Species: Rat
Genes: Trem2, App
Modification: Trem2: Knock-In; App: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Summary
Phenotype Characterization
When visualized, these models will distributed over a 18 month
timeline
demarcated at the following intervals: 1mo, 3mo, 6mo,
9mo, 12mo, 15mo, 18mo+.
Last Updated: 08 Apr 2020
Further Reading
No Available Further Reading
Species: Rat
Genes: App
Modification: App: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Summary
The A673T (“Icelandic”) mutation in APP is associated with protection against Alzheimer's disease and age-related cognitive decline. This knock-in rat model carries the Icelandic mutation and a humanized Aβ sequence within the endogenous rat App gene (Tambini et al., 2020). The initial characterization of these animals showed a gene-dose-dependent decrease in levels of Aβ40 and Aβ42.
Phenotype Characterization
When visualized, these models will distributed over a 18 month
timeline
demarcated at the following intervals: 1mo, 3mo, 6mo,
9mo, 12mo, 15mo, 18mo+.
Last Updated: 08 Apr 2020
Further Reading
No Available Further Reading
Species: Rat
Genes: App
Modification: App: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Summary
Phenotype Characterization
When visualized, these models will distributed over a 18 month
timeline
demarcated at the following intervals: 1mo, 3mo, 6mo,
9mo, 12mo, 15mo, 18mo+.
Plaques
None observed at 3 months.
Tangles
None observed at 3 months.
Neuronal Loss
None observed at 3 months.
Last Updated: 08 Apr 2020
Further Reading
No Available Further Reading
Species: Rat
Genes: App
Modification: App: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Summary
This knock-in model carries a humanized Aβ sequence within the endogenous rat App gene (Tambini et al., 2019).
Levels of App mRNA in brain were similar in 21-day-old rats homozygous for the humanized App gene (Apph/h) and wild-type animals (Appw/w).
Phenotype Characterization
When visualized, these models will distributed over a 18 month
timeline
demarcated at the following intervals: 1mo, 3mo, 6mo,
9mo, 12mo, 15mo, 18mo+.
Plaques
None observed at 3 months.
Tangles
None observed at 3 months.
Neuronal Loss
None observed at 3 months.
Last Updated: 08 Apr 2020
Further Reading
No Available Further Reading
Overview
Name: Venglustat
Synonyms: Ibiglustat, GZ/SAR402671, Genz-682452
Therapy Type: Small Molecule (timeline)
Target Type: alpha-synuclein, Other (timeline)
Condition(s): Parkinson's Disease
U.S. FDA Status: Parkinson's Disease (Inactive)
Company: Genzyme, Sanofi
Background
Venglustat is a brain-penetrant allosteric inhibitor of the enzyme glucosylceramide synthase. GCS catalyzes an early step in the synthesis of many glycolipids. Venglustat is being developed for lysosomal storage diseases, including Gaucher’s, Fabry, and for Parkinson’s caused by mutations in the GBA1 gene. In all these diseases, failure to degrade the glycolipid glucosylceramide leads to its accumulation, resulting in lysosomal dysfunction and organ damage. Venglustat and other GCS inhibitors reduce accumulation of glucosylceramide by preventing its synthesis.
Mutations in GBA1, which encodes the lysosomal glucocerebrosidase (GCase) enzyme, are the leading genetic risk factor for Parkinson’s disease and for dementia with Lewy bodies, two synucleinopathies. Insufficient GBA1 function causes a buildup of both α-synuclein and glucosylceramide (Jun 2011 news; Jul 2011 news). Some work suggests glucosylceramide promotes α-synuclein oligomerization (Mazzulli et al., 2011; Zunke et al., 2017).
In a cell model of GCase deficiency, the GCS inhibitor miglustat reduced glucosylceramide, slowed the conversion of physiological α-synuclein tetramers into toxic conformations, and protected against α-synuclein fibril-induced toxicity (Kim et al., 2018).
No preclinical work is published on venglustat. Sanofi has presented and published results with the related compound GZ667161 (Sardi et al., 2017; Dec 2016 conference news). In a Gaucher disease model, mice carrying a homozygous GBA D409V mutation were fed the inhibitor from 1 month to 10 months of age, or from 6 to 13 months. GZ667161 treatment reduced brain glucosylceramide levels, as well as accumulation of hippocampal α-synuclein and tau deposits. Treatment reportedly improved memory deficits. In a model of α-synuclein toxicity, treatment of mice overexpressing the A53T mutant from age 1.5 to 8 months reduced glucosylceramide levels, hippocampal membrane-associated α-synuclein and tau deposits, and improved cognition.
