The mainstay of current AD management targeting acetylcholinesterase is to make acetylcholine available for synaptic transmission [2, 9–11]. Five drugs (donepezil, rivastigmine, galantamine, memantine, and tacrine) are approved on the market with donepezil approved the earliest, in 1996. These drugs are used for all stages of AD, but inhibition of cholinesterase enzymes works best at the early stage of AD [9, 12].

Among them, a rivastigmine patch or oral capsule is the only acetylcholinesterase inhibitor (ACEI) that provides inhibition for both acetylcholinesterase and butyrylcholinesterase and shows efficacy and safety in helping to relieve the cognitive symptoms of AD (e.g., [13]).

Current therapeutics to ameliorate and control the cognitive and behavioral symptoms by targeting the NMDA receptor prevent Ca²⁺ induced excitotoxicity [2, 9–11], and memantine was approved for this purpose in 2003. Memantine is more effective in providing cognitive and behavioral benefits and approved for patients with moderate to severe AD as monotherapy or combination therapy with donepezil [9, 12]. Finally, memantine is both a non-competitive NMDA receptor antagonist and a dopamine agonist for moderate to severe AD [11].

The FDA has approved two drugs for mild cognitive impairment (MCI) to early, mild stages of AD after years of failed clinical trials. They are aducanemab, and lecanemab, among which aducanemab received accelerated approval [14, 15].

To improve efficacy, single molecule drugs have been designed to incorporate two or more pharmacological structural features of different bioactive drugs acting on different targets. The different structural components can be connected through a tether/linker or merged together [9]. Examples include ANAVAX 2-73 (blarcamesine), lumateperone, idolopiridine, ladostigil, and J-147.

Blarcamesine, combining agonist activities at the muscarinic M1 receptor, the NMDA receptor, and the sigma-1 receptor, targets protein tau and reduces AD neurodegeneration [29]. Two consecutive multicenter phase 2a trials, randomized and open-label, show it improves cognition, dose-dependently, in mini-mental status examination (MMSE) and AD Cooperative Study-Activities of Daily Living Scale (ADCS-ADL) in subjects with mild-to-moderate AD [30]. The ongoing ATTENTION-AD trial (NCT04314934) is a phase 2b/3 open-label extension study to evaluate the effects of blarcamesine on the safety and efficacy of daily treatment with an enrollment of 450 participants globally who have completed the previous ANAVEX2-73-AD-004 double-blind study (clinicaltrials.gov). Lumateperone and iolopiridine targeted both 5-hydroxytryptamine 6 (5-HT6) and AchE, though both were discontinued due to lack of efficacy. Ladostigil is a hybrid molecule combining the carbamate group of rivastigmine and the N-propargyl group of monoamine oxidase (MAO) inhibitors, though it failed to meet the primary endpoint of delaying cognitive impairment in phase 2. J-147 under phase 1 is a multi-target drug including targets like MAO. MAOB activity is increased in AD at reactive astrocytes near amyloid plaques.

The rationales of these early AD drug trials from 2011 to 2020 are based on the Aβ hypothesis. Trials targeting degradation and production from Aβ precursor protein (APP) include those designed to: (1) decrease APP production, for example, posiphen (buntanetap); (2) increase α-secretase (stimulating non-amyloidogenic pathway), such as bryostatin; (3) inhibition of β-secretase to reduce Aβ production, in amyloidogenic pathway) [9], such as atabecestat and lanabecestat [31]; (4) inhibition of gamma-secretase (to reduce Aβ production, in the amyloidogenic pathway), such as LY3202626; (5) target Aβ solubility and aggregation such as Alzhemed (discontinued) and its pro-drug ALZ-801(for its potential efficacy in patients with the APOE4/4 genotype or its carriers), as soluble Aβ aggregates are considered to be the relevant cytotoxic form of the protein [32]; (6) target Aβ clearance by antagonizing RAGE (cell surface receptor linked to an increase in Aβ plaque formation), which primarily targeting neuroinflammation. These trials resulted in failure due to lack of efficacy and/or side effects of toxicity, for example [31] (Table 2).

