What have we learnt from past failures in Alzheimer’s disease drug discovery?

KEYWORDS:

• Alzheimer’s disease
• biomarkers
• drug development
• epigenetics
• immunotherapy
• pathogenic genomics
• pharmacological treatment
• pharmacogenetics

1. Introduction

Alzheimer’s disease (AD) is a priority health problem in advanced societies and in many emerging and developing countries, with high cost for public health services, an overload on the economy of families and the consumption of medical and health resources. The cost of dementia exceeds US$800 billion worldwide (>1% of GDP), with an average cost per patient/year that fluctuates between $30,000 and $60,000, depending on the country, social status, quality of medical care and the stage of the disease. The cost of pharmacological treatment for AD and concomitant pathologies represents 20–30% of the overall costs of the disease (approximately €7,000/year in Europe, $15,000/year in the USA, and JPY18 million/year in Japan) [1,2].

Among different forms of dementia, AD is the most frequent (50–60%). Vascular dementia (30–40%), other forms of degenerative dementia (10–15%), and mixed dementia (>70% in patients over 75 years of age) are also relevant. AD is more prevalent in females than in males (mean prevalence: 1–2% at the age of 60; >35% in people older than 80 years). Epidemiological predictions suggest an increase in the prevalence of dementia of approximately 1–2% per year in parallel with the increase in life expectancy of the population.

AD results from the premature death of neurons caused by different factors, including genomic, epigenomic, cerebrovascular and multiple environmental conditions. The clinical picture resulting from the accumulation of pathogenic factors is characterized by progressive cognitive impairment, behavioral alterations (agitation, anxiety, depression, changes in personality and biorhythms) and functional decline (with compromise of psychomotricity and the management of common activities of daily living) [3].

From a nosological point of view, this form of primary degenerative dementia can be conventionally differentiated into (i) early-onset AD (EOAD)(<65 years), commonly associated with Mendelian mutations in high-penetrance pathogenic genes (sometimes, also called familial AD, FAD), and (ii) late-onset AD (LOAD)(>65 years)(also improperly called sporadic AD, sAD), in which multiple genetic defects (susceptibility single nucleotide polymorphisms, SNPs)(>600 genes) and environmental factors may converge with the involvement of epigenetic aberrations to induce progressive brain damage [4,5].

The neuropathological phenotype of AD is characterized by age-related dendritic desarborization, microglial reactivity, astrogliosis, and neuronal loss in critical regions of the CNS, with the presence of extracellular deposits of aggregated β-amyloid (Aβ) in neuritic plaques and vessels, formed due to abnormal processing of APP, together with synergistic intracellular inclusions of neurofibrillary tangles (NFTs), resulting from the hyperphosphorylation of tau protein in microtubules and neurofilaments. Among neurochemical findings, as a consequence of neurodegeneration, AD brains exhibit neurotransmitter deficits (cholinergic, noradrenergic, dopaminergic, serotonergic, glutamatergic, GABAergic, neuropeptidergic), neurotrophic alterations, biochemical markers of neuroinflammatory reactions and disruption of lipid rafts due to oxidative stress-induced lipid peroxidation. All these deleterious events are accompanied by hypoperfusion-related cerebrovascular damage [5–11].

The main challenges facing the scientific community, the medical services and the pharmaceutical industry today are (i) to deepen into a better understanding of the primary causes of the disease and its pathogenic mechanisms, (ii) the characterization and validation of reliable biomarkers that allow for an early diagnosis, (iii) the identification and development of new drugs and therapeutic strategies able to slow-down or halt the course of the disease, and (iv) under optimal conditions, develop new preventive protocols capable of blocking the evolution of the disease in the population at risk at presymptomatic stages, taking into account that brain damage in AD begins several decades before the clinical manifestation of symptoms of dementia [8,10,11].

2. Pathogenic meltdown and cumulative risks

Over the past 30 years, more than 600 genes distributed throughout the human genome have been linked to the risk of AD. Several pathogenic mutations in the amyloid precursor protein (APP) (>50 mutations), PSEN1 (>300 mutations) and PSEN2 genes (>40 mutations), present in less than 10% of AD cases, confer AD the condition of a brain amyloidopathy; MAPT (microtubule-associated protein tau) gene mutations (>100, responsible for diverse tauopathies: frontotemporal dementia, Pick’s disease) link AD to other tauopathies, although MAPT variants are not specific to prototypal forms of AD. Amyloidopathy and tauopathy have been the two dominant hypotheses in the etiopathogenesis of AD for years [12,13].

Missense APP mutations in EOAD cause AD. Other coding variants (APP A673T) may reduce the risk for AD. AD risk-associated mutations in the APP gene increase Aβ fibrillogenesis and total Aβ levels; in contrast, protective alleles may reduce Aβ levels [12].

Presenilin acts as the catalytic site of γ-secretase and the most dominant mutations associated with familial EOAD occur either in the APP gene encoding the APP substrate or in the PSEN1 and PSEN2 genes encoding the protease (presenilin) responsible for APP cleavage, leading to abnormal Aβ accumulation and deposition in senile plaques and vessels. Apolipoprotein E4 (APOE-4) is the most important risk factor for AD in > 40% of cases. The presence of the APOE-4 allele impairs Aβ clearance from brain tissue. Immunotherapy with different Aβ antibodies (solanezumab, crenezumab, and aducanumab) attempt to reduce Aβ accumulation and slow-down cognitive decline in presymptomatic and/or mild-AD cases, as a novel line of therapeutic intervention [12,13].

In addition to these pathogenic genes, novel mutations have been identified in association with AD in recent NGS (next-generation sequencing) and GWAS (genome-wide association studies) in different ethnic groups, indicating that many pathogenic genes can accumulate in each AD case (Figure 1).

Figure 1. Frequency and accumulation of pathogenic gene variants in patients with Alzheimer’s disease.

This figure shows the pathogenic variants of 18 genes associated with AD that most often accumulate in a single patient. Most patients (>60%) are carriers of several pathogenic genes (>10 pathogenic variants per patient). The genes that most frequently (>50%) accumulate pathogenic variants in the same case of AD are A2M (54.38%), ACE (78.94%), BIN1 (57.89%), CLU (63.15%), CPZ (63.15%), LHFPL6 (52.63%), MS4A4E (50.87%), MS4A6A (63.15%), PICALM (54.38%), PRNP (80.70%) and PSEN1 (77.19%).A2M: alpha-2-macroglobulin; ABCA7: ATP binding cassette subfamily A member 7; ACE: angiotensin I converting enzyme; APOE: apolipoprotein E; BIN1: bridging integrator 1; C9ORF72: chromosome 9 open reading frame 72; CLU: clusterin; CPZ: carboxypeptidase Z; CR1: complement C3b/C4b receptor 1; DISC1: disrupted in schizophrenia 1; LHFPL6: LHFPL tetraspan subfamily member 6; MS4A4E: membrane spanning 4-domains A4E; MS4A6A: membrane spanning 4-domains A6A; NOS3: nitric oxide synthase 3; PICALM: phosphatidylinositol binding clathrin assembly protein; PRNP: prion protein; PSEN1: presenilin 1; TNF: tumor necrosis factor.

A very important aspect in the analysis of any genetic study in polygenic and complex diseases is to weigh the pathogenic load that each gene has in an individual case. Using a panel with the 18 most influential genes in AD (Figure 1), it has been found that (i) no patient is a carrier of a single pathogenic gene, (ii) most patients (>60%) are carriers of several pathogenic genes (>10 pathogenic variants per patient), (iii) a considerable number of cerebrovascular risk variants are present in the genotype of AD patients, and (iv) the genes that most frequently (>50%) accumulate pathogenic variants in the same case of AD are A2M (54.38%), ACE (78.94%), BIN1 (57.89%), CLU (63.15%), CPZ (63.15%), LHFPL6 (52.63%), MS4A4E (50.87%), MS4A6A (63.15%), PICALM (54.38%), PRNP (80.70%) and PSEN1 (77.19%) (Figure 1).

In relation to the pathogenic load that the APOE-4 allele may represent in the clinical expression of AD and in its neuropathological phenotype, the pathogenic influence of the APOE-4 allele, from a quantitative point of view, does not affect more than 35–40% of AD cases. However, the pathogenic role of the genotypes APOE-2/4, APOE-3/4 and especially APOE-4/4 is highly relevant in the age at onset, clinical course, concomitant cardiovascular and cerebrovascular disorders, and therapeutic response to treatment [7–11,14] (Figure 1).

3. Drug development

Approximately, 20% of papers published during the past decade on AD are related to drug development [15]. The most frequently studied pharmacological categories are the following: natural derivatives with pleiotropic activity (26%), anti-amyloid agents (20%), neurotransmitter enhancers (15%), novel drugs for new targets (12%), reanalyzed old drugs (11%), anti-tau drugs (6%), multitarget drugs (3%), stem cell therapy (1.85%), neuroprotective peptides (1.5%), nanotechnology products (1.45%), anti-inflammatory drugs (1.2%), and other products (1%) [15]. Among the neurotransmitter enhancers, cholinergic drugs predominate (>70%) (Table 1), followed by glutamatergic (14.5%), serotonergic (7.5%), dopaminergic (4%), histaminergic (3%), GABAergic (1%), and adrenergic drugs (1%) (Figure 2).