Two other GCS inhibitors—miglustat and eliglustat—are FDA-approved for treating Gaucher disease. Both drugs are said to poorly penetrate the brain. GZ667161 was selected for its ability to cross the blood-brain barrier in preclinical models (Cabrera-Salazar et al., 2012).
Findings
Two Phase 1 safety, tolerability, and pharmacokinetics studies in 99 healthy volunteers were conducted in 2012 and 2013 under the drug name Genz-682452. Results are published (Peterschmitt et al., 2021).
In December 2016, Sanofi began MOVES-PD, a global Phase 2 trial to evaluate safety and efficacy of venglustat in PD patients who are heterozygous for a GBA1 mutation. In the initial, safety phase of the trial, 13 patients took one of three doses daily for up to 36 weeks; four took placebo capsules. Their mean age was 58, mean disease duration, seven years. At the 2019 WORLD Symposium on lysosomal diseases, investigators reported that venglustat caused no serious adverse events or deaths. Side effects were mild or moderate and disappeared on their own, though two participants on drug dropped out due to side effects. Drug levels in plasma and CSF increased in dose-dependently; plasma and CSF glucosylceramide levels declined by up to 75 percent, also dose-dependently (Peterschmitt et al., 2019).
The second part of MOVES-PD randomized 221 participants to a one-year regimen of once-daily drug or placebo, plus two years of follow-up. The primary outcome was change from baseline to one year on the Unified Parkinson's Disease Rating Scale Part II and III; secondary outcomes were change in the PD Cognitive Rating Scale, UPRDS all parts, and Hoehn and Yahr score. The treatment phase finished in December 2020. On February 5, 2021, the company told investors that the trial had missed its primary endpoint, and development was stopped for PD (press release). According to results presented at the March 2021 AD/PD conference, the primary endpoint of the MDS-UPDRS Part II and III worsened more with venglustat than placebo. A similar trend was seen for the MDS-UPRDS total score. There was no improvement, and possible worsening, in the cognitive rating scale. Target engagement was deemed successful: glucosylceramide GL-1 levels decreased about 75 percent in plasma and CSF within two weeks of starting dosing, and stayed in normal limits during the study.
Venglustat continues in Phase 2 for Gaucher, Fabry, Tay-Sachs and Sandhoff diseases, and in Phase 3 for cystic kidney disease.
In 2015, the FDA fast-tracked this drug for Fabry disease.
For details on venglustat trials, see clinicaltrials.gov.
Last Updated: 19 Jul 2021
Further Reading
No Available Further Reading
Overview
Name: Exidavnemab
Synonyms: BAN0805, ABBV-0805
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: alpha-synuclein
Condition(s): Parkinson's Disease
U.S. FDA Status: Parkinson's Disease (Inactive)
Company: AbbVie, BioArctic AB
Background
This is a humanized monoclonal antibody targeting α-synuclein originally developed by the Swedish company BioArctic. Genetic and pathology evidence implicate aggregated forms of α-synuclein in the molecular pathogenesis of Parkinson’s disease and other α-synucleinopathies such as dementia with Lewy bodies (DLB). In 2018, AbbVie licensed this and similar antibodies from BioArctic, and until 2022 developed it for the treatment of PD.
BioArctic has engineered several antibodies that bind oligomeric/protofibrillar α-synuclein with nanomolar affinity and high selectivity over monomeric protein. BioArctic engineered several antibodies that bind oligomeric/protofibrillar α-synuclein with nanomolar affinity and high selectivity over monomeric protein (Lindström et al, 2014; Kallab et al., 2018). Preclinical work with ABBV-0805 showed protection against α-synuclein toxicity, as well as clearance of pathological aggregates and prolonged survival in α-synuclein transgenic mice (Nordström et al., 2021).
ABBV-0805 is one of several α-synuclein antibodies being investigated for PD. Others include BIIB054, TAK-341, LU AF82422, and prasinezumab.
Findings
In March 2019, AbbVie began a Phase 1 study of ABBV-0805 in healthy volunteers in the United States (press release). Data presented at the September 2021 International Congress of Parkinson’s Disease and Movement Disorders reported pharmacokinetic, safety and tolerability data that warranted continuing into Phase 2, with once-monthly dosing. A second Phase 1 study was conducted. An intravenous and a subcutaneous formulation were evaluated in a total of 98 healthy Caucasian, Japanese, and Han Chinese volunteers. Results, including exploratory target engagement data, were published after peer review (Boström et al., 2024).
