Repurposing Proteostasis-Modifying Drugs to Prevent or Treat Age-Related Dementia: A Systematic Review

Abstract

Background: Dementia has a significant impact on quality of life of older individuals. Impaired proteostasis has been implicated as a potential cause of dementia, that can be therapeutically targeted to improve patient outcomes. This review aimed to collate all current evidence of the potential for targeting proteostasis with repurposed drugs as an intervention for age-related dementia and cognitive decline.

Methods: PubMed, Web of Science and Embase databases were searched from inception until 4th July 2017 for studies published in English. Interventional studies of repurposed proteostasis-modifying drugs in Alzheimer's disease (AD), Parkinson's disease (PD), Lewy Body disease, vascular dementia, and cognitive aging, in either animal models or humans with change in cognition as the outcome were included. The SYRCLE and Cochrane tools were used to assess risk of bias for included studies.

Results: Overall 47 trials, 38 animal and 9 human, were isolated for inclusion in this review. Drugs tested in animals and humans included lithium, rapamycin, rifampicin, and tyrosine kinase inhibitors. Drugs tested only in animals included Macrophage and Granulocyte-Macrophage Colony Stimulating Factors, methylene blue, dantrolene, geranylgeranylacetone, minocycline and phenylbutyric acid. Lithium (n = 10 animal, n = 6 human) and rapamycin (n = 12 animal, n = 1 human) were the most studied proteostasis modifying drugs influencing cognition. Nine of ten animal studies of lithium showed a statistically significant benefit in Alzheimer's models. Rapamycin demonstrated a significant benefit in models of vascular dementia, aging, and Alzheimer's, but may not be effective in treating established Alzheimer's pathology. Lithium and nilotinib had positive outcomes in human studies including Alzheimer's and Parkinson's patients respectively, while a human study of rifampicin in Alzheimer's failed to demonstrate benefit. Microdose lithium showed a strongly significant benefit in both animals and humans. While the risk of bias was relatively low in human studies, the risk of bias in animal studies was largely unclear.

Conclusion: Overall, the collective findings support the hypothesis that targeting proteostasis for treatment of dementia may be beneficial, and therefore future studies in humans with repurposed proteostasis modifying drugs are warranted. Larger human clinical trials focusing on safety, efficacy, tolerability, and reproducibility are required to translate these therapeutics into clinical practice.

Introduction

Dementias including Alzheimer's disease, vascular dementia, Parkinson's disease and Lewy body disease, have a significant impact on global health due to the increasing number of older individuals suffering from this disease (Prince et al., 2015). Developing effective methods for preventing, delaying or treating dementia are pressing priorities. The highest risk factor for dementia is chronological age, with an annual incidence of Alzheimer's disease doubling every 5 years past the age of 65 years (Bermejo-Pareja et al., 2008). Dementia subtypes share several pathological processes including abnormal accumulation of misfolded proteins such as; amyloid beta (Aβ) and tau in Alzheimer's disease, and alpha-synuclein in Parkinson's disease and Lewy Body disease (Ganguly et al., 2017). Loss of proteostasis is an important feature during the aging process (López-Otín et al., 2013), suggesting the age-related decline in the ability to refold or degrade damaged proteins may contribute to the exponential rise in dementia incidence observed with increasing age (Yerbury et al., 2016).

Several drugs already approved for their use in humans are known to enhance proteostasis including; lithium, mTOR inhibitors (sirolimus/rapamycin, everolimus), and tyrosine kinase inhibitors (nilotinib). The concept of modifying aging with a repurposed drug to prevent multiple diseases of aging will soon be tested in the Targeting Aging with Metformin (TAME) trial. TAME will examine Metformin's ability to prevent diseases of aging in non-diabetic elderly, including cognitive impairment (Barzilai et al., 2016), via targeting the deregulated nutrient sensing associated with aging. Applying a similar strategy to target the loss of proteostasis could be effective in preventing and/or treating age-related dementia.

This systematic review will examine the evidence for targeting proteostasis with repurposed drugs as an intervention for age-related dementia and cognitive decline.

