Evaluating the effect of rapamycin treatment in Alzheimer's Disease and aging usingin vivoimaging: the ERAP phase IIa clinical study protocol

Evaluating the effect of rapamycin treatment in Alzheimer's Disease and aging using in vivo imaging: the ERAP phase IIa clinical study protocol | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search Evaluating the effect of rapamycin treatment in Alzheimer's Disease and aging using in vivo imaging: the ERAP phase IIa clinical study protocol Jonas E. Svensson , Martin Bolin , Daniel Thor , View ORCID Profile Pete A. Williams , Rune Brautaset , Marcus Carlsson , Peder Sörensson , David Marlevi , Rubens Spin-Neto , Monika Probst , Göran Hagman , Anton Forsberg Morén , Miia Kivipelto , View ORCID Profile Pontus Plavén-Sigray doi: https://doi.org/10.1101/2024.02.19.24302922 Jonas E. Svensson 1 Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet and Stockholm Health Care Services , Region Stockholm, Stockholm, Sweden 2 Theme Inflammation and Aging, Karolinska University Hospital , Stockholm, Sweden Find this author on Google Scholar Find this author on PubMed Search for this author on this site Martin Bolin 1 Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet and Stockholm Health Care Services , Region Stockholm, Stockholm, Sweden Find this author on Google Scholar Find this author on PubMed Search for this author on this site Daniel Thor 3 Department of Medical Radiation Physics and Nuclear Medicine, Karolinska University Hospital , Stockholm, Sweden 4 Department of Oncology-Pathology, Karolinska Institutet , Stockholm, Sweden Find this author on Google Scholar Find this author on PubMed Search for this author on this site Pete A. Williams 5 Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital, Karolinska Institutet , Stockholm, Sweden Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Pete A. Williams Rune Brautaset 5 Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital, Karolinska Institutet , Stockholm, Sweden Find this author on Google Scholar Find this author on PubMed Search for this author on this site Marcus Carlsson 6 Clinical Physiology, Department of Clinical Sciences Lund, Lund University, Skåne University Hospital , Lund, Sweden 7 Department of Clinical Physiology, Karolinska University Hospital, and Karolinska Institutet , Stockholm, Sweden Find this author on Google Scholar Find this author on PubMed Search for this author on this site Peder Sörensson 7 Department of Clinical Physiology, Karolinska University Hospital, and Karolinska Institutet , Stockholm, Sweden 8 Department of Medicine Solna, Karolinska Institutet , Stockholm, Sweden Find this author on Google Scholar Find this author on PubMed Search for this author on this site David Marlevi 7 Department of Clinical Physiology, Karolinska University Hospital, and Karolinska Institutet , Stockholm, Sweden 9 Institute for Medical Engineering and Science, Massachusetts Institute of Technology , Cambridge, Massachusetts, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Rubens Spin-Neto 10 Department of Dentistry and Oral Health, Section for Oral Radiology, Aarhus University , Aarhus C, Denmark Find this author on Google Scholar Find this author on PubMed Search for this author on this site Monika Probst 11 Department of Diagnostic and Interventional Neuroradiology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich , Munich, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site Göran Hagman 2 Theme Inflammation and Aging, Karolinska University Hospital , Stockholm, Sweden 12 Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet , Stockholm, Sweden Find this author on Google Scholar Find this author on PubMed Search for this author on this site Anton Forsberg Morén 1 Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet and Stockholm Health Care Services , Region Stockholm, Stockholm, Sweden Find this author on Google Scholar Find this author on PubMed Search for this author on this site Miia Kivipelto 2 Theme Inflammation and Aging, Karolinska University Hospital , Stockholm, Sweden 12 Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet , Stockholm, Sweden 13 Ageing Epidemiology Research Unit (AGE), School of Public Health, Faculty of Medicine, Imperial College London , UK 14 Institute of Public Health and Clinical Nutrition, University of Eastern Finland , Kuopio, Finland Find this author on Google Scholar Find this author on PubMed Search for this author on this site Pontus Plavén-Sigray 1 Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet and Stockholm Health Care Services , Region Stockholm, Stockholm, Sweden 15 Neurobiology Research Unit, Copenhagen University Hospital , Rigshospitalet, Copenhagen, Denmark Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Pontus Plavén-Sigray For correspondence: pontus.plaven-sigray{at}ki.se Abstract Full Text Info/History Metrics Supplementary material Data/Code Preview PDF ABSTRACT Background Rapamycin is an inhibitor of the mechanistic target of rapamycin (mTOR) protein kinase, and pre-clinical data demonstrate that it is a promising candidate for a general gero- and neuroprotective treatment in humans. Results from mouse models of Alzheimer’s disease have shown beneficial effects of rapamycin including preventing or reversing cognitive deficits, reducing amyloid oligomers and tauopathies and normalizing synaptic plasticity and cerebral glucose uptake. The “Evaluating rapamycin treatment in Alzheimer’s disease using positron emission tomography” (ERAP) trial aims to test if these results translate to humans through evaluating the change in cerebral glucose uptake following six months of rapamycin treatment in participants with early-stage Alzheimer’s disease. Methods ERAP is a six month long, single-arm, open-label, phase IIa biomarker driven study evaluating if the drug rapamycin can be repurposed to treat Alzheimer’s disease. Fifteen patients will be included and treated with a weekly dose of 7 mg rapamycin for six months. The primary endpoint will be change in cerebral glucose uptake, measured using [ 18 F]FDG positron emission tomography. Secondary endpoints will be change in cognitive measures, markers in cerebrospinal fluid as well as cerebral blood flow measured using magnetic resonance imaging. As exploratory outcomes, the study will assess change in multiple age-related pathological processes, such as periodontal inflammation, retinal degeneration, bone mineral density loss, atherosclerosis and decreased cardiac function. Discussion