The main objective of this population-based study was first to test the hypothesis that AC exposure may dose-dependently affect cognitive performances as early as 45 years of age. Another objective was to test whether this association varied according to the AC potency of the considered drugs and according to their drug class.

Moreover, most of these studies either focused only on drugs with marked AC effects or pooled all AC drugs, regardless of the level of their AC potency and drug class. Consequently, their findings about specific AC effects are difficult to interpret, as the most widely prescribed ACs have a low AC potency, 13 and some drug classes (such as anxiolytics) can also exert non-AC-related effects on cognition. 14 Thus, studies of associations between AC drug use and cognitive impairment should specifically consider the level of AC potency and the drug class.

The detrimental effects of AC drug use have been mainly studied in elders without dementia. In France, 7.5%–14% of them are prescribed AC drugs. 5 6 Several observational studies have documented an association between AC drug use and cognitive impairment in elderly patients, 7–10 sometimes with a dose–effect association. 11 However for neurodegenerative diseases such as Alzheimer’s disease and other forms of dementia, the early symptoms develop gradually over the years as a result of progressive brain cell damage. 12 Therefore, to identify potential contributors, exposures must be measured several years before symptom onset, that is, in middle age.

Anticholinergic (AC) drugs are extensively used to treat a broad range of medical conditions. A first group encompasses muscarinic receptor antagonists that block acetylcholine-mediated neurotransmission in the smooth muscle, heart, central and peripheral nervous systems. 1 This effect is expected to induce therapeutic benefits in various conditions such as Parkinson’s disease, overactive bladder syndrome and chronic obstructive airway diseases. For a second group, the therapeutic effect relies on other pharmacological properties and the AC potency is therefore unwanted. Among others, this group includes certain diuretics, antihistamines and psychotropic drugs (eg, antidepressants). For both groups, side effects vary depending on whether the targeted muscarinic receptors are peripheral (dryness of the mouth, constipation, dysuria and mydriasis), 2 central (confusion, delirium, hallucinations, and memory impairments, especially in elderly patients) or both. 3 4

Univariate linear regression models were built to assess the effect of cumulative AC exposure on cognitive performances. For each cognitive test, the z-score was the dependent variable and cumulative exposure was the independent variable. In addition, for each model, we adjusted on lifestyle variables first, then on both lifestyle and health status variables.

Categorical variables were described as percentages and continuous variables as means and SD. Cumulative exposure groups were compared using the χ 2 test for categorical variables and analysis of variance for continuous variables, with α set at 0.05. Sociodemographic variables such as age, gender and education level are known to be associated with cognitive performances. For comparisons of cognitive scores, we therefore computed the adjusted z-scores for age, gender and education level for each cognitive test, using multivariable linear regression according to the Barona method. 31 32

The following lifestyle variables were used: living with versus without a partner, smoking status (never, past or current), alcohol consumption (none; moderate defined as three glasses or less per day for men, and two glasses or less per day for women; and excessive if above), physical activity (on a 7-point scale where 0 indicated none and 6 a high level of activity) and body mass index (in four categories: underweight, <18.5; normal, 18.5–25; overweight, 25–30; and obese, ≥30).

The two parts of the Trail Making Test evaluate attention and visuospatial perception (TMT-A) and shifting abilities (TMT-B); the task is to connect with a pencil as fast as possible and in ascending order a sequence of 25 circles. 28 29 In part A, the circles contain only digits, whereas circles in part B contain digits alternating with letters. For this study, we used the following: (number of correct moves/total time)×10.

The Free and Cued Selective Reminding Test was chosen to assess episodic verbal memory. Sixteen items to be memorised are shown on index cards in groups of four. 24 The participant is asked to remember as many items as possible, first freely then in response to a cue (semantic category—that is, the item to remember ‘grape’ corresponds to the semantic category ‘fruit’) if free recall fails. Trials are carried out three times immediately after the learning phase then 20 min later. For this study, we considered both the immediate free recall score (sum of the number of items retrieved freely at the first three recall trials) and the delayed free recall score (number of items retrieved freely during the delayed trial).

The potential role of the drug class on the association between cumulative AC exposure and cognitive performances was assessed by splitting AC drugs in several groups according to the third level of the ATC classification level. However, AC drugs targeting the gastrointestinal tract or metabolism and AC cardiovascular drugs were grouped according to the first level of the ATC classification to ensure sufficient group size.