Methods

Protocol registration and search strategy

The protocol of this systematic review was registered at PROSPERO International prospective register of systematic reviews (Reg #: CRD42018091645). PubMed, Web of Science and Embase databases were used for this search from inception until 4th July 2017. The complete search strategy is presented in Supplementary Data 1. Key search terms included; “vascular dementia,” “Alzheimer^* disease” “Lewy Body Disease,” “Parkinson^* disease,” “cognitive aging,” “autophag^*,” “lysosom^*,” “proteasome endopeptidase complex,” “molecular chaperone^*,” “unfolded protein response,” “insulin^*,” “mTOR,” “GSK-3,” “akt,” “PI3K,” “AMPK,” “sirtuin^*,” “sirolimus,” “everolimus,” “temsirolimus,” “rapamycin,” “metformin,” “DPP-4,” “GLP-1,” “nicotinamide,” “NAD,” “spermidine,” “imatinib,” “nilotinib,” “dasatinib,” “bosutinib,” “ponatinib,” “bafetinib,” “lithium,” “heat-shock protein,” “calori^* restriction,” “carbohydrate restricted diet,” “protein restricted diet”. In addition to the database search a “snowballing” method was used to identify relevant articles out of the reference section and PubMed citations of each included article. After duplicates were removed studies were then screened for inclusion using Covidence systematic review software (Veritas Health Innovation, Melbourne, Australia).

Eligibility criteria

Type of studies

The search was designed to retrieve all published research studies that investigated the effect of modifying protein homeostasis or deregulated nutrient sensing (DNS) on cognitive function in age-related neurodegenerative disease and normal aging populations. To be included in this review the study had to report on one or more neuropsychological tests measuring change in cognitive function. To meet the criteria of modifying protein homeostasis or deregulated nutrient sensing, the intervention had to be previously demonstrated to modulate these pathways, or data had to be provided proving the intervention's effect on these pathways. Animal in vivo models and human trials were included in this review. The following Dementia populations/models were specifically targeted; Alzheimer's disease, Vascular Dementia, Parkinson's disease and Lewy Body Disease. In addition, normal aging populations, defined as a population not suffering from dementia and over the age of 18 years for human studies, as well as populations likely to have a higher pace of aging such as animal models with diabetes or obesity were included. Randomized controlled trials (RCTs) and non-randomized studies comparing outcomes to either retrospective or prospective controls met the inclusion criteria. Studies were excluded if they met the following criteria; observational studies, exercise as the sole intervention, in vitro data only, conference abstracts, reviews, editorials, letters to the editor, case reports with ≤5 population size, or published in a language other than English.

Outcome

In animals (using mice as an example), cognitive tests would include spatial memory tests (Morris water maze [MWM], radial arm water maze [RAWM], Barnes maze), associative learning tasks (passive avoidance, fear conditioning), alternation tasks (Y-Maze/T-Maze), recognition memory tasks (Novel Object Recognition), attentional tasks (3 and 5 choice serial reaction time), set-shifting tasks, and reversal learning tasks. In human studies examples of neuropsychological measures would be cognitive testing batteries commonly used in clinical or research settings to examine cognitive function, such as the Mini-Mental State Examination (MMSE), Rowland Universal Dementia Assessment Scale (RUDAS), Neuropsychiatry Unit Cognitive Assessment Tool (NUCOG), Montreal Cognitive Assessment (MOCA), Clinical Dementia Rating Scale Sum of Boxes (CDR-SoB), Addenbrooke's Cognitive Examination (ACE) or Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog).

Study selection

Two review authors (DH and CT) independently screened the titles and abstracts and subsequently the full text articles of potentially relevant studies against the inclusion and exclusion criteria. A third reviewer (ABM) resolved any disagreements between the authors.

Included studies were separated into the following four groups for data extraction (1) proteostasis–repurposed drug, (2) proteostasis–novel intervention (defined as a novel molecule, botanical extract, or dietary manipulation), (3) DNS–repurposed drug and (4) DNS–novel intervention. Where an intervention is thought to modify both pathways (for example the mTOR inhibitor, rapamycin) it was included in the loss of proteostasis group. The current paper presents the results of the 1st group: proteostasis—repurposed drugs.