The ERAP study is a clinical trial using in vivo imaging biomarkers to assess the repurposing of rapamycin for the treatment of Alzheimer’s disease. If successful, the study would provide a strong rationale for large-scale evaluation of mTOR-inhibitors as a potential disease modifying treatment in Alzheimer’s disease. Trial Registration ClinicalTrials.gov ID NCT06022068 , date of registration 2023-08-30 BACKGROUND For many decades, the “amyloid hypothesis” has been the dominating scientific lead in understanding and treating Alzheimer’s disease (AD). Clinical trials that directly target amyloid plaques (such as amyloid antibodies) have however resulted in mixed success ( 1 ). Only recently have two amyloid antibodies been given accelerated approval by the FDA. The drugs are prohibitively priced and questions about their efficacy and safety profile remain ( 2 ). It is therefore crucial to explore new scientific approaches to find an efficient disease-modifying intervention. One such approach is to focus on the single largest risk factor for AD: advancing age. It is estimated that the risk of developing AD doubles every five years over the age of 65 ( 3 ), and the risk of death from AD increases by about 700 times between the ages of 55 and 85 ( 4 ). Within the field of geroscience, which focuses on the biology of aging, an increasing number of interventions have been shown to enhance the lifespan of model organisms and slow down or prevent age-related pathology ( 5 ). One promising approach to understand and treat age-related diseases like AD is to study the effects of such interventions; defined as “geroprotective compounds”, in humans ( 6 ). Pre-clinical data suggest that the drug rapamycin is a promising candidate for this purpose ( 6 , 7 ). Rapamycin, also known as sirolimus , is an immunosuppressive drug which has been in clinical use for more than two decades. In mice, treatment with rapamycin increases average lifespan by 10 to 15% ( 8 ). The drug has also been shown to increase healthspan in model organisms, by delaying the onset of age-related diseases ( 9 ). For example, preclinical data support a beneficial effect of rapamycin (or it’s analogous) on periodontitis( 10 ), retinal pathologies ( 11 , 12 ), atherosclerosis ( 13 , 14 ); cardiac dysfunction ( 15 , 16 ), and bone mass loss ( 17 , 18 ). Such diseases are commonly manifested with increasing age and are considered frequent comorbidities to AD ( 19 – 31 ). There is a large body of preclinical data suggesting that repurposing rapamycin to treat AD could be effective ( 6 , 7 ). In several independent mice models of AD, rapamycin has been shown to prevent and reverse cognitive deficits ( 32 , 33 ), reduce amyloid oligomers and tauopathies ( 34 , 35 ), normalize synaptic plasticity ( 36 ), cerebral glucose uptake and ( 33 ) vascular cognitive impairment ( 37 ). Additionally, in transgenic rodent models of AD, rapamycin has demonstrated neuroprotective effects, by restoring blood-brain barrier function ( 32 ) and improving neurovascular coupling ( 38 ). Despite promising preclinical data supporting rapamycin as an effective agent in alleviating or reversing AD pathology, no large-scale human clinical studies have been initiated. Currently, only one phase II trial is ongoing ( ClinicalTrials.gov ID: NCT04629495 ). Conducting randomized controlled trials (RCTs) with symptom ratings (such as cognitive ability) as endpoints is challenging due to the need for large sample sizes and high costs. An alternative approach is to assess the impact of candidate interventions on AD biomarkers before initiating such large-scale RCTs. By focusing on well-established and precise biomarkers of the disease, rather than symptom ratings, evidence of slowing or even reversal of pathology can be obtained with much smaller sample sizes ( 39 , 40 ). The purpose of the study “Evaluating rapamycin treatment in Alzheimer’s disease using positron emission tomography” (ERAP) is to assess the effect of rapamycin in treating early-stage AD. This will be done by measuring change in biomarkers using in vivo imaging modalities, such as positron emission tomography (PET) and magnetic resonance imaging (MRI), as well as biomarker changes in cerebrospinal fluid (CSF). We will test the hypothesis that rapamycin can reverse AD-associated brain pathologies, resulting in, primarily, an increase in neuronal glucose metabolism, and secondarily, an improved cerebral blood flow and a decrease in tau and amyloid protein aggregates in the CSF. We will also record the occurrence of adverse events and investigate pharmacokinetic properties of the drug. Further, we aim to explore the effect of rapamycin on other age-related pathologies in the body, using different imaging techniques to assess change in i) periodontal inflammation, ii) retinal structures, iii) bone mineral density, iv) atherosclerosis, as well as v) cardiac function. The results from this phase IIa trial will be used to inform on the feasibility of conducting a larger controlled trial in the future. METHODS Study Design ERAP is a single-centre, open-label, one-arm, phase IIa intervention study. Fifteen patients diagnosed with early-stage AD will be recruited from the Karolinska University Hospital, Medical Unit Aging Memory clinic, located in Solna, Stockholm, Sweden. The unit is a specialized outpatient clinic that examines individuals referred by general practitioners in primary and occupational health care in the northern catchment of Stockholm, as well as individuals younger than 70 years in the entire Stockholm region ( 41 ). Following baseline measurements, all participants will receive a weekly oral dose of 7 mg rapamycin (Tablet Rapamune®) for a duration of six months. Throughout the study, participants will be continuously monitored for safety and adverse events. By the end of the treatment period, follow-up measurements will be conducted. Figure 1 presents a schematic overview of the study timeline for each participant. Download figure Open in new tab Figure 1. Study timeline for each participant. Participants The study will enrol patients with early-stage AD, defined as fulfilling criteria for Alzheimer’s clinical syndrome, with either mild cognitive impairment (MCI) or mild dementia of the Alzheimer’s type, according to the NIA-AA (National Institute of Aging-Alzheimer’s Association) 2018 criteria ( 42 ) (see Box 1 for specific study eligibility criteria). Study drug Rapamycin was approved in 1999 in the USA and in 2001 in Europe