SYSTEMATIC REVIEW published: 08 January 2020 doi: 10.3389/fnagi.2019.00344 Benzodiazepines and Related Drugs as a Risk Factor in Alzheimer’s Disease Dementia Miren Ettcheto 1,2,3,4*, Jordi Olloquequi 5† , Elena Sánchez-López 4,6,7 , Oriol Busquets 1,2,3,4 , Amanda Cano 4,6,7 , Patricia Regina Manzine 8 , Carlos Beas-Zarate 9 , Rubén D. Castro-Torres 9 , Maria Luisa García 4,6,7 , Mónica Bulló 2,10,11 , Carme Auladell 3,4,12 , Jaume Folch 2,4† and Antonio Camins 1,3,4,5*† 1 Departament de Farmacologia, Toxicologia i Química Terapèutica, Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona, Barcelona, Spain, 2 Departament de Bioquímica i Biotecnologia, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Reus, Spain, 3 Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain, 4 Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Madrid, Spain, 5 Laboratory of Cellular and Molecular Pathology, Facultad de Ciencias de la Salud, Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Talca, Chile, 6 Unitat de Farmàcia, Tecnologia Farmacèutica i Fisico-química, Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona, Barcelona, Spain, 7 Institute of Nanoscience and Nanotechnology (IN2UB), Universitat de Barcelona, Barcelona, Spain, 8 Department of Gerontology, Federal University of São Carlos (UFSCar), São Carlos, Brazil, 9 Laboratorio de Regeneración y Desarrollo Neural, Departamento de Biología Celular y Molecular, Instituto de Neurobiología, CUCBA, Guadalajara, Mexico, 10 Institut d’Investigació Sanitària Pere Virgili (IISPV), Reus, Spain, 11 Centro de Investigación Edited by: Biomédica en Red Fisiopatologia de la Obesidad y la Nutrición (CIBEROBN), Institut de Salud Carlos III, Madrid, Spain, Ines Moreno-Gonzalez, 12 Departament de Biologia Cellular, Fisiologia i Immunologia, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain University of Málaga, Spain Reviewed by: Zheng Chen, Benzodiazepines (BZDs) and Z-drugs are compounds widely prescribed in medical University of Texas Health Science practice due to their anxiolytic, hypnotic, and muscle relaxant properties. Yet, Center at Houston, United States their chronic use is associated with cases of abuse, dependence, and relapse Claudia Duran-Aniotz, University of Chile, Chile in many patients. Furthermore, elderly people are susceptible to alterations in *Correspondence: pharmacodynamics, pharmacokinetics as well as to drug interaction due to Miren Ettcheto polypharmacy. These situations increase the risk for the appearance of cognitive e_miren60@hotmail.com Antonio Camins affectations and the development of pathologies like Alzheimer’s disease (AD). In the camins@ub.edu present work, there is a summary of some clinical studies that have evaluated the effect † These authors share of BZDs and Z-drugs in the adult population with and without AD, focusing on the senior authorship relationship between their use and the loss of cognitive function. Additionally, there is an assessment of preclinical studies focused on finding molecular proof on the pathways Received: 27 June 2019 Accepted: 26 November 2019 by which these drugs could be involved in AD pathogenesis. Moreover, available data Published: 08 January 2020 (1990–2019) on BZD and Z-drug use among elderly patients, with and without AD, was Citation: compiled in this work. Finally, the relationship between the use of BZD and Z-drugs for Ettcheto M, Olloquequi J, the treatment of insomnia and the appearance of AD biomarkers was analyzed. Results Sánchez-López E, Busquets O, Cano A, Manzine PR, Beas-Zarate C, pointed to a vicious circle that would worsen the condition of patients over time. Likewise, Castro-Torres RD, García ML, it put into relevance the need for close monitoring of those patients using BZDs that Bulló M, Auladell C, Folch J and Camins A (2020) Benzodiazepines also suffer from AD. Consequently, future studies should focus on optimizing strategies and Related Drugs as a Risk Factor in for insomnia treatment in the elderly by using other substances like melatonin agonists, Alzheimer’s Disease Dementia. which is described to have a much more significant safety profile. Front. Aging Neurosci. 11:344. doi: 10.3389/fnagi.2019.00344 Keywords: benzodiazepines, Alzheimer’s disease, dementia, cognition, risk factors Frontiers in Aging Neuroscience | www.frontiersin.org 1 January 2020 | Volume 11 | Article 344 Ettcheto et al. Benzodiazepines as a Risk Factor in Alzheimer’s Disease INTRODUCTION against anxiety, nervousness, convulsive states, depression, and psychosis. They also act as skeletal muscle relaxants and Sleep disturbances have been reported to increase Amyloid hypnotics for the treatment of short-term acute insomnia Beta (Aβ) levels in the cerebrospinal fluid of healthy subjects, (Dolder et al., 2007). On a molecular level, BZDs and Z-drugs contributing to the advancement of neurodegeneration and the facilitate the inhibitory activity of the neurotransmitter gamma- appearance of mild cognitive impairment (MCI) (Lopez et al., aminobutyric acid (GABA) on its receptor (Duke et al., 2018), 1999; Virta et al., 2007; Modabbernia et al., 2011; Consensus favoring the flow of chlorine ions through the ionotropic channel and Statements, 2014; Di Meco et al., 2014; Benedict et al., bound to the receptor and producing the hyperpolarization 2015; Gage et al., 2015; Chen et al., 2016; Gaugler et al., 2016; of neuronal membranes (Sigel and Ernst, 2003). The GABAA Kincheski et al., 2017; La Frenais et al., 2017; Livingston et al., receptor is an ionotropic receptor composed of five protein 2017; Atkin et al., 2018; Burke et al., 2018). At preclinical subunits that mediate different behavioral and pharmacological level, it has been described that sleep deprivation in 3xTg responses (Mehdi, 2012; Duke et al., 2018). The α1 subunit of the mice acts as a chronic stressor, favoring the decrease of Cyclic GABAA receptor is thought to be responsible for sedative effects, adenosine monophosphate (cAMP) response element binding while the α2 and α3 subunits exert anxiolytic and antidepressant (CREB) and affecting synaptic plasticity and cognitive functions activities. Finally, the α5 subunit is involved in the control of (Di Meco et al., 2014) (Figure 1). It has been described that cognitive functions such as memory and learning (Rissman et al., sleep restriction increases susceptibility to Amyloid beta (Aβ)- 2007; Savić et al., 2010). induced memory impairment in mice (Kincheski et al., 2017), From a pharmacokinetic point of view, BZDs and related accompanied by increased plasma levels of corticosterone, just drugs are divided into three groups according to their half-life. like higher levels of brain pro-inflammatory cytokines [tumor It can either be long (over 24 h), intermediate (between 6 and necrosis factor alfa (TNFα), interleukin 1 beta (IL1-β) and IL-6], 24 h), or short (<6 h). Usually, short and intermediate-acting which contributed to memory impairment and synapse damage. BZDs are prescribed for