In March 2020, AbbVie started what was going to be a multicenter, placebo-controlled Phase 1 study in 32 people with idiopathic, mild to moderate Parkinson’s. It was going to randomize them to three escalating doses of antibody or placebo, delivered by intravenous infusion every 28 days, with a fourth dose being added pending initial results. Primary outcomes were going to be adverse events and antibody pharmacokinetics in blood and cerebrospinal fluid. In July 2020, the company withdrew this trial, citing strategic reasons.
On April 20 2022, BioArctic announced that AbbVie had terminated its collaboration on α-synuclein antibodies, including ABBV-0805 (press release). BioArctic said it is looking for ways to continue development.
For details on ABBV-0805 trials, see clinicaltrials.gov.
Last Updated: 10 Sep 2024
Further Reading
No Available Further Reading
Overview
Name: ASN90
Synonyms: ASN120290, ASN-561
Therapy Type: Small Molecule (timeline)
Target Type: Tau (timeline)
Condition(s): Progressive Supranuclear Palsy
U.S. FDA Status: Progressive Supranuclear Palsy (Phase 1)
Company: Asceneuron SA
Background
ASN90 is an inhibitor of O-GlcNAcase, the glycoside hydrolase enzyme that removes O-linked N-acetylglucosamine (N-GlcNAc) from proteins. The function of numerous proteins is regulated by O-linked glycosylation of serine and threonine residues, which is reversed by O-GlcNAcase.
N-GlcNAcylation of the microtubule-associated protein tau reduces its propensity to form toxic aggregates (Gong et al., 2005; Liu et al., 2004). A similar anti-aggregation effect of O-GlcNAc modification was recently reported for α-synuclein protein (Levine et al., 2019).
By increasing tau glycosylation, inhibitors of the O-GlcNAcase enzyme (OGA) appear to stabilize tau in a soluble, non-pathogenic form. In two different mouse strains expressing P301L mutant human tau, the OGA inhibitor thiamet G was reported to increase N-GlcNAc-modified tau, reduce tau neurofibrillary tangle numbers, and decrease neuronal cell loss (Yuzwa et al., 2012; Graham et al., 2014; Hastings et al., 2017). One lab found that thiamet G treatment of a third mutant tau strain resulted in better motor skills, higher body weight, and longer lifespan (Borghgraef et al., 2013).
In preclinical work, daily oral dosing with ASN90 in P301S tau transgenic mice enhanced brain tau glycosylation, prevented the development of tau tangles, improved motor behavior and breathing, and prolonged survival (Permanne et al., 2022). In this study, tau glycosylation in peripheral blood cells mirrored modification in the CNS, and thus was suggested as a potential pharmacodynamic marker of OGA inhibition for clinical trials. Also in this work, ASN90 was shown to enhance α-synuclein glycosylation, and slow the progression of motor impairment in a transgenic model of Parkinson’s disease.
ASN90 is being developed as a potential treatment for progressive supranuclear palsy and other tau-related dementias.
Findings
In 2017, Asceneuron conducted a randomized, placebo-controlled Phase I safety and tolerability study of oral ASN120290 in healthy adult and aged volunteers. As presented July 2018 at AAIC, it enrolled 61 subjects, who received single ascending doses, or multiple doses for up to 10 days. The drug was reported to be have been well-tolerated at single doses of up to 1,000 mg, or 500 mg twice a day. No dose-limiting toxicities, severe adverse events, or dropouts due to adverse events were reported. Plasma pharmacokinetics were dose-proportional and affected by food. In aged participants, ASN120290 rapidly appeared in the cerebrospinal fluid after dosing, at concentrations similar to those in plasma (see abstract). Data were not published in a peer-reviewed journal.
In July 2018, ASN120290 received Orphan Drug Designation by the U.S. FDA for treatment of the primary tauopathy, progressive supranuclear palsy.
In November 2018, the company announced a trial using PET imaging with labeled ASN120290. This study will assess target engagement by quantifying binding of a radioactive ASN120290 tracer in the brains of healthy volunteers, both alone and after pre-administration of the inhibitor (see press release). According to results presented at the July 2021 AAIC, the tracer displayed high binding throughout the human brain and was fully displaced by a single, oral dose of 500 or 300 mg ASN120290.
Asceneuron is also developing a second generation OGA inhibitor. ASN51 is claimed to be a longer-acting form of ASN120290, suitable for once-a-day dosing. It is in Phase 1 testing for Alzheimer’s and Parkinson’s disease.