Figure 2. Pharmacological categories in drug development for the treatment of Alzheimer’s disease.

Table 1 Novel cholinesterase inhibitors with potential preclinical effects in AD models (PubMed 2010–2020)

Selective, dual and multi-target Acetylcholinesterase inhibitors
(3-[2-({4-[(Dimethylamino)methyl]-2-oxo-2 H-chromen-7-yl}oxy)ethoxy]-6,7-dimethoxy-2 H-chromen-2-one
(Benz)imidazolopyridino tacrines
(E)-2-(5,7-dibromo-3,3-dimethyl-3,4-dhihydroacridin-1(2 H)-ylidene)hydrazinecarboxamide
(E)-2-(5,7-dibromo-3,3-dimethyl-3,4-dihydroacridin-1(2 H)-ylidene)hydrazinecarbothiomide
[3-(2/3/4-methoxyphenyl)-6-oxopyridazin-1(6 H)-yl]methyl carbamate derivatives ([3-(2-methoxyphenyl)-6-oxopyridazin-1(6 H)-yl]methyl heptylcarbamate), [3-(2-methoxyphenyl)-6-oxopyridazin-1(6 H)-yl]methyl (4-methylphenyl)carbamate)
{4-[(3,5-dichloro-2-hydroxyphenyl)sulfonyl]-1-piperazinyl}(2-furyl)methanone
1-(5-Amino-2-methyl-4-(1-methyl-1 H-imidazol-2-yl)-6,7,8,9-tetrahydro-4 H-pyrano[2,3-b]quinolin-3-yl)ethan-1-one
1-(5-amino-4-(2-chloro-7-methoxyquinolin-3-yl)-2-methyl-6,7,8,9-tetrahydro-4 H-pyrano [2,3-b]quinolin-3-yl)éthanone
1, 3-Dihydroxyxanthone Mannich base derivatives
1,2,3,4,5,6-hexahydroazepino[4,3-b]indole
1,2,3,4-tetrahydro-1-acridone analogues
1,2,3-Triazole-based acetylcholinesterase inhibitors
1,2,3-triazole-chromenone carboxamide derivatives (N-(1-benzylpiperidin-4-yl)-7-((1-(3,4-dimethylbenzyl)-1 H-1,2,3-triazol-4-yl)methoxy)-2-oxo-2 H-chromene-3-carboxamide)
1,2-Oxazine-based small molecules
1,3,5-triazine-benzenesulfonamides
1,3-Dihydroxyxanthone derivatives
1,8-cineole
1-Benzylamino-2-hydroxyalkyl Derivatives
1-benzyl-N-(1-methyl-3-oxo-2-phenyl-2,3-dihydro-1 H-pyrazol-4-yl) piperidine-4-carboxamide
1-benzyl-N-(5,6-dimethoxy-8 H-indeno[1,2-d]thiazol-2-yl)piperidine-4-carboxamide
1-butanoyl-3-arylthiourea derivatives
1 H-pyrazolo[3,4-b]pyridine derivatives
2-((4-(1,3-dioxoisoindolin-2-yl)benzyl)amino)-2-oxoethyl-2-(4-methoxyphenyl)acetate
2-(2-(4-(2-Oxo-2-phenylethyl)piperazin-1-yl) ethyl)Isoindoline-1,3-dione derivatives
2-(2-(4-Benzoylpiperazin-1-yl)ethyl)isoindoline-1,3-dione derivatives
2-(9-acridinylamino)-2-oxoethyl piperazine/piperidine/morpholinecarbodithioate derivatives
2-(Benzylamino-2-Hydroxyalkyl)Isoindoline-1,3-Diones Derivatives (12 (2-(5-(benzylamino)-4-hydroxypentyl)isoindoline-1,3-dione)
2-(Naphthalen-1-yl)-7-(8-(pyrrolidin-1-yl)octyloxy)-4 H-chromen-4-one
2-(piperazin-1-yl)N-(1 H-pyrazolo[3,4-b]pyridin-3-yl)acetamides
2,4,5-trisubstituted imidazoles
2,5-dihydroxyterephthalamide derivatives
2,6-Disubstituted pyridazinone derivatives
2-acetyl-5-O-(amino-alkyl)phenol derivatives
2-amino-4 H-pyrans
2-arylbenzofuran derivatives
2-Arylbenzofurans from Artocarpus lakoocha
2-Arylidene-4-methoxy (or hydroxy)-7-methyl-1-indanone derivatives
2-benzofuran carboxamide-benzylpyridinum salts
2-Butenediamide and oxalamide derivatives.
2-Chloroquinolin-3-yl substituted PyranoTacrines (PTs)
2-Furoic piperazide derivatives (2-furoic piperazide (1; 1-(2-furoyl)piperazine), 3,5-dichloro-2-hydroxybenzenesulfonyl chloride)
2-Furyl(1-piperazinyl)methanone
2’-Hydroxychalcones
2-Hydroxy-N-phenylbenzamides
2-methylimidazole and alkyl/aryl halides
2-Phenoxy-indan-1-one derivatives (PIOs)
2-pyrazoline derivatives
2-pyridylpiperazine and 5-phenyl-1,3,4-oxadiazoles hybrids
2-substituted benzo[d]oxazol-5-amine derivatives
2-vinyl chromones
3-(4-(Aminoalkoxy)benzylidene)-chroman-4-ones
3,5-dichloro-2-hydroxybenzenesulfonyl chloride
3,5-dimethylorsellinic acid-based meroterpenoids
3-[3-(Amino) propoxy] benzenamines
3-arylcoumarins
3-phenylcoumarin-lipoic acid conjugates
4-(1,3-Dioxoisoindolin-2-yl)-N-Phenyl Benzamide derivatives
4-(2-fluorophenyl)-3-(3-methoxybenzyl)-1 H-1,2,4-triazol-5 (4 H)-one
4,6-Diphenylpyrimidine Derivatives
4-aminoquinolines
4-arylcoumarins derivatives (multitarget)
4-arylthiazole-2-amine derivatives
4-Hydroxycoumarin derivatives containing substituted benzyl-1,2,3-triazole moiety
4-Isochromanone hybrids
4-isochromanone hybrids bearing N-benzyl pyridinium
4-N-phenylaminoquinoline derivatives
4-N-phenylaminoquinolines
4’-OH-flurbiprofen Mannich base derivatives
5-(Aroylhydrazinocarbonyl)escitalopram
5,10,15,20- Tetrakis (4-sulfonatophenyl) porphyrinato Iron(III) Chloride (FeTPPS)
5,10,15,20-Tetrakis (4-sulfonatophenyl) porphyrinatoIron(III) nitrosyl Chloride (FeNOTPPS)
5,6-dimethoxy-1-oxo-2,3-dihydro-1 H-inden-2-yl 1-benzylpiperidine-4-carboxylate
5,6-dimethoxybenzo[d]isothiazol-3(2 H)-one-N-alkylbenzylamine derivatives
5’-/6’-Isonucleosides and Theobromine-Containing N-Isonucleosidyl Derivatives
5-Amino-2-phenyl-4 H-pyrano[2,3-b]quinoline-3-carboxylates
5-methyl-2,4-dihydro-3 H-1,2,4-triazole-3-one’s aryl Schiff base derivatives
5-Oxo-4,5-dihydropyrano[3,2-c]chromene derivatives
6-Chloro-pyridonepezils
6-Chlorotacrine
6 H-Benzo[c]chromen-6-one, and 7,8,9,10-tetrahydro-benzo[c]chromen-6-one derivatives
6-Methyluracil derivatives
6-substituted-3(2 H)-pyridazinone-2-acetyl-2-(nonsubstituted/4-substituted benzenesulfonohydrazide) derivatives
7-Aminoalkyl-substituted flavonoid derivatives
7-chloro-4-aminoquinoline Schiff bases
7 H-Thiazolo-[3,2-b]-1,2,4-triazin-7-one derivatives
7-MEOTA (2 homodimers linked by 2 C4-C5 chains and 5 N-alkylated C4-C8 side chain derivatives)
7-MEOTA-tryptophan hybrids
7-methoxy tacrine derivates (7-MEOTA)
7-Methoxytacrine-adamantylamine heterodimers
9-Amino-1,2,3,4-tetrahydroacridine derivatives with iodobenzoic acid
9 H-Carbazole derivatives containing the N-Benzyl-1,2,3-triazole moiety
9-Methylfascaplysin)
9-Substituted acridine derivatives
9-Substituted acridine derivatives (9-aryl(heteroaryl)-N-methyl-9,10-dihydroacridines, 9-aryl(heteroaryl)-N-methyl-acridinium tetrafluoroborates, 9-heterocyclic amino-N-methyl-9,10-dihydroacridine)
Acalypha alnifolia
Acetamide Derivatives of Chromen-2-ones
acetohydroxamate-chalcones
Acridone-1,2,4-oxadiazole-1,2,3-triazole hybrids
Acrine-ebselen hybrids
Adamantyl derivatives
Albumin-derived peptides
Alkaloid extracts from kola nuts (Cola acuminata and Cola nitida)
Alkaloids from Coptis chinensis (quaternary protoberberines)
Alkaloids from Crinum, Habranthus and Zephyranthes species (caranine, N-demethylgalanthamine, lycoramine)
Alkaloids from Hieronymiella species (Hieronymiella aurea, H. caletensis, H. clidanthoides, H. marginata, and H. speciose)
Alkaloids of Amaryllidaceae (extracts of Crinum jagus: Galanthamine, galanthamine N-oxide, powelline)
alkyl bis(4-amino-5-cyanopyrimidine) derivatives.
Allium sativum essential oil
Allobetulin derived seco-oleananedicarboxylates
Aminoalkyl-substituted coumarin derivatives
Amino-Alkyl-Substituted Fluoro-Chalcones derivatives
Andrographis paniculata and Spilanthes paniculata components (3,4-di-o-caffeoylquinic acid, apigenin, 7-o-methylwogonin)
anethole
Annona cherimola Mill. Derivatves (anonaine, glaucine, xylopine)
Anthemis cotula L. extracts
Anthocleista vogelii (Planch) extracts
Anthraquinone from Rumex abyssinicus Jacq (Helminthosporin)
Aporphines
aporphinoid alkaloids (dual)(liriodenine, cassythicine, Laurotetatine clorhydrate, Pachyconfine)
Arachidonic acid carbamate derivatives
Arylbenzofurans from the Root Bark of Morus alba
Arylimides
azaanthraquinone derivatives
Azomethine-dihydroquinazolinone conjugates
Bacopa monnieri derivatives (bacoside X, bacoside A, 3-beta-D-glucosylstigmasterol, daucosterol)
Bacopa monnieri L. Wettst. Centella asiatica L. Urb.
benzamide and picolinamide derivatives
Benzamide and picolinamide derivatives containing dimethylamine side chain
benzamide derivatives
Benzimidazole derivatives
Benzimidazole Derivatives
Benzimidazole-derived Compounds
Benzochromenoquinolinones-Tacrine Analogs (14-amino-13-(3-nitrophenyl)-2,3,4,13-tetrahydro-1 H-benzo[6,7]chromeno[2,3-b]quinoline-7,12-dione)
Benzodiazepine-1,2,3-triazole hybrid derivatives (3,3-dimethyl-11-(3-((1-(4-nitrobenzyl)-1 H-1,2,3-triazol-4-yl)methoxy)phenyl)-2,3,4,5,10,11-hexahydro-1 H-dibenzo[b,e][1,4]diazepin-1-one)
Benzofuran-based chalconoids
Benzofuran-derived benzylpyridinium bromides
Benzofuran-Indole
Benzofuran-tetrazole derivatives
benzohomoadamantane‒chlorotacrine hybrids
Benzoic acid-derived nitrones
benzothiazole/piperazine derivative (2-[(6-Nitro-2-benzothiazolyl)amino]-2-oxoethyl4-[2-(N,N-dimethylamino)ethyl] piperazine-1 carbodithioate)
Benzothiazole/piperazine derivatives (2-[(6-Nitro-2-benzothiazolyl)amino]-2-oxoethyl4-[2-(N,N-dimethylamino)ethyl] piperazine-1 carbodithioate)
benzoxazine (indole-benzoxazinones and benzoxazine-arylpiperazine derivatives)
Benzylidene-benzofuran-3-ones containing cyclic amine side chain
Benzylpiperidine/piperazine-Dantrolene
Benzylpiperidine-linked 1,3-dimethylbenzimidazolinones (1,3-dimethylbenzimidazolinone derivatives)
Bergenia ciliata (Haw.) Sternb. rhizomes (Saxifragaceae)
Betula platyphylla var. japonica
betulinic acid
bi-Aryl Pyrimidine heterocycles
Binary Conjugates of γ-Carbolines
Biphenyl-3-oxo-1,2,4-triazine linked piperazine derivatives
bis (Heptyl)-cognitin (B7C)
bis(3)-Tacrine
bis(7)-Tacrine and cystamine-tacrine dimer
Bis(9)-(-)-Meptazinol
bis[5-(1’,2’,3’,4’-Tetrahydroacridin-9’-ylamino)pentyl]disulfide
bis-sulfone derivatives
bivalent β-carboline derivatives
Boana pulchella (Anura: Hylidae) derivatives (Hp-1935)
Brominated 2-phenitidine derivatives
Brominated Phenylacetic Acid/Tacrine Hybrids
bromophenol derivatives
Broussonin A
Buchanania axillaris, Hemidesmus indicus and Rhus mysorensis extracts
BYZX, [(E)-2-(4-((diethylamino)methyl)benzylidene)-5,6-dimethoxy-2,3-dihydroinden-one]
Caliphruria subedentata (Amaryllidaceae) drivatives
Carbamate derivatives (Bambuterol derivatives (BMC-3, BMC-16))
Carbamate-substituted thymol/carvacrol derivatives
Carbazole-Bearing Oxazolones