insomnia, while longer-acting BZDs Consequently, sleep alterations have become major risk factors are reserved for anxiety, but their effects can vary with age and for the development of sporadic pathologies like AD and need liver metabolic capacity. Old age is associated with a decrease of to be properly managed by drugs that will restore balanced oxidative metabolism, causing an extension on drug half-life due physiological sleep periods (Kincheski et al., 2017; Hennawy to changes in pharmacokinetics and pharmacodynamics (Taipale et al., 2019). et al., 2015; Hessmann et al., 2018). In fact, the prolonged use Benzodiazepines (BZDs) and their analogous Z-drugs of these drugs (over 2 months) in advanced age has shown to are psychotropic drugs commonly used in medical practice produce serious side effects, causing tolerance and dependence, FIGURE 1 | Schematic representation of potential pathways by which insomnia and benzodiazepines could increase AD risk. Insomnia is a CNS stressor, which induces microglial activation and oxidative stress. Likewise, oxidative stress may be involved in cognitive impairment by decreasing phosphorylation levels of p-CREB and altering dendritic spines and synapses. Moreover, sleep disturbances prevent clearing toxic metabolites such as β-amyloid. These lead to an increased production of inflammatory cytokines and the formation of Aβ-plaques. In turn, BZDs activate GABAA receptors, thus interfering excitatory synapses and decreasing cognitive reserve. Moreover, these drugs have been shown to decrease BDNF as well as increase β-amyloid precursor protein (APP) mRNA levels and tau phosphorylation. All these mechanisms could increase the risk of cognitive impairment through neuroinflammation, decrease synaptic plasticity and brain insulin signaling as well as accumulation of Aβ plaques and neurofibrillary tangles. Frontiers in Aging Neuroscience | www.frontiersin.org 2 January 2020 | Volume 11 | Article 344 Ettcheto et al. Benzodiazepines as a Risk Factor in Alzheimer’s Disease increased risk of falls and fractures as well as an impairment of uncertain, several hypotheses have been suggested (Gage et al., cognitive processes (Pharmd et al., 2003; Obradovi et al., 2005; 2015). These mechanisms are summarized in Figure 1. Stewart, 2005; Rissman et al., 2007; Savić et al., 2010; Rosenberg One hypothesis states that elderly long-term consumers of et al., 2012; Makaron et al., 2013; Biétry et al., 2017; Nørgaard BZDs show limited cognitive reserve capacity. This concept et al., 2017; Duke et al., 2018; Picton and Pharm, 2018; Underlien refers to the ability to tolerate age-related and disease-related et al., 2018; Scott and Aricescu, 2019). changes in the brain due to the existence of strong and The effects of BZDs and other hypnotic drugs on cognition redundant synaptic connections in the brain. This mechanism in elderly patients are intensive areas of research nowadays would allow resisting longer neurodegenerative pathologies (Carlisle, 2017). In a recent study, Kurlawala et al. reported a without developing clear cognitive clinical symptoms or case of a 76-year-old male who presented onset of short-term memory loss (Stern, 2012). Since BZDs and Z-drugs are positive memory loss after a 3 year treatment with a BZD (Kurlawala GABAA receptor modulators, they decrease brain activation et al., 2018). Magnetic resonance imaging studies revealed that and reduce synaptic plasticity, affecting the patient’s ability to cognitive loss could be a result of atrophy in the hippocampus create a new memory. Thus, BZDs interfere with the function and cortex (Barker et al., 2004; Hessmann et al., 2018; Kurlawala of excitatory synapses, which is required for memory. In et al., 2018; Picton and Pharm, 2018). Studies performed by addition, the loss of social networks in aging people could act the groups of Glass et al. and Kripke et al. reported that the as an additional factor that may also affect cognitive function. adverse effects of hypnotics outweigh the benefit they achieve Likewise, BZD treatment for sleep disturbances in aging in the population older than 60 years, going so far as to could limit the capacity to create social communication increase mortality risk in some patients (Glass et al., 2005; Kripke networks and precipitate the development of dementia et al., 2012; Hammond and Esclapez, 2015). Consequently, these (Wan et al., 2004; Pariente et al., 2016; Mohamad et al., 2019). results have led the National Institutes of Health and the Beers The composition of GABAA receptors could also be involved Criteria of the American Geriatric Society to list molecules, in cognitive alterations related to hypnotic drugs. It has been such as eszopiclone, zolpidem, and zaleplon, as “potentially reported that the binding of BZDs to the α5GABAA subunit, inappropriate medications” (Consensus and Statements, 2014; which is almost exclusively found in the hippocampus and deep Investigations, 2015; Taipale et al., 2015; Wennberg et al., 2018). layers of the cortex, impairs memory for contextual information It was determined that BZDs should be avoided or should only in monkeys (Wan et al., 2004; Mohamad et al., 2019). Of be prescribed for short and specific situations (Letter, 2019; note, Zolpidem did not impair the performance of a task based Walsh and Roth). However, BZDs and Z-drugs are still widely on visual cues which could be explained by its affinity for inappropriately prescribed in sleepless patients (Gunja, 2013; the α1GABAA , instead of α5GABAA (Mohamad et al., 2019). Pariente et al., 2016; Nørgaard et al., 2017; Richardson et al., Moreover, it has been reported that the memory-impairing 2018). effects of BZDs are not blocked by the α1GABAA-selective BZD Luckily, alternatives to BDZs exist to treat situations of antagonist β-carboline-3-carboxylate-3-butyl-ester, whereas the sleep deprivation. Sateia et al. published a clinical practice guideline for the treatment of insomnia in the Journal of Clinical α5GABAA antagonist XLi-093 blocked the effects of triazolam Sleep Medicine (Sateia et al., 2017a,b). In their manuscript, but not zolpidem (Caraiscos et al., 2004; Mohamad et al., 2019). the authors suggest ramelteon for sleep-onset insomnia. This These findings suggest a specific role of α5GABAA receptor in drug selectively binds to the melatonin receptors, avoiding BZD-related cognitive impairment. Furthermore, recent reports dependence and other important side effects associated with suggest that the modulation of extrasynaptic tonic inhibition of BZD long-term treatment. In the same paper, the authors also α5GABAA in the CA1 hippocampus and cerebral cortex could recommend Z-drugs or BZD hypnotics for sleep maintenance in improve and regulate memory processes in the hippocampus. insomnia (Sateia et al., 2017a). In 2018, the U.S. Food and Drug Therefore, negative modulation of α5GABAA could be a suitable Administration (FDA) approved several non-BZD compounds target for the development of