Prevalence and incidence of young onset dementia and associations with comorbidities: A study of data from the French national health data system

Laure Carcaillon-Bentata; Cécile Quintin; Marjorie Boussac-Zarebska; Alexis Elbaz

doi:10.1371/journal.pmed.1003801

. 2021 Sep 23;18(9):e1003801. doi: 10.1371/journal.pmed.1003801

Prevalence and incidence of young onset dementia and associations with comorbidities: A study of data from the French national health data system

Laure Carcaillon-Bentata ^1,^*, Cécile Quintin ¹, Marjorie Boussac-Zarebska ¹, Alexis Elbaz ^1,²

Editor: Perminder Singh Sachdev³

PMCID: PMC8496799 PMID: 34555025

Abstract

Background

Dementia onset in those aged <65 years (young onset dementia, YOD) has dramatic individual and societal consequences. In the context of population aging, data on YOD are of major importance to anticipate needs for planning and allocation of health and social resources. Few studies have provided precise frequency estimates of YOD. The aim of this study is to provide YOD prevalence and incidence estimates in France and to study the contribution of comorbidities to YOD incidence.

Methods and findings

Using data from the French national health data system (Système National des Données de Santé, SNDS) for 76% of the French population aged 40 to 64 years in 2016 (n = 16,665,795), we identified all persons with dementia based on at least 1 of 3 criteria: anti-Alzheimer drugs claims, hospitalization with the International Classification of Diseases-10th Revision (ICD-10) dementia codes (F00 to F03, G30, G31.0, G31.1, or F05.1), or registration for free healthcare for dementia. We estimated prevalence rate (PR) and incidence rate (IR) and estimated the association of comorbidities with incident YOD. Sex differences were investigated. We identified 18,466 (PR_standardized = 109.7/100,000) and 4,074 incident (IR_standardized = 24.4/100,000 person-years) persons with prevalent and incident YOD, respectively. PR and IR sharply increased with age. Age-adjusted PR and IR were 33% (95% confidence interval (CI) = 29 to 37) and 39% (95% CI = 31 to 48) higher in men than women (p < 0.001 both for PR and IR). Cardio- and cerebrovascular, neurological, psychiatric diseases, and traumatic brain injury prevalence were associated with incident YOD (age- and sex-adjusted p-values <0.001 for all comorbidities examined, except p = 0.109 for antihypertensive drug therapy). Adjustment for all comorbidities explained more than 55% of the sex difference in YOD incidence. The lack of information regarding dementia subtypes is the main limitation of this study.

Conclusions

We estimated that there were approximately 24,000 and approximately 5,300 persons with prevalent and incident YOD, respectively, in France in 2016. The higher YOD frequency in men may be partly explained by higher prevalence of cardiovascular and neurovascular diseases, substance abuse disorders, and traumatic brain injury and warrants further investigation.

In an observational study, Laure Carcaillon-Bentata and colleagues investigate the prevalence and incidence of dementia onset among adults younger than 65 years of age using data from the French national health data system from 2016.

Author summary

Why was this study done?

Dementia onset in people aged <65 years (young onset dementia, YOD) has dramatic individual and societal consequences.
To the best of our knowledge, there is a lack of data regarding the frequency of YOD in France.
Few data are available regarding the contribution of comorbidities to YOD incidence.

What did the researchers do and find?

Using data from the French national health data system for 76% of the French population, we estimated YOD prevalence and incidence in individuals aged 40 to 64 years and examined the contribution of comorbidities to YOD incidence.
Standardized prevalence rate (PR) and incidence rate (IR) were 109.7/100,000 and 24.4/100,000 person-years, respectively, and were higher in men than women.
Cardiovascular and neurovascular, neurological, psychiatric diseases, and traumatic brain injury explained >55% of the sex difference in YOD incidence.

What do these findings mean?

We extrapolate that there were approximately 24,000 and approximately 5,300 persons with prevalent and incident YOD, respectively, in France in 2016.
YOD incidence is higher in men than women, and this could possibly be due, at least in part, to the higher prevalence of cardiovascular and neurovascular diseases and substance abuse disorders in men.

Introduction

Dementia represents a major worldwide public health concern as the number of people affected doubled between 1990 and 2016 and will continue to rise due to population aging [1]. Although dementia mainly occurs during old age, it can develop earlier. Young onset dementia (YOD), also referred to as early onset dementia, generally refers to dementia occurring before 65 years [2]. Among people older than 60 years, 6% to 9% of all dementia cases occurred before 65 years [3].

Compared with individuals with late onset dementia (LOD), those suffering from YOD usually present more atypical symptoms; memory loss complaints are not systematically reported, while behavioral problems (e.g., mood disturbances and psychosis) often coexist [4]. These individuals face major psychological, familial, and socioeconomic challenges, while often still active professionally [5]. YOD has a major impact on the quality of life of people with the disease and their caregivers [6,7]. YOD burden is high for the health and social care systems in charge of young individuals affected by a chronic disease requiring a high and costly level of care.

In the context of population aging, data on YOD are of major importance to anticipate needs for planning and allocation of health and social resources [8]. Some field and register studies provided heterogeneous estimates of YOD prevalence, ranging from 38 to 420/100,000 between 30 and 64 years [9–17]. Fewer studies are available regarding YOD incidence, and methodological differences likely explain inconsistent results between them [9–11,16–19]. In France, to our knowledge, only 1 study reported on the prevalence of young onset Alzheimer disease and found it to be 41.2/100,000 before the age of 60 years in 1998 [20].

There is a growing interest in using administrative health databases to estimate the burden of chronic diseases, including dementia [21,22]. Given the high number of undiagnosed and untreated dementia in the population [23], these sources suffer from poor sensitivity [24]. However, their sensitivity may be higher in younger individuals [25,26]. In France, a preliminary study compared dementia prevalence based on administrative data to those from cohort studies and showed that administrative data underestimated prevalence after 70 years but yielded consistent estimates for YOD [27]. We hypothesized that the dramatic impact of YOD on patient’s lives is more likely to lead younger individuals to be in contact with the health system than older ones.

In this paper, we used more recent data from the French national health data system for 76% of the French population to estimate YOD prevalence and incidence in 2016, overall and by age and sex, and to examine the contribution of comorbidities to YOD incidence.

Methods

Data sources

Data come from the French national health data system, Système National des Données de Santé (SNDS) [22]. It includes data on ambulatory healthcare consumption (including drug reimbursements and laboratory tests) and hospitalization records in all public/private hospitals since 2006. Drugs are coded using the anatomical therapeutic chemical classification (ATC). Data on hospitalizations in short-stay departments, rehabilitation, psychiatry, and at home are available. After each hospital stay, a discharge summary is filed, including a principal diagnosis (DP) as well as related (DR) and associated (DA) diagnoses coded using the International Classification of Diseases-10th Revision (ICD-10). In addition, in France, individuals with long-term chronic diseases (LTDs), including dementia, can benefit from free healthcare, and this information is registered in SNDS. Demographic information (age, sex, and vital status) is available.