Clinical studies of ASN120290 are not listed in Clinicaltrials.gov or other registries, though the company's website lists ASN120290 as being in Phase 2/3.
Last Updated: 15 Dec 2022
Further Reading
No Available Further Reading
Overview
Name: Valacyclovir
Synonyms: Valtrex, Valaciclovir, 256U87
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: GlaxoSmithKline (GSK)
Approved for: Herpes virus outbreaks
Background
A thymidine kinase inhibitor, valacyclovir is a prescription drug, and widely available as a generic. Valacyclovir is used to shorten outbreaks of genital herpes or cold sores caused by Herpes simplex virus (HSV) 1 and 2. It is also used to treat outbreaks of varicella zoster, which causes shingles and chickenpox. Taken as oral tablets, valacyclovir inhibits replication of viral DNA. It is most active against HSV-1 and HSV-2.
The rationale for testing valacyclovir in Alzheimer’s disease stems from the hypothesis that viral infection, particularly with HSV-1, may cause AD or contribute to its progression (reviewed in Itzhaki, 2018; Devanand, 2018; Itzhaki, 2014). Data suggest viruses could act by causing inflammation, seeding amyloid aggregation, or altering expression of AD-related genes (Jun 2018 news; Jun 2018 news; May 2019 news). Epidemiological studies indicate antiviral treatment can reduce the risk of dementia in people with HSV-1 or other viral infections, but the overall evidence is not convergent (Tzeng et al., 2018; Itzhaki and Lathe, 2018, Jan 2021 news).
In a trial to treat cognitive deficits in HSV-1-positive people with schizophrenia, 18 weeks of valacyclovir improved measures of working memory, verbal memory, and visual object memory (Prasad et al., 2013). In people with multiple sclerosis, it produced trends toward clinical improvement, but no change in objective measures of disease (Friedman et al., 2005).
Findings
In May 2013, an open-label pilot study of valacyclovir in 30 HSV-seropositive people with Alzheimer’s disease began at the University of Helsinki. The trial was to treat for 12 weeks, then measure changes in cognition and function on the ADAS-Cog and ADCS-ADL. Results were not published.
In December 2016, VALZ-Pilot, an open-label study in HSV-positive people with early AD, started up at two sites in Sweden, in Umea and Uppsala. The 36 participants had to carry the ApoE4 allele, which is associated with greater susceptibly to neurological effects of HSV infection. They received 1.5 grams valacyclovir daily for one week, then 3 grams daily for another three weeks. The primary outcome was feasibility, tolerability, safety, and change in CSF total tau and neurofilament light levels; additional endpoints included other CSF biomarkers and drug levels, PET measures of HSV replication in the CNS, and MMSE. According to published results, 32 of 33 enrollees completed the full dose regimen, with only mild and temporary adverse events. CSF valacyclovir levels achieved therapeutic range. CSF total tau and NfL levels were unchanged, though CSF sTREM2 rose. A one-point increase in MMSE after treatment was statistically significant. The PET portion of the study failed due to the tracer’s lack of brain penetration (Weidung et al., 2022).
In February 2018, a Phase 2, placebo-controlled trial began at New York University and New York State Psychiatric Institute. It will enroll 130 HSV-seropositive-people who have a clinical diagnosis of Alzheimer’s disease and mild dementia, or of mild cognitive impairment with imaging or CSF biomarker evidence of AD. Half receive 4 grams valacyclovir daily for 18 months, half placebo. Primary outcomes are change in cognition and function as per the ADAS-Cog11 battery and ADCS-ADL; secondary measures are change in brain amyloid and tau accumulation on florbetapir and MK-6240 PET scans; exploratory measures include cortical thinning on MRI, olfactory deficits, and change in antiviral antibody titers from baseline to 78 weeks. A substudy in participants who agree to repeat lumbar puncture will measure CSF Aβ42, total and phosphorylated tau, and levels of valacyclovir. Funded by the NIA, the trial is expected to end in December 2023. The protocol is published (Devanand et al., 2020).
In February 2021, a second Phase 2 trial in New York began recruiting 50 people with mild cognitive impairment, biomarker evidence of AD, and HSV seropositivity. Treatment will be 4 g/day or placebo for one year, against outcomes of change in amyloid PET, the Preclinical Alzheimer’s Cognitive Composite, and the ADCS-ADL-Prevention Instrument. Completion is expected in December 2023.