potential therapies against cognitive for the treatment of insomnia (Richardson et al., 2018). These dysfunction in neurological diseases (Caraiscos et al., 2004). include antidepressants with anxiolytic or sedative action, such Contrarily, Joksimović et al. demonstrated that α1GABAA as escitalopram, doxepin, trimipramine, and amitriptyline as subunit receptor activation may affect the spatial learning well as heterocyclic drugs like trazodone and mirtazapine performance in rodents (Joksimović et al., 2013). They also (Gunja, 2013; Richardson et al., 2018). reported that α1GABAA subunit is involved in anterograde The objective of this article was to review and discuss amnesia, sedation, motor incapacitation, and anticonvulsant published material on the risk of BZD and Z-drug use and their BZD effects. role in the appearance of cognitive loss in cases of AD. On another front, the “GABAergic deafferentation hypothesis of brain aging” introduced by Marczynski is based on the fact that administration of diazepam to rats causes a diminution of glucose THE POTENTIAL MOLECULAR utilization in the brain (Marczynski, 1995, 1998). Since a decrease MECHANISMS INVOLVED IN in cellular adenosine triphosphate (ATP) levels is a feature of BENZODIAZEPINES AND RELATED DRUG the aging process and AD, it would be logical to consider a INDUCED COGNITIVE IMPAIRMENT potential metabolic influence of BZDs–GABA receptor complex in the brain, predisposing to AD in aging (Marczynski, 1995). Although the molecular mechanisms by which BZDs and Regarding this, the administration of flumazemil, an antagonist psychotropic drugs could induce cognitive impairment are of BZDs, increases glucose utilization in rodents (Marczynski, Frontiers in Aging Neuroscience | www.frontiersin.org 3 January 2020 | Volume 11 | Article 344 Ettcheto et al. Benzodiazepines as a Risk Factor in Alzheimer’s Disease 1998). Thus, a potential mechanism explaining the deleterious useful in guiding physicians about avoiding BZD prescription in effects of BZDs on cognitive processes could be the depolarization at risk patients. Finally, Stonnington and collaborators reported and the depressive action of BZD agonists leading to brain that acute 2 mg dose of lorazepam given to middle aged (50–65 energy metabolism deficit. In addition, BZD agonists may years) cognitive normal adults caused higher decline in verbal inhibit the effects of paracrine-autocrine neurotrophin family. episodic memory and visuospatial memory/executive function in Indeed, it is well-known that nerve growth factor (NGF)-related ε4 carriers compared to non-carriers (Stonnington et al., 2009). proteins participate in the regulation of survival, growth, and However, Aβ might also have indirect effects on the maintenance of neurons. In this sense, Zhao et al. reported inhibitory GABAergic transmission as a result of the dynamic that mice under long-term diazepam administration showed GABAergic balance modulation of the other two excitatory behavior alterations and reduced hippocampal synaptophysin systems (cholinergic and glutamatergic neurotransmission). and brain-derived neurotrophic factor (BDNF) levels (Zhao Interestingly, it has recently been suggested that the imbalance et al., 2012). This is a matter of importance since BDNF between excitatory and inhibitory systems underlies the synaptic influences the functional aspects of synaptic transmission by dysfunction caused by Aβ (Rissman et al., 2007). (i) enhancing the number of α-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA) receptors in the postsynaptic CLINICAL STUDIES membrane, (ii) enhancing Long term potentiation (LTP), and (iii) reducing GABAA receptor expression and decreasing Between November 2018 and February 2019, we performed a inhibitory GABA-ergic neuro-transmission in the hippocampus literature review on clinical studies linked to the research topic (Jovanovic, 2004). Through this mechanism, BZDs could inhibit in three acknowledged databases: Web of Science, Scopus, and the axonal transport in both directions, increase the formation of PubMed. The collocated keywords were as follows: Alzheimer’s neurofibrillary tangles, and also induce the βAPP-mRNA gene disease AND benzodiazepines, Benzodiazepines AND cognitive expression, thus increasing the risk of AD. Furthermore, the impairment, Benzodiazepines AND cognitive decline, hypnotics glutamate levels could also be affected by destabilizing neuronal AND cognitive decline, Z-drugs AND cognitive impairment, Ca2+ homeostasis, and neurons could be more sensitized to the hypnotics AND Alzheimer’s disease. The keywords were effects of glutamate (Jovanovic, 2004). combined and integrated in the database and journal searches. Recently, an interesting study of Whittington and The terms used were searched using AND to combine the collaborators reported that midazolam increased tau keywords listed and using OR to remove search duplication phosphorylation in C57BL/6 mice (Whittington et al., 2019). where possible. References of retrieved articles that the authors’ Consequently, the authors suggested that the effects of the searches may have missed or could have been ignored were most frequently used BZDs on tau phosphorylation should be also assessed. evaluated in deep since they could be strongly involved in the All these studies were fully investigated and considered under increase of AD risk. Indeed, pathogenic forms of tau, including the following inclusion criteria: soluble tau oligomers, can promote neuronal dysfunction and cognitive loss by several mechanisms at the early stages of • All articles had to be published studies conducted on human disease (Forner et al., 2017; Tracy and Gan, 2018). Likewise, subjects up to February 2019. Marciniak and collaborators reported that tau protein could be • All articles had to be written in English. involved in the regulation of brain insulin signaling, which plays • The primary outcome had to be focused on cognitive decline a fundamental role in the cognitive process (Marciniak et al., and Alzheimer’s disease. 