SNDS gathers data from various social security schemes (which depend on occupation), covering >98% of the French population. Our analyses are restricted to the general scheme that includes persons employed in the private sector and spouses if unemployed (76% of the French population). As the SNDS was initially developed for the general scheme, data for its affiliates are more exhaustive than for other schemes, especially for historical data. We excluded from our analyses workers in public services (11%), farmers, agricultural workers and their spouses if unemployed (5%), self-employed workers (6%), and workers from other smaller health systems (2%). As a governmental agency in charge of health surveillance in France, Santé publique France has a full access to SNDS data according to the French law to achieve its missions (French public health code, article R1461-14.1); the current project falls within the surveillance missions of Santé publique France.

Identification of persons with YOD

We identified persons with dementia among all individuals aged 40 to 64 years old and alive on December 31, 2016. Dementia ascertainment relied on the presence of at least 1 of the following criteria: (1) ≥2 reimbursements over a 1-year period of anti-Alzheimer drugs (acetylcholinesterase inhibitors: Donepezil, ATC code N06DA02; Rivastigmine, N06DA03; Galantamine, N06DA04; Memantine, N06DX01); (2) LTD registration for dementia (ICD-10 codes: F00 to F03, G30, G31.0, G31.1, or F05.1); and (3) at least 1 hospitalization with a DP, DR, or DA diagnosis of dementia (same ICD-10 codes as above). To reduce the number of false positives and increase specificity, we excluded individuals who were identified only by one hospitalization with a DA or DR dementia diagnosis.

We previously showed that data collected over a 1-year period had poor sensitivity to identify prevalent dementia [28]. Consequently, in order to identify prevalent dementia in 2016 and 2015, the 3 criteria were searched over 5-year periods (2012 to 2016 and 2011 to 2015, respectively). Persons with incident dementia in 2016 were those identified in 2016 but not prevalent in 2015. We excluded persons with incident dementia without any healthcare use over 3 years before 2016, in whom we could not determine the exact incidence date.

Comorbidities ascertainment

Based on the literature on YOD and LOD, we selected cardio- and cerebrovascular diseases and treatments, metabolic conditions, psychiatric diseases, psychotropic drugs, other neurological diseases, and traumatic brain injury as potential risk factors for YOD [29–35].

The identification of all comorbidities, except traumatic brain injury, relied on algorithms developed by SNDS experts in collaboration with the institution in charge of the SNDS, the Caisse Nationale d’Assurance Maladie des Travailleurs Salariés (CNAMTS) [36]. We identified traumatic brain injury using ICD-10 codes recommended by a literature review on ascertainment of neurotrauma in administrative databases [37]. A detailed description of the algorithms is available as S1 Table.

Statistical analysis

Characteristics of individuals with prevalent and incident YOD overall and by sex are presented using means (standard deviation, SD) and number (proportions). Differences between sexes were tested using Student t test and Pearson chi-squared for continuous and categorical variables, respectively.

To estimate the YOD prevalence rate (PR) in 2016, we divided the number of individuals with prevalent dementia, aged 40 to 64 years old and alive on December 31, 2016, by the number of individuals affiliated to the general scheme of the social security at the same date provided by the French national health insurance register (Répertoire National Interrégimes des Bénéficiaires de l’Assurance Maladie, RNIAM). The YOD incidence rate (IR) in 2016 was estimated by dividing the number of individuals with incident dementia in 2016 by the number of person-years affiliated to the general scheme in 2016, from which we subtracted the number of individuals with prevalent YOD in 2016.

PR and IR were computed overall and by sex and 5-year age groups. We used Poisson regression to estimate 95% confidence intervals (CI) and male-to-female prevalence (PRR_M/W) and incidence (IRR_M/W) rate ratios and 95% CI, overall (adjusted for age) and by age. We tested whether PRR_M/W and IRR_M/W changed with continuous age by including an interaction term between age and sex. We estimated age- and sex-standardized PR and IR using the French population as the reference (National Institute of Statistics and Economic Studies) [38].

The number of persons with prevalent and incident YOD in France in 2016 were extrapolated by applying age- and sex-specific PR and IR to the French population.

We compared the prevalence of comorbidities in incident YOD and the total population aged 40 to 64 years old affiliated to the general scheme in 2016; it comprised all persons without YOD who were reimbursed at least 1 healthcare intervention or hospitalized within 3 years before 2016. For each comorbidity, we computed odds ratios (ORs, 95% CI) using logistic regression adjusted for age and sex.

Analyses regarding prevalence, incidence, and associations of comorbidities with incident YOD were preplanned. As we found a strong difference in YOD incidence by sex, we further examined the contribution of comorbidities to sex differences in YOD incidence by estimating the percentage reduction in the association between sex and YOD after adjustment for comorbidities. Traumatic brain injury was included in our analyses after the main analyses were completed in response to a reviewer’s suggestion.

This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline (S1 STROBE Checklist).

Results

In 2016, we identified 18,466 persons with prevalent YOD (54.2% men, 45.8% women; Table 1). Their mean age was 57.3 (SD = 6.1) years. Hospitalization records and LTD registration for dementia were present in 56.3% and 53.4% of prevalent YOD, respectively. More women (32.2%) than men (23.5%) had anti-Alzheimer drug claims (p < 0.0001). Women (12.7%) more often met all 3 criteria for inclusion compared to men (7.9%) (p < 0.0001).

Table 1. Characteristics of prevalent and incident YOD, overall and by sex, in France (2016).

	Prevalent YOD				Incident YOD
	Overall	Men	Women	p-value	Overall	Men	Women	p-value
Characteristics	n = 18,466	n = 10,011	n = 8,455		n = 4,074	n = 2,256	n = 1,818
Age, mean (SD)	57.3 (6.1)	57.0 (6.3)	57.6 (5.9)	<0.001	57.2 (6.0)	57.0 (6.3)	57.4 (6.0)	0.065
Dementia criteria, n (%)
Hospitalization record	10,402 (56.3)	5,578 (55.7)	4,824 (57.1)	0.404	2,180 (53.5)	1,197 (53.1)	983 (54.0)	0.532
Anti-Alzheimer drug claim	5,072 (27.5)	2,352 (23.5)	2,720 (32.2)	<0.001	741 (18.2)	351 (15.6)	390 (21.4)	<0.001
LTD registration for dementia	9,863 (53.4)	5,231 (52.3)	4,632 (54.8)	0.003	2,003 (49.2)	1,116 (49.5)	887 (48.8)	0.675
Number of dementia criteria, n (%)				<0.001				<0.001
One criteria alone	13,549 (72.9)	7,654 (76.5)	5,805 (68.7)		3,372 (82.7)	1,918 (85)	1,453 (80.0)
Two criteria	3,143 (17.0)	1,564 (15.6)	1,579 (18.7)		556 (13.6)	268 (11.9)	288 (15.8)
Three criteria	1,864 (10.1)	793 (7.9)	1,071 (12.7)		147 (3.6)	70 (3.1)	77 (4.2)
Combination of dementia criteria, n (%)				<0.001				<0.001
Hospitalization alone	6,439 (34.9)	3,669 (36.7)	2,770 (32.8)		1,662 (40.8)	944 (41.8)	718 (39.5)
Anti-Alzheimer drug claim alone	1,521 (8.2)	788 (7.9)	733 (8.7)		316 (7.8)	154 (6.8)	162 (8.9)
LTD registration alone	5,499 (29.8)	3,197 (31.9)	2,302 (27.2)		1,394 (34.2)	820 (36.3)	573 (31.5)
Hospitalization + anti-Alzheimer drug claim	643 (3.5)	323 (3.2)	320 (3.8)		93 (2.3)	42 (1.9)	51 (2.8)
Hospitalization + LTD registration	1,456 (7.9)	793 (7.9)	663 (7.8)		278 (6.8)	141 (6.3)	137 (7.5)
Anti-Alzheimer drug claim + LTD registration	1,044 (5.7)	448 (4.5)	596 (7.1)		185 (4.5)	85 (3.8)	100 (5.5)

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LTD, long-term chronic disease; SD, standard deviation; YOD, young onset dementia.