as an immunosuppressive drug to prevent organ rejection in renal transplantation ( 44 ). The drug and structurally analogues compounds (known as “rapalogs”), such as everolimus, have been approved for the treatment of several solid tumours ( 45 , 46 ), and is currently the only pharmacological option when treating tuberous sclerosis complex (TSC) ( 47 ). Rapamycin exerts its effect by inhibiting the intracellular protein kinase mTOR, which stands for “mechanistic target of rapamycin”. mTOR has been shown to be central in the regulation of several important functions in mammalian cells, such as cell growth and proliferation, protein synthesis, and autophagy ( 48 ). The bioavailability of orally administered rapamycin is low (approximately 15%) and highly variable (SD = 9%). The drug is metabolized in the liver, primarily by CYP3A4, with a terminal half-life of 62 hours, though also here with large interindividual variability (SD = 16 hours) ( 43 ). Adverse events, mitigation strategies and dosing The side effect profile of rapamycin is well known, from a large number of clinical trials, and from long clinical use. The treatment is generally well tolerated, but common side effects, as described in the product information ( 44 ), are; stomatitis, diarrhea, and nausea. Changes in clinical laboratory values observed during rapamycin treatment include increased blood levels of cholesterol and triglycerides, and bone marrow depression manifesting as thrombocytopenia and anemia. The incidence of bacterial infections has been reported as increased in cancer patients treated with rapamycin, along with reports of cases of non-infectious pneumonitis ( 45 ). Notably, the data on side effects is based on the use of rapamycin following organ transplantation, where the drug is commonly used together with other immunosuppressants. In the ERAP trial, we plan to deviate from the standard dosing of rapamycin in two ways. Typically, when used as an immunosuppressant, rapamycin is administered orally at a daily dose of 2 mg or above ( 44 ). We will instead administer an overall lower dose but in an intermittent fashion; a weekly oral dose of 7 mg. This change is aimed at reducing the risk of adverse events. The rationale behind this is that positive effects of rapamycin are hypothesized to be caused by inhibition of the mTOR1 complex, while many of the side effects are hypothesized to be due to inhibition of the mTOR2 complex. While mTOR1 is sensitive to acute dosing treatment, mTOR2 requires sustained exposure of the drug in order to be effectively inhibited ( 46 ). Patients will be monitored for side effects during the study, including collection of blood samples at follow-up visits (see Table 1 ). These samples will be analyzed for standard clinical measures, including parameters that are known to be affected by rapamycin: complete blood count with differential and platelet count, sodium, potassium, chloride, albumin, creatinine, bilirubin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, glucose, cholesterol, triglycerides, calcium, phosphorus, and creatine phosphokinase. View this table: View inline View popup Download powerpoint Table 1. Visits, follow-ups and their corresponding assessments/examinaCons. Blood-brain-barrier passage It has not been thoroughly explored to which degree rapamycin passes the blood-brain-barrier (BBB) in humans. Rapamycin is a large molecule (molecular weight 914.2) and a substrate, albeit with low affinity, for the efflux pump P-glycoprotein ( 47 ). Drugs with these properties are often considered unlikely to pass from intestine to blood and bind an intracellular target ( 48 ). It is however known, from long clinical use, that oral treatment with rapamycin in humans leads to intracellular mTOR inhibition. The passage through cell walls, likely facilitated by high lipophilicity (logP estimated to be 4.3), supports BBB passage despite the large size of the molecule. Following oral dosing, detectable rapamycin concentration in the brain of rodents has been established ( 49 , 50 ), and a large number of studies show clear effects in the central nervous system of animals ( 7 ). Support for cerebral target engagement ( i . e . mTOR inhibition) in humans can be found from the use of rapamycin as a first-line treatment for the cerebral manifestations of TSC ( 51 ). TSC is a genetic disorder that activates the mTOR pathway, leading to the growth of benign tumors in organs, including the brain. Inhibition of mTOR with rapamycin analogues is the only approved pharmacological treatment of the disease, and the only feasible mechanism of action is mTOR inhibition in cells behind the BBB. Visits and data collection Table 1 and Supplementary Information [Additional file 1] outlines the study visits, follow-ups, and corresponding assessments. In brief, participants will be invited to a first screening visit together with a study partner. During the visit the study will be explained in detail and written informed consent will be obtained. Basic clinical and demographic information will be collected, and the study eligibility criteria will be assessed (see Box 1 ). Before initiating of study treatment, the following baseline examinations will be performed: [ 18 F]Fluorodeoxyglucose ([ 18 F]FDG) PET/CT imaging, brain and head MR imaging, cardiological MR imaging, retinal optical coherence tomography, lumbar puncture for collection of a CSF sample, as well as neuropsychological testing and physical aptitude. At the end of the treatment period the same set of follow-up examinations will be performed. During the treatment period, participants will attend three clinical follow-up visits. At every visit, information on side effects will be collected. During the second clinical follow-up, blood will be collected at four time points over 48 hours to study the drug’s pharmacokinetic properties (just before and 1,3, and 48 hours after intake of the weekly dose). At the third clinical follow-up visit, which will occur after the final dose of the study drug, neuropsychological cognitive tests will be performed and a CSF sample will be collected. Additionally, each participant will have at least two scheduled phone calls during the study to assess adverse events or changes in concomitant medications/supplements. Objectives and endpoints Table 2 presents the study objectives along with their respective outcomes and endpoints. View this table: View inline View popup Download powerpoint Table 2. Study objecCves and endpoints Primary objective