7, 14, 21, and 28 mg; as a 2 mg/mL solu ion, and in 10 mg able s, wi h an ini ial dose o 5 mg/day o he i s week. The ea e , he dose is inc eased o 5 mg wice a day du ing he second week, and in he hi d week, 15 mg is adminis e ed in he o m o one 10 mg able in he mo ning and hal o ano he able in he a e noon. F om he ou h week on, ea men can be con inued a he ecommended main enance dose o 20 mg a day (one able wice a day) [ 63 , 65 ]. The adminis a ion o meman ine in pa ien s wi h mode a e o se e e AD showed a small imp o emen in global clinical a ing: 0.21 poin s on he CIBIC-Plus, in cogni i e unc ioning: 3.11 poin s on he Se e e Impai men Ba e y (SIB), in pe o mance in ac i i ies o daily li ing: 1.09 poin s on he ADCS-ADL scale, and in beha iou and mood: 1.84 poin s on he Neu opsychia ic In en o y [ 66 ]. Howe e , acco ding o ecen me a-analyses, meman ine does no seem o be equally e ec i e in pa ien s wi h mild AD, as no signi ican di e ences we e ound wi h espec o placebo in he p e iously men ioned pa ame e s [50,66]. In e ms o ad e se e ec s, he ollowing should be no ed: dizziness, headache, con usion, dia hea, and cons ipa ion, al hough a igue, pain, hype ension, weigh gain, hallucina ion, con usion, agg essi e beha io , omi ing, abdominal pain, and u ina y incon inence may also appea less equen ly [67]. On he o he hand, he combina ion o meman ine wi h donepezil (Namza ic ® ) o he symp oma ic ea men o mode a e o se e e Alzheime ’s disease is also app o ed by he FDA. Howe e , ano he d ug based on meman ine hyd ochlo ide and donepezil hyd ochlo ide, known comme cially as Ac escen ® , has no been app o ed by he Eu o- pean Medicines Agency, due o a lack o consis en e idence o i s e ec i eness in his pa hology [ 68 , 69 ]. This combina ion o d ugs p e en s he oxic e ec s associa ed wi h excess glu ama e, as well as he b eakdown o ace ylcholine in he b ain. Acco ding o scien i ic e idence, Meman ine plus donepezil is mo e e ec i e in imp o ing cogni ion, as assessed by he ADAS-Cog and SIB scale, global assessmen , daily ac i i ies, and neu opsy- chia ic symp oms compa ed wi h placebo, bu has lowe accep abili y han mono he apy o placebo [ 70 ]. Rega ding he cos -e ec i eness o his ea men , he scien i ic li e a u e does no show comple ely clea esul s. While au ho s such as Cappel e al. o Weycke e al. sugges ha combina ion he apy is mo e cos -e ec i e han donepezil alone, Knapp e al. ound no signi ican di e ences be ween he wo ea men s [71–73]. Pha maceu ics 2022,14, 1117 7 o 20 2.2. Pha macological T ea men s unde In es iga ion Due o he absence o , and he high demand o success ul ea men s o p e en and slow he p og ession o AD, esea ch in ecen decades has ocused on he ypical pa hophysiological mechanisms o he disease [ 74 ] (Figu e 2). In ela ion o A β pa hology, he main pha macological ea men s unde in es iga ion can be classi ied in o hose ha dec ease A β 42 p oduc ion, hose ha educe A β load in SP, and hose ha enhance A β clea ance (Table 1). In he case o au pa hology, ea men s unde s udy include inhibi o s o au p o ein hype phospho yla ion and agg ega ion, as well as hose ha po en ia e au p o ein clea ance [75] (Table 2). Pha maceu ics 2022, 13, x FOR PEER REVIEW 7 o 21 e idence, Meman ine plus donepezil is mo e e ec i e in imp