In 2016, 4,074 persons (55.4% men and 44.6% women) developed YOD. Their mean age was 57.2 (SD = 6.0) years, similar in men and women (p = 0.065). Hospitalization records and LTD registration for dementia were present in 53.5% and 49.2% of incident YOD, respectively. Anti-Alzheimer drug claims were less frequent in incident than prevalent YOD, but remained more frequent in women (21.4%) than men (15.6%) (p < 0.0001).

PR and IR

Fig 1 and S2 and S3 Tables show PR and IR of YOD. Crude PR and IR were 105.4/100,000 persons and 23.4/100,000 person-years, respectively. Age- and sex-standardized PR and IR were 109.7/100,000 persons and 24.4/100,000 person-years, respectively. PR increased from 25.2/100,000 between 40 and 44 years to 284.8 between 60 and 64 years. Similarly, IR increased from 6.0/100,000 person-years in the younger age category to 62.3 in the older one.

By applying age/sex-specific rates to the French population, we estimate that approximately 24,000 persons (13,400 men and 10,600 women) aged 40 to 64 years had YOD in 2016 and that approximately 5,300 persons (3,000 men and 2,300 women) developed YOD in 2016.

Age-standardized PR and IR were higher in men (PR_men = 125.5/100,000; IR_men = 28.5/100,000 person-years) than women (PR_women = 94.8/100,000; IR_women = 20.5/100,000 person-years). The age-adjusted PRR_M/W was 1.33 (95% CI = 1.29 to 1.37), and the age-adjusted IRR_M/W was 1.39 (95% CI = 1.31 to 1.48). PRR_M/W decreased with age (Fig 2). It was 1.66 (95% CI = 1.45 to 1.89) between 40 and 44 years, and it progressively decreased to 1.26 (95% CI = 1.21 to 1.31) between 60 and 64 years (p-interaction between sex and continuous age <0.001). Age-specific IRR_M/W were similar to corresponding age-specific PRR_M/W, and there was a similar trend of decreasing IRR_M/W with continuous age, but it was not statistically significant (p-interaction = 0.494), possibly due to insufficient statistical power as the number of incident cases in each age group was considerably smaller than the number of prevalent cases. The attenuation of the difference between men and women with increasing age is due to a faster increase of PR and IR with age in women than men (Fig 1).

Fig 2 — Black bars represent 95% CIs. CI, confidence interval; IR, incidence rate; PR, prevalence rate.

Contribution of comorbidities to YOD

Table 2 shows a higher prevalence of all comorbidities in YOD than in the general population, in particular of cerebrovascular and neurological diseases, substance abuse, schizophrenia and psychotic disorders, and traumatic brain injury. In persons without YOD, all comorbidities were more frequent in men than women (S4 Table).

Table 2. Prevalence of comorbidities in incident YOD and in persons without YOD from the French population (40 to 64 years) in 2016.

	Incident YOD (2016)		Overall French population without YOD (2016)^a
	n	(%)	n	(%)	Crude OR^b	(95% CI)	p-value	Adjusted OR^b^,^c	(95% CI)	p-value
Male sex	2,256	(55.4)	7,490,943	(46.2)	1.45	(1.36 to 1.54)	<0.001	1.48	(1.39 to 1.57)	<0.001
Cardiovascular, cerebrovascular, and metabolic diseases and drug-related therapies
Morbid obesity	368	(9.0)	729,979	(4.5)	2.11	(1.09 to 2.35)	<0.001	1.75	(1.57 to 1.95)	<0.001
Diabetes	549	(13.5)	1,068,192	(6.6)	2.21	(2.02 to 2.42)	<0.001	1.36	(1.24 to 1.49)	<0.001
Acute cerebrovascular disease (excluding transient attacks)	121	(3.0)	20,523	(0.1)	24.17	(20.16 to 28.97)	<0.001	16.27	(13.55 to 19.52)	<0.001
Sequelae of cerebrovascular disease or history of acute cerebrovascular disease	468	(11.5)	148,449	(0.9)	14.05	(12.76 to 15.48)	<0.001	9.64	(8.75 to 10.63)	<0.001
Acute ischemic heart disease	23	(0.6)	27,128	(0.2)	3.40	(2.25 to 5.11)	<0.001	2.29	(1.52 to 3.45)	<0.001
Chronic ischemic heart disease or history of acute ischemic heart disease	257	(6.3)	381,042	(2.3)	2.80	(2.47 to 3.18)	<0.001	1.55	(1.36 to 1.76)	<0.001
Cardiac arrhythmias and conduction disorders	220	(5.4)	181,704	(1.1)	5.04	(4.40 to 5.77)	<0.001	3.00	(2.61 to 3.44)	<0.001
Antihypertensive drug therapy	1,275	(31.3)	3,276,569	(20.2)	1.80	(1.68 to 1.92)	<0.001	1.06	(0.99 to 1.13)	0.109
Neurological diseases other than dementia
Parkinson disease	274	(6.7)	26,575	(0.2)	43.94	(38.85 to 49.70)	<0.001	26.21	(23.15 to 29.68)	<0.001
Epilepsy	371	(9.1)	93,330	(0.6)	17.31	(15.56 to 19.27)	<0.001	16.06	(14.43 to 17.89)	<0.001
Multiple sclerosis	98	(2.4)	49,170	(0.3)	8.11	(6.63 to 9.91)	<0.001	8.99	(7.35 to 10.97)	<0.001
Psychiatric disorders and related drug therapies
Substance abuse disorders (drugs, alcohol, and cannabis)	594	(14.6)	154,415	(1.0)	17.76	(16.28 to 19.38)	<0.001	18.34	(16.79 to 20.04)	<0.001
Schizophrenia and psychotic disorders	328	(8.1)	204,721	(1.3)	6.85	(6.11 to 7.67)	<0.001	7.12	(6.36 to 7.97)	<0.001
Traumatic brain injury	259	(6.4)	66,133	(0.4)	16.58	(14.61 to 18.81)	<0.001	14.02	(12.35 to 15.92)	<0.001

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^a Overall French population without YOD include individuals aged 40 to 64 years old and affiliated to the general security scheme in 2016.