The primary objective of ERAP is to evaluate the effect of rapamycin on the progression of early-stage AD. The primary endpoint will be the change in [ 18 F]FDG PET uptake in the cerebral grey matter between baseline and the end of the study. Multiple studies have demonstrated that cerebral glucose metabolism, as assessed using [ 18 F]FDG PET, declines progressively with normal aging and is further impaired in AD ( 52 , 53 ). Consequently, brain [ 18 F]FDG uptake is commonly utilized as a diagnostic tool for AD and has served as a biomarker for disease progression when assessing the effectiveness of potential AD treatments ( 54 ). Secondary endpoints for assessing treatment efficacy will be change between baseline and end-of-study in cerebral grey matter perfusion (blood-flow) measured using MRI and a pseudo-continuous arterial spin-labelling sequence; CSF levels of amyloid beta 42, phosphorylated tau and total tau, as well as change in the neuropsychological test the Montreal Cognitive Assessment (MoCA) total score. Secondary objectives The safety and tolerability of intermittently dosed rapamycin in early-stage AD will be assessed. We will monitor and record the incidence of treatment-emergent adverse events (AE), severe adverse events (SAE) by clinical follow-up examinations, where vital signs and blood tests will be assessed (see Supplementary Information 2 and 3 [Additional file 1]). The pharmacokinetic profile of rapamycin has not been thoroughly studied in the setting of an intermittent dosing scheme. As a secondary objective, we will assess the differences in whole blood concentration of the study drug among individuals by comparing peak (C max ), trough (C trough ), and area-under-the-curve (AUC) concentrations. This will also allow us to assess if any potential differences in the treatment effect are associated with drug whole blood concentration among participants. Exploratory objectives An exploratory objective of this study is to quantify changes in multiple age-related tissue pathologies before and after treatment with rapamycin, using a set of imaging techniques (see Table 2 ). If a beneficial effect on multiple such pathologies can be shown, it will lend support to the hypothesis that the study drug has a general geroprotective effect in humans. Exploratory outcomes will consist of assessments of change between baseline and end-of-study imaging outcomes including retinal nerve fibre layer thickness, periodontal oedema, arterial stiffness and [ 18 F]FDG uptake in arterial plaques, cardiac diastolic function, myocardial strain, cardiac microvascular function as well as bone mineral density. Adverse events Safety and tolerability will be assessed through monitoring and recording of all adverse events and serious adverse events. Clinically significant deviations in vital signs, laboratory evaluations, and physical examinations will be considered as adverse events and will be followed up. To the extent that it is possible, all adverse events will be described by their severity grade, duration and relationship to the study drug. Statistics Based on the relatively low variability in long-term test-retest data of [ 18 F]FDG in humans ( 55 , 56 ), a sample size of N = 15 is estimated to be sufficient to detect a 5% change in cerebral grey matter metabolic rate at 80% power with a significance level of 0.05. Such a hypothesized effect size is considered feasible given previous trials of AD using [ 18 F]FDG as an outcome measure ( 57 , 58 ). The change in estimated metabolic rate of grey matter [ 18 F]FDG between baseline and follow-up imaging will be assessed using a paired t-test. Additionally, grey matter differences in standardized uptake value ratios, using the cerebellum as a pseudo-reference region (denominator), will be evaluated as a complementary outcome measure of [ 18 F]FDG uptake. The level of significance will be set at 0.05. Paired t-tests will also be used to assess differences between baseline and end-of-study secondary outcome measures. We will also explore if pharmacokinetics parameters are correlated with 1) each other, 2) side effect burden, 3) treatment effect using linear models. Ethical and Regulatory Considerations The study will be conducted in accordance with the Declaration of Helsinki’ and the International Conference on Harmonisation for Good Clinical Practice (ICH GCP E6). The study protocol and relevant documents were approved by the Swedish Medical Products Agency (Läkemedelsverket, number: 5.1-2023-8283), and the Swedish Ethical Review Authority (Etikprövningsmyndigheten, number: 2023-03075-02 and 2023-00611-01), EudraCT number: 2023-000127-36. The trial has been registered at ClinicalTrials.gov ( NCT06022068 , first release August 30, 2023). Prior to study enrolment, informed consent will be obtained from each participant and their study partner. DISCUSSION The ERAP trial is a phase IIa, one-arm, open-label, single-centre study designed to investigate the potential of the drug rapamycin to be repurposed as a treatment for early-stage AD. Repurposing an approved drug for a new indication has the potential to substantially reduce the cost and time of drug development ( 59 ). In the field of AD treatment research, 37% of candidate agents in the pipeline are repurposed drugs ( 60 ). Possible mechanisms of action Pre-clinical data suggests that rapamycin may be an effective drug for treating neurodegenerative disorders ( 6 , 7 ). Several non-mutually exclusive mechanisms have been hypothesized to underlie this putative effect: Autophagy Regulation: Inhibition of mTOR is known to upregulate cellular macro-autophagy ( 9 ). Deteriorating autophagy and increased mTOR activity have been observed in normal aging and in the progression of AD ( 61 , 62 ). Autophagy plays a central role in clearing intracellular toxic aggregate-prone proteins. Stimulation of autophagy by rapamycin could facilitate intercellular clearance of misfolded proteins central to the pathophysiology of AD. Vasculoprotection : Reduced cerebral perfusion and compromised integrity of the blood brain barrier (BBB) have been suggested as drivers behind AD pathology ( 63 , 64 ), supported by observations of cerebrovascular dysfunction as one of the earliest detectable changes in AD patients ( 65 ). Rapamycin has been shown to improve cerebral perfusion and BBB integrity in rodent models of AD, supporting the notion of the mTOR pathway as a potential target for brain vasculoprotection in AD ( 66 ). Immunomodulation : A sustained