o ing cogni ion, as assessed by he ADAS-Cog and SIB scale, global assessmen , daily ac i i ies, and neu opsychia ic symp oms compa ed wi h placebo, bu has lowe accep abili y han mono he apy o pla- cebo [70]. Rega ding he cos -e ec i eness o his ea men , he scien i ic li e a u e does no show comple ely clea esul s. While au ho s such as Cappel e al. o Weycke e al. sugges ha combina ion he apy is mo e cos -e ec i e han donepezil alone, Knapp e al. ound no signi ican di e ences be ween he wo ea men s [71–73]. 2.2. Pha macological T ea men s unde In es iga ion Due o he absence o , and he high demand o success ul ea men s o p e en and slow he p og ession o AD, esea ch in ecen decades has ocused on he ypical pa ho- physiological mechanisms o he disease [74] (Figu e 2). In ela ion o Aβ pa hology, he main pha macological ea men s unde in es iga ion can be classi ied in o hose ha de- c ease Aβ42 p oduc ion, hose ha educe Aβ load in SP, and hose ha enhance Aβ clea - ance (Table 1). In he case o au pa hology, ea men s unde s udy include inhibi o s o au p o ein hype phospho yla ion and agg ega ion, as well as hose ha po en ia e au p o ein clea ance [75] (Table 2). Figu e 2. Molecula pa hways in ol ed in he pa hology and in ea men s unde in es iga ion o AD. Table 1. Pha macological ea men s unde in es iga ion ela ed o Aβ pa hology. Pha macological T ea men s unde In es iga ion Mechanism o Ac ion Agen Aβ pa hology γ-sec e ase inhibi o s Semagaces a (LY-450139) A agaces a (BMS-708163) Ta en lu bil β-sec e ase inhibi o s Lanabeces a Ve ubeces a A abeces a Elenbeces a (E2609) Umibeces a (CNP520) α-sec e ase modula o s E azola o (EHT0202) APH-1105 ID1201 Agg ega ion inhibi o s Scyllo-inosi ol (ELND005) Figu e 2. Molecula pa hways in ol ed in he pa hology and in ea men s unde in es iga ion o AD. Table 1. Pha macological ea men s unde in es iga ion ela ed o Aβpa hology. Pha macological T ea men s unde In es iga ion Mechanism o Ac ion Agen Aβpa hology γ-sec e ase inhibi o s Semagaces a (LY-450139) A agaces a (BMS-708163) Ta en lu bil β-sec e ase inhibi o s Lanabeces a Ve ubeces a A abeces a Elenbeces a (E2609) Umibeces a (CNP520) α-sec e ase modula o s E azola o (EHT0202) APH-1105 ID1201 Agg ega ion inhibi o s Scyllo-inosi ol (ELND005) Pep idomime ics (KLVFF, γ-AA) Me al in e e ing d ugs Dyshomeo aisis (coppe , i on o zinc) De e ip ona PBT2 D ugs ha enhance Aβ clea ance (immuno he apy) Ac i e immuno he apy CAD106 CNP520 AB ac40 GV1001 ACC-001 UB-311 AF20513 Passi e immuno he apy C enezumab Gan ene umab LY3002813 Pha maceu ics 2022,14, 1117 8 o 20 Table 2. Pha macological ea men s unde in es iga ion ela ed o au pa hology. Pha macological T ea men s unde In es iga ion Mechanism o Ac ion Agen Tau pa hology Inhibi o s o au p o ein hype phospho yla ion GSK3βinhibi o s Li hium Chlo ide Tideglusib Tau p o ein agg ega ion inhibi o s Me hylene blue TRx0237 (LMTM) D ugs ha p omo e he clea ance o au (immuno he apy) Ac i e immuno he apy AAD ac-1 ACI-35 Passi e immuno he apy C2N-8E12 (Tilayonemab) Bep anemab (UCB0107) O he an i- au mAbs BII076 JNJ-63733657 LY3303560 2.2.1. AβPa hology 1. γ-sec e ase inhibi o s One o he he apeu ic a ge s in he ea men o AD is he inhibi ion o γ -sec e ase, which ac s on he APP h ough i s sequen ial clea age. Howe e , his enzyme