Data extraction and quality assessment

The following variables were extracted independently by two reviewers (DH and CT): author, year of publication, study design, species, animal model/population (dementia subtype or normal aging), sample size, age, sex, baseline cognition/stage of disease, duration of study, cognitive outcome, drug, comparator, setting, hallmark(s) of aging targeted by the intervention, and journal citation. For binary outcomes the number of events and total number in group, percentage of events or ratios with confidence intervals; for continuous outcomes, mean or median, standard deviation, standard error, confidence intervals or interquartile range, and number of participants; other reported results such as mean difference and p-values of measures of cognitive function.

Risk of bias was assessed by two reviewers (DH, CT) using the Cochrane Risk of Bias tool (Higgins et al., 2011) for human studies and SYRCLE's risk of bias tool for animal studies. The SYRCLE RoB tool is an adaptation of the Cochrane tool for use in systematic reviews of laboratory animal studies (Hooijmans et al., 2014).

Registered human trials

To establish the progress of repurposed drugs into human studies which have not yet been completed, clinicaltrials.gov was searched for registered studies of the drugs identified in our search in Alzheimer's disease, Parkinson's disease, Lewy Body Disease and Vascular Dementia.

Results

Study selection and characteristics

The literature search and selection process for this review is illustrated in Figure 1. After exclusion of duplicates the remaining 1,687 studies were screened for Title and Abstracts of which 413 underwent full text screening. An additional 22 studies were identified via snowballing. Overall, 47 articles specifically investigating a proteostasis intervention on Dementia and cognitive aging were included in this review. The repurposed drugs used in these intervention studies are outlined in Tables 1, 2 and Supplementary Table 1. The following drugs were found testing the modification of cognition in animal and human studies; lithium (n = 10 animal, n = 6 human), rapamycin (n = 12 animal, n = 1 human), rifampicin (n = 1 animal, n = 1 human), tyrosine kinase inhibitors (bosutinib n = 1 animal, nilotinib n = 1 human), Macrophage Colony Stimulating Factor (M-CSF; n = 1 animal), Granulocyte Macrophage Colony Stimulating Factor (GM-CSF; n = 1 animal), methylene blue (n = 4, animal), geranylgeranylacetone (GGA; n = 2 animal), dantrolene (n = 3 animal), minocycline (n = 2 animal) and phenylbutyric acid (n = 1 animal). Doxycycline was tested in a single human trial only. Of these drugs only lithium, rapamycin, rifampicin, and the tyrosine kinase inhibitors have been tested in both animal and human studies (Figure 2).

Figure 1

Figure 2

Lithium and cognitive aging

Lithium was the most investigated proteostasis modulator for cognitive aging. Overall 16 studies (6 humans, 6 mice, 2 rats, 1 drosophila, and 1 zebrafish) investigating the influence of lithium on cognitive aging were found. The majority of these studies utilized an Alzheimer's animal model or were conducted in an Alzheimer's population (Tables 1, 2). The findings of these studies were largely positive with all animal studies, bar one (Caccamo et al., 2007), reporting the use of lithium as having a statistically significant beneficial impact on at least one cognitive outcome irrespective of treatment duration (Table 3). The findings of the animal studies are consistent with the lithium human studies (Table 4), with three randomized controlled studies showing a statistically significant benefit of the use on lithium on either the ADAS-Cog or MMSE (Leyhe et al., 2009; Forlenza et al., 2011; Nunes et al., 2013). The other three studies, two of which were open-label (Pomara et al., 1983; Macdonald et al., 2008) and one RCT (Hampel et al., 2009), did not show cognitive benefits after treatment with lithium.

Rapamycin and cognitive aging

Rapamycin has been identified as the second most frequently investigated (n = 13 studies) proteostasis modulator. Twelve animal studies (10 mice, 2 rats), predominately using an Alzheimer's disease model, investigated the influence of rapamycin on cognitive aging (Table 1). Overall, nine out of twelve animal studies reported a statistically significant benefit on at least one cognitive outcome, irrespective of treatment duration (Table 3). One human study investigating safety, efficacy and tolerability of rapamycin in humans (Kraig et al., 2018), did not report any significant benefit to overall cognition in an older population (Table 4).