Carbazole-Bearing Oxazolones
carbazole-benzyl piperazine, -benzyl piperidine, -pyridine, -quinoline, -isoquinoline
carboxamide and propanamide derivatives
carvacrol
carvacrol-substituted amide derivatives (2-(5-Isopropyl-2-methylphenoxy)-N-(quinolin-8-yl)acetamide)
Cativic acid derivatives.
Centaurea saligna (K.Koch) Wagenitz
Ceratonia siliqua L. extract (Rutin)
chalcone Mannich base derivatives
chalcone, heterochalcone and bis-chalcone derivatives
Chalcone-based carbamates
chalcone-O-alkylamine derivatives
chalcone-O-carbamate derivatives
Chilean Rhodophiala (Amaryllidaceae)
Chitosan (Chitooligosaccharide)
Chlorinated tacrine analogs (4-(chlorophenyl)tetrahydroquinoline derivatives
Chlorophenoxy derivatives-Histamine H3 receptor ligands
Cholinesterase inhibitor 6-chlorotacrine
Chroman-4-One linked to N-Benzyl Pyridinium derivatives
chromanone-dithiocarbamate hybrids
chromen-4-one based compounds
Chromenone Derivatives
Chromones
CID57390505
CID71605390
cinnamic acid-tryptamine hybrids
Citrus Flavanones (hesperidin)
Citrus Limon Peel derivatives (neoeriocitrin, isonaringin, naringin, hesperidin, neohesperidin, limonin)
Clinanthus microstephium (Amaryllidaceae) derivatives
conjugates of γ-carbolines, carbazoles, tetrahydrocarbazoles, phenothiazines, and aminoadamantanes
Contilisant
Corydalis cava (Papaveraceae) alkaloids ((+)-thalictricavine and (+)-canadine)
Coumarin derivatives
coumarin derivatives
Coumarin derivatives (3-(4-aminophenyl)-coumarin derivatives, Coumarin-3-carboxamide-N-morpholine Hybrids: N-[3-(morpholin-4-yl)propyl]-2-oxo-2 H-chromene-3-carboxamide, 6-bromo-N-[2-(morpholin-4-yl)ethyl]-2-oxo-2 H-chromene-3-carboxamide; 3-Aryl Coumarin derivatives: 3-(3,4-Dichlorophenyl)-7-[4-(diethylamino)butoxy]-2 H-chromen-2-one
coumarin hybrids
Coumarin linked thiourea derivatives.
Coumarin-3-carboxamides bearing N-benzylpiperidine moiety
Coumarin-3-carboxamides bearing tryptamine moiety
coumarin-benzofuran hybrids
coumarin-chalcone hybrids
Coumarin-dithiocarbamate hybrids
coumarin-dithiocarbamate hybrids
Coumarin-piperazine derivatives
Coumarins from Zosima absinthifolia Link (Apiaceae family)(coumarin-bergapten, imperatorin, pimpinellin, umbelliferone)
Coumarinyl Thiazoles and Oxadiazoles
Coumestrol and Puerarol from Pueraria lobate
Cubebin (dibenzylbutyrolactone lignan from Piper cubeba)
Cyclopentaquinoline Analogues (6-chloro-N-[2-(2,3-dihydro-1 H-cyclopenta[b]quinolin-9-ylamino)-hexyl]]-nicotinamide hydrochloride)
cyclopentaquinoline hybrids
Dehydroabietylamine derivatives
Deoxyvasicinone-Donepezil Hybrids
Dialkyl-3-cyanopropylphosphate derivatives
Diaryl pyrazoline derivatives
Dichocarpum auriculatum (Franch.) W.T. Wang & P. K. Hsiao derivatives (columbamine, palmatine, dauricine, jatrorrhizine, berberine)
Difluoropyrido[4,3-b]indoles
Dihydroactinidiolide
dihydroberberine (Coptis chinensis)
Dihydroquinoline Carbamate derivatives
dihydroxanthyletin-type coumarins from Angelica decursiva (decursidin)
Dimethyl sulfoxide (DMSO)
Dimethyl sulfoxide (DMSO)
Diphenyl Substituted Pyridazinone Derivatives (diphenyl-2-(2-(4-substitutedpiperazin-1-yl)ethyl)pyridazin- 3(2 H)-one derivatives)
Dipropargyl substituted diphenylpyrimidines
dispiropyrrolodinyl-oxindole based alkaloids
DL0410
Donepezil analogues
Donepezil-butylated hydroxytoluene (BHT) hybrids
Donepezil-chromone-melatonin hybrids
Donepezil-flavonoid hybrids with sigma-1 affinity (N-(2-(1-Benzylpiperidin-4-yl)ethyl)-6,7-dimethoxy-4-oxo-4 H-chromene-2-carboxamide)
Donepezil-Ginkgo Ketoester
Donepezil-hydrazinonicotinamide hybrids
Donepezil-like 1,4-Dihydropyridines
Donepezil-related benzylpiperidine/benzylpiperazine derivatives (benzimidazole or benzofuran)
EGb761 constituents
Elatostema papillosum leaves
Ellagic acid
Embelin (3-undecyl-1,4-benzoquinone from Embelia ribes)
Erucamide from Radish leaf (Raphanus sativus L.) extracts
Ester Derivatives of Cinnamic Acid (p-coumaric acid 3,4-dihydroxyphenethyl ester, p-coumaric acid phenethyl ester)
Ethyl 5-amino-4-(2-chloroquinolin-3-yl)-2-methyl-6,7,8,9-tetrahydro-4 H-pyrano[2,3-b]quinoline-3-carboxylate
Ethyl Acetate Extract of Terminalia chebula (N-(N-benzyloxycarbonyl-beta-l-aspartyl)-beta-d-glucosaminide)
Ethynylphenyl carbonates and carbamates
Fascaplysin
Fasudil hydrochloride
Ferulic acid derivatives
Flavanone glycosides (naringenin, didymin, prunin, poncirin)
flavones, chromen-4-ones and C-glucosyl derivatives (p-morpholinyl flavones, C-glucosylflavones)
Flavonoid compounds (Galangin, N,N-dibenzyl(N-methyl)amine hybrids)
flavonoid derivatives
Flavonoids
Flavonoids (myricetin, morin, rutin, quercetin, fisetin, kaempferol, apigenin, glycitein)
flavonoids from Atalantia monophylla (L.) DC (atalantraflavone, atalantoflavone, racemoflavone, 5,4’-dihydroxy-(3″,4″-dihydro-3″,4″-dihydroxy)-2″,2″-dimethylpyrano-(5″,6″:7,8)-flavone, lupalbigenin, anabellamide, citrusinine I, p-hydroxybenzaldehyde, frideline)
Flavonols and 4-thioflavonols
Flurbiprofen-chalcone hybrid Mannich base derivatives
Forsythiaside
Fused Thiazolo[3,2-a]Pyrimidines
Galantamine derivatives
Galanthamine-Peptide Derivatives
Gelidiella acerosa
genipin derivatives
genistein-O-alkylamine derivatives
ginger (Zingiber officinale) extract ((E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hept-4-en-3-on, 1-(3,4-dihydroxy-5-methoxyphenyl)-7-(4-hydroxy-3- ethoxyphenyl) heptane-3,5-diyl diacetate)
ginger root (Zingiber officinale Roscoe) extract
Ginkgo biloba extract, EGb 761®.
ginseng stem-leaf saponins
Glycosides from Cassia obtusifolia (rubrofusarin, rubrofusarin 6-O-β-d-glucopyranoside, rubrofusarin 6-O-β-d-gentiobioside, nor-rubrofusarin 6-O-β-d-glucoside, isorubrofusarin 10-O-β-d-gentiobioside, rubrofusarin 6-O-β-d-triglucoside)
glycyrrhizin
Guanylhydrazones
Guazuma ulmifolia
Halogenated Thiophene Chalcones
Hancornia speciosa Gomes (Brazil mangaba tree)
Haplophyllum sahinii and H. vulcanicum Extracts
Harmaline
Harmine
hemp seed protein-derived peptides
Heracleum verticillatum, Heracleum sibiricum, Heracleum angustisectum, and Heracleum ternatum Extracts
Heterocyclic β-d-Gluco- and β-d-Galactoconjugates
Heterometallic Ruthenium(II)-Platinum(II) Polypyridyl Complexes
Hibiscus sabdariffa L. (Sorrel) Calyx
HuperTacrines
Huperzine A derivatives
Hydroethanolic extracts of Ecklonia maxima, Gelidium pristoides, Gracilaria gracilis, and Ulva lactuca
Hydroxybenzoic acid derivatives
Hydroxyoxindoles
Hydroxypyridinone-benzofuran hybrids ((3-hydroxy-4-pyridinone)-benzofuran hybrids, O-benzyl-hydroxypyridinone hybrids)
Hyperforin
Hypericum perforatum L. prenylated β-diketones (2,6,9-trimethyl-8-decene-3,5-dione, 3,7,10-trimethyl-9-undecene-4,6-dione)
Hypsiboas cordobae and Pseudis minuta (Anura: Hylidae)
Hyuganin C
Imidazo pyranotacrines
imidazole analogues (2-Substituted-4,5-diphenyl-1 H-imidazole)
Indazolylketones
indole-3-acetic acid (IAA)-tacrine hybrids
indoloquinoline alkaloid cryptolepine
Indolotacrine analogs
iridoid glucosides from Anarrhinum pubescens (6-O-, 6’-O-di-trans-cinnamoyl-antirrhinoside, 5-O-, 6-O-difoliamenthoyl-antirrhinoside, 6-O-foliamenthoyl-(6’-O-cinnamoyl)-antirrhinoside)
Irvingia gabonensis (Aubry-Lecomte ex O’Rorke) Baill bark
Isoalloxazine derivatives
isoflavone analogs
Isoindoline-1,3-dione derivatives
Isotalatizidine hydrate
Isothio- and isoselenochromanone derivatives bearing N-benzyl pyridinium moiety
Isothiocyanates
Kampo products (kihito (Gui-Pi-Tang), kamikihito (Jia-Wei-Gui-Pi-Tang))
KojoTacrines (11-amino-2-(hydroxymethyl)-12-(3-methoxyphenyl)-7,9,10,12-tetrahydropyrano [2’,3’:5,6] pyrano[2,3-b]quinolin-4(8 H)-one)
Lactucopicrin
Ligustrazine Derivatives
Limonium brasiliense
Linarin (flavonoid glycoside in Flos chrysanthemi indici)
L-tetrahydropalmatine
macelignan (Myristica fragrans)
marine-derived Streptomyces sp. UTMC 1334
Matrine
MCULE-5872671137-0-1
Memantine-6-Chlorotacrine
metal chelator
Metformin-sulfonamide derivative
methanesulfonate derivatives
Methanosarcina species-derived Phenazines
methyl(4-phenylbutyl){2-[2-(4-propylpiperazin-1-yl)-1,3-thiazol-5-yl]ethyl}amine
Millettia pachycarpa Benth flavonoids
MLC901 (Neuroaid II)
Mono- and bis-spirooxindole-hexahydropyrrolidines
Mono- and bis-spiro-pyrrolidines
Mulberry Diels-Alder-type adducts from Morus alba (mulberrofuran C, mulberrofuran K, mulberrofuran G, isomulberrofuran G)
Multitarget Tacrine derivatives
N-((1-(2-Chlorobenzyl)-1 H-1,2,3-triazol-5-yl)methyl)-8-methoxy-2-oxo-2 H-chromene-3-carboxamide
N-(4-methoxyphenethyl)-N-(substituted)-4-methylbenzenesulfonamides
N-(alkyl/aralkyl)-N-(2,3-dihydro-1,4-benzodioxan-6-yl)-4-chlorobenzenesulfonamides (N-(2,3-dihydro-1,4-benzodioxan-6-yl)-4-chlorobenzenesulfonamide, N-2-phenethyl-N-(2,3-dihydro-1,4-benzodioxin-6-yl)-4-chlorobenzenesulfonamide, N-(1-butyl)-N-(2,3-dihydro-1,4-benzodioxin-6-yl)-4-chlorobenzenesulfonamide)
N-{2-[4-(1 H-Benzimidazole-2-yl)phenoxy]ethyl}substituted amine derivatives
N1-Substituted derivatives of 2,3-dihydroquinazolin-4(1 H)-one
N-allyl/propargyl tetrahydroquinolines
nanodandelion tin(IV) complex-carbacylamidophosphate (Sn(CH3)2Cl2}NC5H4C(O)NHP(O)[NHC6H11]2}2)
Narcimatuline
Narcissus poeticus cv. Pink Parasol
N-Benzyl pyridinium
N-Benzylpiperidine analogs
N-benzylpiperidine carboxamide derivatives
N-Benzylpiperidine derivatives
N-benzyl-piperidinyl-aryl-acylhydrazone derivatives
N-benzylpyridinium-based benzoheterocycles
Neonicotinoids
nepitrin from Rosmarinus officinalis
N-phenylcarbamates
N-Phenylthiazol-2-Amine derivatives
N-Phosphorylated/N-Tiophosphorylated Tacrine
N-Substituted Aryl Sulfonamides
N-substituted pyrazole derived α-aminophosphonates
N-substituted rhodanines
o/p-propoxyphenylsubstituted-1 H-benzimidazole derivatives
Ochna obtusata
Octohydroaminoacridine
Oenothera biennis L.