Aβ clearance by immunotherapy was first demonstrated in an ischemic mouse model showing amyloid plaques can disappear with injections of human β-amyloid-(1-42)-peptide for some months [33]. Aiming for elimination of Aβ aggregation has two approaches: passive immunization and active immunization. Passive immunotherapies with monoclonal antibodies against Aβ in clinical trials went through three generations of development [11, 34], with FDA approval of two drugs for MCI to early stage of AD. First-generation antibody against N-terminus aggregated amyloid plaque, bapineuzumab, has no efficacy, due to low potency [35]. Second-generation anti-amyloid antibody against soluble monomeric Aβ (solanezumab), insoluble monomeric Aβ (gantenezumab), and monoclonal antibody against multiple Aβ forms (crenezumab) failed to have efficacy in improving cognitive functions for mild and moderate AD in several clinical trials (Table 2, for example [36]). The third generation of human immunoglobulin monoclonal antibody (hmAB; aducanumab, donanemab, and lecanemab) directed against insoluble, modified, N-terminal truncated form of Aβ, targeting Aβ plaque clearance, seems to benefit MCI or AD with mild dementia patients [34, 37]. Aducanumab and lecanemab are the first agents in two decades to demonstrate efficacy in clinical studies.

Aducanemab’s benefits are controversial [38, 39]. Four aducanumab phase 3 trials against Aβ fibrils were carried out; two were terminated due to futility analysis, and two trials (ENGAGE and EMERGE) showed benefit by reducing AD biomarkers, Aβ and tau proteins, in early-onset AD in certain patients [9]. Sub-studies for the two trials showed a dose-dependent reduction of Aβ and clinical dementia rating-sum of boxes (CDR-SB) a global measure of both cognition and function. In the EMERGE trial (NCT 02484547), aducanumab at a high dose significantly reduced dementia rating score CDR-SB (clinicaltrials.org, for a review see [14]). In 2024, the marketing of aducanumab was discontinued by the manufacture. Donanemab (under FDA review) can effectively reduce the cerebral spinal fluid (CSF) level of amyloid protein and plasma P-tau and T-tau [40, 41], provides a benefit of slowing down cognitive declines and improving function, and meet the primary endpoint, the integrated AD Rating Scale (IADRS), for those who are at the earliest stage of AD with a low level of tau proteins, and to a lesser extent those who carry APOE4 [42]. Lecanemab, directed against amyloid protofibrils, is approved for MCI/mild AD dementia based on the clarity AD trial (NCT03887455). This is an 18-month, multicenter, double-blind, phase 3 trial with early AD (MCI or mild dementia due to AD) with evidence of amyloid on PET or CSF testing. The administration of this antibody manifested significant (27%) slower progress in cognitive decline in the patients based on the primary end points, the change from baseline at 19 months in the score on the CDR-SB (with higher scores being greater impairment), and secondary endpoints, the change in the 14-item cognitive subscale of the AD assessment scale (ADAS-cog 14; higher scores being greater impairment), the AD composite score (ADCOMS; higher being worse) and the score on the ADCS-ADL for MCI (ADCS-MCL-ADL; lower scores being greater impairment). Overall, lecanemab significantly reduced amyloid burden with modestly less decline in measures of cognition and function in early-stage AD patients [34, 39, 43].

For cognitively normal individuals who are at high risk carrying AD genes, clinical trials were also started to prevent AD from onset or delay its onset. In one AD trial, crenezumab was tested for its preventative effect. The benefits of crenezumab on cognitively unimpaired autosomal dominant AD participants wait to be understood based on the recently closed phase 2 clinical trial (NCT 01998841) [44, 45].