activation of microglia and ensuing inflammation is a central feature of neurodegenerative disorders, including in AD ( 67 ). Rapamycin’s effect on immune function is complex; while its main clinical use has been as an immunosuppressant, it has also been shown to augment immunity to certain pathogens ( 68 ), and improve response to influenza vaccination in elderly individuals ( 69 ). Beneficial immunomodulatory effects could be driven by an increase in T-regulatory (Treg) cell function. Tregs might play an important role in the treatment of AD by suppressing microglia-mediated inflammation ( 70 ). In line with this, a reduction in inflammatory CNS markers has been shown following rapamycin treatment ( 71 ), suggesting that this could be a potential mechanism for a treatment effect on AD. Assessment of general geroprotective properties In addition to its potential as a treatment for AD, rapamycin has also been hypothesized to have a general geroprotective effect by slowing multiple age-related processes in the human body. In the ERAP trial, we aim to collect data on a wide range of age-related pathological processes using imaging techniques such as PET, MRI, CT, and retinal OCT. If positive changes are observed in multiple outcomes reflecting various age-related pathologies in different organs and tissues, it would support the hypothesis that rapamycin has a general geroprotective effect. The logistics of collecting and quantifying the listed exploratory imaging outcomes in Table 2 are facilitated by the fact that participants are already undergoing whole-body PET/CT examinations and MRI procedures for the trial’s primary and secondary endpoints. Adding sequences to quantify potential changes in additional pathologies can therefore be done with acceptable levels of additional discomfort and/or radiation exposure to participants. Limitations The main limitations of this study are the absence of a control group, the small sample size and short trial duration. Without a control group, detecting any potential inhibition of AD progression is not possible, and the current design relies on an increase in cerebral glucose metabolism in a relatively short time to demonstrate a positive treatment effect. However, ERAP is a phase IIa trial aimed at generating exploratory data on the effect of rapamycin on AD, and assessing the feasibility of conducting a larger, longer and controlled clinical trial using imaging outcomes as endpoints in the future. CONCLUSIONS The study will measure a set of AD biomarkers before and after a 6-month dosing scheme, with the primary endpoint being change in [ 18 F]FDG PET uptake in the cerebral grey matter, a well-established diagnostic and prognostic biomarker of AD disease progression. The findings from this repurposing effort of rapamycin can provide evidence of a novel treatment alternative for Alzheimer’s disease and form the basis for larger controlled phase IIb or III trials. This study will also investigate the potential general geroprotective effects of rapamycin on various age-related pathologies in the human body. Data Availability The data collected as part of the trial will be shared in accordance with institutional regulations. DECLARATIONS Ethical Approval and consent to participate The study protocol and relevant documents were approved following review by the Swedish Medical Products Agency (Läkemedelsverket, number: 5.1-2023-8283), and the Swedish Ethical Review Authority (Etikprövningsmyndigheten, number: 2023-03075-02 and 2023-00611-01), EudraCT number: 2023-000127-36. The trial has been registered at ClinicalTrials.gov ( NCT06022068 , first release August 30, 2023). Prior to study enrolment, informed consent will be obtained from each participant and their study partner. Consent for publication Not applicable Availability of data and materials Not applicable Competing Interest The authors declare that they have no competing interests. Funding The study is supported by a Longevity Impetus grant from the Norn Group, Åhlén Stiftelsen, Demensfonden, The Swedish Society of Medicine (SLS), Loo and Hans Osterman Stiftelse, Stiftelsen för Ålderssjukdomar Karolinska Institutet, Stiftelsen för Gamla Tjänarinnor, Tore Nilssons Stiftelse för Medicinsk Forskning, Stiftelsen Stockholms Sjukhem, Region Stockholm (ALF grant), The Swedish Brain Foundation (PS2021-0012), and KI CIMED. None of the funding bodies had any role in the design of the study or in writing the manuscript. Authors’ Contribution All authors contributed to the development and/or the preparation of the study protocol; PPS and JS are responsible for conception and overall design of the study and obtained funding. PPS and JS prepared the first draft of the manuscript; all authors reviewed and approved the final version of the manuscript. Box 1. Eligibility Criteria STUDY ELIGIBILITY CRITERIA Inclusion criteria Age 55-80 years. Has an available “study partner” that can accompany the participant to planned visits. Has a clinical diagnosis of MCI (mild cognitive impairment), or dementia of Alzheimer’s type, and: At inclusion, the participant meets the criteria for “Alzheimer’s clinical syndrome”, MCI or mild dementia of the Alzheimer’s type, according to the NIA-AA (National Institute of Aging-Alzheimer’s Association) 2018 criteria ( 42 ). At inclusion, the participant is amyloid positive, established with either amyloid PET imaging, or a CSF beta amyloid 1-42 assay, or a CSF beta amyloid 1-42/ beta amyloid 1-40 assay. 3.1 For participants with dementia, the disease should be in an early stage, operationalized as: Having stage 4 mild dementia or lower, according to the NIA-AA 2018 clinical staging criteria ( 42 ). Having a clinical Dementia Rating Scale (CDR) global score of 1 or lower. Having a Montreal Cognitive Assessment (MoCA) score of ≥ 18 or a Rey Auditory Verbal Learning Test (RAVLT) > 4 words after 30 minutes. 3.2 For participants with a diagnosis of MCI, a cognitive deficit with >-1SD in at least one of the following cognitive tests: Wechsler Adult Intelligence Scale subtest to assess processing speed/attention, Rey Auditory Verbal Learning Test (learning and delayed recall) or Rey Complex Figure Test. 4. Is proficient in the Swedish language. 5. Has a normal or clinically acceptable medical history, physical examination, and vital signs. 