also wo ks a o he le els, clea ing ansmemb ane p o eins such as he No ch 1 ecep o , an impo an componen in cell communica ion and di e en ia ion. [ 76 ]. This could explain he ailu e o ea men s based on his pa hway in a ious clinical ials o da e. Fo example, a phase 3 clinical ial showed ha Semagaces a (LY-450139) did no imp o e cogni i e abili ies and, in he case o pa ien s ecei ing a highe dose, caused a wo sening o unc ional capaci y, as well as an inc eased isk o skin cance and in ec ions [ 77 ]. In he case o A agaces a (BMS-708163), a g ea e p og ession o disease symp oms and b ain a ophy was also obse ed compa ed o he con ol g oup, as well as nume ous side e ec s including skin cance and enal dys unc ion [ 78 ]. Ano he he apeu ic al e na i e included in his g oup is Ta en lu bil, a γ -sec e ase inhibi o adminis e ed in anasally. Howe e , he phase 3 clinical ial based on his d ug was s opped due o poo b ain pene a ion [ 79 ]. Due o he side e ec s o γ -sec e ase inhibi o s, hei ole in he pha macological app oach o AD is cu en ly being challenged [80]. 2. β-sec e ase inhibi o s β -sec e ase inhibi o s aim o lowe A β le els in CSF, and include d ugs such as Lanabeces a , Ve ubeces a , A abeces a , Elenbeces a and Umibeces a . [ 81 ]. Howe e , cu en ly only wo o hese a e s ill unde s udy: Elenbeces a (E2609) and Umibeces- a (CNP520) in phase 2 and 3, espec i ely [ 80 ]. Subjec s included in hese ials we e indi iduals a high isk o AD: age in he ange o 60–75 yea s, APOE4 geno ype and he e ozygo es (APOE ε 2/ ε 4 o ε 3/ ε 4), and high le els o amyloid in he b ain [ 82 ]. The emaining ea men s we e discon inued due o lack o e icacy o ad e se e ec s associa ed wi h hei use, such as ash, li e oxici y, and neu opsychia ic symp oms [ 83 – 85 ]. Despi e hese inciden s, i is no ewo hy ha all ea men s signi ican ly educed CSF A β le els, al hough his did no esul in cogni i e o unc ional imp o emen [86]. 3. α-sec e ase modula o s The non-amyloidogenic pa hway is igge ed a e he clea age o APP by α -sec e ase, so ano he pha macological a ge could be he modula ion o his enzyme. Acco ding o he scien i ic li e a u e, he ac i a ion o α -sec e ase is media ed h ough he phospha idyli- nosi ol 3-kinase (PI3K)/Ak pa hway ia γ-aminobu y ic acid (GABA) ecep o signaling. Thus, d ugs ha can ac i a e his pa hway, o whose ac ion esembles ha o selec i e GABA ecep o modula o s, could cons i u e a new he apeu ic app oach in AD [ 75 ]. Wi hin his g oup is E azola e (EHT0202), a GABA ecep o modula o ha has al eady Pha maceu ics 2022,14, 1117 9 o 20 been es ed in a phase 2 clinical ial demons a ing i s sa e y in pa ien s wi h mild o mode a e AD. Howe e , a phase 3 ial is s ill pending [ 87 ]. On he o he hand, APH-1105 and ID1201 a e d ugs ha ac i a e he PI3K/Ak pa hway and a e cu en ly being s udied in ph ase 2 clinic al ials. APH-1105 is an in anasal d ug whose sa e y, ole abili y, and e icacy a e being e alua ed o he ea men o subjec s wi h mild-mode a e AD. ID1201 is a Melia oosendan ui ex ac o use in subjec s wi h mild o mode a e AD [80]. 