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. (2002)	To investigate link between BZD and dementia in a large representative cohort of French community dwelling population. Data from PAQUID (Personnes Agées Quid) Research Program in Bordeaux.	1989–1997	150 cases and 3,519 controls. Age ≥ 65. Data from the UK-based Clinical Practice Research Datalink	Cognitive impairment was evaluated using the Mini- Mental Status Evaluation (MMSE) and CT scanner. Diagnosis was based on Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R) and NINCDS-ADRDA	BZD consumption constitutes a risk factor for dementia in the elderly.
Wu et al. (2009)	To explore the association between long-term BZD use and the risk of dementia. Nested case–control study (Taiwan)	1997–2004	4,626 control subjects, and 779 dementia patients treated with hypnotics. Age ≥ 45.	Cumulative dose DDD of sedative-hypnotics and average days, per year.	Long-term use of hypnotic-sedative drugs increases AD risk.
Wu et al. (2011)	To explore if BZDs discontinuation affects the risk of dementia. Nested case–control study (Taiwan)	1997–2007	8,434 patients with dementia and 16.706 control subjects. Age ≥45.	BZD discontinuation.	The risk of AD increases with BDZs, but it decreases with BZDs discontinuation.
Billioti de Gage et al. (2012)	To evaluate the association between use of BZDs and dementia.	1987–1989	1,063 community dwelling people. Age ≥ 65.	Dementia evaluated based on the Diagnostic and Statistical Manual of Mental Disorders, third edition, revised (DSM-III-R).	The use of BDZs was associated with increased risk of dementia.
Billioti de Gage et al. (2014)	To evaluate the association between former BZD use and the risk of AD and to investigate the potential dose–effect relation (Canada)	2000–2009	1,796 AD patients and 7.184 controls. Age >66.	First diagnosis (index date) of AD (ICD-9 (international classification of disease, ninth revision)	No dose-effect relation between BZDs and increased 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 of dementia.	1998–2013	16,823 subjects with AD and 9,636 subjects with vascular dementia and each being randomly matched (age, sex, general practice and duration of follow-up) with one control. Age ≥ 65. The time of study with these BZDs was 2 years from the diagnostic of AD and 3 years from vascular dementia	An algorithm based on recordings of specific dementia tests [e.g., Mini-Mental State Examination (MMSE), Clock Drawing Test (CDT), or Abbreviated Mental Test (7-Min Screen)], referrals to specialists, brain imaging [computed tomography (CT), magnetic resonance imaging (MRI), or single photon emission computed tomography (SPECT)] symptoms (memory impairment, aphasia, apraxia, or agnosia) supportive of a diagnosis of a specific dementia subtype.	Long-term BZDs use is not associated with an increased risk of AD or vascular dementia.
Gomm et al. (2016)	To explore the association between BDZ and Z-drug consumption and dementia in a large German population over 60 years old in German public health insurance data Allgemeine Ortskrankenkassen (AOK), which covers about 50% of the population at least 80 years old	2004–2011 follow-up.	21,145 cases (any dementia) and 84,580 controls, over 60 years of age.	Cognitive tests.	Regular use of BDZs and Z-drugs in the elderly induces a significantly increased risk of dementia.
Saarelainen et al. (2016)	The authors evaluated the effect of BZDs and Z-drugs administered 2 years before and three years after the diagnosis of AD. MEDALZ cohort in Finland.	2005–2011	51,981 patients with AD and 159.974 controls.	AD diagnoses based on the National Institute of Neurologic and Communicative Disorders and Stroke and the Alzheimer's disease and Related Disorders Association as well as the Diagnostic and Statistical Manual, Fourth Edition, criteria.	BZD use is higher in AD patients. BDZs could decrease the effectiveness of anti-AD drugs.
Biétry et al. (2017)	The association between former BDZ use and the risk of AD. Data from the Helsana Group, a large Swiss health insurance provider.	2013–2014	1,438 AD patients and 1,438 controls.	Diagnosis of AD in 2013 or 2014 via recorded first-time use of acetylcholinesterase inhibitors or the N-methyl-D-aspartate receptor antagonist memantine (agents commonly used to treat AD) using anatomic therapeutic chemical classification (ATC) codes N06DA02 for donepezil, N06DA03 for rivastigmine, N06DA04 for galantamine, or N06DX01 for memantine	BZD use in the 2 years preceding dementia diagnosis was not associated with an increased risk of developing AD.
Saarelainen et al. (2018)	To investigate the risk of death associated with new BZD and related drug (BZDR) use in a nationwide cohort of persons with AD. MEDALZ cohort in Finland. (Finland)	2005–2011	70,718 AD patients.	AD diagnoses based on the National Institute of Neurologic and Communicative Disorders and Stroke and the Alzheimer's disease and Related Disorders Association as well as the Diagnostic and Statistical Manual, Fourth Edition criteria.	BZD use is associated with an increased risk of death in persons with AD.
Tapiainen et al. (2018)	To assess the association between BDZ and related drug use and risk of AD, considering cumulative consumption and duration of treatment.	2005–2011	70,719 subjects with clinically verified AD diagnosis in 2005–2011 and 282,862 matched controls.	AD diagnosis based on DSM-IV and NINCDS-ADRDA criteria. Several confounding factors were considered, such as chronic diseases (COPD, asthma, cerebrovascular dementia, diabetes), abuse of other substances, socioeconomic status and the use of antidepressants or antipsychotics 5 years before the diagnosis of AD.	BZD and related drug use was associated with a modestly increased risk of AD. No major differences were observed among different subcategories of BZDs (BZDs, Z drugs, short-/medium-acting or long-acting BZDs)