6. For female participants, the participant has no childbearing potential, meaning that she is surgically sterile or post-menopausal, or a negative pregnancy test following a menstrual period AND use of an acceptable effective contraceptive measure, which must be continued at least 12 weeks after stopping the study drug. Exclusion criteria Has a history of any major disease that may interfere with safe engagement in the intervention (especially severe liver or kidney disease, or uncontrolled diabetes). Has a history of a major neurological disorder, central nervous system infarct, infection or focal lesions of clinical significance on MRI scans. There is evidence of a clinically relevant or unstable psychiatric disorder, based on Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria, including schizophrenia or other psychotic disorder, or bipolar disorder. Fulfill any contraindication for the use of rapamycin, including (but not restricted to): Current or planned medication with a strong inhibitor of CYP3A4 or P-gp. Current or planned medication with a strong inducer of CYP3A4 or P-gp. Other current medications with known serious interaction risks with rapamycin. Known allergy or hypersensitivity to rapamycin. Has significant obesity, per the investigator’s judgement. Has untreated hyperlipidemia that is clinically significant, per the investigator’s judgement. Has undergone treatment with immunosuppressive medications within the last 90 days, or treatment with chemotherapeutic agents for malignancy within the last 3 years. Has had major surgery within 3 months prior to the planned start of rapamycin treatment, or has major surgery planned during the period of the trial. Has used experimental medications for AD or any other investigational medication or device within the last 60 days of inclusion. Participants who have been involved in a monoclonal antibody study are excluded unless it is known that they were receiving placebo in that trial. Acknowledgments We would like to thank Edvin Johansson, Martin Schain and Lars Johansson from Antaros Medical for their assistance with the design of MRI and PET imaging protocols. We would like to thank Lars Farde for his mentorship and feedback on the study design. Footnotes Title revised, abstract updated, funding information added. REFERENCES 1. ↵ Ackley SF , Zimmerman SC , Brenowitz WD , Tchetgen Tchetgen EJ , Gold AL , Manly JJ , et al. Effect of reductions in amyloid levels on cognitive change in randomized trials: instrumental variable meta-analysis . BMJ . 2021 Feb 25; 2. ↵ Thambisetty M , Howard R. Lecanemab trial in AD brings hope but requires greater clarity . Nat Rev Neurol . 2023 ; 19 ( 3 ): 132 – 3 . OpenUrl CrossRef 3. ↵ Prince MJ , Wimo A , Guerchet MM , Ali GC , Wu YT , Prina M. World Alzheimer Report 2015 - The Global Impact of Dementia . An analysis of prevalence, incidence, cost and trends . London : Alzheimer’s Disease International ; 2015 . 4. ↵ Qiu C , Kivipelto M , von Strauss E. Epidemiology of Alzheimer’s disease: occurrence, determinants, and strategies toward intervention . Dialogues Clin Neurosci . 2009 ; 11 ( 2 ): 111 – 28 . OpenUrl CrossRef PubMed 5. ↵ Nadon NL , Strong R , Miller RA , Harrison DE . NIA Interventions Testing Program: Investigating Putative Aging Intervention Agents in a Genetically Heterogeneous Mouse Model . EBioMedicine . 2017 Jul ; 21 : 3 – 4 . OpenUrl 6. ↵ Kaeberlein M , Galvan V. Rapamycin and Alzheimer’s disease: Time for a clinical trial ? Sci Transl Med . 2019 Jan ; 11 ( 476 ). 7. ↵ Querfurth H , Lee HK . Mammalian/mechanistic target of rapamycin (mTOR) complexes in neurodegeneration . Mol Neurodegener . 2021 Jul 2; 16 ( 1 ). 8. ↵ Mannick JB , Lamming DW . Targeting the biology of aging with mTOR inhibitors . Nat Aging . 2023 ; 3 : 642 – 60 . OpenUrl 9. ↵ Johnson SC , Sangesland M , Kaeberlein M , Rabinovitch PS . Modulating mTOR in Aging and Health . In: Interdisciplinary Topics in Gerontology and Geriatrics . 2015 . p. 107 – 27 . 10. ↵ An JY , Quarles EK , Mekvanich S , Kang A , Liu A , Santos D , et al. Rapamycin treatment attenuates age-associated periodontitis in mice . Geroscience . 2017 ; 39 : 457 – 63 . OpenUrl 11. ↵ Harder JM , Guymer C , Wood JPM , Daskalaki E , Chidlow G , Zhang C , et al. Disturbed glucose and pyruvate metabolism in glaucoma with neuroprotection by pyruvate or rapamycin . Proceedings of the National Academy of Sciences [Internet]. 2020 Dec 29; 117 ( 52 ): 33619 – 27 . Available from : doi: 10.1073/pnas.2014213117 OpenUrl Abstract / FREE Full Text 12. ↵ Nakahara T , Morita A , Yagasaki R , Mori A , Sakamoto K. Mammalian Target of Rapamycin (mTOR) as a Potential Therapeutic Target in Pathological Ocular Angiogenesis . Biol Pharm Bull . 2017 ; 40 ( 12 ): 2045 – 9 . OpenUrl 13. ↵ de Munck DG , de Meyer GRY , Martinet W. Autophagy as an emerging therapeutic target for age-related vascular pathologies . Expert Opin Ther Targets [Internet]. 2020 Feb 1; 24 ( 2 ): 131 – 45 . Available from : doi: 10.1080/14728222.2020.1723079 OpenUrl CrossRef 14. ↵ Silva AL , Fusco DR , Nga HS , Takase HM , Bravin AM , Contti MM , et al. Effect of sirolimus on carotid atherosclerosis in kidney transplant recipients: data derived from a prospective randomized controlled trial . Clin Kidney J [Internet]. 2018 Dec 1; 11 ( 6 ): 846 – 52 . Available from : doi: 10.1093/ckj/sfy041 OpenUrl CrossRef 15. ↵ Quarles E , Basisty N , Chiao YA , Merrihew G , Gu H , Sweetwyne MT , et al. Rapamycin persistently improves cardiac function in aged, male and female mice, even following cessation of treatment . Aging Cell [Internet]. 2020 Feb 1; 19 ( 2 ): e13086 . Available from : doi: 10.1111/acel.13086 OpenUrl CrossRef 16. ↵ Urfer SR , Kaeberlein TL , Mailheau S , Bergman PJ , Creevy KE , Promislow DEL , et al. A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs . Geroscience [Internet]. 2017 ; 39 ( 2 ): 117 – 27 . Available from : doi: 10.1007/s11357-017-9972-z OpenUrl CrossRef 17. ↵ Luo D , Ren H , Li T , Lian K , Lin D. Rapamycin reduces severity of senile osteoporosis by activating osteocyte autophagy . Osteoporosis International [Internet]. 2016 ; 27 ( 3 ): 1093 – 101 . Available from : doi: 10.1007/s00198-015-3325-5 OpenUrl CrossRef PubMed 18. ↵ Wu J , Wang A , Wang X , Li G , Jia P , Shen G , et al. Rapamycin improves bone mass in high-turnover osteoporosis with iron accumulation through positive effects on osteogenesis and angiogenesis . Bone [Internet]. 2019 ; 121 : 16 – 28 . Available from: https://www.sciencedirect.com/science/article/pii/S8756328218304691 OpenUrl 19. ↵ Abbayya K , Chidambar YS , Naduwinmani S , Puthanakar N. Association between periodontitis and alzheimer′s disease . N Am J Med Sci . 