^b ORs, 95% CIs, and p-values were computed using logistic regression.

^c OR adjusted for age and sex.

CI, confidence interval; OR, odds ratio; YOD, young onset dementia.

The age-adjusted OR of YOD for men compared to women was 1.48 (95% CI = 1.39 to 1.57, p < 0.001). Table 3 shows the contribution of comorbidities to this association; cardiovascular and neurovascular and metabolic diseases and substance abuse disorders explained 23.5% and 29.2% of the association, respectively. After adjustment for all comorbidities, the association decreased by 55.6% (OR = 1.19, 95% CI = 1.11 to 1.27, p < 0.001).

Table 3. Percentage reduction of the association between male sex and YOD incidence due to comorbidities.

Model	OR men versus women^a	95% CI	Percentage reduction (%)^b
Model 1 adjusted for age	1.48	(1.39 to 1.57)	—
Model 1 + covariates
Morbid obesity	1.48	(1.39 to 1.58)	0.0
Diabetes	1.46	(1.37 to 1.55)	3.5
Antihypertensive drug therapy	1.48	(1.39 to 1.57)	0.0
Acute cerebrovascular disease (excluding transient attacks)	1.45	(1.36 to 1.53)	5.2
Sequelae of cerebrovascular disease or history of acute cerebrovascular disease	1.41	(1.32 to 1.50)	12.4
Acute ischemic heart disease	1.48	(1.39 to 1.57)	0.0
Chronic ischemic heart disease or history of acute ischemic heart disease	1.44	(1.36 to 1.53)	7.0
Cardiac arrhythmias and conduction disorders	1.44	(1.36 to 1.53)	7.0
All cardiovascular, cerebrovascular, and metabolic disease and related drug therapies	1.35	(1.27 to 1.43)	23.5
Parkinson disease	1.46	(1.37 to 1.55)	3.5
Epilepsy	1.43	(1.34 to 1.52)	8.8
Multiple sclerosis	1.51	(1.42 to 1.60)	−5.1
All neurological diseases other than dementia	1.44	(1.35 to 1.53)	7.0
Substance abuse disorders (drugs, alcohol, and cannabis)	1.32	(1.24 to 1.40)	29.2
Schizophrenia and psychotic disorders	1.46	(1.37 to 1.55)	3.5
All psychiatric disorders and related drug therapies	1.31	(1.23 to 1.39)	31.1
Traumatic brain injury	1.41	(1.33 to 1.50)	12.4
All comorbidities	1.19	(1.11 to 1.27)	55.6

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^a ORs, 95% CIs, and p-values were computed using logistic regression. All ORs are significant at p < 0.001.

^b Percentage reduction = 100 × (logOR_{Model 1} − logOR_{Model 1 + covariates})/logOR_{Model 1}.

CI, confidence interval; OR, odds ratio; YOD, young onset dementia.

Discussion

We used data from the French national health data system for 76% of the French population to estimate the PR and IR of YOD in people aged 40 to 64 years old. In 2016, age and sex-standardized PR and IR were 109.7/100,000 persons and 24.4/100,000 person-years, respectively. By applying these rates to the French population, we estimate that approximately 24,000 persons aged 40 to 64 years old had YOD in 2016, and approximately 5,300 persons developed YOD in 2016. Rates of YOD were higher in men compared to women, and we identified that this association was attenuated by 56% after adjustment for all comorbid conditions considered, suggesting a potential role for comorbid conditions in the relationship between sex and YOD.

Burden of YOD in France and comparison with other studies

Previous field studies have provided inconsistent results regarding YOD prevalence, with PR ranging from 90 to 420/100,000 between 30 and 64 years [11,14,39,40]. Our estimation is compatible with the only previous French study [20], although it reported a slightly lower prevalence in people aged 41 to 60 years (PR = 41.2/100,000, n = 39 versus PR = 67.7/100,000 in our study for the same age group) probably due to the inclusion of young onset Alzheimer disease only, not all-cause dementia. Our results are also in line with 2 studies: one performed in the province of Modena in Italy (2006 to 2019, PR = 119.9/100,000) [41] and the other in 4 catchment areas of eastern Sydney, Australia (2007 to 2008, PR = 133/100,000 between 45 and 64 years; the PR for this age group in our study was 127/100,000) [11]. Regarding incidence, 2 recent field studies provided IR that were consistent with our findings; in the Italian study mentioned above, the IR was 22.8/100,000, and it was 25.0/100,000 between 45 and 64 years in a population-based study in Norway (2015 to 2017) [11,17].

In registry-based studies, PR ranged from 81 to 143/100,000 between 45 and 65 years, in line with our study findings [9,12,13,15,16,40–42]. In addition, 4 registries provided IR. Our estimate (24.4/100,000 person-years) is close to that from a Spanish study (2007 to 2009) that estimated IR to be 22.8/100,000 person-years between 40 and 65 years [16]. Other studies conducted in Scotland (1974 to 1988) [18], England (2000 to 2006) [19], and Japan (2018 to 2019) [43] yielded much lower IR of 2.7, 11.5, and 2.5/100,000 person-years, respectively. The inclusion of psychiatric hospitals records only in the Scottish study, the small catchment area and thus small number of incident cases in the English study, and a large population a denominator (18 to 64 years) in the Japanese study are the main explanations for the low incidence estimates in these studies.

Other studies used national or regional administrative databases [44–46], with important differences regarding study design, data sources, and criteria used to define YOD. Recently, the European medical information framework consortium analyzed 6 electronic health databases from 5 countries to estimate dementia PR and IR [45]. Our results are comparable to those from 2 databases identifying dementia using general pharmacy and hospital records: 1 from Tuscany (Italy, 50 to 70 years: PR = 100/100,000; IR = 30/100,000 person-years) and 1 from the northern and central regions of Jutland (Denmark, 50 to 70 years: PR = 300/100,000; IR = 58/100,000 person-years). In our study, the PR between 50 and 65 years was 100/100,000, and the IR was 37/100,000 person-years. Most studies that included primary care data provided estimates similar to our own [44,45], but one reported higher rates [46]; it ascertained dementia using 4 linked administrative health databases from the Saskatchewan Province (Canada), a wide range of ICD-10 codes, and cognitive testing data, but not functional tests, which may have led to an overestimation of the YOD frequency.

Given the heterogeneity of the information available in administrative databases in each country, comparisons of YOD frequency are difficult, and differences should be interpreted with caution. A recent review on the accuracy of dementia diagnosis in routinely collected datasets reported good specificity and positive predictive value but moderate sensitivity [24]. Based on 12 studies, sensitivity was comprised between 21% and 86%, with only 3 of 12 studies reporting estimates ≥60%. However, some studies found sensitivity to be higher at younger ages [25,26]. There are 2 major reasons for reduced sensitivity in administrative databases: first, 1 to 3 persons with dementia is undiagnosed and therefore undetected in administrative databases [23]; second, criteria used to identify dementia lack sensitivity since not all persons with dementia are treated with anti-Alzheimer drugs or hospitalized [21,27]. Regarding younger individuals with YOD, cognitive decline and dementia are often associated with behavioral disturbances [4], and they face a more aggressive course with a steeper rate of cognitive decline [47]. Therefore, the disease has a major impact on individuals’ lives, which likely explains higher sensitivity of administrative databases in younger individuals who are more likely to seek medical care and integrate the health system than their older counterparts.