2017). They demonstrated that the alteration of insulin signaling in preclinical models of AD could occur through alterations Case–Control Studies of tau. Data from studies reviewed in this section can be found It is also well-known that apolipoprotein E (APOE) 4 allele in Table 1. is a risk factor of AD (Stonnington et al., 2009). The presence In a nested case–control study, Lagnaoui et al. concluded of this allele is associated with an increased Aβ accumulation that there was a small increased risk of dementia after the as well as with an increase in cognitive decline and disease administration of GABAA activators (Lagnaoui et al., 2002). development when compared to other APOE allelic variants. Notwithstanding, the authors acknowledged that the effect of In this respect, Pomara and collaborators reported an increased exposure to other non-evaluated drugs with possible Central sensitivity to the cognitive adverse effects of acute doses of Nervous System (CNS) effects, such as antipsychotics, could lorazepam in elderly carriers of the APOE4 allele (Pomara have biased the results. In another study, the same group et al., 2011). Thus, it seems that APOE4 could also be a risk evaluated the prevalence of BZD use in AD patients for 3 for psychotropic drug-mediated cognitive decline. Likewise, the months, raising awareness about the use of BZDs in elderly AD same group suggested that subjects who carry the very long patients (Lagnaoui et al., 2002). The same authors conducted Translocase of Outer Mitochondrial Membrane 40 Homolog a case–control study with data from a large representative (TOMM40) Poly-T Length and do not possess the ǫ4 allele cohort of Canadian older women in order to examine the might also be at increased risk for BZD-related cognitive loss. association between BZDs and AD. They found a non-significant Therefore, the influence of APO E genotype on hypnotics as risk tendency toward an association between former use of BZDs factors for AD seems relevant, and APOE4 genotyping could be and increased risk of cognitive decline. Perhaps the low number Frontiers in Aging Neuroscience | www.frontiersin.org 4 January 2020 | Volume 11 | Article 344 Frontiers in Aging Neuroscience | www.frontiersin.org Ettcheto et al. TABLE 1 | Overview of selected case–control studies exploring the effect of BZDs and Z-drugs on the delay of cognitive decline in the elderly and Alzheimer’s disease patients. References Objective Intervention Number of subjects Main outcome measures Findings Lagnaoui et al. To investigate link between BZD and dementia 1989–1997 150 cases and 3,519 controls. Cognitive impairment was evaluated using the Mini- BZD consumption constitutes (2002) in a large representative cohort of French Age ≥ 65. Data from the UK-based Mental Status Evaluation (MMSE) and CT scanner. a risk factor for dementia in the community dwelling population. Data from Clinical Practice Research Datalink Diagnosis was based on Diagnostic and Statistical elderly. PAQUID Manual of Mental Disorders (DSM-III-R) and (Personnes Agées Quid) Research Program in NINCDS-ADRDA Bordeaux. Wu et al. (2009) To explore the association between long-term 1997–2004 4,626 control subjects, and 779 Cumulative dose DDD of sedative-hypnotics and Long-term use of BZD use and the risk of dementia. Nested dementia patients treated with average days, per year. hypnotic-sedative drugs case–control study (Taiwan) hypnotics. Age ≥ 45. increases AD risk. Wu et al. (2011) To explore if BZDs discontinuation affects the 1997–2007 8,434 patients with dementia and BZD discontinuation. The risk of AD increases with risk of dementia. Nested case–control study 16.706 control subjects. Age ≥45. BDZs, but it decreases with (Taiwan) BZDs discontinuation. Billioti de Gage To evaluate the association between use of 1987–1989 1,063 community dwelling people. Dementia evaluated based on the Diagnostic and The use of BDZs was et al. (2012) BZDs and dementia. Age ≥ 65. Statistical Manual of Mental Disorders, third edition, associated with increased risk revised (DSM-III-R). of dementia. Billioti de Gage To evaluate the association between former 2000–2009 1,796 AD patients and 7.184 First diagnosis (index date) of AD (ICD-9 No dose-effect relation et al. (2014) BZD use and the risk of AD and to investigate controls. Age >66. (international classification of disease, ninth revision) between BZDs and increased the potential dose–effect relation (Canada) risk of AD was found in older people treated previously for more than 3 months. Imfeld et al. (2015) To assess the association of BZD use with risk 1998–2013 16,823 subjects with AD and 9,636 An algorithm based on recordings of specific Long-term BZDs use is not of dementia. subjects with vascular dementia and dementia tests [e.g., Mini-Mental State Examination associated with an increased 5 each being randomly matched (age, (MMSE), Clock Drawing Test (CDT), or Abbreviated risk of AD or vascular sex, general practice and duration of Mental Test (7-Min Screen)], referrals to specialists, dementia. follow-up) with one control. Age ≥ 65. brain imaging [computed tomography (CT), The time of study with these BZDs magnetic resonance imaging (MRI), or single photon was 2 years from the diagnostic of AD emission computed tomography (SPECT)] and 3 years from vascular dementia symptoms (memory impairment, aphasia, apraxia, or agnosia) supportive of a diagnosis of a specific dementia subtype. Gomm et al. (2016) To explore the association between BDZ and 2004–2011 21,145 cases (any dementia) and Cognitive tests. Regular use of BDZs and Benzodiazepines as a Risk Factor in Alzheimer’s Disease Z-drug consumption and dementia in a large follow-up. 84,580 controls, over 60 years of age. Z-drugs in the elderly induces German population over 60 years old in German a significantly increased risk of public health insurance data Allgemeine dementia. Ortskrankenkassen (AOK), which covers about 50% of the population at least 80 years old Saarelainen et al. The authors evaluated the effect of BZDs and 2005–2011 51,981 patients with AD and 159.974 AD diagnoses based on the National Institute of BZD use is higher in AD January 2020 | Volume 11 | Article 344 (2016) Z-drugs administered 2 years before and three controls. Neurologic and Communicative Disorders and patients. BDZs could decrease years after the diagnosis of AD. MEDALZ Stroke and the Alzheimer’s disease and Related the effectiveness of anti-AD cohort in Finland. Disorders Association as well as the Diagnostic and drugs. Statistical Manual, Fourth Edition, criteria. (Continued) Ettcheto et al. Benzodiazepines as a Risk Factor in Alzheimer’s Disease of cases (n = 73) and controls (n = 437) prevented reaching BZD and related drug use was increased risk of AD. No major among different subcategories BZD use is associated with an preceding dementia diagnosis statistical significance. increased risk of developing was not associated with an associated with a modestly differences were observed increased risk of death in of BZDs (BZDs, Z drugs, short-/medium-acting or BZD use in the 2 years Wu et al. conducted two case–control studies in Taiwan using the National Health Insurance Research Database (NHIRD) with long-acting BZDs) persons with AD. data of people aged ≥45 from 1997 to 2004 (Wu et al., 2009). The main conclusions of the study were that long-term use of Findings BZDs or similar drugs might be associated with increased risk for dementia and cognitive alterations in prevalent and chronic users AD. over a maximum follow-up of 8 years. The authors also suggested rivastigmine, N06DA04 for galantamine, or N06DX01 first-time use of acetylcholinesterase inhibitors or the that risk of dementia was associated with higher cumulative antidepressants or antipsychotics 5 years before the Disorders Association as well as the Diagnostic and (ATC) codes N06DA02 for donepezil, N06DA03 for factors were considered, such as chronic