Finally, trials on active immunotherapies targeting Aβ are limited. The first active immunization in humans, with the AN 1792 vaccine, was terminated due to its ineffectiveness in removing Aβ deposits from the brain or slowing cognitive decline, and adverse effects [46]. Later vaccine development resulted in improvement of cognition and reduction of Aβ accumulation; for example, active AD vaccine UB-311 has shown promising results for mild AD patients, able to generate a high response rate (100%) of antibody production in a phase 2 trial, with plans for a clinical phase 3 trial (Table 2) [9, 47].

Although amyloid remains the most common pharmaceutical target, targeting the tau protein, which is downstream to Aβ oligomers and contributes to intracellular neurofibrillary tangles, has received attention in recent years (Table 3; Clinicaltrials.org) [14, 48]. A tau imaging study showed tau accumulates slowly in large neocortical areas, taking approximately 15–20 years, with the highest rates of tau accumulation at the temporal, parietal, and lateral occipital cortex [49]. Currently, there is more evidence that hyperphosphorylated tau plays an important role in AD pathogenesis, reducing synaptic transmission at the nerve terminals and leading to tangle formation [37].

So far, three generations of anti-tau non-immunotherapy drugs failed clinical trials. First-generation anti-tau drugs target reversing post-translation hyperphosphorylation modifications that induce tau aggregation or inhibit tau aggregation directly, for example, nicotinamide and curcumin [50]. However, the tau aggregation inhibitor leuco-methylthioninium bis (hydromethanesulphonate), (LMTM, TRX 0237) trial, treating mild and moderate AD and frontotemporal dementia (2018), was terminated and failed at both primary endpoints (Alzforum.org). Second-generation anti-tau, Saracatinib (AZD0530), is a dual kinase inhibitor of Src and Ab1 family kinases and a repurposed drug originally treating cancer. Third-generation anti-tau drug Atuzagnstat (COR 388), for mild to moderate AD (2019–2022), failed due to adverse gastrointestinal (GI) effects and subject withdrawal.

On the other hand, the anti-tau immunotherapeutic approach is more complicated due to the various isoforms of tau protein, with at least six monoclonal antibodies against tau now in phase 2 and phase 3 clinical trials [11, 51]. Earlier phase 1 clinical trials targeting tau failed due to lack of recruitment; these agents reduce tau build-up via histamine H3 receptor antagonists and calcium-dependent cysteine protease inhibitors for mild to moderate AD. Later anti-tau therapeutic design includes antibody against different forms of tau proteins, mostly targeting the N-terminus such as semorinemab and gonsuranemab, or microtubule-binding regions such as AADvac1 and zagotenemab which are shown to reduce CSF P-tau level [50] (Table 3). Semorinemab and R07105705 are active against all six isoforms of tau, whereas, RG7345 is only active against phosphorylated-tau. Semorinemab was ineffective and did not slow the decline in a primary cognitive outcome for early AD in the phase 2 trial [52].

Active vaccine AADvac1, a synthetic tau peptide, reduces tau deposit by attacking the conformational epitope of tau for mild to moderate AD and has been well tolerated in clinical trial phase 1–2. A subgroup analysis of younger AD patients (participants 67 years or younger) showed significant beneficial changes in biomarker plasma neurofilament light chain (NfL) and cortical atrophy [51]. A post hoc subgroup analysis of the participants positive for amyloid and tau from phase 2 trial (NCT02579252) found the vaccine slowed AD-related decline on the CDR-SB and ADL scores in an antibody-dependent manner, and brain volume was preserved with treatment compared with control [48]. Phase 3 trial of active vaccine against tau protein is anticipated for treating mild AD [51].