We used the Anticholinergic Cognitive Burden (ACB) scale to characterise AC potency. 20 21 A panel of healthcare experts assigned a score to each drug: ACB-1, possible AC effect on cognition based on in vitro results or affinity for muscarinic receptors but without relevant clinical evidence; and ACB-2 or ACB-3, clinically documented AC effect on cognition, with ACB-3 indicating greater ability to cross the blood–brain barrier and to induce confusion. 22 We assembled drugs with a clinically confirmed AC effect (ACB-2 and ACB-3) into a single category (ACB-2/3).

For each drug delivered, the following information was collected from the insurance database: drug name according to the Anatomical Therapeutic Chemical (ATC) classification, date the drug was dispensed and amount dispensed (number of packages, number of tablets per package or total volume for liquids, tablet strength or concentration for liquids) and route of administration. 18 Total dose (in mg) dispensed at each prescription fill was computed by multiplying the number of tablets per package by tablet strength and by number of packages dispensed. Then, we calculated the standardised daily dose (SDD) for each prescription fill by dividing the total dose dispensed by the defined daily dose (DDD, a reference dose defined by international experts from the WHO as the average dose recommended for the main indication in an adult weighing 70 kg, for each ATC-5th level code and route of administration). 19 All medications prescribed by a physician (including medications-as-needed) were taken into account. Since DDDs are not available for eye-drops and topical steroids, these drugs were excluded from our analyses.

We included cohort participants enrolled between February 2012 and June 2016 who were 45 or over at recruitment, and used data collected through baseline questionnaires, medical examination and cognitive tests; information about drugs used during the previous 3 years was extracted from the insurance administrative database to calculate the cumulative exposure to AC drugs.

This population-based study relied on individuals enrolled in the CONSTANCES cohort. CONSTANCES is a large (200 000 participants at the end of the recruitment planned early 2019), population-based, prospective cohort composed of a randomly selected sample of adults living in France and aged 18–70 years at recruitment. The general design of CONSTANCES is detailed elsewhere. 15 Briefly, eligible individuals were invited by mail and completed a self-administered questionnaire on lifestyle, health status, medical history, socioprofessional status and lifetime employment history. Each participant attended a health screening centre for a comprehensive evaluation including a physical examination and laboratory tests. Participants aged 45–70 years underwent a battery of cognitive tests. 16 The CONSTANCES cohort is also linked to the electronic database of the French statutory health insurance administrative database. 17

The association between cumulative exposure to AC drugs and cognitive scores was heterogeneous across AC drug classes ( table 5 ). For executive functions, it was large among antipsychotics (DSST, β=−0.658 (p<0.001); TMT-A, β=−0.590 (p<0.001); TMT-B, β=−0.511 (p<0.001)), small and medium among drugs targeting the gastrointestinal tract or metabolism (DSST, β=−0.154 (p=0.17); TMT-A, β=−0.287 (p=0.01); TMT-B, β=−0.344 (p=0.002)), and small among anxiolytics (DSST, β=−0.197 (p=0.005); TMT-A, β=−0.176 (p=0.01); TMT-B, β=−0.170 (p=0.01)) ( table 5 ). For episodic memory, it was medium among antipsychotics (immediate free recall, β=−0.433 (p<0.001); delayed free recall, β=−0.493 (p<0.001)) and small among opioids (immediate free recall, β=−0.161 (p=0.15); delayed free recall, β=−0.101 (p=0.37)) and anxiolytics (delayed free recall, β=−0.185 (p=0.01)). Only exposure to AC antipsychotic was associated with impaired verbal fluency (semantic fluency, β=−0.380 (p<0.001); phonemic fluency, β=−0.262 (p=0.009)). There was a significant dose–effect in all cognitive scores for exposure to AC antipsychotics ( table 5 ): for example, the effect size in DSST in the group >1 year (β=−0.658 (p<0.001)) was almost twice that of the group <1 year (β=−0.347 (p<0.001)) (p trend <0.001). Of note, no significant association was found between exposure to AC antihistamines, AC antidepressants or AC drugs for the cardiovascular system and cognitive performance.

Table 3 shows the associations between cumulative AC exposure and cognitive test z-scores. In univariate analyses, being exposed to ACs was negatively associated with all cognitive test z-scores for most of the exposure levels. In all the studied tests, the effect size increased with the cumulative AC exposure (p trend <0.001). After adjustment for cofounders, this association remained highly significant—although smaller—for the executive function tests, that is, the DSST (β=−0.193 (p<0.001)) and the TMT (A: β=−0.167 (p<0.001); B: β=−0.163 (p<0.001)) within individuals highly exposed to AC drugs (>3 years). The association with verbal fluency was no longer significant after adjustment. A significant association persisted for the episodic memory tests with a small effect size (immediate free recall: β=−0.103 (p=0.018); delayed free recall: β=−0.125 (p=0.004)). In addition, after adjustment, significant associations with a gradient were observed for the 1–3 years and more than 3 years’ exposure levels in DSST and TMT-A (p trend <0.001). The results of sensitivity analysis according to age group (<65 vs 65+) are displayed in online supplementary e-table 2 .