Sex differences in YOD incidence and role of comorbidities

Many studies examined sex differences in dementia, and their results remain equivocal [48,49]. Previous studies mostly reported no differences between men and women for LOD incidence [50,51]. Studies with higher rates in women mostly found differences restricted to the oldest age group [52,53]. For YOD, we found that the PRR_M/W was 1.33 and the IRR_M/W 1.39 and that this difference decreased with age. Two Japanese multicenter population-based studies (n = 2,469 [42] and n = 4,077 [39] YOD) reported higher YOD prevalence in men than women (PRR_M/W = 1.59, 95% CI = 1.56 to 1.53 and mean PRR_M/W = 1.4, respectively). Also consistent with our findings, in both the hospital-based Italian and Danish studies discussed above, PRR_M/W/IRR_M/W <70 years were 1.11/1.25 in the Italian (n = 2,659 YOD) and 1.45/1.25 in the Danish study (n = 2,183 YOD) [45] and decreased thereafter. Other studies found no significant sex differences for prevalence [11,12,16,40,46] or incidence [11,16,46,50].

Differences between men and women in dementia rates are likely to arise both from differences related to sex (i.e., biological) and gender (i.e., behaviors, such as addictions; sociocultural, such as education or occupation) [49]. A number of reasons may thus account for higher YOD rates in men. First, there are important sex differences in middle age for several comorbidities associated with dementia. The incidence of cardio- and cerebrovascular disease is higher in middle-aged men than women [54]. There is increasing evidence that these conditions are associated with cognitive decline and LOD [31,33]. Although additional studies are needed to better understand their role in YOD, in our study, cardio- and cerebrovascular diseases or metabolic disease explained approximately 23% of the association between male sex and YOD, thus suggesting an important contribution of vascular dementia to YOD. In addition, other disorders associated with cognitive decline and dementia (e.g., substance abuse [55], Parkinson disease [29], epilepsy [35], and traumatic brain injury [56]) are more common in men than women and explained an important part of the association between male sex and YOD. Second, women may benefit from neuroprotective effects of estrogens regarding cerebrovascular disease and dementia [57]. Third, compared to men, women may have a reduced or delayed use of healthcare services for memory complaints. According to the French national Alzheimer Database that includes information for all individuals who attend memory clinics, in 2012, women were older than men (77.5 versus 74.4 years) and had a lower Mini-Mental State Examination (MMSE) score (20.5 versus 21.6 points) at the time of first visit [58]. However, these findings may reflect the higher proportion of older women in France rather than a delayed used of medical care services. Unfortunately, YOD data were not available in this study.

Strengths and limitations of the study

The main strengths of our study are its large size, the inclusion of all persons aged 40 to 64 years old affiliated to the general scheme of the French social security, and the ascertainment of all persons with dementia who required medical care within that population. The large number of persons with YOD allowed us to estimate PR, IR, and sex ratios with precise CIs. The comparison with a reference cohort of persons without YOD yielded a sex difference similar to the incidence analysis and provides insights about the role of comorbidities in sex differences in YOD incidence.

The main limitation of our study is that we were unable to identify undiagnosed persons and those who were not in contact with the medical system. As discussed above, this is less likely to occur in this age group than in older individuals. In addition, we used the first date of contact for dementia with the medical system to define age at incidence, which could be delayed relative to the actual age at incidence, leading to misclassification of some individuals with YOD as having LOD [59,60]. No data are available in France on the delay between dementia diagnosis and anti-Alzheimer drugs initiation, LTD registration, or first hospitalization. However, French health authorities recommend to provide LTD registration for dementia at the time of diagnosis [61]; in addition, at the time of this study, anti-Alzheimer drugs were fully reimbursed for individuals with LTD registration, while only 15% of their cost were reimbursed to people without registration. These recommendations are likely to lead to a short delay between diagnosis and LTD registration and treatment. Another important limitation pertains to the lack of accurate information regarding dementia subtypes; one of the reasons may be variability in how ICD-10 codes are attributed in different hospitals and by different doctors all over France. Among the 3 criteria used to identify dementia, LTD registrations and hospitalizations have associated ICD-10 codes that could be used for this purpose. However, the accuracy of these codes and their relevance to identify dementia subtypes remain unclear, and additional validation studies are needed before they can be used for this aim. In addition, the use of anti-Alzheimer medications to identify YOD could have shifted our selection toward the inclusion of a higher number of persons with Alzheimer disease compared to other dementia subtypes. However, the majority of persons with YOD was identified through LTD registration or hospitalizations and only 8% by anti-Alzheimer medications alone. In addition, in France, some of the anti-Alzheimer medications can also be prescribed for other causes of dementia, such as Parkinson disease, dementia with Lewy bodies, or mixed dementia. Regarding study sample selection (76% of the French population), the participants excluded from our study are very heterogeneous. Public services concentrate a higher number of women and well-educated individuals, while agricultural and self-employed workers are 2 groups constituted of more men and with a large heterogeneity in terms of educational level. Therefore, and given the low amount of individuals that are missing, it is unlikely that the selection lead a systematic bias in our analysis. Other limitations include the lack of information on cognitive status and dementia severity and risk or protective factors (e.g., education level, occupation, smoking, alcohol drinking, physical activity, and diet). Finally, drug claims are not available in SNDS for persons in nursing home with an internal pharmacy, but this has little influence on our results given that these institutions are only available in France for persons ≥60 years.

Policy and research implications

We provide French YOD frequency estimates that help increase awareness on its burden. In addition, we show the important contribution of cardio- and cerebrovascular, metabolic, neurological (other than dementia), psychiatric diseases, and traumatic brain injury in explaining sex differences in YOD incidence. The higher YOD frequency in men deserves further investigation to clarify the role of sex-associated risk factors and comorbidities as well as differences in healthcare access. Our results may suggest that preventive approaches targeting cardiovascular risk factors in midlife, substance abuse disorders, and prevention and management of traumatic brain injury could be further investigated as strategies for reducing or postponing YOD.

Supporting information

S1 STROBE Checklist. Checklist of items that should be included in reports of cross-sectional studies.

STROBE, Strengthening the Reporting of Observational Studies in Epidemiology.

(DOCX)

Click here for additional data file.^{(31.5KB, docx)}

S1 Table. Algorithms for the identification of comorbidities and treatments of interest in the SNDS.

SNDS, Système National des Données de Santé.

(DOCX)

Click here for additional data file.^{(16.5KB, docx)}

S2 Table. PRs (per 100,000 persons) of YOD in France on December 31, 2016.

PR, prevalence rate; YOD, young onset dementia.