2015 ; 7 ( 6 ): 241 – 6 . OpenUrl 20. Wu H , Qiu W , Zhu X , Li X , Xie Z , Carreras I , et al. The Periodontal Pathogen Fusobacterium nucleatum Exacerbates Alzheimer’s Pathogenesis via Specific Pathways . Front Aging Neurosci . 2022 ; 14 . 21. Czakó C , Kovács T , Ungvari Z , Csiszar A , Yabluchanskiy A , Conley S , et al. Retinal biomarkers for Alzheimer’s disease and vascular cognitive impairment and dementia (VCID): Implication for early diagnosis and prognosis . Geroscience . 2020 ; 42 : 1499 – 525 . OpenUrl 22. Mutlu U , Colijn JM , Ikram MA , Bonnemaijer PWM , Licher S , Wolters FJ , et al. Association of retinal neurodegeneration on optical coherence tomography with dementia: a population-based study . JAMA Neurol . 2018 ; 75 ( 10 ): 1256 – 63 . OpenUrl 23. Tini G , Scagliola R , Monacelli F , La Malfa G , Porto I , Brunelli C , et al. Alzheimer’s Disease and Cardiovascular Disease: A Particular Association . Cardiol Res Pract . 2020 ; 2020 : 1 – 10 . OpenUrl PubMed 24. Qiu C , Winblad B , Marengoni A , Klarin I , Fastbom J , Fratiglioni L. Heart Failure and Risk of Dementia and Alzheimer Disease . Arch Intern Med . 2006 ; 166 ( 9 ): 1003 – 8 . OpenUrl CrossRef PubMed Web of Science 25. Hughes TM , Craft S , Lopez OL . Review of ‘the potential role of arterial stiffness in the pathogenesis of Alzheimer’s disease.’ Neurodegener Dis Manag . 2015 ; 5 ( 2 ): 121 – 35 . OpenUrl CrossRef PubMed 26. Kalaria RN , Akinyemi R , Ihara M. Does vascular pathology contribute to Alzheimer changes ? J Neurol Sci . 2012 ; 322 ( 1–2 ): 141 – 7 . OpenUrl CrossRef PubMed 27. Peng TC , Chen WL , Wu LW , Chang YW , Kao TW . Sarcopenia and cognitive impairment: A systematic review and meta-analysis . Clinical Nutrition . 2020 ; 39 ( 9 ): 2695 – 701 . OpenUrl 28. Waite SJ , Maitland S , Thomas A , Yarnall AJ . Sarcopenia and frailty in individuals with dementia: A systematic review . Arch Gerontol Geriatr . 2021 ; 92 . 29. Lary CW , Ghatan S , Gerety M , Hinton A , Nagarajan A , Rosen C , et al. Bone mineral density and the risk of incident dementia: A meta-analysis . J Am Geriatr Soc . 2023 ; 194 – 200 . 30. Bliuc D , Tran T , Adachi JD , Atkins GJ , Berger C , van den Bergh J , et al. Cognitive decline is associated with an accelerated rate of bone loss and increased fracture risk in women: a prospective study from the Canadian Multicentre Osteoporosis Study . Journal of Bone and Mineral Research . 2021 ; 36 ( 11 ): 2106 – 15 . OpenUrl 31. ↵ Sui SX , Balanta-Melo J , Pasco JA , Plotkin LI . Musculoskeletal deficits and cognitive impairment: Epidemiological evidence and biological mechanisms . Curr Osteoporos Rep . 2022 ; 20 ( 5 ): 260 – 72 . OpenUrl CrossRef 32. ↵ Van Skike CE , Jahrling JB , Olson AB , Sayre NL , Hussong SA , Ungvari Z , et al. Inhibition of mTOR protects the blood-brain barrier in models of Alzheimer’s disease and vascular cognitive impairment . American Journal of Physiology-Heart and Circulatory Physiology . 2018 Dec ; 314 ( 4 ): 693 – 703 . OpenUrl 33. ↵ Lin AL , Jahrling JB , Zhang W , DeRosa N , Bakshi V , Romero P , et al. Rapamycin rescues vascular, metabolic and learning deficits in apolipoprotein E4 transgenic mice with pre-symptomatic Alzheimer’s disease . Journal of Cerebral Blood Flow & Metabolism . 2017 Dec ; 37 ( 1 ): 217 – 26 . OpenUrl 34. ↵ Jiang T , Yu JT , Zhu XC , Zhang QQ , Cao L , Wang HF , et al. Temsirolimus attenuates tauopathy in vitro and in vivo by targeting tau hyperphosphorylation and autophagic clearance . Neuropharmacology . 2014 ; 85 : 121 – 30 . OpenUrl CrossRef PubMed 35. ↵ Caccamo A , Majumder S , Richardson A , Strong R , Oddo S. Molecular Interplay between Mammalian Target of Rapamycin (mTOR), Amyloid-beta and Tau: effects on cognitive impairments . Journal of Biological Chemistry . 2010 Apr ; 285 ( 17 ): 13107 – 20 . OpenUrl Abstract / FREE Full Text 36. ↵ Wang H , Fu J , Xu X , Yang Z , Zhang T. Rapamycin Activates Mitophagy and Alleviates Cognitive and Synaptic Plasticity Deficits in a Mouse Model of Alzheimer’s Disease . The Journals of Gerontology: Series A . 2021 Oct ; 76 ( 10 ): 1707 – 13 . OpenUrl 37. ↵ Jahrling JB , Lin AL , DeRosa N , Hussong SA , Van Skike CE , Girotti M , et al. mTOR drives cerebral blood flow and memory deficits in LDLR−/− mice modeling atherosclerosis and vascular cognitive impairment . Journal of Cerebral Blood Flow & Metabolism . 2018 ; 38 ( 1 ): 58 – 74 . OpenUrl 38. ↵ Van Skike CE , Hussong SA , Hernandez SF , Banh AQ , DeRosa N , Galvan V. mTOR Attenuation with Rapamycin Reverses Neurovascular Uncoupling and Memory Deficits in Mice Modeling Alzheimer’s Disease . The Journal of Neuroscience . 2021 May ; 41 ( 19 ): 4305 – 20 . OpenUrl Abstract / FREE Full Text 39. ↵ Hampel H , Wilcock G , Andrieu S , Aisen P , Blennow K , Broich K , et al. Biomarkers for Alzheimer’s disease therapeutic trials . Prog Neurobiol . 2011 ; 95 ( 4 ): 579 – 93 . OpenUrl CrossRef PubMed 40. ↵ Herholz K. Use of FDG PET as an imaging biomarker in clinical trials of Alzheimer’s disease . Biomark Med . 2012 ; 6 ( 4 ): 431 – 9 . OpenUrl CrossRef PubMed 41. ↵ Rosenberg A , Ö hlund-Wistbacka U , Hall A , Bonnard A , Hagman G , Rydén M , et al. β-Amyloid, Tau, Neurodegeneration Classification and Eligibility for Anti-amyloid Treatment in a Memory Clinic Population . Neurology . 2022 ; 99 ( 19 ): 2102 – 13 . OpenUrl 42. ↵ Jack CR , Bennett DA , Blennow K , Carrillo MC , Dunn B , Haeberlein SB , et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease . Alzheimer’s & Dementia . 2018 Apr ; 14 ( 4 ): 535 – 62 . OpenUrl 43. ↵ Moes DJAR , Guchelaar HJ , de Fijter JW . Sirolimus and everolimus in kidney transplantation . Drug Discov Today . 2015 Oct ; 20 ( 10 ): 1243 – 9 . OpenUrl CrossRef PubMed 44. ↵ Pfizer . Sirolimus (RAPAMUNE)[package insert]. U.S . Food and Drug Administration website . https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021083s059,021110s076lbl.pdf . Accessed November 29, 2023 . 45. ↵ Sankhala K , Mita A , Kelly K , Mahalingam D , Giles F , Mita M. The emerging safety profile of mTOR inhibitors, a novel class of anticancer agents . Target Oncol . 2009 Jun 21; 4 ( 2 ): 135 – 42 . OpenUrl CrossRef PubMed Web of Science 46. ↵ Lamming DW . Rapamycin and rapalogs . In: Anti-Aging Pharmacology . Elsevier ; 2023 . p. 89 – 118 . 47. ↵ Yacyshyn BR , Bowen-Yacyshyn MB , Pilarski LM . Inhibition by Rapamycin of P-Glycoprotein 170-Mediated Export from Normal Lymphocytes . Scand J Immunol [Internet]. 1996 Apr 1; 43 ( 4 ): 449 – 55 . Available from : doi: 10.1046/j.1365-3083.1996.d01-52.x OpenUrl CrossRef PubMed 48. ↵ Lipinski CA , Lombardo F , Dominy BW , Feeney PJ . Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings . Adv Drug Deliv Rev . 2001 ; 46 ( 1–3 ): 3 – 26 . OpenUrl CrossRef PubMed Web of Science 49. ↵ Serkova N , Jacobsen W , Niemann CU , Litt L , Benet LZ , Leibfritz D , et al. Sirolimus, but not the structurally related RAD (everolimus), enhances the negative effects of cyclosporine on mitochondrial metabolism in the rat brain . Br J Pharmacol [Internet]. 2001 Jul 1; 133 ( 6 ): 875 – 85 . Available from : doi: 10.1038/sj.bjp.0704142 OpenUrl CrossRef PubMed Web of Science 50. ↵ Gottschalk S , Cummins CL , Leibfritz D , Christians U , Benet LZ , Serkova NJ . Age and sex differences in the effects of the immunosuppressants cyclosporine, sirolimus and everolimus on rat brain metabolism . Neurotoxicology [Internet]. 2011 ; 32 ( 1 ): 50 – 7 . Available from: https://www.sciencedirect.com/science/article/pii/S0161813X10002160 OpenUrl CrossRef PubMed Web of Science 51. ↵ Northrup H , Aronow ME , Bebin EM , Bissler J , Darling TN , de Vries PJ , et al. Updated International Tuberous Sclerosis Complex Diagnostic Criteria and Surveillance and Management Recommendations . Pediatr Neurol [Internet]. 2021 ; 123 : 50 – 66 . Available from: https://www.sciencedirect.com/science/article/pii/S088789942100151X OpenUrl CrossRef PubMed 52. ↵ Jiang J , Sun Y , Zhou H , Li S , Huang Z , Wu P , et al. Study of the influence of age in 18F-FDG PET images using a data-driven approach and its evaluation in Alzheimer’s disease . Contrast Media Mol Imaging . 2018 ; x2018 . 53. ↵ Landau SM , Harvey D , Madison CM , Koeppe RA , Reiman EM , Foster NL , et al. Associations between cognitive, functional, and FDG-PET measures of decline in AD and MCI . Neurobiol Aging . 2011 ; 32 ( 7 ): 1207 – 18 . OpenUrl CrossRef PubMed Web of Science 54. ↵ Chételat G , Arbizu J , Barthel H , Garibotto V , Law I , Morbelli S , et al. Amyloid-PET and 18F-FDG-PET in the diagnostic investigation of Alzheimer’s disease and other dementias . Lancet Neurol . 2020 ; 19 ( 11 ): 951 – 62 . OpenUrl PubMed 55. ↵ Fällmar D , Lilja J , Kilander L , Danfors T , Lubberink M , Larsson EM , et al. Validation of true low-dose 18F-FDG PET of the brain . Am J Nucl Med Mol Imaging . 2016 ; 6 ( 5 ): 269 – 76 . OpenUrl 56. ↵ Schaefer SM , Abercrombie HC , Lindgren KA , Larson CL , Ward RT , Oakes TR , et al. Six-month test-retest reliability of MRI-defined PET measures of regional cerebral glucose metabolic rate in selected subcortical structures . Hum Brain Mapp . 2000 May ; 10 ( 1 ): 1 – 9 . OpenUrl CrossRef PubMed Web of Science 57. ↵ Gejl M , Gjedde A , Egefjord L , Møller A , Hansen SB , Vang K , et al. In Alzheimer’s disease, 6-month treatment with GLP-1 analog prevents decline of brain glucose metabolism: randomized, placebo-controlled, double-blind clinical trial . Front Aging Neurosci . 2016 ; 8 ( 108 ). 58. ↵ Kadir A , Andreasen N , Almkvist O , Wall A , Forsberg A , Engler H , et al. Effect of phenserine treatment on brain functional activity and amyloid in Alzheimer’s disease . Ann Neurol . 2008 ; 63 ( 5 ): 621 – 31 . OpenUrl CrossRef PubMed Web of Science 59. ↵ Cummings J , Lee G , Nahed P , Kambar MEZN , Zhong K , Fonseca J , et al. Alzheimer’s disease drug development pipeline: 2022 . Alzheimer’s & Dementia: Translational Research & Clinical Interventions . 2022 Jan 4; 8 ( 1 ). 60. ↵ Pushpakom S , Iorio F , Eyers PA , Escott KJ , Hopper S , Wells A , et al. Drug repurposing: progress, challenges and recommendations . Nat Rev Drug Discov . 2019 Jan 12; 18 ( 1 ): 41 – 58 . OpenUrl CrossRef PubMed 61. ↵ Oddo S. The role of mTOR signaling in Alzheimer disease . Frontiers in bioscience . 2012 ; 4 : 941 . OpenUrl 62. ↵ Karabiyik C , Frake RA , Park SJ , Pavel M , Rubinsztein DC . Autophagy in ageing and ageing-related neurodegenerative diseases . Ageing and Neurodegenerative Diseases [Internet]. 2021 ; 1 ( 2 ). Available from : doi: 10.20517/and.2021.05 OpenUrl CrossRef 63. ↵ Zlokovic B v. Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders . Nat Rev Neurosci [Internet]. 2011 ; 12 ( 12 ): 723 – 38 . Available from : doi: 10.1038/nrn3114 OpenUrl CrossRef PubMed 64. ↵ Galvan V , Hart MJ . Vascular mTOR-dependent mechanisms linking the control of aging to Alzheimer’s disease . Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease . 2016 May ; 1862 ( 5 ): 992 – 1007 . OpenUrl 65. ↵ Iturria-Medina Y , Sotero RC , Toussaint PJ , Mateos-Pérez JM , Evans AC , Weiner MW , et al. Early role of vascular dysregulation on late-onset Alzheimer’s disease based on multifactorial data-driven analysis . Nat Commun [Internet]. 2016 ; 7 ( 1 ): 11934 . Available from : doi: 10.1038/ncomms11934 OpenUrl CrossRef PubMed 66. ↵ van Skike CE , Galvan V. A Perfect sTORm: The Role of the Mammalian Target of Rapamycin (mTOR) in Cerebrovascular Dysfunction of Alzheimer’s Disease: A Mini-Review . Gerontology . 2018 ; 64 ( 3 ): 205 – 11 . OpenUrl CrossRef 67. ↵ Kinney JW , Bemiller SM , Murtishaw AS , Leisgang AM , Salazar AM , Lamb BT . Inflammation as a central mechanism in Alzheimer’s disease . Alzheimer’s & Dementia: Translational Research & Clinical Interventions [Internet]. 2018 Jan 5; 4 ( 1 ): 575 – 90 . Available from: https://onlinelibrary.wiley.com/doi/abs/10.1016/j.trci.2018.06.014 OpenUrl 68. ↵ Wolf S , Hoffmann VS , Sommer F , Schrempf M , Li M , Ryll M , et al. Effect of Sirolimus vs . Everolimus on CMV-Infections after Kidney Transplantation—A Network Meta-Analysis. J Clin Med . 2022 Jul 20; 11 ( 14 ): 4216 . OpenUrl 69. ↵ Mannick J , Giuseppe DG , Maria L M. VN , Jens P , Baisong H , et al. mTOR inhibition improves immune function in the elderly . Sci Transl Med . 2014 Dec ; 6 ( 268 ). 70. ↵ Faridar A , Thome AD , Zhao W , Thonhoff JR , Beers DR , Pascual B , et al. Restoring regulatory T-cell dysfunction in Alzheimer’s disease through ex vivo expansion . Brain Commun . 2020 Jul 1; 2 ( 2 ). 71. ↵ Richardson A , Galvan V , Lin AL , Oddo S. How longevity research can lead to therapies for Alzheimer’s disease: The rapamycin story . Exp Gerontol [Internet]. 2015 ; 68 : 51 – 8 . Available from: https://www.sciencedirect.com/science/article/pii/S0531556514003490 OpenUrl View the discussion thread. Back to top Previous Next Posted February 29, 2024. Download PDF Supplementary Material Data/Code Email Thank you for your interest in spreading the word about medRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. 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