TABLE 2.
Summary of drugs and drug targets for the treatment of Alzheimer’s disease.
| Drug class | Drugs | Status and use | Properties and common side effects | Key references and notes |
|---|---|---|---|---|
| AChE inhibitors (AChEIs) | Tacrine (CognexR), donepezil (AriceptR), rivastigmine (ExelonR), galantamine (ReminylR) | Used for both mild to moderate AD. | All AChEIs inhibit both AChE and butyrl (pseudo) BuChE but with different affinities | Tacrine |
| Tacrine approved in 1993 but withdrawn in 2021 due to liver toxicity; donepezil, approved in 1996 | Tacrine is a non-specific AChEI; donepezil has ∼1000 selectivity for AChE and also has a long plasma half-life (60–90 h) that facilitates daily dosing and also close to 100% bioavailability; rivastigmine, is a non-specific AChEI, which in addition to oral formulations is also available as a transdermal patch; galantamine in addition to AChEI actions is also a positive allosteric inhibitor of nicotinic receptors | Gracon et al., 1998; Jarrott, 2017; Watkins et al., 1994; Blackard et al., 1998; Samuels and Davis, 1997 | ||
| Meta-analysis by Birks and Harvey, 2018, concluded that donepezil use resulted in better scores on ADL (activity of daily living) | The common side-effects are similar for all AChEIs and mainly | Donepezil | ||
| Donepezil is widely used and in combination with the NMDA receptor modulator, memantine for symptomatic relief, and in in 2001 for severe AD. | GI-related, but reportedly less for donepezil–see Ali et al., 2015 | Atri, 2019; Birks and Harvey, 2018; Marucci et al., 2021; Fish 2011 | ||
| The third AChEI to be approved was rivastigmine in 1997, and the fourth, galantamine, was approved in 2001 | Sugimoto et al. (2000) | |||
| Rivastigmine | ||||
| Birks and Harvey, 2018 | ||||
| Marucci et al., 2021 | ||||
| Multum, 2019 | ||||
| Galantamine | ||||
| Wang et al., 2007 | ||||
| Mohammad et al., 2017; Brodaty et al., 2005; Kavanagh et al., 2011; Jiang et al., 2015 | ||||
| NMDA Receptor Antagonist | Memantine (AxuraR, EbixaR, NamendaR) | A low-affinity uncompetitive antagonist of NMDAR. Approved by FDA in 2003 for symptomatic relief of mild to moderate AD and based on the results of two clinical trials (Kavirajan, 2009) Memantine is available in oral formulations including extended-release (ER). Memantine has high bioavailability (approaching100%) and a plasma half-life of 60–70 h. Frequently used in combination with donepezil | Well-tolerated with headache, blurred vision, dizziness as infrequent side effects (Kuns et al., 2024) | (I). Affinity for NMDAR versus other receptors |
| Memantine is safe with co-morbidities (diabetes, and co-administration with metformin or glyburide); co-use with AChEIs is safe | Chen and Lipton, 2005; Johnson and Kotermanski, 2006; Seeman et al., 2008. (ii). Supportive clinical trial data: Kavirajan et al., 2009; Periclou et al., 2004; Noetzli and Eap, 2013 | |||
| Based on meta-analysis (Blanco-Silveste et al. (2018) discontinuation rates for memantine are higher than for placebo | Matsunaga et al., 2015 | |||
| Kishi et al., 2017. (iii) Cochrane Report: McShane et al., 2019 | ||||
| (iii) Use with co-morbidities | ||||
| Freudenthaler et al. (1998), Periclou et al. (2004), Shua-Haim et al. (2008) | ||||
| Combination therapy AChEI plus NMDAR antagonist (donepezil + memantine) | Donepezil + memantine. (NamzaricR) | Fixed dose combinations approved in 2014 for patients with moderate to severe AD. | Overall, the evidence suggests that side-effects of combination therapy is more effective than monotherapy and that side effects are no greater than for monotherapy treatment with either AChEI or memantine (Kuns et al., 2024) | (i). Positive data based on ADCS-ASL scores (Tariot et al., 2004; Grossberg et al., 2013) |
