The results were published on December 17, 2021, in the journal Brain.
This is among the very first published medical studies to show a considerable effect on the protein Tau, which forms neurofibrillary tangles in the brain in Alzheimers. In 39 individuals with moderate cognitive problems (MCI), 6 months of treatment with atomoxetine reduced levels of Tau in research study individuals cerebrospinal fluid (CSF), and normalized other markers of neuro-inflammation.
The research study points towards an alternative drug strategy against Alzheimers that does not rely on antibodies against Tau or another Alzheimers- associated protein, beta-amyloid. A current FDA-approved drug, adacanumab, targets beta-amyloid however its benefits are questionable amongst experts in the field.
Larger and longer research studies of atomoxetine in MCI and Alzheimers are warranted, the Emory scientists concluded. The drug did not have a significant result on cognition or other medical results, which was expected offered the relatively brief research study period.
” One of the major advantages of atomoxetine is that it is currently FDA-approved and known to be safe,” states senior author David Weinshenker, PhD, teacher of human genes at Emory University School of Medicine. “The helpful impacts of atomoxetine on both brain network activity and CSF markers of swelling warrant optimism.”
” We are encouraged by the results of the trial,” says lead author Allan Levey, MD, PhD, teacher of neurology at Emory University School of Medicine and director of the Goizueta Institute @Emory Brain Health. “The treatment was safe, well tolerated in individuals with moderate cognitive disability, and regulated the brain neurotransmitter norepinephrine just as we assumed. Our exploratory studies reveal appealing outcomes on imaging and spinal fluid biomarkers which need to be followed up in bigger research studies with longer period of treatment.”
Emory researchers selected atomoxetine, which is commercially readily available as Strattera, with the objective of boosting brain levels of norepinephrine, which they believed could stabilize a vulnerable region of the brain versus Alzheimers- related neurodegeneration..
Norepinephrine is produced generally by the locus coeruleus, an area of the brainstem that appears to be the first to show Alzheimers- related pathology– even in healthy, middle-aged individuals. Norepinephrine is believed to decrease swelling and to encourage trash-removing cells called microglia to clean out aggregates of proteins such as beta-amyloid and Tau. Increasing norepinephrine levels has favorable results on cognition and pathology in mouse and rat designs of Alzheimers.
” Something that may appear obvious, however was definitely vital, was our finding that atomoxetine profoundly increased CSF norepinephrine levels in these clients,” Weinshenker states. “For numerous drugs and trials, it is extremely challenging to prove target engagement. We had the ability to directly examine target engagement.”.
Weinshenker also highlighted that the trial grew out of pre-clinical research study conducted in animal designs, which showed the capacity for norepinephrine..
” The entire idea of utilizing atomoxetine to deal with moderate cognitive impairment and Alzheimers disease originated from research using rodents to model and manipulate elements of these conditions, and would not have actually been possible without funding from the National Institutes of Health, the Alzheimers Association, the Alzheimers Drug Discovery Foundation, and private donors,” he states. “Supporting animal research study is essential for biomedical developments in the neurodegeneration field.”.
The Emory research study was conducted in between 2012 and 2018 with a cross-over style, such that half the group received atomoxetine for the first 6 months and the other half received placebo– then individuals switched. It is possible that individuals who received atomoxetine for the very first six months experienced carryover effects after treatment stopped, so their second six month duration wasnt always a pure placebo.
Research study individuals were all detected with moderate cognitive impairment and had markers of potential development to Alzheimers in their CSF, based upon measuring Tau and beta-amyloid. More information about addition requirements is offered at clinicaltrials.gov.
Researchers determined levels of lots of proteins in participants CSF; the decrease of Tau from atomoxetine treatment was small– about five percent over six months– however if sustained, it might have a larger impact on Alzheimers pathology. No substantial result on beta-amyloid was seen.
In addition, in participants taking atomoxetine, scientists were able to spot a boost in metabolic process in the medial temporal lobe, vital for memory, through PET (positron emission tomography) brain imaging.
Research study participants began with a low dose of atomoxetine and ramped up to a higher dose, as much as 100 mg per day. Participants did experience weight-loss (4 pounds, usually) and a boost in heart rate (about 5 beats per minute) while on atomoxetine, however they did not show a substantial increase in blood pressure. Some individuals reported side effects such as gastrointestinal symptoms, dry mouth or lightheadedness.
The FDA approved atomoxetine in 2002 for ADHD (attention deficit hyperactivity disorder) in grownups and children, and the drug has actually been revealed to be safe in older adults. It is thought about to have low abuse potential, compared with conventional stimulants that are commonly prescribed for ADHD..
Looking ahead, it is now possible to visualize the integrity of the locus coeruleus in living individuals utilizing MRI strategies, so that might be a vital part of a larger follow-up research study, Weinshenker says. Atomoxetines results were recently studied in individuals with Parkinsons disease– the benefits appear to be greater in those who have actually lowered integrity of the locus coeruleus.
Referral: “A stage II research study repurposing atomoxetine for neuroprotection in moderate cognitive impairment” by Allan I. Levey, Deqiang Qiu, Liping Zhao, William T. Hu, Duc M. Duong, Lenora Higginbotham, Eric B. Dammer, Nicholas T. Seyfried, Thomas S. Wingo, Chadwick M. Hales, Malú Gámez Tansey, David S. Goldstein, Anees Abrol, Vince D. Calhoun, Felicia C. Goldstein, Ihab Hajjar, Anne M. Fagan, Doug Galasko, Steven D. Edland, John Hanfelt, James J. Lah and David Weinshenker, 17 December 2021, Brain.DOI: 10.1093/ brain/awab452.
Financing for the research study was provided by the Cox and Kenan Family foundations and the Alzheimers Drug Discovery Foundation.
Our exploratory studies show promising outcomes on imaging and spinal fluid biomarkers which need to be followed up in bigger studies with longer period of treatment.”
Increasing norepinephrine levels has favorable impacts on cognition and pathology in mouse and rat models of Alzheimers.
” Something that might seem apparent, however was absolutely necessary, was our finding that atomoxetine profoundly increased CSF norepinephrine levels in these clients,” Weinshenker states. Study participants started with a low dose of atomoxetine and ramped up to a greater dose, up to 100 mg per day. Participants did experience weight loss (4 pounds, on average) and a boost in heart rate (about 5 beats per minute) while on atomoxetine, but they did not show a considerable boost in blood pressure.
Enhancing norepinephrine decreases neuroinflammation markers in MCI.
Improving levels of the neurotransmitter norepinephrine with atomoxetine, a repurposed ADHD medication, might have the ability to stall neurodegeneration in individuals with early indications of Alzheimers disease, a research study carried out at Emory Brain Health Center recommends.