Rifampicin, tetracycline antibiotics, tyrosine kinase inhibitors and cognitive aging

Rifampicin, tetracycline antibiotics and tyrosine kinase inhibitors have been tested in both animal and human models (Tables 1, 2). The two rifampicin studies (1 mouse, 1 human; Tables 3, 4) investigating its therapeutic effects for Alzheimer disease had opposite findings, with positive cognitive outcomes in mice (Umeda et al., 2016), but no benefit found in the human study (Molloy et al., 2013).

Studies of tetracycline antibiotics showed similar results to rifampicin, with minocycline showing cognitive benefits in two studies using rat and chicken models of Alzheimer disease (Supplementary Table 1, Supplementary Table 2), while another tetracycline, doxycycline, showed no benefit in human AD patients, either alone or in combination with rifampicin (Molloy et al., 2013).

The tyrosine kinase inhibitor, bosutinib, was reported in mouse models of Alzheimer's disease as statistically beneficial to cognitive function, and another tyrosine kinase inhibitor, nilotinib, was found to improve scores on the MMSE and SCOPA-Cog in an open-label study in patients with Parkinson's disease, however the statistical significance was not reported (Tables 3, 4).

Other proteostasis-modifying drugs

There were six proteostasis modulators that have been tested to improve cognitive outcomes in animal models but are yet to be studied in human populations—M-CSF, GM-CSF, methylene blue, GGA, dantrolene, and phenylbutyric acid (Supplementary Table 1). Both of the M/GM-CSF studies indicated beneficial outcomes with the use of these therapeutics in mouse models of Alzheimer's disease, as was the case with methylene blue, GGA and phenylbutyric acid (Supplementary Table 2). Studies of dantrolene to improve cognitive outcomes showed a statistically significant improvement in one mouse model of Alzheimer's (Peng et al., 2012) but no benefit to cognition in another (Wu et al., 2015), with one study in aged rats indicating a trend toward benefit on Morris water maze performance.

Risk of bias

Table 5 shows the SYRCLE risk of bias ratings for animal studies. The majority of animal studies had an unclear risk of bias, as specific details of randomization and blinding were often not provided. Most studies provided information on the baseline characteristics of animals, and some studies did specify that the investigator performing behavioral assessments of the animals was blinded to the treatment status of the animal, indicating low risk of bias where this was the case. Overall the risk of bias was similar across studies regardless of the drug being tested.

Table 6 shows the Cochrane risk of bias rating for human studies. There was significant heterogeneity among lithium studies, with (Pomara et al., 1983; Macdonald et al., 2008) scoring high risk of bias across most or all domains due to an open label design and not reporting all quantitative outcome data. (Hampel et al., 2009) had an intermediate risk of bias as investigators were aware of patient treatment status. Studies by Leyhe et al. (2009), Forlenza et al. (2011) and Nunes et al. (2013) scored a lower risk of bias due to randomized, double-blind designs, though details of sequence generation and allocation concealment were not reported. Studies of rapamycin (Kraig et al., 2018) and rifampicin (Molloy et al., 2013) scored a low risk of bias across most domains. The study using nilotinib (Pagan et al., 2016) was rated as having a high risk of bias across most domains, due to an open label design.

Registered human trials

Figure 2 shows the progress of the drugs identified in our search from animal into human studies, including planned or ongoing studies registered on clinicaltrials.gov. Nilotinib has two phase 2 studies registered, one in Alzheimer's disease and one in Parkinson's disease. Lithium has one phase 4 study registered, while GM-CSF and phenylbutyric acid each have one phase 2 study registered in Alzheimer's disease.

Discussion

In this review we have summarized all current animal and human research studies that have investigated the effect of proteostasis modulators on cognitive function. Overall, the therapeutic alteration of proteostasis pathways using repurposed drugs is a promising approach to the treatment of dementia and age-related cognitive decline with a reasonable research translation between animal and human studies showing similar conclusions observed across the studies.

Lithium

Lithium was the most studied proteostasis modifying drug identified in this review, and the furthest progressed in translation to treatment of age-related dementia. All except one of the animal studies included in this review showed a benefit to at least one cognitive outcome despite heterogeneity in species, model, dose, stage of disease at intervention and duration of treatment. Three of six human studies also found benefit, and consistent with the results in mice the largest effect was observed with microdoses and long duration of treatment (Nunes et al., 2013). The only negative RCT used a high dose for a short duration (Hampel et al., 2009). Taken together, these studies show lithium has a consistent benefit in Alzheimer's disease in animal models and humans, which appears more pronounced with lower doses, longer durations of treatment, and when commenced at an earlier stage of disease.