Olaparib analogues
Olive Biophenolsfrom (Olea europaea L.)(rutin, verbascoside)
onion flavonols
Onobrychis argyrea subsp isaurica extracts
Organoselenium compounds from purines (6-arylselanylpurines, 6-((4-fluorophenyl)selanyl)-9 H-purine)
Origanum onites extracts
Ovalbumin-derived peptides
oxazolidinone
Oxoisoaporphine-tetrahydroisoquinoline hybrids
oxopyrrolidine derivatives (ethyl 2-(2-(2, 6-dimethylphenylcarbamoyl)- 5-oxopyrrolidin-1-yl) acetate, 1-((4-(4-chlorophenyl) piperazin-1-yl) methyl)-N-(2,6-dimethylphenyl)-5- oxopyrrolidine- 2-carboxamide)
p-aminobenzoic acid derivatives
Panax ginseng drivatives
Papaver somniferum
Papaverine
Paullinia cupana
Pavetta indica
PC-37 and PC-48 (7-Methoxytacrine-Donepezil-Like Compounds)
Peganum harmala Linn ingredients (Deoxyvasicine)
Pharbitis nil Chosy
Phenanthroline-Tetrahydroquinolines
phenolic extracts from Irvingia gabonensis (Aubry-Lecomte ex O’Rorke) Baill bark.
Phlorotannins from Ecklonia cava-An (eckol, dieckol, 8,8’-bieckol)
Phosphazine and Phosphazide derivatives
phthalimide-alkylamine derivatives
Phthalimide-derived N-Benzylpyridinium Halides
Phthalimide-Dithiocarbamate Hybrids
Physostigma venenosum Balf.
Physostigma venenosum Balf.
Pinoresinol
Piperazine derivatives (1-(1,4-Benzodioxane-2-carbonyl) piperazine, 4-(4-methyl)-benzenesulfonyl-1-(1,4-benzodioxane-2-carbonyl) piperazine, 4-(4-Chloro)-benzenesulfonyl-1-(1,4-benzodioxane-2-carbonyl) piperazine)
Piperazinediones (3,6-Diphenyl-1,4-bis(phenylsulfonyl)piperazine-2,5-dione derivatives)
Piperidine and Piperazine Derivatives
Piperidone grafted spiropyrrolidines
piperidone grafted spiropyrrolidines
Piperonyl-based 4-thiazolidinone derivatives
Pistacia khinjuk essential oil
Platanus orientalis L. extracts
Poincianella pluviosa
polycyclic polyprenylated acylphloroglucinols from Hypericum perforatum.
Polyphenol-rich Boswellia serrata gum
Polyphenols (quercetin, resveratrol, curcumin, gallocatechins, cinnamic acid, caffeine, caffeic acid)
polysaccharide extracts from the fungi Coprinus comatus and Coprinellus truncorum
Prangos ferulacea extracts
Propargylamine-derived compounds
propargylamine-modified 4-aminoalkyl imidazole substituted pyrimidinylthiourea derivatives
propargylamine-modified pyrimidinylthiourea derivatives
Prunella vulgaris var. lilacina NAKAI
Pterosin derivatives from Pteridium aquilinum ((2 R)-Pterosin B, (2 R,3 R)-Pteroside C)
pterostilbene β-amino alcohol derivatives
pulmonarin B
Pyndazinone derivatives (6-substituted-3(2 H)-pyridazinone-2-acetyl-2-(nonsubstituted/4-substituted benzenesulfonohydrazide) derivatives)
Pyranopyrazolotacrines
Pyranotacrines (Benzo)Chromeno-PyranoTacrines (11-amino-12-(3,4,5-trimethoxyphenyl)-7,9,10,12-tetrahydro-8 H-chromeno[2,3- b]quinolin-3-ol, 14-(3,4-dimethoxyphenyl)-9,11,12,14-tetrahydro-10 H-benzo[5,6] chromeno [2,3-b] quinolin-13-amine)
pyrazole and spiropyrazoline analogs
pyrazoline derivatives (1-aroyl-3-(5-(4-chlorophenyl)-1,2,4-triazole-3-thioneaminylthioureas, 4-amino-5-(4-chlorophenyl)-4 H-1,2,4-triazole-3-thiol, 1-(3-(4-aminophenyl)-5-phenyl-4,5-dihydro-1 H-pyrazol-1-yl)-2-(4-isobutylphenyl)propan-1-one, 2-(4-isobutylphenyl)propanehydrazide)
pyrazolo[1,5-c][1,3]benzoxazin-5(5 H)-one derivatives
pyridine amine derivative
pyridinium/isoquinolium derivatives
Pyrido[2,3-b]pyrazine derivatives
PyridoTacrines
Pyrrolizine-based compounds
Quercetin-Metal Complexes
Quinoline-chalcone derivatives
Quinoline-ferulic acid hybrids
Quinoline-Piperonal Hybrids
Quinolinone-dithiocarbamate derivatives
Quinolone-benzylpiperidine derivatives
quinolone-triazole hybrids
Quinoxaline derivatives
QuinoxalineTacrine QT78
Racemic chromenotacrines (11-Amino-12-aryl-8,9,10,12-tetrahydro-7 H-chromeno[2,3-b]quinolin-3-ols)
Rivastigmine drivatives
Rutacecarpine derivatives
Rutin
Rutin from Dianthus calocephalus Boiss
S 47445 (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)
Safflower (Carthamus tinctorius L.) Seed Oil Cake ((±)-carthatins A-F, sinapyl alcohol, coniferyl alcohol, serotobenine, feruloylserotonin)
Sailuotong
salicylamide derivatives
Salvia miltiorrhiza components (miltirone, salvianolic acid A)
sargachromanol I and G (Sargassum siliquastrum)
Saururus chinensis (Lour.) Baill.
Schisandra chinensis (Chinese magnolia vine)(dibenzocyclooctadiene lignans, 6-O-benzoylgomisin, deoxyschisandrin, gomisin A, gomisin G, schisandrin, schisandrin C, schisanhenol, schisantherin A and schisantherin B)
Scrophularia lucida L. derivatives (rosmarinic acid, hesperidin)
Semicarbazones ((E)-2-(5,7-Dibromo-3,3-dimethyl-3,4-dihydroacridin-1(2 H)-ylidene)hydrazinecarbothiomide, (E)-2-(5,7-Dibromo-3,3-dimethyl-3,4-dhihydroacridin-1(2 H)-ylidene)hydrazinecarboxamide)
semisynthetic O-alkylcoumarin derivatives
Sideritis albiflora and Sideritis leptoclada extracts
Silymarin
Spirocyclohexadienones
Spiro-dioxolane-containing meroterpenoids from Aspergillus terreus Thom
Spiropyrrolidine/spiroindolizino[6,7-b]indole heterocyclic hybrids
Streblus asper leaf ethanolic extract
Stryphnodendron adstringens
Substituted 4-methyl-2-oxo-2 H-chromen-7-yl phenyl carbamates
Substituted Aminobenzothiazole Derivatives of Tacrine
substituted chromones (3-cyanochromone, 7-amino-3- methylchromone)
sulfamate derivatives of mentol
Synthetic Chalcones
Tacrine derivatives
Tacrine (10)-hupyridone
Tacrine-(β-carboline) hybrids
Tacrine, phenolic acid and ligustrazine hybrids
Tacrine/acridine anticholinesterase inhibitors with piperazine and thiourea linkers
tacrine-1,2,3-triazole derivatives
Tacrine-1,2,4,-thiadiazole derivatives
tacrine-4-oxo-4 H-Chromene hybrids
tacrine-acridine hybrids
Tacrine-based pyrano[2,3-c]pyrazoles
Tacrine-Based Pyrano[3’,4’:5,6]pyrano[2,3-b]quinolinones
Tacrine-Benzimidazole-based human cannabinoid receptor subtype 2 agonist
Tacrine-Benzofuran hybrids
Tacrine-benzofuran hybrids
tacrine-benzyl quinolone carboxylic acid hybrids
tacrine-bifendate conjugates
tacrine-cinnamic acid hybrids
Tacrine-coumarin and Tacrine-7-chloroquinoline Hybrids with Thiourea Linkers
Tacrine-coumarin hybrids
tacrine-coumarin hybrids linked to 1,2,3-triazole
Tacrine-deferiprone hybrids
tacrine-ferulic acid hybrids
Tacrine-Hydroxyphenylbenzimidazole hybrids
Tacrine-multialkoxybenzene hybrids
Tacrine-Phenylbenzothiazole
Tacrine-propargylamine derivatives
Tacrine-pyranopyrazole derivatives
tacrine-pyrazolo[3,4-b]pyridine hybrids
Tacrine-Scutellarin hybrids
Tacrine-Squaramide Derivatives
Tacrine-tianeptine hybrids
Tacrine-Trolox hybrids
tacrine-tryptophan hybrids (S-K1035)
tacrine-valmerin hybrids
Tacripyrimidines (tacrine-dihydropyrimidine hybrids) (5-amino-4-aryl-3,4,6,7,8,9-hexahydropyrimido [4,5-b]quinoline-2(1 H)-thiones)
Tacripyrines (4’-metoxytacripyrine (S)-ITH122)
Tadalafil Derivatives
Tannic acid
tanshinones and salvianolic acids from Salvia miltiorrhiza
Tea polyphenols
Termitomyces albuminosus Sesquiterpenoids
Terpenes and Phenylpropanoids (methyl jasmonate; 1 R-(-)-nopol; 1,4-cineole; allo-aromadendrene; nerolidol; β-ionone; and (R)-(+)-pulegone)
Terpenoids from I. wightii (Bentham) H. Hara
Tetraclinis articulata essential oil
tetrahydroacridine derivatives (tiocyanates, selenocyanates, ureas, selenoureas, thioureas, isothioureas, disulfides, diselenides and several tacrine homo- and hetro-hybrids)
Tetrahydroacridine derivatives with dichloronicotinic acid
tetrahydrocarbazole benzyl pyridine hybrids
Tetrahydrochromeno [3’,4’:5,6]pyrano[2,3-b]quinolin-6(7 H)-one derivatives
Tetrahydrocurcuminoid dihydropyrimidinone analogs
Tetrahydropyranodiquinolin-8-amines
Tetrahydroquinoline-Isoxazole/Isoxazoline Hybrid Compounds
Tetraphenylporphinesulfonate (TPPS)
tetrasubstituted thiazoles
Tetrazole-1,2,5,6-tetrahydronicotinonitriles
Thiazole acetamide derivatives
Thiazole-substituted benzoylpiperazine derivatives
Thiazolylhydrazone Derivatives
thymohydroquinone
trachyloban-19-oic acid from Syncephalastrum racemosum
trans-tephrostachin from Tephrosia purpurea (L.) Pers.
Trianthema portulacastrum phenols
Triazole derivatives
Triazole-Quinoline derivatives
Triazolothiadiazole and triazolothiadiazine
Trichilia catigua
tris-chalcones
tris-chalcones
uracil derivatives
Ursolic and oleanolic acid derivatives
Usnic acid (active dibenzofuran derivative)
vasicine enantiomers
VB-037
vilazodone-tacrine hybrids
Vitis vinifera L. flavones
Withania somnifera L. Dunal.
Xanthene derivatives (Spiro[indoline3,9-xanthene]-trione, Hydroxy-spiro[indoline-3,9-xanthene]-trione)
xanthohumol, naringenin, and acyl phloroglucinol derivatives from Humulus lupulus L.
Yinhuang Oral Liquid
ZT-1, a prodrug of Huperzine A
α- and β-asarone
α-pinene
β-amino di-Carbonyl Derivatives
β-Crinane Amaryllidaceae Alkaloid Haemanthamine derivatives (11-O-(2-methylbenzoyl)-haemanthamine, 11-O-(4-nitrobenzoyl)-haemanthamine)
δ-3-carene
δ-sultone-fused pyrazoles
Selective Butyrylcholinesterase inhibitors
(3-(4-phenyl-piperazin-1-ylmethyl)-phenyl phenylcarbamate
[3-(2/3/4-methoxyphenyl)-6-oxopyridazin-1(6 H)-yl]methyl carbamate derivatives ([3-(2-methoxyphenyl)-6-oxopyridazin-1(6 H)-yl]methyl heptylcarbamate)
[3-(2-methoxyphenyl)-6-oxopyridazin-1(6 H)-yl]methyl (4-methylphenyl)carbamate Heterocyclic β-d-Gluco- and β-d-Galactoconjugates
1,2,3,4,5,6-hexahydroazepino[4,3-b]indole
2-pheynlbenzofuran derivatives
2-vinyl chromones
aryl-1,2,3-triazolyl benzylpiperidine inhibitors
benzamide derivatives
benzofuran appended benzothiazepine derivatives
Carbazole-based BChEIs (Carbazol-9-yl)methyl)-1-(4-chlorobenzyl)pyridin-1-ium chloride)
coumarin/1,2,4-oxadiazole hybrids
ferulic and dihydrocaffeic acids
N-phthaloylglycine
tricyclic pyrazolo[1,5-c][1,3]benzoxazin-5(5 H)-one
Tricyclic pyrazolo[1,5-d][1,4]benzoxazepin-5(6 H)-one scaffold derivatives
Tryptophan-derived inhibitors