| Meta-analysis suggests combination many be more effective for non-AD dementias | (ii). Contradictory data: Atri et al., 2008; Porseinsson et al., 2008; Howard et al., 2012; Chen et al., 2017a) | |||
| Also see | ||||
| Deardorff and Grossberg, 2016; Calhoun et al., 2018; Saint-Laurent Thibault et al., 2015 | ||||
| (iii). Meta-analysis for combination therapy AD versus other dementias | ||||
| Blanco-Silvente et al., 2018; Knight et al., 2018; Veroniki et al., 2022 | ||||
| MABs directed at amyloid (Aβ) proteins | Bapineuzumab, solanezumab | First generation chimeric humanized zumabs failed clinical trials | Infusion reactions are the most common SEs with an incidence of ∼25% | (i). Based on Aβ accumulation in post-mortem brains |
| (Anti- Aβ MABs) | crenezumab | Aducanumab (a numab–fully human MAB) approved with considerable controversy in 2021, but Biomega announced availability will end in late 2024 | Reports of cerebral edema in addition to cost of drug and associated costs of CSF and MRI monitoring for ARIAs may limit use and wider global use | Glenner and Wong, 1984; Hardy and Allsop, 1991; Hardy and Higgins, 1992 |
| aducanumab (AduhelmR) | Lecanemab approved in 2023 and based on positive data from CLARITY-AD trial. Based on TRAILBLAZER-ALZ 2 RCT approval of docanemab anticipated in late 2024 | Insufficient data to know long-term therapeutic efficacy and effects of anti-Aβ MABs | Also see: Spirling et al., 2011 | |
| lecanemab (LeqembiR) | Considerable controversy over the approval and effectiveness of anti-Aβ MABs | Mahase 2021a, b, c | ||
| gantenerumab | Rahman et al., 2023 | |||
| docanemab (LY3002813, or N3pG) | Wojtnik-Kulesza et al. (2023) | |||
| Controversies | ||||
| Teich and Arancio 2012; Ackley et al., 2021; Reiss et al., 2021; Richards et al., 2021; Herrup, 2022; Whitehouse and Saini, 2022; Kaur et al., 2024 | ||||
| Additional and longer clinical trials with lecanemab are ongoing (van Dyck et al., 2023) - results should help clarify how beneficial this class of drugs are re. long-term treatment of AD and whether anti- Aβ MABs slow cognitive decline | ||||
| β-secretase (BACE1) inhibitors) | Atabecestat; verubecestat | Failed Phase 2/3 clinical trials | Low clinical efficacy with cognitive decline greater than with placebo and concerns over psychiatric side effects. High incidence of side effects linked to ‘on target’ effects of β-secretase on proteins other than APP. | Henley et al., 2019 |
| Lanabecestat | Egan et al., 2019; Wessels et al., 2020 | |||
| Targets APP (amyloid precursor protein) | See also McDade et al., 2021 | |||
| γ-secretase | Selective modulators (GSMs) of γ-secretase predicted to have fewer side effects than BACE1 inhibitors | None tested | Hur (2022) | |
| Tau-inhibitors | Semoriinemab, tilavonemab, gosuranemab target the N-terminal region of tau | Failed to show significant benefits as in the TANGO trial with the humanized MAB, gosuranemab | Insufficient data to determine significance of side effects in humans; studies in mice did not show significant issues | Hoskin t al., 2019; Shulman et al., 2023; Sperling, 2023 |
| RNA-bases anti-sense oligonucleotide targeting tau (IONIS in partnership with Roche). Phase 1b study in progress (NCT03186989) | Data suggests that more specific targets are needed and/or combined therapy with multiple targets | Teng et al., 2022 | ||
| Panza and Lozupone (2022) | ||||