(DOCX)

Click here for additional data file.^{(14.8KB, docx)}

S3 Table. IRs (per 100,000 person-years) of YOD in France in 2016.

IR, incidence rate; YOD, young onset dementia.

(DOCX)

Click here for additional data file.^{(14.4KB, docx)}

S4 Table. Association between comorbidities and sex in persons without YOD from the French population in 2016 (40 to 64 years).

YOD, young onset dementia.

(DOCX)

Click here for additional data file.^{(20.1KB, docx)}

Abbreviations

ATC: anatomical therapeutic chemical classification
CI: confidence interval
CNAMTS: Caisse Nationale d’Assurance Maladie des Travailleurs Salariés
ICD-10: International Classification of Diseases-10th Revision
IR: incidence rate
LOD: late onset dementia
LTD: long-term chronic disease
MMSE: Mini-Mental State Examination
OR: odds ratio
PR: prevalence rate
RNIAM: Répertoire National Interrégimes des Bénéficiaires de l’Assurance Maladie
SD: standard deviation
SNDS: Système National des Données de Santé
STROBE: Strengthening the Reporting of Observational Studies in Epidemiology
YOD: young onset dementia

Data Availability

Data cannot be shared as access to the SNDS has to be approved by the French Data Protection Authority. Interested investigators can request their own access to the data according to the French law. Information on obtaining access to SNDS data can be found at https://www.snds.gouv.fr/SNDS/Processus-d-acces-aux-donnees. Requests for access to SNDS data must be submitted to the National Institute for Health Data (INDS) (https://www.health-data-hub.fr/demarches-reglementaires).

Funding Statement

The author(s) received no specific funding for this work.

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Decision Letter 0

Caitlin Moyer

11 Feb 2021

Dear Dr Carcaillon-Bentata,

Thank you for submitting your manuscript entitled "Early-onset dementia in France: sex-differences in prevalence, incidence, and role of comorbidities" for consideration by PLOS Medicine.

Your manuscript has now been evaluated by the PLOS Medicine editorial staff as well as by an academic editor with relevant expertise and I am writing to let you know that we would like to send your submission out for external peer review.

However, before we can send your manuscript to reviewers, we need you to complete your submission by providing the metadata that is required for full assessment. To this end, please login to Editorial Manager where you will find the paper in the 'Submissions Needing Revisions' folder on your homepage. Please click 'Revise Submission' from the Action Links and complete all additional questions in the submission questionnaire.

Please re-submit your manuscript within two working days, i.e. by .

Once your full submission is complete, your paper will undergo a series of checks in preparation for peer review. Once your manuscript has passed all checks it will be sent out for review.

Feel free to email us at plosmedicine@plos.org if you have any queries relating to your submission.

Kind regards,

Caitlin Moyer, Ph.D.

Associate Editor

PLOS Medicine

PLoS Med. doi: 10.1371/journal.pmed.1003801.r002

Decision Letter 1

Caitlin Moyer

2 Jun 2021

Dear Dr. Carcaillon-Bentata,

Thank you very much for submitting your manuscript "Early-onset dementia in France: sex-differences in prevalence, incidence, and role of comorbidities" (PMEDICINE-D-21-00532R1) for consideration at PLOS Medicine.

Your paper was evaluated by a senior editor and discussed among all the editors here. It was also discussed with an academic editor with relevant expertise, and sent to four independent reviewers, including a statistical reviewer. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:

[LINK]

In light of these reviews, I am afraid that we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to consider a revised version that addresses the reviewers' and editors' comments. Obviously we cannot make any decision about publication until we have seen the revised manuscript and your response, and we plan to seek re-review by one or more of the reviewers.

In revising the manuscript for further consideration, your revisions should address the specific points made by each reviewer and the editors. Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments, the changes you have made in the manuscript, and include either an excerpt of the revised text or the location (eg: page and line number) where each change can be found. Please submit a clean version of the paper as the main article file; a version with changes marked should be uploaded as a marked up manuscript.

In addition, we request that you upload any figures associated with your paper as individual TIF or EPS files with 300dpi resolution at resubmission; please read our figure guidelines for more information on our requirements: http://journals.plos.org/plosmedicine/s/figures. While revising your submission, please upload your figure files to the PACE digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at PLOSMedicine@plos.org.

We expect to receive your revised manuscript by Jun 23 2021 11:59PM. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

We ask every co-author listed on the manuscript to fill in a contributing author statement, making sure to declare all competing interests. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. If new competing interests are declared later in the revision process, this may also hold up the submission. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT. You can see our competing interests policy here: http://journals.plos.org/plosmedicine/s/competing-interests.

Please use the following link to submit the revised manuscript:

https://www.editorialmanager.com/pmedicine/

Your article can be found in the "Submissions Needing Revision" folder.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

We look forward to receiving your revised manuscript.

Sincerely,

Caitlin Moyer, Ph.D.

Associate Editor

PLOS Medicine

plosmedicine.org

-----------------------------------------------------------

Requests from the editors:

. Title: Please revise your title according to PLOS Medicine's style. Your title must be nondeclarative and not a question. It should begin with main concept if possible. "Effect of" should be used only if causality can be inferred, i.e., for an RCT. Please place the study design ("A randomized controlled trial," "A retrospective study," "A modelling study," etc.) in the subtitle (ie, after a colon).

2. Data Availability Statement: The Data Availability Statement (DAS) requires revision. For each data source used in your study:

a) If the data are freely or publicly available, note this and state the location of the data: within the paper, in Supporting Information files, or in a public repository (include the DOI or accession number).

b) If the data are owned by a third party but freely available upon request, please note this and state the owner of the data set and contact information for data requests (web or email address). Note that a study author cannot be the contact person for the data.

c) If the data are not freely available, please describe briefly the ethical, legal, or contractual restriction that prevents you from sharing it. Please also include an appropriate contact (web or email address) for inquiries (again, this cannot be a study author).

3. Line numbers: Please provide line numbers throughout the manuscript with the revised version.

4. Author Summary: Please move the Author Summary so that it follows the Abstract. Please format using bullet points, with 2-3 points for each section. This text is subject to editorial change and should be distinct from the scientific abstract. Please see our author guidelines for more information: https://journals.plos.org/plosmedicine/s/revising-your-manuscript#loc-author-summary

5. Abstract: Methods and Findings: Please provide some more detail on the study population. Please quantify the main results (with 95% CIs and p values) and please include the important dependent variables that are adjusted for in the analyses. * In the last sentence of the Abstract Methods and Findings section, please describe the main limitation(s) of the study's methodology.

6. Abstract: Conclusions: * Please address the study implications without overreaching what can be concluded from the data; the phrase "In this study, we observed ..." may be useful.

7. In-text citations: Please use numbers within square brackets for in-text citations. Where more than one reference is indicated, please do not include spaces within brackets.

8. Methods: Please ensure that the study is reported according to the STROBE guideline, and include the completed STROBE checklist as Supporting Information. Please add the following statement, or similar, to the Methods: "This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline (S1 Checklist)."