Within the group of cholinergic drugs, acetylcholinesterase inhibitors (AChEIs) represent 76% of the total (many of them derivatives of donepezil>tacrine>rivastigmine>galantamine) (Table 1), butyrylcholinesterase inhibitors (BuChEIs) 3.75%, dual inhibitors of AChE and BuChE 3%, dual inhibitors of AChE and monoamine oxidase (MAO) 2.75%, muscarinic receptor agonists 6%, and nicotinic receptor agonists 8%. Other subcategories of pharmaceutical products include dopaminergic (DA D₁, D_2/3, and D₅ receptor agonists; MAO-A (MAOAIs) and MAO-B inhibitors (MAOBIs); serotonergic (5-HT_2A, 5-HT₄ and 5-HT₇ receptor agonists; 5-HT₃ and 5-HT₆ receptor antagonists); glutamatergic (NMDA receptor antagonists related to memantine, NMDA inhibitors, metabotropic glutamate receptor modulators, AMPA receptor modulators, glutamate modulators, glycine transporter 1 (GlyT1) inhibitors and vesicular glutamate transporter inhibitors); GABAergic (allosteric modulators of GABA_A receptors, GABA_A and GABA_B receptor agonists); histaminergic (HA H₃ receptor antagonists, other antihistaminics); and adrenergic drugs (β₁ adrenergic receptor (ADRB1) agonists, α2 adrenergic receptor agonists (α2ARA) and selective α_2C adrenoceptor antagonists) [15]. In addition, over 150 multi-target drugs, belonging to different pharmacological categories, have been screened in search for anti-dementia properties [15] (Table 2). Most multi-target drugs are dual AChEIs and BuChEIs with anti-amyloidogenic activity (Table 2). Some of these novel drugs are complex derivatives of classical AChEIs and others belong to the category of bioproducts derived from natural sources. However, many other classes of multi-target drugs, with diverse activity, have been reported, such as dual GSK3β inhibitors and Nrf2 inducers (2,4-Dihydropyrano[2,3-c]pyrazoles; drugs with anti-amyloidogenic and anti-inflammatory properties (CNI-1493); novel dual inhibitors of MAO-A, MAO-B and amyloid-β aggregation (Coumarin-pargyline hybrids); dual-acting AChEI and H3R antagonists (7-(3-(piperidin-1-yl)propoxy)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1 H)-one)(UW-MD-72); multifunctional iminochromene-2 H-carboxamide derivatives containing aminomethylene triazole with BACE1 inhibitory, neuroprotective and metal chelating properties; multifunctional thioxanthone derivatives with AChE, MAOs and β-amyloid aggregation inhibitory activities; multi-target-directed oxoisoaporphine derivatives with anti-AChE, anti-β-amyloid aggregation and enhanced autophagy activity; and many others (Table 2).