| September 2023 IONIS entered into an agreement with Roche for the further development of antisense RNA therapies for the treatment of AD and Huntington’s Disease (https://ir.ionispharma.com/news-releases/news-release-details/ionis-enters-agreement-roche-two-novel-rna-targeted-programs) | ||||
| NSAIDs | Numerous NSAIDs including aspirin, naproxen, ibuprofen, and coxibs (celecoxib) | Early positive data based on retrospective studies not supported by later meta-analysis and Cochrane Review in 2012 that concluded there was no evidence to support either the use of aspirin, NSAIDs, selective COX-2 inhibitors (coxibs), or steroids for the prevention or treatment of AD. | Chronic use of NSAIDs linked to risk of increase in GI and cardiovascular morbidity and mortality, and elevated cardiovascular risk for coxibs–Schjerning et al., 2020 | (i). Supportive: McGeer et al., 1990, 1996; Szekely et al., 2004 |
| The results of the 2019 clinical trial, INTREPAD, with the NSAID, naproxen were negative | In t’Veld et al., 2001; Pasinetti 2002 | |||
| (ii). Cochrane Review Jaturapatporn et al., 2012 | ||||
| (ii). INTREPAD data (with naproxen)–no benefits in AD (Meyer et al., 2019) | ||||
| (iii). NSAIDs and coxib use and elevated risk in elderly patients (Wehling, 2014) | ||||
| Anti-diabetes drugs | Metformin and GLP-1 receptor agonists | Support provided by pre-clinical and retrospective clinical data as well genetic analysis. Diabetes increases the risk of AD and benefits of drugs may be secondary to improving metabolic control in patients | Side effects with metformin are primarily GI. | El-Mir et al., 2008 |
| Metformin in Alzheimer’s–a Phase II/III trial (NCT04098666) with long-acting metformin in non-diabetes subjects with early and late MCI. Results expected in late 2026 | GLP-1 receptor agonists frequently cause nausea, vomiting, loss of appetite | Campbell et al., 2018 | ||
| Zheng et al., 2022 | ||||
| Nogaard et al., 2022 | ||||
| Nowell, et al. (2023) | ||||
| ApoE and statins | Gene therapy to target ApoE4 homozygotes | Lexeo Therapeutics, Phase I/II Clinical Trial, NCT03634007, on-going | Data on gene therapy clinical trial expected in late 2024 | Controversy re statins are beneficial in AD Wagstaff et al., 2003; Zandi et al., 2005 |
| See Rosenberg et al., 2018 | Using an adeno-associated virus gene transfer vector that expresses the cDNA coding for human APOE2 | Statins may reduce risk of AD, cognitive decline and mortality Kostapanos and Elisaf, 2017; Jeong et al., 2021; Nowak et al., 2022; Olmastroni et al., 2022; Murphy et al., 2023 | ||
| Targeting APOE4–see Hunsberger et al., 2019; Vecchio et al., 2022 | ||||
| Expression of ApoE4 damages pericyte function and integrity of BBB | ||||
| Armulik et al., 2010; Nishitsuji et al., 2011; Halliday et al., 2016; Zhou et al., 2022) | ||||
| Viruses and Vaccinations | Several viruses have been linked to increasing the risk of AD including Herpes Simplex (HSV-1), SARS-CoV-2 | Viral infections linked to increase in neuroinflammation, and increases in β- and γ-secretase activities and enhancing APP processing and tau kinases | Vaccinations have been shown to reduce the risk of AD (Wu et al., 2022) | Wozniak et al., 2007 |
| A prospective study (n = 49), with the Bacillus Calmette–Guérin (BCG) vaccine for tuberculosis has provided positive data that vaccines against AD (Dow et al., 2022) | De Vlieger et al., 2022 | |||
| Kitazawa et al. (2011) | ||||
| Patients with “Long COVID” experience sleep disruption, fatigue, anxiety, depression and what has been referred to as “brain-fog” (inability to focus, loss of memory, and difficulty to conduct normal activities) that can persist for months (Venkataramani and Winkler, 2022). Whether protection is provided by COVID-19 vaccinations remains to be analysed |