Moreover, the antibody against tau protein can recognize extracellular tau (in most cases) or intracellular tau, or both. Antibody recognizing extracellular tau is thought to block the spread of tau across synapses [53], though it may not be perfect, for example, BIIB092, CN2-8E12, tilavonemab, and LY3303560 that recognize extracellular tau protein lack efficacy (Table 3). To target production and degradation of the intracellular tau, antisense oligonucleotides and small interfering ribonucleic acids (siRNAs) treatment is used to reduce tau production. In addition, proteolysis-targeting chimeras are used to enhance tau proteasomal degradation in early AD [50]. A current phase 2 clinical trial is investigating whether upstream gene activation, triggering receptor expressed on myeloid cells 2 (TREM-2) dependent microglia activation, can halt tau accumulation inside the cells (NCT04592874). One might assume that an antibody recognizing both extracellular and intracellular tau protein will be the most efficacious. However, this is not the case; for example, RG7345 that can bind to both intracellular and extracellular tau proteins has an unfavorable pharmacokinetic profile (Table 3).

Repurposing pharmacological agents has advantages from a drug development standpoint. Based on FDA regulation, an application that contains reports of safety and effectiveness in at which at least some of the information required for approval comes from studies conducted for a previously approved product receives much shortened review, leading to a speedy approval compared to a new drug. There are numerous repurposed drug trials that had encouraging results. Masitinib targets (inhibiting) tyrosine kinase and modulated neuroinflammation in 2012–2020 phase 2/3 trials for mild to moderate AD [9]. Minocyclin is a repurposed drug on trial for mild AD. Riluzole, a D2 receptor agonist approved for ALS, completed its phase 2 trial for mild AD as well and showed promise in improving glucose metabolism [54]. Rasagiline, an MAOB inhibitor approved for Parkinson’s disease, showed a favorable effect on neuroimaging biomarker tau and some benefit in quality of life in patients with mild to moderate AD [55]. Nabilone, an antiemetic and synthetic cannabinoid completed a phase 3 trial in 2019 and showed its promise in controlling agitation, a challenging and the most prevalent neuropsychiatric symptom, through anti-inflammatory effects in moderate-to-severe AD patients [56, 57].

Considering the complexity of AD pathogenesis, using combination drug therapy on two or more different targets presents the potential for improved efficacy and outcomes, as targeting multiple pathways or mechanisms might have a synergistic effect on therapeutic outcomes. For example, Namzaric, a fixed dose-combination of donepezil and memantine, is used for the treatment of AD patients with moderate to severe AD dementia [9]. However, adding the 5-HT6 receptor antagonist, masupirdine (SUVN-502), as adjuvant to donepezil and memantine, demonstrated no additional palliative benefits in a phase 2 clinical trial (NCT02580305) [58, 59]. It was suggested that memantine interferes with the effect of 5-HT6 antagonist masupirdine.

Other pharmacological combination therapy includes targeting both neuroinflammation and Aβ clearance as in t-octhylphenol 1 (T-OP1), combining a mast cell stabilizer and an Aβ aggregation inhibitor (cromolyn) with a nonsteroidal anti-inflammatory drug (NSAID) [60], and targeting tau (with antibody or a microtubule stabilizer) and acetylcholinesterase inhibitors (AChEI) therapy, the latter of which worked better when targeting mild to moderate stage AD in clinical trial. However, most of these trials failed to meet each trial’s specific cognitive endpoints, for example, clinical trials of Aβ clearance agent Rosiglitazone as an add-on therapy for patients with AD on donepezil or other AChEIs [37].

Current research suggests that amyloid and tau have a synergistic interaction and effect in promoting neurodegeneration and cognitive decline [61], and therefore, clinical trials that target both removing Aβ protein and tau burden with lecanemab are ongoing with the results yet to be released (Table 4). Other ongoing clinical trials aim to remove Aβ plaques with hmAB such as aducanumab, donanemab, gantenezumab, and lecanemab, and continuously monitor their safety and efficacy. Lastly, with the hope that tau is a promising candidate, ongoing clinical trials target intracellular tau and different regions of extracellular tau to block the spread of prion-like tau, for example, JNJ63733657 and UCB0107 (Bepranemab) targeting microtubule binding and tau mid-region, respectively (Table 4).

These interventions include exercise, diet, cognitive training, sleep-related intervention, neurostimulation (with devices), combination therapy, and others (such as environmental enrichment) based on Common Alzheimer’s Disease Research Ontology (CADRO).