Table 2. Selected multi-target drugs in development for the treatment of Alzheimer’s disease

(-)-Meptazinol carbamates
1,5-Diarylimidazoles
1-Methyl-4-propan-2-ylbenzene
1-Phenyl-3-hydroxy-4-pyridinone derivatives
2,4-Dihydropyrano[2,3-c]pyrazoles
2-[4-(4-substitutedpiperazin-1-yl)phenyl]benzimidazole derivatives
2-Arylethenyl-N-methylquinolinium derivatives
4’-Aminochalcone-rivastigmine hybrids
5-Methoxyisatin 3-(4-isopropylphenyl)hydrazone
7-Methoxytacrine-adamantylamine heterodimers
9-Amino-1,2,3,4-tetrahydroacridine derivatives with 2-fluorobenzoic acid or 3-fluorobenzoic acid moiety
ARN14140, a Memantine/Galantamine-Based Multi-Target Compound
Aurone Mannich base derivatives
Benzazepine derivatives, with the core structure of 3-methyltetrahydro-3 H-benzazepin-2-one
Chromen-4-one based compounds
Chromone derivatives
Cinnamamide-dibenzylamine hybrids
CNI-1493
Coumarin-pargyline hybrids
Dihydropyrimidinone (DHPM)-derived selenoesters
Donepezil based multi-functional agents: (E)-5,6-dimethoxy-2-(4-(4-substituted piperazin-1-yl)benzylidene)-2,3-dihydro-1 H-inden-1-ones
7-(3-(piperidin-1-yl)propoxy)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1 H)-one (UW-MD-72)
Ferulic acid-O-alkylamine derivatives
Feruloyl-donepezil hybrids
Fused Donepezil-Curcumin derivatives
Hesperetin derivatives
Heterodimeric isoindoline-1,3-dione derivatives
Icos-huprine hybrids
Isoflavone derivatives
Kinesin MKLP-2 inhibitors
Meserine
Multifunctional iminochromene-2 H-carboxamide derivatives
Multifunctional thioxanthone derivatives
Multitarget compound ASS234
Multitarget-directed oxoisoaporphine derivatives
N-(2-((4,6-di(1,4,7,10-tetraazacyclododecan-1-yl)-1,3,5-triazin-2-yl)amino)ethyl)-2-oxo-2 H-chromene-3-carboxamide
New Ferulic (Lipoic) acid plus Melatonin-modified Tacrines
New phthalimide and saccharin derivatives: (26, [2-(2-(4-benzylpiperazin-1-yl)ethyl)benzo[d]isothiazol-3(2 H)-one 1,1-dioxide]; 52, 2-(2-(3-(3,5-difluorobenzylamino)piperidin-1-yl)ethyl)isoindoline-1,3-dione)
N-Propargylpiperidines with naphthalene-2-carboxamide or naphthalene-2-sulfonamide moieties
Phenothiazine derivatives: toluidine blue O (TBO) and thionine (TH)
Pyrimidinylthiourea derivatives
Quinazolinone-based hydrazones
Racemic benzochromenopyrimidinetriones: 13-aryl-2,3,4,13-tetrahydro-1 H,12 H-benzo[6,7]chromeno[2,3-d]pyrido[1,2-a]pyrimidine-7,12,14-triones; 15-aryl-8,9,10,11,12,15-hexahydro-14 H-benzo[6’,7’]chromeno[2’,3:4,5] pyr-imido [1,2-a]azepine-5,14,16-triones; 13-phenyl-2,3,4,13-tetrahydro-1 H,12 H-benzo[6,7]chromeno[2,3-d]pyrido[1,2-a]pyrimidine-7,12,14-trione
Ranitidine analogs
Rivastigmine-hydroxycinnamic acid hybrids
Scutellarein-O-acetamidoalkylbenzylamines
Tacrine-(hydroxybenzoyl-pyridone) hybrids
Tacrine-(β-Carboline) hybrids
Tacrine-Ferulic Acid Hybrids
Tacrine-Resveratrol fused hybrids
Tacrine-Scutellarin Hybrids
Triazine-triazolopyrimidine hybrids
Xanthone derivatives
β-Carbolines