4. Agg ega ion inhibi o s This g oup o d ugs aims o p e en he o ma ion o A β 42 ibe s cha ac e is ic o A β pa hology. Scyllo-inosi ol (ELND005) was he las agg ega ion inhibi o es ed in humans in a phase 2 clinical ial. I was discon inued due o limi ed e idence o suppo i s bene i , as well as dose-dependen oxici y om i s use. [ 88 ]. Cu en ly, esea ch is di ec ed owa ds he use o pep idomime ics, which inhibi o e e se he agg ega ion o A β 42. These include KLVFF, whose pep ide sequence is simila o he hyd ophobic co e po ion o A β and g adually eplaces i . Howe e , i s ac ion is no limi ed o p e en ing agg ega ion, bu can also dissol e oligome s ha a e esis an o p o eoly ic b eakdown [ 89 ]. A new class o pep idomime ics unde in es iga ion a e he γ -AApep ides, which may be up o 100 imes mo e e icien han KLVFF as agg ega ion inhibi o s. The la e ha e ye o be es ed in in i o ials [90]. 5. Me al in e e ing d ugs Ano he e iological ac o ela ed o he de elopmen o AD is dyshomeos asis, o abno mal accumula ion o me al ions such as coppe , i on, o zinc [ 76 ]. In his ega d, de e ip one ac s as a chela ing agen ha helps o dec ease i on s o es. This ea men is cu en ly being s udied in a phase 2 clinical ial o subjec s wi h mild and p od omal AD [ 91 ]. Ano he d ug in his g oup is PBT2, which showed p omising esul s in p eclinical ials and is cu en ly in a phase 2 clinical ial. This d ug has demons a ed he abili y o dec ease A β in CSF by 13%, as well as a dose-dependen imp o emen in execu i e unc ions in subjec s wi h ea ly AD [92,93]. 6. D ugs ha enhance Aβclea ance (immuno he apy) This g oup o d ugs belongs o he immuno he apeu ic app oach and includes wo possible modali ies: ac i e and passi e immuno he apy [ 94 ]. Ac i e immuno he apy in ol es he use o whole p o eins o p o ein agmen s ha p omo e he c ea ion o an ibodies by B cells, he eby de eloping he pa ien ’s immune esponse [ 86 ]. Passi e immuno he apy in ol es he passi e inocula ion o monoclonal an ibodies (mAbs) o polyclonal an ibodies ha ac agains A β pep ides, making he in lamma o y p ocess de eloped by T cells unnecessa y [95]. Wi h ega d o ac i e immuno he apy, six d ugs a e cu en ly unde s udy in phase 1, 2 and 3 clinical ials. On he one hand, CAD106 and CNP520 ha e been s udied in wo simul aneous phase 3 ials in subjec s a isk o AD. Howe e , in 2020 hese s udies we e s opped due o he de ec ion o changes in cogni i e unc ion, b ain olume loss, and body weigh [ 82 ]. In addi ion, accines ha e been de eloped o c ea e an i-A β 40 an ibodies, including AB ac40, GV1001, ACC-001, UB-311, and AF20513. These accines, wi h he excep ion o AF20513, a e s ill in phase 2 clinical ials and ha e ob ained gene ally p omising esul s. Thus, ea men wi h AB ac40 esul ed in he de elopmen o A β 40 an ibodies in 92% o pa ien s adminis e ed he d ug [ 96 ]. In he case o ACC-001, his was adminis e ed in subjec s wi h mild o mode a e AD, wi h highe Ig G and an i-A β 40 le els han in he o he g oups [ 97 ]. UB-311 induced an immune esponse in 100% o he sample, as well as a slowing o cogni i e decline. In addi ion, only mild ad e se e ec s, such as swelling a he punc u e si e and agi a ion, we e obse ed [98]. As o passi e immuno he apy based on mAbs, we can cu en ly iden i y se e al d ugs in de elopmen . On he one hand, c enezumab has been associa ed wi h an im- p o emen in ADAS-Cog sco es in indi iduals wi h low ad anced AD, being su icien ly sa e and ole able [ 99 ]. 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