diseases using anatomic therapeutic chemical classification dosage and longer duration of BZD exposure (Wu et al., 2009). memantine (agents commonly used to treat AD) Stroke and the Alzheimer’s disease and Related AD diagnoses based on the National Institute of NINCDS-ADRDA criteria. Several confounding Neurologic and Communicative Disorders and Diagnosis of AD in 2013 or 2014 via recorded In the second study, the same group stated that this association (COPD, asthma, cerebrovascular dementia, N-methyl-D-aspartate receptor antagonist Statistical Manual, Fourth Edition criteria. was reversible since BZD discontinuation could decrease the risk diabetes), abuse of other substances, socioeconomic status and the use of of dementia (Wu et al., 2011). AD diagnosis based on DSM-IV and In 2012, Billioti de Gage et al. performed a study in a French population. The main conclusion was that the new use Main outcome measures of BZDs was associated with an about 50% increase in the risk of AD (Billioti de Gage et al., 2012). In 2014, the same group diagnosis of AD. assessed the effects of exposure to BZDs among 10 up to 5 for memantine years before the diagnosis of AD, considering both the doses and the reason for prescription (anxiety, depression, insomnia) in a population of aged individuals of Quebec (Canada) (Billioti de Gage et al., 2014). They concluded that the chronic use of BZDs was associated with a higher risk of AD when daily doses 1,438 AD patients and 1,438 controls. 70,719 subjects with clinically verified ranged between 91 and 180 mg/kg (cumulative dose expressed AD diagnosis in 2005–2011 and as prescribed daily, during 3–6 months), and increased further 282,862 matched controls. with doses higher than 180 mg/kg (during more than 6 months of exposure). Number of subjects 70,718 AD patients. Gomm et al. reported that the risk of dementia increased by 21% in patients receiving regular hypnotic drug prescriptions when compared to non-users (odds ratio [OR] 1.21, 95% confidence interval [CI] 1.13–1.29; p < 0.001) (Gomm et al., 2016). The authors also reported the existence of a period of about 3 years from the first prescription of the BZDs to the diagnosis of dementia. This study did not create specific Intervention selection methods for those individuals with higher potential 2013–2014 2005–2011 2005–2011 risk of AD, such as those with APOE4 allele or low educational level. Likewise, the study only focused on the analysis of regular hypnotic users. nationwide cohort of persons with AD. MEDALZ Saarelainen et al. conducted a study in a Finnish cohort the risk of AD. Data from the Helsana Group, a To investigate the risk of death associated with The association between former BDZ use and To assess the association between BDZ and related drug use and risk of AD, considering of 70,718 subjects diagnosed with AD between 2005 and 2011 new BZD and related drug (BZDR) use in a cumulative consumption and duration of in order to investigate the effects of BZDs and Z-drugs in a large Swiss health insurance provider. population of AD patients compared with matched controls (Saarelainen et al., 2016). The authors concluded that these psychotropic drugs could inhibit the beneficial effects of the cohort in Finland. (Finland) drugs used in the treatment of AD, either anticholinesterases or memantine. Furthermore, AD patients treated with BZDs showed a risk of mortality up to 41% higher than those who did not use such drugs. Z-drugs did not increase the risk of death, Objective treatment. but authors suggested that they could not be considered safer in persons with dementia (Saarelainen et al., 2018). Another study was performed in a wide population of Finland TABLE 1 | Continued for 6 years (Tapiainen et al., 2018). Currently, this is the Biétry et al. (2017) Saarelainen et al. Tapiainen et al. largest study assessing the effect of BZDs and Z-drugs on AD References risk. Moreover, the authors concluded that BZDs and Z-drugs modestly increased AD risk since the Off Ratios (OR) after (2018) (2018) adjusting for another concomitant psychotropic medication was Frontiers in Aging Neuroscience | www.frontiersin.org 6 January 2020 | Volume 11 | Article 344 Ettcheto et al. Benzodiazepines as a Risk Factor in Alzheimer’s Disease TABLE 2 | Cohort studies. References Objective Intervention Number of subjects Main outcome Findings measures Lopez et al. (1999) To examine the association of 1983–1988 179 patients with Cognitive impairment BZDs increase the risk of AD psychotropic medication use Alzheimer’s disease was evaluated using the with cognitive, functional, and age 82.2 mean 6.6 Mini-Mental Status AD Evaluation (MMSE) Ellul et al. (2007) To examine the effects of Not reported 257 patients with The diagnosis of Antipsychotics and BZDs were several drugs on the Alzheimer’s disease Alzheimer’s disease was associated with a greater progression of disease in age 82.2 mean 6.6 made according to cognitive decline in patients patients with Alzheimer’s standard deviation NINCDS-ADRDA criteria treated with these drugs. disease. Rosenberg et al. To examine the longitudinal Not reported 335 participants were Cognitive impairment Psychotropic medication use (2012) association of psychotropic diagnosed with incident was Mini-Mental State was associated with more medication through the AD Evaluation (MMSE) and rapid cognitive and functional Persistency Index, which Clinical Dementia Rating decline in AD represents years of drug use divided by years of observation following AD diagnosis with cognitive, functional, and neuropsychiatric symptom among community-ascertained incident AD cases from the Cache County Dementia Progression Study Hessmann et al. To evaluate the continuity of 2014–2015 1,298 subjects with Diagnosis of dementia in The use of long acting BZD (2018) BZDs prescriptions in patients dementia. 2014, identified should be avoided in dementia with dementia insured in a according to the patients. German public sickness fund International (Allgemeine Ortskrankenkasse Classification of AOK, 2018) in Lower Saxony, Diseases Germany Lee et al. (2018) Association between 2002–2015 268,170 subjects. Comparison between The risk of AD was higher in sedative-hypnotic use and the follow-up. Age ≥ 50 the ever exposed, who subjects exposed to risk of AD, in a Korean The dosage of were prescribed over 30 sedative-hypnotics. (GABAA population through a sedative-hypnotics was DDD of receptor agonists). Patients retrospective cohort study from standardized by defined sedative-hypnotics and exposed to over 360 DDD of the National Health Insurance of daily dose (DDD). the non-exposed. sedative-hypnotics showed a Korea database higher risk of dementia when compared to non-treated patients Grande et al. (2019) To investigate the effect of BDZs Not reported 4,249 subjects (mean age Evaluation of cognitive BZD use is not associated on first cognitive alterations in 77.0 ± 8.2) enrolled by function by ad hoc with an increased risk of poorer primary care patients suffering 353 General Practitioners trained GPs, using the cognitive early cognitive alterations. Data (GPs) in the Milan Mini Mental State performance in primary care comes from the metropolitan area.) Examination (MMSE). patients with first cognitive REMIND—REteMilanese complaints. INtegrata per le Demenze— database. 