The STROBE guideline can be found here: http://www.equator-network.org/reporting-guidelines/strobe/

When completing the checklist, please use section and paragraph numbers, rather than page numbers.

9. Methods: Prospective Analysis Plan: Did your study have a prospective protocol or analysis plan? Please state this (either way) early in the Methods section.

a) If a prospective analysis plan (from your funding proposal, IRB or other ethics committee submission, study protocol, or other planning document written before analyzing the data) was used in designing the study, please include the relevant prospectively written document with your revised manuscript as a Supporting Information file to be published alongside your study, and cite it in the Methods section. A legend for this file should be included at the end of your manuscript.

b) If no such document exists, please make sure that the Methods section transparently describes when analyses were planned, and when/why any data-driven changes to analyses took place.

c) In either case, changes in the analysis-- including those made in response to peer review comments-- should be identified as such in the Methods section of the paper, with rationale.

10. Results: Please provide p values and 95% confidence intervals for all statistical comparisons, and please present both unadjusted and adjusted results (at least in tables, if not in the text.) Where p values are presented, please clarify the statistical tests used.

11. Discussion: First sentence: Please avoid claims of primacy, or if necessary, please temper with “to the best of our knowledge” or similar.

12. Discussion: If relevant for sex/gender differences, please consider discussing head trauma/ injury, which could be associated with motor vehicle accidents or sports related and may be more prominent in men, and this seems like it could potentially contribute to differences as a risk factor for cognitive decline and dementia.

13. Discussion: Please present and organize the Discussion as follows: a short, clear summary of the article's findings; what the study adds to existing research and where and why the results may differ from previous research; strengths and limitations of the study; implications and next steps for research, clinical practice, and/or public policy; one-paragraph conclusion.

14. References: Please use the "Vancouver" style for reference formatting, and see our website for other reference guidelines https://journals.plos.org/plosmedicine/s/submission-guidelines#loc-references

15. Table 2 and Table 3: Please provide both adjusted and unadjusted analyses.

16. Supplementary Table 1: Please define all abbreviations in the legend.

17. Supplementary Table 4: Please provide both the adjusted and unadjusted analyses.

Comments from the reviewers:

Reviewer #1: Using the French national health data system, this study attempts to estimate EOD prevalence and incidence in 2016 of French individuals aged 40-64y and study the contribution of comorbidities to EOD incidence.

Comments:

2016 is five years ago now. Can the analysis be updated so it is more relevant to todays prevalence and incidence rates?

"Based on the LOD literature, we selected cardio- and cerebro-vascular diseases and treatments, metabolic conditions, psychiatric diseases, psychotropic drugs, and other neurological diseases that may be EOD risk factors."

Could the authors please provide citations for reference here?

The application of Poisson regression to estimate 95% confidence intervals (CI), and male-to-female prevalence (PRRM/W) and incidence (IRRM/W) rate ratios and 95% CI, overall (adjusted for age) and by age, as well as including an interaction term between age and sex, is a technically appropriate and robust methodological approach.

"The IRRM/W was 1.61 (95% CI=1.23-2.11) between 40-44 years and it progressively decreased to 1.41 (95% CI=1.29-1.54) between 60-64 years. "

These results show overlapping CIs, that suggest that in fact the difference is not statistically significant? Did the authors consider undertaking any trend analyses?

Can the authors please present the uncertainty (i.e. the confidence intervals, as shown in supplementary tables 2 and 3) in the PR and IR's in Figure 1?

Can the authors please complete statistical testing of differences between groups in Table 1?

Table 2: Can the authors please include parentheses for the percentage figures?

Reviewer #2: The manuscript of Carcaillon-Bentata et al provides EOD prevalence and incidence estimates in France and the contribution of comorbidities to EOD incidence. To this aim, the authors used the French national health data system. The results they found were they were around 24.000 EOD cases in France in 2016. Further, cardio and cerebrovascular, neurological, and psychiatric disease prevalence explained more than 50% of the sex difference in EOD incidence. The authors highlight that this result supports the idea of preventive approaches aimed at reducing or postponing the onset of dementia by acting on cardiovascular risk factors in mid-life.

This manuscript has strengths that should be noted. First, the use of the French national health data system which covers more than 98% of the French population. Second, the well-written manuscript. However, I have some doubts about the relevance and the interpretation of the results.

My first main concern is regarding the interpretation of the findings. The authors have only explored the incidence of EOD encompassing the different types of dementia. It is well-known that the incidence of different types of dementia differs. Due to the higher sample, I would strongly suggest doing a breakdown of the prevalence of different dementia subgroups showing the results in a table with the frequency of clinical diagnosis among EAD cases and incidence rate per 100.000 person-years. Knowing the difference between subgroups would allow for a more powerful discussion of the findings. Also, the impact of comorbidities depends on the type of dementia. Furthermore, previous literature has shown the sex differences in some kinds of dementia, such as Alzheimer's Disease (Ferretti, et al. 2020) and Behavioural Variant of Frontotemporal Dementia (Illán-Gala, et al. 2021). However, the sex difference in the incidence of subtypes of EOD is lacking and deserves further study. Therefore, authors should consider adding this analysis to the current manuscript.

Following the sex difference topic, in the current manuscript is not clear if the analysis of sex differences in EOD is one of the main aims or a secondary one. In my opinion, I would say that it is one of the main aims because in the methods part the authors specify that "we want to assess the contribution of comorbidities to sex-differences in EAD incidence". If this is correct, I was wondering why they analyzed it, have the authors a previous hypothesis? The manuscript should be rewritten focusing on this topic and giving it more prominence. For instance, in the introduction, there is no information about sex differences in EOD found in the previous literature. Besides, sex differences should be included as a keyword. However, I would strongly encourage the authors to keep this focused on the current manuscript. Elucidating sex differences in dementia, also in its incidence, will allow to development of a precision medicine approach encompassing sex-sensitive strategies for prevention and detection.

It is well-known the difference between the concepts of sex and gender, referring to biology and social construct respectively. In this line, I was wondering if the gender factors can have an impact on the incidence of EAD as well.

Reviewer #3: This paper addresses an important topic. Good prevalence and incidence rates for young onset dementia have been lacking and it is important to know these for purposes of policy, service provision and research. This paper therefore makes a welcome contribution to the literature. The report is clear and succinct. The discussion provides a very good comparison with others' findings and the conclusions make a valuable contribution to knowledge in this area.

I have only four points for consideration:

1. In terms of your data source, I notice you accessed an impressive level (76% of the population) but this excludes those in public service. I wondered whether or not there is any systematic bias here that you could comment upon.

2. You did not refer to other comparable studies and their methods, strengths and limitations in the introduction, as might be conventional, but left this to the discussion. I think it would help to set the context to refer to these, at least briefly, in the introduction.

3. I am not a statistician so cannot comment on details of the analysis; however, as a lay person in this respect, I understood the expression, except for the correction used in calculating the incidence rate. This will be only my ignorance but, if shared with other readers, it may be worth considering how to make this more readily understandable.

4. At the very end of the discussion section, you state that institutionalisation is [only?] available to those >60 years. This seems strange - may I check that this actually correct?