Valacyclovir is also being evaluated in several types of cancer including gliomas, and for other viral infections. For details on valacyclovir trials, see clinicaltrials.gov.
Last Updated: 05 Apr 2022
Further Reading
No Available Further Reading
Overview
Name: Dapagliflozin
Synonyms: Farxiga, Forxiga, BMS 512148
Chemical Name: (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1/2)
Company: AstraZeneca, Bristol-Myers Squibb
Background
Dapagliflozin is a once-daily prescription pill that is FDA-approved to treat Type 2 diabetes and reduce risk of heart failure in people with diabetes. It belongs to the gliflozin class of glucose-lowering agents that includes empagliflozin. These drugs inhibit the sodium-glucose cotransporter-2 (SGLT2), which is responsible for 90 percent of glucose reabsorption in the kidney. As a result, glucose is secreted via the urine. This lowers blood glucose, thus alleviating glucose toxicity, improving insulin sensitivity, and promoting weight loss. In clinical trials, dapagliflozin also reduced the chance of hospitalization for heart failure in people with Type 2 diabetes and cardiovascular disease.
Type 2 diabetes is a risk factor for developing dementia, and people with Alzheimer’s disease display signs of insulin resistance in the brain. These findings have spurred testing of multiple classes of diabetes drug for the treatment or prevention of AD (for example, see nasal insulin, pioglitazone, metformin, liraglutide and semaglutide).
There is no published data on dapagliflozin in preclinical Alzheimer’s models. In rats and mice rendered obese and diabetic by high-fat diets, dapagliflozin reportedly improved cognition, as well as brain mitochondrial function, insulin signaling, neurogenesis, synaptic density, and hippocampal synaptic plasticity (Sa-Nguanmoo et al., 2017; Millar et al., 2017).
In a large Danish epidemiological study, use of SGLT2 inhibitors and other diabetes drugs reduced the risk of dementia in diabetics (Wium-Andersen et al., 2019).
Findings
In January 2019, a study began at the University of Kansas Medical Center to test dapagliflozin’s effect on brain metabolic markers in people with AD. The trial is enrolling 48 people with a clinical diagnosis of probable AD and a Mini-Mental State Exam score of 15 to 26. Participants may have diabetes, if they have been treated only with metformin. They will be randomized 2:1 to receive 10 mg dapagliflozin daily or placebo for 12 weeks. The primary outcome is change in brain n-acetyl aspartate (NAA), measured by magnetic resonance spectroscopy. NAA is synthesized in mitochondria, and its levels are reduced in many neurological conditions, including Alzheimer’s disease; the investigators are using it as a proxy for mitochondrial mass. Other endpoints include NAA levels in blood and urine, FDG-PET, markers of systemic glucose and fat metabolism, mitochondrial function, and inflammation, as well as cognitive measures and safety and tolerability. The trial will run through October 2020. It is funded by AstraZeneca.
In May 2019, a trial at Nanjing University Hospital began comparing dapagliflozin to liraglutide, and to the anti-diabetic medication acarbose, for their respective effects on cognitive and olfactory function in 87 overweight people whose Type 2 diabetes is poorly controlled with metformin alone. Outcome measures of this 16-week trial include fMRI of odor-induced brain activity, change on the MoCA cognition screen, and an odor-detection test. This trial is set to end in February 2021.
Dapagliflozin is also being studied in Type 1 diabeties, kidney diseases, hepatitis, and other conditions. For details, see clinicaltrials.gov.
Last Updated: 09 Mar 2020
Further Reading
No Available Further Reading
Overview
Name: Empagliflozin
Synonyms: Jardiance, BI-10773
Chemical Name: (2S,3R,4R,5S,6R)-2-[4-Chloro-3-[[4-[(3S)-oxolan-3-yl]oxyphenyl]methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: Boehringer Ingelheim, Eli Lilly & Co.
Approved for: Type 2 Diabetes, Cardiovascular disease
Background
Empagliflozin is a once-daily prescription pill that is FDA-approved to treat Type 2 diabetes and reduce risk of cardiovascular death in adults with the illness (2016 FDA press release).
Empagliflozin belongs to the gliflozin class of glucose-lowering agents that includes dapagliflozin. These drugs inhibit the sodium-glucose cotransporter-2 (SGLT2), which is responsible for 90 percent of glucose reabsorption into the kidney. As a result, excess glucose is secreted via the urine, helping reduce blood glucose, alleviate glucose toxicity, improve insulin sensitivity, and promote weight loss. Empagliflozin also lowers the risk of death from heart attack and stroke in people with Type 2 diabetes and cardiovascular disease.