After AChEIs, the most intensively developed anti-dementia products were anti-Aβ agents (>20% of the total), including immunotherapy (>80 new products)(40% of anti-Aβ agents), β-secretase (BACE) inhibitors (>60 new products), ϒ-secretase modulators (≈40 products), and diverse Aβ aggregation inhibitors (>220 new products), together with APP modulators, Aβ scavengers, β-sheet breakers, δ-secretase inhibitors, α-secretase modulators, and Notch inhibitors [15,16].

Other drugs and/or therapeutic strategies in development, with minor quantitative impact so far, include anti-tau agents (with a 50% increase over the past 10 years), APOE modulators, anti-inflammatory drugs, polyunsaturated fatty acids, neurotrophic factors, neuroprotective peptides, nootropic-like cognitive enhancers, epigenetic drugs, gene therapy, stem cell therapy, nanotherapeutics, and some different combination drug regimes, the most frequent of which are donepezil + memantine or AChEIs in combination with other neuroprotectants [7–11,15,17–19].

Strikingly, natural products and derivatives with pleiotropic activity plus novel drugs for new targets represented >40% of contributions to drug development in AD for the past decade. Only in the 2013–2017 interval, over 1,500 new natural products and 500 novel drugs were discovered and characterized [15].

Of the 121 drugs studied in 2020 for the treatment of AD, 22% were in phase-I trials, 54% in phase-II trials and 24% in phase-III trials. About 10% of these drugs were cognitive enhancers, another 10% were tested to treat neuropsychiatric symptoms of dementia, and 80% were medications aimed at slowing-down the course of the disease [20].

The only winner of this intense race to identify a useful drug for the treatment of AD was Aducanumab, formally approved by the FDA on 7 June 2021 as the first drug with a putative disease-modifying mechanism for AD, although not devoid of controversy in the scientific community [21–27]. Aducanumab is a human monoclonal antibody with selective activity on aggregated Aβ. Aducanumab penetrates into the brain, binds parenchymal Aβ, and dose-dependently reduces soluble and insoluble Aβ. One year of monthly intravenous infusions of aducanumab in patients with incipient cognitive disorder or mild-AD reduces brain Aβ in a time- and dose-dependent manner, with parallel slowing of cognitive decline [22–25].

Aducanumab and other injectable antibodies (gantenerumab, BAN2401), and a small molecule oral agent, ALZ-801, are amyloid-targeting drugs with variable efficacy and safety, and differential effects in terms of brain penetration, time-to-peak brain exposure, plasma half-life, and selectivity for Aβ oligomers. Recent studies show that the degree of selectivity for Aβ oligomers and brain exposure drive the magnitude and onset of clinical efficacy; in contrast, the clearance of plaques with the highest doses of aducanumab and BAN2401 induces vasogenic brain edema, especially in APOE4 carriers [26,27]. ALZ-801, an optimized oral prodrug of tramiprosate with selective anti-oligomer activity shows efficacy in homozygous APOE4/4 AD subjects, without evidence of vasogenic edema [26].

4. Expert opinion

Although from a theoretical perspective and 100 years of history, AD appears to be pathogenically defined, the accumulation of multiple genetic defects in AD patients suggest that the current pathogenic conception of AD does not fully explain its more intimate pathogenic mechanisms. This would partly explain the therapeutic failure derived from concentrating all pharmacological research efforts on the cholinergic hypothesis in the years 1980–2000 and the amyloidogenic-tauopathic hypothesis from 2000 to the present, using biased animal models with results which could not be replicated in humans [28]. There are still many pathogenic unknowns to be clarified. More than fifty genes encoding transporter proteins are altered in a certain number of patients with AD. The role of glia in the process of premature neuronal death remains an enigma. Recent studies indicate that astrocytes actively kill neurons in neurodegenerative disorders. APOE- and APOJ-contained saturated lipids may mediate astrocyte-induced neurotoxicity and these effects can be neutralized by eliminating the formation of long-chain saturated lipids in astrocytes through inhibition of the elongation of very long chain fatty acids-like 1 enzyme encoded by the ELOVL1 gene (1p34.2) [29].

We still need to dig much deeper into the molecular mechanisms that induce premature neuronal death when the brain stops maturing and neurodegenerative mechanisms are activated decades before the onset of dementia symptoms. We also need presymptomatic biomarkers that allow us to identify the risk to intervene in asymptomatic periods of the disease.

Even before we find a preventive treatment for AD, we cannot forget that in over 90% of cases of dementia, multifactorial treatment is needed, which involves the simultaneous administration of several pharmaceutical categories (>10 drugs/day) with the consequent risk of adverse drug reactions (ADRs) and drug-drug interactions (DDIs) [11,14,19]. According to the phenotypic profile of patients with mild-to-moderate dementia, the most frequent concomitant diseases are the following: behavioral disorders (95%), functional decline (90%), cerebrovascular disorder (90%), obesity (70%), depression (65%), anxiety (60%), cardiovascular disease (40%), hypercholesterolemia (40%), hypertension (28%), diabetes (26%), hypertriglyceridemia (20%), metabolic syndrome (20%), hyperbilirubinemia (15%), metabolic deficits (15%), transaminitis (11%), cancer (10%), anemia (7%), and endocrine disorders (5%). Cardiovascular disorders and blood pressure changes in AD are currently reported in association with increased risk of brain damage and increased cognitive deterioration. Furthermore, APOE variants are associated with AD, cardiovascular disorders, atherosclerosis, and cerebrovascular damage in dementia [7,8,17]. Lipid metabolism disorder and the cerebrovascular component of AD have been extensively studied, and alterations in cholesterol, changes in cell membrane lipids and arteriosclerosis lead to ischemia and cerebral hypoperfusion that contributes to accelerating the premature death of neurons in patients with predisposition to AD [8].

The only manner to reduce ADRs and DDIs in AD patients treated with antidementia agents plus drugs for the management of concomitant diseases, is the incorporation of pharmacogenetics into the daily clinic to personalize pharmacological treatments [30].

The pharmacoepigenetic machinery responsible for the safety and efficacy of any type of drug is composed of a set of at least 400 genes that encode proteins, enzymes and receptors related to the target that each drug has to reach and the process of deactivation and elimination of metabolites and residual products. More than 90% of the drugs act as substrates, inducers or inhibitors of the products of these pharmagenes. The expression or repression of these genes is under the strict control of the epigenetic apparatus, which acts promiscuously and redundantly for safety reasons, and whose functional failure can lead to pharmacological ineffectiveness and/or the appearance of ADRs [31,32].