The apparent superiority of lower doses of lithium is encouraging, as at standard psychiatric dose it can have renal and thyroid-related side effects that limit tolerability and is toxic at levels only slightly above the therapeutic range (Timmer and Sands, 1999). Higher lifetime exposure to natural microlevels of lithium in drinking water is associated with a reduced incidence of dementia (Kessing et al., 2017), a finding which adds plausibility to the idea that microdoses of lithium rather than the current therapeutic doses might be beneficial for the treatment of dementia.

A possible explanation for lithium's non-linear dose response involves the interaction between lithium's autophagy-enhancing inhibition of inositol triphosphate receptor (IP3R) signaling, and its autophagy-reducing inhibition of GSK-3B, a tau-phosphorylating kinase (Sarkar et al., 2008). Genetic reduction of IP3R signaling in drosophila rescues Alzheimer's disease phenotypes in the same way lithium does (McBride et al., 2010), suggesting lithium's inhibition of IP3R signaling via reducing the formation of inositol triphosphate (IP3) may be sufficient to cause its benefits. This is mechanistically plausible, as inhibition of IP3R signaling enhances autophagy through decreasing calcium release from the endoplasmic reticulum, enhancing proteostasis (Sarkar et al., 2005). However; lithium's inhibition of GSK3B has also been postulated to have beneficial effects in Alzheimer's disease via reducing tau phosphorylation and neurofibrillary tangle formation as well as inhibiting autophagy via increasing mTOR signaling (Sarkar et al., 2008). Although, this latter theory is less likely to explain the positive influence of microdoses of lithium as lower levels of lithium do not inhibit GSK-3B in mice (Nunes et al., 2015). However, this GSK-3B mechanism may explain the reduced efficacy of lithium observed with increasing doses. Increased mTOR signaling due to GSK3B inhibition counteracts the autophagy-enhancing effects of reduced IP3R activation beyond a certain dose (Sarkar et al., 2009). If increased mTOR activity limits the effective dose of lithium, this raises the question of whether an mTOR inhibitor such as rapamycin combined with lithium would have beneficial synergistic effects in dementia or cognitive aging. A synergistic benefit of lithium and rapamycin has been demonstrated in a drosophila Huntington's disease model (Sarkar et al., 2008), but to our knowledge this has not been explored in models of Alzheimer's disease.

Rapamycin

Predictably, rapamycin the known inhibitor of mTOR was also one of the most studied proteostasis modulators investigated, more so in animal models then in humans. Overall, the trials indicated a positive therapeutic effect of rapamycin on cognitive outcomes. Cognitive benefits via rapamycin was demonstrated in models of normal aging (Majumder et al., 2011, 2012; Neff et al., 2013; Wang et al., 2014), vascular dementia (Jahrling et al., 2017), and transgenic Alzheimer's disease models (Spilman et al., 2010; Majumder et al., 2011; Lin et al., 2013; Zhang et al., 2017), which suggests rapamycin has potential to rescue cognitive decline caused by a range of pathologies. This breadth of efficacy is a promising characteristic, as autopsy studies have demonstrated that mixed pathology is common in dementia sufferers (Nelson et al., 2016).

Majumder et al. (2011) reported a possible mechanism explaining their findings that rapamycin while effective in preventing cognitive decline before pathology develops, fails as a treatment once Alzheimer's pathology is established. They found rapamycin induces autophagy strongly both before and after Alzheimer's pathology is present. However, increased autophagy induction fails to reduce levels of amyloidβ in mice with established disease and leads to accumulation of enlarged autophagosomes containing undigested material. This finding suggests deficient substrate clearance and is consistent with previous findings that autophagy in Alzheimer's disease is principally defective at the stage of autolysosomal proteolysis (Nixon and Yang, 2011; Bordi et al., 2016). Therefore, to be effective in established Alzheimer's dementia rapamycin may need to be combined with a drug that can enhance autophagy at the stage of autolysosomal digestion.