Table 2 shows the frequency of AC drugs dispensing across ACB scores and drug classes. Among AC drug users, 12 220 (76%) received at least one ACB-1 drug, 822 (5%) at least one ACB-2/3 drug, and 3130 (19%) at least one drug in both ACB categories. Exposure to two or more different AC drugs was recorded for 52.4% of AC drug users ( table 2 ). The distribution of AC drug classes by AC potency is detailed in online supplementary e-table 1 .

Between February 2012 and June 2016, 37 304 participants with a mean age of 57.8 years undertook the cognitive tests. Study population corresponded to participants with available data to compute cognitive z-scores (N=34 267 participants presenting all cognitive z-scores). Table 1 shows the main characteristics of participants. During the 3-year period preceding inclusion, AC drugs were dispensed at least once to 16 172 (47.2 %) participants. For nearly two-thirds of these AC drug users, cumulative exposure was less than 3 months. Elderly, women and individuals with low education levels were more likely to have a high cumulative AC exposure ( table 1 ).

Discussion

This cross-sectional study of 34 267 individuals aged 45–70 demonstrated a negative association between overall cumulative exposure to AC drugs and cognitive performance. This association was medium for executive functions (DSST, TMT-A and TMT-B) and less pronounced for episodic memory (immediate and delayed free recall). To our knowledge, the present study is the first reporting such an association in middle-aged adults, consistent with what has been observed in older individuals, whether regarding impairments in executive functions,34 episodic memory35 and risk of dementia.6 11 Another novel finding of our study is that association between exposure to AC drug and cognitive performance was highly heterogeneous across drug classes: the effect size was medium for antipsychotics and small for drugs targeting the gastrointestinal tract or metabolism, opioids and anxiolytics. More specifically, a substantial proportion of the initially reported association between overall cumulative exposure to AC drugs and cognitive performance seems ascribable to individuals exposed to AC antipsychotics.

Strengths and limitations To our knowledge, this is the first study assessing the association between exposure to AC drugs and cognitive performance within such a young population. Most of the previous studies on AC drugs and cognition included individuals aged 65 or over, whereas this study included individuals aged 45–70 (mean age: 57.8). In addition, this study combines high-quality data on both cognitive functions and exposure to AC drugs. A comprehensive set of well-established cognitive tests was administered by neuropsychologists who were specially trained and monitored, while precise quantification of the doses of AC drugs used and limited impact of recall bias were possible using claims national reimbursement databases. Also, the large sample size provided enough statistical power for considering each drug class separately contrary to most of the earlier observational studies which relied on analyses pooling all ACs regardless of drug class. In contrast, we studied the association between cumulative exposure to ACs and cognitive performance according to their level of AC potency and their drug class and highlighted an important heterogeneity of this association across ACB scores and drug classes. Besides, we used a more precise approach than a simple computation of the AC burden, which does not take into account either the drug dosage or the duration of exposure. Another strength of our study is the wide panel of variables collected on CONSTANCES participants, which allowed us to correct for many potential confounders associated with either cognitive performance or prescription of AC drugs. Finally, the dose–effect relationship provides an additional argument for discussing a causal association. In the literature, authors already used it and found a dose–effect association between AC drug use and cognitive performances.11 One of the limitations of our study is that AC exposure quantification was based on the amount of AC drugs dispensed and not on the amount actually taken by the participants. However, this bias may be limited for participants with regular prescriptions. Therefore, it is very unlikely to affect our findings. Another limitation is that we did not include AC drugs for which a DDD was not available, that is, ocular solutions and topical glucocorticoids. These drugs are mainly topical and accounted for only 3% of AC drugs dispensed to the study participants; consequently, their exclusion is unlikely to have a substantial effect on our results. Finally, non-refundable medicines were not taken into account due to the lack of available data in the reimbursement databases. Finally, because our study focuses on the side effects of treatments rather than efficacy, we have not corrected our results for multiple comparisons. This practice is consistent with the literature in observational epidemiology.36 However, given this point, it is possible that some of our results may be falsely positive, especially when the effect size is small.