1.06 (95% CI 1.04–1.08). They did not find significant differences between 2 and 3 years before [aOR 0.99 (0.84–1.17)] (Imfeld between BZD subcategories (long or short action). et al., 2015). In the same line, Biétry et al. evaluated the Controversially, there are some studies questioning the notion risk of AD after a period of 2 years of BZD and related that BZDs/Z-drugs increase the risk of cognitive loss. For drug treatment before AD diagnosis (Biétry et al., 2017). The instance, in a study performed by Infeld et al., the results results of the study indicated that the risk of developing AD showed that long term use of BZDs did not increase the risk was not associated with BZDs or Z-drugs. Likewise, the half- of AD (Imfeld et al., 2015). Adjusted odds ratios (aORs) were life of BZDs was not linked with AD risk (Biétry et al., calculated with 95% confidence intervals (CIs) of developing 2017). AD or VaD in relation to previous BZD use, stratified by duration and benzodiazepine type. The OR of developing AD Cohort Studies for those who started BZDs 1 year before AD diagnosis was Data from studies reviewed in this section can be found 2.20 (1.91–2.53) and fell to the null for those who started in Table 2. Frontiers in Aging Neuroscience | www.frontiersin.org 7 January 2020 | Volume 11 | Article 344 Ettcheto et al. Benzodiazepines as a Risk Factor in Alzheimer’s Disease Several prospective and retrospective cohort studies which follow-up of 7 years (Gray et al., 2016). They reported have assessed the association of BZDs/Z-drugs and related drugs a small increased risk of dementia in people with low on cognitive function reported controversial results. or moderate BZD treatment. However, the study concluded For example, the study of Lopez et al. concluded that the use that BZDs do not increase the risk of AD (Gray et al., of BZDs in AD patients should be done with great caution and 2016). Furthermore, another team examined patients with its use would not be adequate due to the risks of falls (Lopez recently diagnosed mild AD which were treated with anti- et al., 1999). Also, in the treatment of insomnia, they suggested dementia medications such as acetylcholinesterase inhibitors the use of other medications such as antihistaminic drugs. Also, (donepezil, galantamine, rivastigmine) and memantine. The Ellul et al. suggested that the prescription of antipsychotics and authors reported an association between AD and an increased BZDs can accelerate cognitive decline in patients with AD (Ellul use of psychotropic drugs (Törmälehto et al., 2017). However, et al., 2007). In the prospective long-term “Caerphilly study,” the administration of psychotropic medications was not related results also evidenced the association between the use of BZDs to alterations in cognitive performance (Törmälehto et al., 2017). and the increased risk of developing both vascular and non- Finally, Grande and collaborators showed that patients treated vascular dementia (Gallacher et al., 2012). The authors studied with short- and long-acting BZDs presented adjusted MMSE a representative sample of men with a follow-up rate over mean scores of 25.4; 95% CI 25.1–25.7, while non-treated patients 22 years. They reported a significant higher risk for dementia had 25.9; 95% CI 25.3–26.4 (short acting BZDs); 25.3; 95% CI with the use of BZDs. Moreover, Rosenberg et al. suggested 25.2–25.5 (long-acting BZDs); (p = 0.156) (Grande et al., 2019). that antipsychotics and BZDs showed an increase in cognitive Therefore, the authors stated that the use of BZDs was not loss associated with a high Persistency Index (Rosenberg et al., associated with an increase in cognitive loss in patients suffering 2012). Lee et al. evaluated the risk of AD after the use of initial cognitive alterations. sedative-hypnotic antidepressants and antipsychotic drugs (Lee et al., 2018). Interestingly, the risk of AD was higher in patients Longitudinal Studies receiving a defined daily dose over 30 defined daily dose (DDD). Data from studies reviewed in this section can be found Likewise, in this study, different groups of BZDs were evaluated, in Table 3. and intermediate BZDs were associated with the highest risk In a study performed in a young adult population, Boeuf- of dementia. This study concluded that the risk of AD was Cazou et al. concluded that, although long-term exposure to associated with BZDs and sedative-hypnotic drugs, and that this BZDs leads to specific impairment in long-term memory only in association was dose-dependent (Lee et al., 2018). In another women, a longer period of observation is necessary to ascertain if study performed in Taiwan, Chen et al. used data from the these alterations are associated with a risk of developing dementia NHIRD, which covered 23 million registered patients from 1995 in old age (Boeuf-Cazou et al., 2011). to 2010, accounting for 99% of the population (Chen et al., 2012). Yet, in a large population-based cohort study named “The The authors clearly indicated the hypnotic drugs used which Three-City Study,” Shash et al. compared short- vs. long-half-life were classified into two groups: BZDs and Z-drugs. The results BZDs as well as the effects of other psychotropic medications on suggested that both hypnotics should be considered risk factors dementia on non-institutionalized individuals aged ≥65 starting for dementia in patients with long-term insomnia. Likewise, an in 1999. The authors concluded that users of long half-life association between higher prescribed dosages of BZDs and Z- BZDs had a 60% increased risk of developing dementia (Shash drugs and risks of dementia was found, which is in agreement et al., 2016). Also, it was examined whether the chronic use with previous studies (Tapiainen et al., 2018). of BZDs over 4 years was associated with an increased risk of It has been proposed that older people with anxiety may have cognitive decline (Paterniti et al., 2002). The study demonstrated a higher risk of AD development and involved an increase of that prolonged use of BZDs was a significant risk factor for Aβ levels in adults with MCI and AD (Pietrzak et al., 2015). the cognitive decline in the elderly which was evaluated by the Thus, Burke et al. investigated the role of anxiolytic drugs MMSE, the Trail Making Test, and the Digit Symbol Substitution. in the risk of AD. Likewise, they evaluated the association of Finally, it had been described that BZDs decrease cognitive APOE ε4, currently the most important risk factor in LOAD performance, although the effects were small. In addition, they (Burke et al., 2018). One important finding of the study was suggested that higher BZD