Rapamycin's demonstrated ability to improve phenotypes of aging in animals has recently led to human trials assessing safety and efficacy in older adults (Kraig et al., 2018). Despite demonstrating low-dose rapamycin can be used safely in older adults, they were unable to show significant enhancement of cognition. However, larger trials are required to determine the potential benefit of rapamycin's for cognitive aging in humans.

Rifampicin, tetracycline antibiotics and tyrosine kinase inhibitors

Rifampicin was more effective when started earlier in the disease process, and when used at a higher dose (Umeda et al., 2016). Cohorts treated with the lower dose at a later stage of disease did not show an improved cognitive benefit, a finding which is relevant to interpreting the DARAD study of rifampicin in Alzheimer's disease by Molloy et al. (2013).

In the DARAD study, rifampicin was tested in Alzheimer's patients at a low dose and showed either no benefit or on some measures a significant worsening of cognition compared to placebo. A possible explanation for this failure is an insufficient dose and treatment duration. Data supporting this view is provided by Iizuka et al. (2017), who in an observational study determined that a minimum dose rifampicin of 450 mg/day for at least 12 months was required before any cognitive improvement was observed (Iizuka et al., 2017).

Doxycycline also failed to produce benefit for human Alzheimer's disease patients in the DARAD study (Molloy et al., 2013), despite positive animal studies with closely related tetracycline antibiotic minocycline (Choi et al., 2007; Gibbs and Gibbs, 2013). It is difficult to know what implications this has for minocycline's repurposing potential, however currently there are no upcoming human studies registered on clinicaltrials.gov for either doxycycline or minocycline in dementia.

Lonskaya et al examined bosutinib in two mouse models of established Alzheimer's disease, and demonstrated statistically significant benefits after 3 weeks of treatment. Beneficial effects on cognition were also observed in human Parkinson's disease patients by Pagan et al. although the small size and open label design of the study mean the results require confirmation in larger randomized trials. These promising findings have led to significant interest in repurposing these drugs, to the extent phase 2 clinical trials are currently assessing the effect of these drugs in Alzheimer's and Parkinson's disease cohorts.

Other proteostasis-modifying drugs

Three other proteostasis-modifying drugs have excited interest in translating promising animal study findings into humans—GM-CSF, methylene blue and phenylbutyric acid have registered phase 2 studies on clinicaltrials.gov to test their use in Alzheimer's disease.

Dantrolene is a drug of interest due to similarities it shares with lithium, in that it enhances autophagy by reducing calcium efflux from the endoplasmic reticulum (Wang et al., 2017). Unlike lithium however it acts by inhibition of the ryanodine receptor rather than IP3R signaling, raising the possibility of a complementary mechanism of action (Vervliet et al., 2017). This suggests dantrolene is worth testing in human trials to determine whether it can provide similar benefits to lithium, and in combination with lithium in animal models for potential synergistic effects. Currently however, no human trials are registered on clinicaltrials.gov for dantrolene in dementia.

Limitations

Our study has several limitations. Our search strategy was based primarily on key terms related to the mechanisms of proteostasis, with the addition of a selection of drugs well known to modulate these processes. Therefore, our search may have missed studies that examine proteostasis-modifying drugs not named in our search and not mentioning proteostasis related key terms. However, we addressed this by adding relevant articles by snowballing.

Secondly, because the present study's focus is restricted to approved drugs, it does not provide an adequate overview of the translational pipeline where a repurposed drug is used as the basis for novel molecules that proceed into later stage studies.

Third, we cannot exclude publication bias, particularly in animal studies which are unlikely to be registered beforehand and may be less likely to be published if results are negative.

Conclusions

The results of this review support the concept of a translational approach to repurposing proteostasis modifying drugs for the treatment of age-related dementia and cognitive decline. However, larger clinical trials assessing the influence of these drugs particularly, lithium and rapamycin are required before they are ready for the clinic. In addition, animal models assessing whether the combination of proteostasis modulators can act in synergy to improve cognitive outcomes are required. A translational strategy based on systematic screening of rational drug combinations starting in simple model organisms such as C. elegans may provide a pipeline of novel candidate therapies to advance into human studies.

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