Type 2 diabetes is a risk factor for developing dementia, and people with Alzheimer’s disease display signs of insulin resistance in the brain. These findings have spurred evaluation of multiple classes of diabetes drug for the treatment or prevention of AD (for example, see nasal insulin, pioglitazone, metformin, liraglutide, semaglutide).
In a mixed mouse model of Alzheimer’s disease and Type 2 diabetes, treatment with empagliflozin for 22 weeks helped maintain insulin levels, reduced neuronal loss, microgliosis, amyloid load, and brain hemorrhage. The mice were reported to show improvement in cognitive deficits (Hierro-Bujalance et al., 2020). Similar results were reported in a different Type 2 diabetes/AD model (Sim et al., 2023).
In a large Danish epidemiological cohort, use of SGLT2 inhibitors, among other diabetes drugs, reduced the risk of dementia in people with Type 2 diabetes (Wium-Andersen et al., 2019). More recent cohort studies concur, finding 11 to 29 percent lower dementia risk in people who take empagliflozin, compared to other glucose-lowering medications (Siao et al., 2022; Wu et al., 2023; Chen et al., 2024). In a Korean cohort study, use of SGLT2 inhibitors was associated with a 39 percent reduction in the risk for Alzheimer’s disease compared to other diabetes drugs (Shin et al., 2024). One study reported a lower risk of Parkinson’s disease as well (Mui et al., 2021).
Besides lowering glucose, SGLT2 inhibitors increase production of ketone bodies. Formed by the breakdown of fatty acids, ketone bodies provide an alternative to glucose as a fuel source in the brain. Because brain glucose metabolism is impaired in AD, there has been interest in ketogenic food products or diets as potential treatments (e.g., tricaprilin; Taylor et al., 2018). Empagliflozin may offer an additional way to induce moderate chronic ketosis.
An excess of ketone bodies can cause a life-threating acidification of the blood. Occurrence of this ketoacidosis was negligible in empagliflozin trials, but has since been reported in some people taking the drug (Yamamoto et al., 2019; McGill and Subramian, 2019; Kaku et al., 2020).
Findings
In March 2019, a Phase 1 proof-of-concept study started up at the National Institute on Aging’s Clinical Trials Unit in Baltimore. It tested empagliflozin’s effect on ketone body production in adults older than 55 without diabetes. Thirty-nine participants underwent a two-week observation period, followed by two weeks of taking 25 mg empagliflozin per day. Investigators planned to measure ketone bodies, insulin, glucose, glucagon, and fatty acids in blood; markers of ketone body metabolism in blood exosomes; and brain metabolism by magnetic resonance spectroscopy (MRS), before and after treatment. The study was completed in December 2021, and results are published (Avgerinos et al., 2022). After empagliflozin treatment, blood levels of the ketone body β-hydroxybutyrate rose, but another ketone body, acetoacetate, fell. No change in brain β-hydroxybutyrate was detected. Insulin signaling was activated in neuron-derived exosomes after the first dose of empagliflozin, but not after two weeks dosing.
In September 2021, a Phase 2 trial started to test empagliflozin alone or in combination with nasal insulin in people with AD. Empagliflozin was recently reported to improve the brain response to nasal insulin in people with prediabetes (Kullmann et al., 2022). The single-site study at Wake Forest University planned to enroll 60 participants with elevated brain amyloid and normal cognition, MCI, or early dementia. The four-arm protocol compared 40 IU nasal insulin four times daily, one 10 mg empagliflozin pill daily, or both, to placebo. The primary outcome was safety; other outcomes included cognitive measures, CSF Aβ and tau, and brain blood flow. The study finished in September 2024, and results were reported at that year’s CTAD conference (Nov 2024 news). Out of 47 participants enrolled, 42 completed the study. No treatment-related adverse events or changes in blood glucose or blood pressure were reported. On exploratory outcomes, insulin treatment alone or with empagliflozin was associated with improvement on the PACC5 cognitive measure, and an increase in white matter. Empagliflozin with or without insulin decreased CSF total tau. Each intervention caused distinct changes in immune and inflammation markers in CSF and plasma.
Empagliflozin is also being trialed for the treatment of Type 1 diabetes, diabetic kidney disease, and congestive heart failure. For details on empagliflozin trials for Alzheimer’s disease, see clinicaltrials.gov.
Last Updated: 06 Jan 2025
Further Reading
No Available Further Reading
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