treatment duration and cumulative that ε4 carriers had a statistically higher significant risk of AD doses were responsible for the negative effects on cognition in development; however, this effect was moderated by the use of elderly patients (Bierman et al., 2007). anxiolytics. Anxiolytics, alprazolam, lorazepam, paroxetine, or venlafaxine, specifically, may improve the association of anxiety Cross-Sectional Studies on MCI and AD development. However, in the same study Data from studies reviewed in this section can be found the authors reported that clonazepam conferred a statistically in Table 4. significant increased risk of MCI development among users of ε4 Mura et al. conducted a cross-sectional and longitudinal with anxiety, suggesting that there is a molecular mechanism on study to evaluate the effects of chronic BZD use on cognitive cognition that is altered by clonazepam. decline in people over 65 years old in France (Mura et al., Divergently, the prospective population-based cohort study 2013). A total of 5,195 persons were included in the study, published by Gray et al. investigated the risk of dementia 969 of which were chronic users of BZDZs. The results associated with cumulative dosage of BZDs after an average showed that chronic BZD use was associated with poorer Frontiers in Aging Neuroscience | www.frontiersin.org 8 January 2020 | Volume 11 | Article 344 Ettcheto et al. Benzodiazepines as a Risk Factor in Alzheimer’s Disease TABLE 3 | Longitudinal studies. References Objective Intervention Number of subjects Main outcome measures Findings Bierman et al. To evaluate the effects of BZD 9 year 2,105 subjects aged 55 General cognitive functioning The duration of treatment and (2007) use on cognitive function in the follow-up to 85 years. measured by cumulative exposure to BZD elderly. Data from the means of the Mini-mental State; use had a negative effect on Longitudinal Aging Study Episodic memory measured with the cognitive function of elderly Amsterdam (LASA), a a Auditory Verbal Learning Test; people. However, this effect population-based study Fluid intelligence was small. measured by means of two sub-sets of 12 items (A and B) from Raven’s Colored Progressive Matrices; Information processing speed measured by means of an adjusted version of the Coding task. Boeuf-Cazou To investigate the impact of 10 year 1,660 men and 1,577 Cognitive function was assessed Long-term use of BDZs leads et al. (2011) long-term BZD consumption on follow-up women aged 32, 42, 52, using five cognitive tests to specific impairment in cognitive function Population and 62 years, classified (immediate free recall test, long-term memory in women. from the VISAT study (Aging, according to the use of delayed free recall test, Health and Work) (France). A BDZs into non-users, recognition test, Digit Symbol prospective cohort study. occasional users and Substitution Subtest and visual log-term users. search speed test). TABLE 4 | Cross-sectional studies. References Objective Intervention Number of subjects Main outcome Findings measures Taipale et al. To investigate the prevalence of 2002–2006 The number of persons included The diagnosis of AD The long-term use of BDZs (2015) BZD and related-drug in the study was 24,966 for based on the may impair cognition and may consumption, especially those individuals with AD and 24,985 INCDS-ADRDA and be associated with serious of long-term, and its associated for individuals without AD. The DSM-IV criteria. adverse events. factors among community research was based on data dwelling individuals with and from the MEDALZ-2005 without AD. (Medication use and Alzheimer’s disease) cohort, which includes all community-dwelling individuals, diagnosed with AD in Finland at the end of 2005 and matched individuals without AD. To evaluate the continuity 2014–2015 98 subjects with dementia. Diagnosis of dementia in The use of long acting BZD Hessmann et al., of BZD prescriptions among 2014, identified according should be avoided by 2019 dementia patients in Lower to the International dementia patients. Saxony, Germany. Classification of Diseases cognitive performance, but not with accelerated cognitive However, the risk of hemorrhagic stroke was not increased decline with age. However, the authors stated that BZDs (Tolppanen et al., 2017). could deteriorate cognitive performance, increase the depletion Contrarily, Zhang et al. who collected data from the National of cognitive reserves and precipitate the onset of dementia Institute on Aging (NIA) ADCs, reported no association between (Mura et al., 2013). Later, another team aimed to evaluate BZDs and cognitive decline (Zhang et al., 2016). the prevalence of BZD and Z-drug use in a population of Finland (Taipale et al., 2015). The authors concluded that Meta-Analyses approximately half of the people with AD used BZDs and Z- Zhong et al. investigated the association of long-term BZD drugs during the 4 years of follow-up, and that AD patients use and dementia in a meta-analysis including five studies, used more BZDs in the long term that those without AD. which involved 45,391 participants and 1,891 dementia cases. In In another study, the same group investigated the risk of addition, the authors evaluated the potential risk of dementia any stroke (ischemic or hemorrhagic) associated with BZDs associated with an increase of BZD dose by 22% (risk ratio 1:22, and Z-drugs in patients with AD taken from the MEDALZ- 95% CI 1.18–1.25). They concluded that long-term BZD users 2005 population. They found an increase of 20% in the risk had an increased risk of dementia compared with non-users of ischemic stroke in AD patients using BZDs and Z-drugs. (Zhong et al., 2015). Frontiers in Aging Neuroscience | www.frontiersin.org 9 January 2020 | Volume 11 | Article 344 Ettcheto et al. Benzodiazepines as a Risk Factor in Alzheimer’s Disease In turn, He et al. pooled 10 studies to assess the association here we have discussed some specific hypotheses. Thanks to between BZDs and risk of dementia. PubMed and Embase molecular biology, the α1 subunit of the GABA has been shown databases were systematically searched for relevant publications to play an important role in BZD-mediated cognitive loss. up to September 2017. The literature search focused on Hence, it has been reported that higher activity at the α1GABAA observational studies that analyzed the relationship between the receptors induced by positive allosteric modulation at the BZD long-term use of BDZs and the risk of dementia. Their main site is responsible for spatial learning and memory incapacitation findings pointed to a significantly increased risk of dementia in in preclinical models. Besides, activation of the α5 subunit, which the elderly population using BZDs. This effect was associated is mainly expressed in the hippocampus, could in part explain with the use of BZDs with a longer half-life and with a longer the memory deficit states induced by BZDs. Therefore, α5GABA- treatment duration (He et al., 2019). targeting compounds could improve cognition, thus having Finally, a meta-analysis of 12 prospective and retrospective therapeutic potential in AD and other dementias (Adrienn et al., cohort studies and case–control studies about the risk of BZDs 2017). It is conceivable that BZDs influence cognition and and AD was reported. The team concluded that the use of probably increase the risk of AD acting through hippocampal BZDs—mainly those of long-action—and Z-drugs was associated α5GABAA , while Z-drugs (α5GABAA -independent) confer a with the development of dementia. However, the study showed lower risk. In addition, the neuroinflammatory process is per some limitations since it did not differentiate between BZDs se a risk factor for AD. The brain microglia play a prominent effects on AD and vascular dementias, neither between long- and role in neuroinflammation, and it is associated with the secretion short-acting BZDs (Lucchetta, 2018). of pro-inflammatory cytokines. Likewise, α5GABAA receptor activity is enhanced by the inflammatory process, a fact that DISCUSSION is probably critical in inflammation-induced memory deficits (Marczynski, 1998). Moreover, BZDs and other drugs may In the present review, we discussed the evidence pointing to increase cognitive loss and AD risk through the phosphorylation BZDs as risks factors for cognitive decline in aging and AD of tau protein, which can also inhibit the signaling of the (Paterniti et al., 2002; Zhang et al., 2016; Picton and Pharm, brain insulin receptor (Jovanovic, 2004; Whittington et al., 2018). 2019). Sleep disorders increase with age, altering clearance of toxic In spite of these described effects, it could be hypothesized and waste products from the brain, including Aβ (Clinton that BZDs may indirectly exert a protective effect against et al., 2011). It has been reported that sleep disturbances the development of AD by improving sleep (through their could contribute to neurodegeneration and AD by altering clinical effects on sleep latency, number of awakenings, physiological metabolic functions, increasing oxidative stress, and duration and quality of sleep) (Guzmán et al., 2018). and the accumulation of Aβ as well as due to the appearance This paradigm states that the enhancement of GABAA of neuroinflammatory responses (Phan and Malkani, 2019) receptor activity by BZDs could inhibit glutamatergic (Figure 1). In addition, insomnia is also associated with neurotransmission, thereby protecting against the excitotoxic hypertension, diabetes, and a higher obesity risk; all of them effects of glutamate on the pathogenesis of AD (Fastbom et contributing to AD (Clarke et al., 2018; Frozza et al., 2018). al., 1998). Moreover, it is noteworthy that some clinical trials Bearing this in mind and considering the increase in insomnia reported no association between BZDs and risk of cognitive loss diagnostics, especially in the elderly, this situation has led to and AD. higher consumption of hypnotic drugs in the adult population In conclusion, we do not have enough data to ensure a to improve sleep quality. Notwithstanding, and seeing the causal relation between psychotropic drugs and cognitive possible consequences derived from their intake, there needs loss. However, a therapeutic strategy based on BZDs and to be a significant increase in awareness about their risks. Z-drugs in elderly people should be extensively evaluated In fact, there have been some studies reporting that the and monitored (Monzani et al., 2015; Yi et al., 2018). consumption of BZDs favors the appearance of cognitive After reviewing the available data, a controversial question affectations and increases the number of deaths in patients remains: is it safe to prescribe BZDs and Z-drugs to improve with AD (Imfeld et al., 2015; Saarelainen et al., 2017; Grande sleep in older patients, despite the potential cognitive loss et al., 2019). Yet, as we have already assessed, there is risk? We strongly believe that there are enough data controversy, and other researchers defend that BDZs have supporting an extremely cautious attitude with Z-drugs no such detrimental effects (Picton and Pharm, 2018). Thus, and the avoidance of BZD prescription in elderly people even though BZDs improve various measures of insomnia with AD. in the aged population, their clinical value is debatable, and melatonin agonists could be a much safer choice when trying to manage sleep disorders (Investigations, 2015). For AUTHOR CONTRIBUTIONS the treatment of anxiety in the elderly, the administration of other medications such as serotonin uptake inhibitors All the co-authors of this research (ME, ACan, OB, (sertraline) or other compounds could be more adequate PM, RC-T, CB-Z, MG, JO, CA, JF, and ACam) have (Consensus and Statements, 2014; Investigations, 2015). directly participated in the planning, execution of the In the end, the mechanisms by which BZDs and Z-drugs could manuscript. All authors have read and approved the final increase the risk of cognitive loss and AD remain to be clarified; version submitted. Frontiers in Aging Neuroscience | www.frontiersin.org 10 January 2020 | Volume 11 | Article 344 Ettcheto et al. Benzodiazepines as a Risk Factor in Alzheimer’s Disease FUNDING Generalitat de Catalunya. CB-Z was supported by grants from CONACyT Mexico (No. 0177594) and RDCT from Grodman The Spanish Ministry of Science and Innovation SAF2017- Academic International Specialization Stays 2018 B (University 84283-R, PI2016/01, CB06/05/0024 (CIBERNED) and the of Guadalajara Foundation USA). PM was supported by grants European Regional Development Funds supported this work. 2015/26084-1 and 2017/13224-5, São Paulo Research Foundation Research team from UB and URV belongs to 2017SGR625 from (FAPESP) – Brazil. REFERENCES Consensus, N. I. H., and Statements, S. (2014). NIH state-of-the-science conference statement on manifestations and management of chronic insomnia Adrienn, P., Gunn, B. G., Brown, A. R., Livesey, M. R., Monteiro, O., Belelli, D., in adults. 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This is an symptoms, cognition and functional performance in Alzheimer’s disease over open-access article distributed under the terms of the Creative Commons Attribution a three-year period: Kuopio ALSOVA study. Int. Psychogeriatr. 29, 1723–1733. License (CC BY). The use, distribution or reproduction in other forums is permitted, doi: 10.1017/S1041610217001090 provided the original author(s) and the copyright owner(s) are credited and that the Tracy, T. E., and Gan, L. (2018). Tau-mediated synaptic and neuronal original publication in this journal is cited, in accordance with accepted academic dysfunction in neurodegenerative disease. Curr. Opin. Neurobiol. 51, 134–138. practice. No use, distribution or reproduction is permitted which does not comply doi: 10.1016/j.conb.2018.04.027 with these terms. Frontiers in Aging Neuroscience | www.frontiersin.org 13 January 2020 | Volume 11 | Article 344