From a didactic point of view, there are at least five categories of genes related to the genomic device that modulates the pharmacogenetic complex: pathogenic genes associated with AD (Figure 1); the mechanistic genes that encode components of the biochemical pathways that explain the mechanism of action of each drug; metabolic genes encoding phase-I and II enzymes responsible for hepatic and tissue metabolism, as well as the elimination of drugs; genes encoding xenobiotic agent transport proteins that facilitate the flux and efflux of drugs in the brain, allowing their access to the target or preventing their penetration through the blood-brain barrier; and hundreds of pleiotropic genes that participate in a multitude of metabolomic pathways since a xenobiotic agent penetrates an organism, circulates in blood, reaches the target and disintegrates in the form of metabolites that have to be processed in the tissues and liver prior to their subsequent elimination by urine, feces, bile or sweat [30,31] (Figure 3).

Figure 3. Frequency and accumulation of defective pharmagene variants in patients with Alzheimer’s disease.

There is an accumulation of defective pharmagenes in approximately 85% of AD patients. Of a cluster of 60 genes potentially involved in the pharmacogenetics of common drugs in AD, the most dysfunctional genes frequently found (>20%) in AD are the following: CYP1A1 (31.47%), CYP1B1 (82.23%), MAOB (47.72%), CES1 (96.45%), CHAT (36.04%), COMT (30.96%), GSTM1 (54.82%), GSTT1 (25.38%), NAT2 (43.65%), SOD2 (67.51%), ABCB1 (44.16%), ABCG2 (90.36%), FABP2 (90.86%), SLCA2 (59.90%), SLC22A1 (34.52%), SLC30A8 (48.22%), ADRB2 (41.62%), AGT (42.13%), APOE (30.96%), CHRNA7 (42.13%), DRD2 (45.18%), GABRA1 (55.33%), HMGCR (73.60%), HTR1A (65.48%), HTR2C (79.19%), OPRM1 (69.54%), PPARG (81.73%), PRKCE (41.62%), and VKORC1 (65.99%).ABCB1: ATP binding cassette subfamily B member 1; ABCC2: ATP binding cassette subfamily C member 2; ABCG2: ATP binding cassette subfamily G member 2 (Junior blood group); ADRA2A: adrenoceptor alpha 2A; ADRB2: adrenoceptor beta 2; ADRB3: adrenoceptor beta 3; AGT: angiotensinogen; APOE: apolipoprotein E; BCHE: butyrylcholinesterase; CES1: carboxylesterase 1; CHAT: choline O-acetyltransferase; CHRNA7: cholinergic receptor nicotinic alpha 7 subunit; COMT: catechol O-methyltransferase; CYP1A1: cytochrome P450 family 1 subfamily A member 1; CYP1A2: cytochrome P450 family 1 subfamily A member 1; CYP1B1: cytochrome P450 family 1 subfamily B member 1; CYP2A6: cytochrome P450 family 2 subfamily A member 6; CYP2B6: cytochrome P450 family 2 subfamily B member 6; CYP2C19: cytochrome P450 family 2 subfamily C member 19; CYP2C9: cytochrome P450 family 2 subfamily C member 9; CYP2D6: cytochrome P450 family 2 subfamily D member 6; CYP2E1: cytochrome P450 family 2 subfamily E member 1; CYP3A4: cytochrome P450 family 3 subfamily A member 4; CYP3A5: cytochrome P450 family 3 subfamily A member 5; CYP4F2: cytochrome P450 family 4 subfamily F member 2; DPYD:dihydropyrimidine dehydrogenase; DRD2: dopamine receptor D2; FABP2: fatty acid binding protein 2; G6PD: glucose-6-phosphate dehydrogenase; GABRA1: gamma-aminobutyric acid type A receptor alpha1 subunit; GSTM1: glutathione S-transferase mu 1; GSTP1: glutathione S-transferase pi 1; GSTT1: glutathione S-transferase theta 1; HMGCR: 3-hydroxy-3-methylglutaryl-CoA reductase; HTR2A: 5-hydroxytryptamine receptor 2A; HTR2C: 5-hydroxytryptamine receptor 2C; IFNL3: interferon lambda 3; MAOB: monoamine oxidase B; MTHFR: methylenetetrahydrofolate reductase; NAT2: N-acetyltransferase 2;NBEA: neurobeachin; OPRM1: mu-type opioid receptor; PPARG: peroxisome proliferator activated receptor gamma; PRKCE: protein kinase C epsilon; PTGS2: prostaglandin-endoperoxide synthase 2; RYR1: ryanodine receptor 1; SLC22A1: solute carrier family 22 member 1; SLC2A2: solute carrier family 2 member 2; SLC2A9: solute carrier family 2 member 9; SLC30A8: solute carrier family 30 member 8; SLC39A8: solute carrier family 39 member 8; SLC6A2: solute carrier family 6 member 2; SLC6A3:solute carrier family 6 member 3; SLC6A4: solute carrier family 6 member 4; SLCO1B1:solute carrier organic anion transporter family member 1B1; SOD2: superoxide dismutase 2; SOD3: superoxide dismutase 3; TPMT: thiopurine S-methyltransferase; UGT1A1: UDP glucuronosyltransferase family 1 member A1; VKORC1: vitamin K epoxide reductase complex subunit 1.

Furthermore, in the general population and among AD cases only 20–30% are normal metabolizers for major enzymes of the CYP gene family [8,10,14,30].

Of a cluster of 60 genes potentially involved in the pharmacogenetics of common drugs, the most dysfunctional genes frequently found (>20%) in AD are the following: CYP1A1 (31.47%), CYP1B1 (82.23%), MAOB (47.72%), CES1 (96.45%), CHAT (36.04%), COMT (30.96%), GSTM1 (54.82%), GSTT1 (25.38%), NAT2 (43.65%), SOD2 (67.51%), ABCB1 (44.16%), ABCG2 (90.36%), FABP2 (90.86%), SLCA2 (59.90%), SLC22A1 (34.52%), SLC30A8 (48.22%), ADRB2 (41.62%), AGT (42.13%), APOE (30.96%), CHRNA7 (42.13%), DRD2 (45.18%), GABRA1 (55.33%), HMGCR (73.60%), HTR1A (65.48%), HTR2C (79.19%), OPRM1 (69.54%), PPARG (81.73%), PRKCE (41.62%), and VKORC1 (65.99%) (Figure 3). There is an accumulation of defective pharmagenes in approximately 85% of AD patients (Figure 3). AD-related pathogenic genes and pharmagenes are under the redundant and promiscuous control of the epigenetic machinery (DNA methylation/demethylation, histone/chromatin remodeling, miRNA regulation) which regulates their expression and/or repression in the brain and other tissues [31].

Whatever new drugs we develop in the future to effectively treat AD, drug development procedures should not ignore pharmacogenetics to optimize resources, time, and money. Aducanumab is a good example: potentially useful in APOE-3 carriers, but harmful in patients homozygous for the APOE-4 allele (27). In most pharmacogenetic studies, APOE-3 carriers tend to be good responders and APOE-4 carriers usually respond poorly in different studies [7–11,17–19,30].

Various regulatory hurdles and rigidity of criteria by regulatory agencies in dominant countries have contributed to hindering the development of new treatments for AD. For more than 30 years, much of the outcome measures for validating an anti-dementia drug focused on a simple improvement in cognitive and/or behavioral functions, with little reference to an anti-neurodegenerative effect, in part due to the lack of efficient biomarkers. Costly long-term clinical trials, laxity in patient selection – mainly based on neuropsychological criteria – inspecificity of the few existing biomarkers and concomitant diseases – which required additional treatments – have also been limiting factors for the development of new drugs. But perhaps the most damaging factor has been to focus attention on symptomatic treatments in impaired patients, when the disease has already killed billions of neurons, without ignoring that symptomatic treatments are also necessary once the disease has manifested itself phenotypically at the cognitive, behavioral and functional levels. The present and future development of new anti-dementia treatments forces us to modify this regulatory and protocol paradigm in pre-symptomatic and symptomatic clinical trials in which new outcome measures must be incorporated and the regulatory rigidity prevailing until now must be made more flexible.

In conclusion, in light of current knowledge, the potential causes of therapeutic failure in AD may be related to the following: misconceptions in the pathogenic cascade of deleterious events leading to AD-specific neurodegeneration; erratic procedures in drug development, inadequate animal models and drug targets; delay in the implementation of the treatment, which should be in early periods of the disease and, optimally, in asymptomatic phases identified with highly reliable biomarkers; inertial obsession to look for a single drug instead of a multitarget product to treat a multifactorial neurodegenerative process; absence of pharmacogenetic procedures to personalize and optimize the development of new drugs and redefine the utility old drugs with neuroprotective properties; and inappropriate regulations.

Declaration of interest

The author is President and a stockholder of EuroEspes SA and the International Agency for Brain Research and Aging SL (IABRA). The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

The author would like to thank his collaborators Natalia Cacabelos, Vinogran Naidoo and Juan C. Carril, at the International Center of Neuroscience and Genomic Medicine, for technical assistance.

Additional information

Funding

This manuscript was not funded.