I have two small suggestions in relation to writing style/terminology.

* Terms used to describe young onset dementia vary but 'young onset dementia' has become the most common, superseding 'early onset dementia', since the latter can become confused with 'early-stage dementia'. I would suggest that you change your terminology to young onset dementia to ensure best fit with emerging nomenclature.

* People living with dementia are very keen to be recognised and respected as whole human beings, especially as the condition is often equated with loss of personhood. In line with this, I would strongly urge you to consider replacing the term 'patient', where possible, with alternatives, e.g. in the first line of the abstract, you could say 'Dementia onset in those aged < 65 years….' And in the first paragraph of the background, you could say '…as the number of people affected….'. This helps to shift attitudes.

Reviewer #4: This a well written, much needed study on the epidemiology of early onset dementia (EOD), a condition with dramatic consequences for the individual patients, their families and the society. It will be important to raise awareness about this condition and for improving planning and allocation of health and social resources. I strongly recommend its publication but I would advise to address the following comments to further improve it:

1) It should made clear since the beginning, i.e. in the title and in the abstract, the fact that the epidemiological data on EOD where established from a register covering about 76% of the population of France. The current title and abstract give the uncorrect impression that the authors analysed data from the entire population of France.

2) One major problem of the manuscript in its current version is the scarcity of references to previous epidemiological studies on early onset dementia, some of which are very recent (see as an example Chiari et al 2020). Sentences such as "Few studies have provided precise frequency estimates of EOD" (abstract) and "Some EOD frequency estimates come from registries but they are probably biased due to the inclusion of small numbers of selected patients referred to specialized centers" (introduction) need to be either played down or become more specific about what is actually not precise or lacking in recent work on the epidemiology EOD.

3) The authors identified dementia cases among all individuals aged 40-64 years old. However, EOD can also occur before the age of 40. It would be very helpful if the authors could extend their analysis to include people aged 30-64. This will be more informative while also allowing a comparison with previous registry-based studies on the epidemiology of EOD (such as Garre-Olmo et al 2010). Please do specify in the first sentence of the Discussion that PR and IR are given for population aged 40-64 (again, I strongly suggest that you also add data regarding the 30-64 age group)

4) One of the strategies for cases identification was the presence of reimbursements over a one-year period of anti-dementia drugs. Please note that acetylcholinesterase inhibitors and memantine are not generically anti-dementia but are specifically licensed for Alzheimer's disease. Although Alzheimer's disease is the most frequent cause of dementia, there are several other diseases causing EOD that especially present in young patients, such as frontotemporal dementia. Please change 'anti-dementia' to a more specific terminology and mention in the discussion that the inclusion of such a strategy may have biased case identification towards AD, possibly missing other dementias that do not have specific medications.

5) In the discussion, the sentence "Field studies provided inconsistent results regarding EOD" needs to be re-framed. Actually, it may be argued that this sentence is outdated, as the only reference provided is a review paper of 2014, which includes studies published before 2014. Please add and discuss recently published original studies.

Similarly, the sentence "these estimates were generally based on few cases and imprecise" should be reframed. Please only consider stating that others' work is imprecise unless you have clear evidence and can prove with exact numbers such a strong judgment.

6) In the discussion please clearly consider that the lack of information about the type/etiology of dementia is a major limitation of the study, as this may be a much important limitation than the other limitations listed in the same sentence or at least equally important to the lack of information regarding dementia severity. Related to this please mention that the study is likely to be biased towards Alzheimer's disease, given that it is the only type of dementia that has specific medications (as for point 4)

Minor comments:

The sentence "After 60 years, 6-9% of all dementia cases occurred before 65 years" in the first paragraph of the introduction is not easily readable. Doo the authors mean "Among the people older than 60,. …"

What is the reference for the study mentioned in "one from Tuscany (Italy, 50-70 years: PR=100/100,000; IR=30/100,000 person-years)"?

Re the sentence "important contribution of cardio-and cerebro-vascular, metabolic, neurological, and psychiatric diseases in explaining sex-differences in EOD incidence" in the conclusion: since dementia is a neurological disorder, please specify "other-than dementia neurological disorders"

Any attachments provided with reviews can be seen via the following link:

[LINK]

PLoS Med. 2021 Sep 23;18(9):e1003801. doi: 10.1371/journal.pmed.1003801.r003

Author response to Decision Letter 1

23 Jul 2021

Attachment

Submitted filename: Point by point response.docx

Click here for additional data file.^{(89.8KB, docx)}

PLoS Med. doi: 10.1371/journal.pmed.1003801.r004

Decision Letter 2

Caitlin Moyer

18 Aug 2021

Dear Dr. Carcaillon-Bentata,

Thank you very much for re-submitting your manuscript "Young onset dementia: prevalence, incidence, and role of comorbidities using French administrative databases" (PMEDICINE-D-21-00532R2) for review by PLOS Medicine.

I have discussed the paper with my colleagues and the academic editor and it was also seen again by four reviewers.

Provided the remaining editorial and production issues are dealt with we are planning to accept the paper for publication in the journal.

However, there are a number of remaining editorial issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:

[LINK]

In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.

Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. If you haven't already, we ask that you provide a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract.

We expect to receive your revised manuscript within 1 week. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

We ask every co-author listed on the manuscript to fill in a contributing author statement. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT.

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript.

Please note, when your manuscript is accepted, an uncorrected proof of your manuscript will be published online ahead of the final version, unless you've already opted out via the online submission form. If, for any reason, you do not want an earlier version of your manuscript published online or are unsure if you have already indicated as such, please let the journal staff know immediately at plosmedicine@plos.org.

If you have any questions in the meantime, please contact me or the journal staff on plosmedicine@plos.org.

We look forward to receiving the revised manuscript by Aug 25 2021 11:59PM.

Sincerely,

Caitlin Moyer, Ph.D.

Associate Editor

PLOS Medicine

plosmedicine.org

------------------------------------------------------------

Requests from Editors:

1. Title: Reviewer 3 makes a specific suggestion for the title; however, we suggest: “Prevalence and incidence of young-onset dementia and associations with comorbidities: A study of data from the French national health data system” or similar.

2. Data availability statement: The statement requires revision, as it currently reads that data are found in the supporting information files, which is not the case. Please include information explaining how individuals may request data access, such as: We suggest: “Data cannot be shared as access to the SNDS has to be approved by the French Data Protection Authority. Interested investigators can request their own access to the data according to the French law. Information on obtaining access to SNDS data can be found at https://www.snds.gouv.fr/SNDS/Processus-d-acces-aux-donnees. Requests for access to NSDS data must be submitted to the National Institute for Health Data (INDS)[[please provide a link or contact email]].”

3. Throughout: Please replace "subject" with participant, patient, individual, or person.

4. Abstract: Methods and findings: Please include the number of individuals that are included among the 76% of the French population in the French National Health Data System, and please specify the name (Système national des données de santé (SNDS)). Please provide p values for the comparison of PR and IR between men and women. Please provide the result (OR with 95% CI and p value) for the association between specific comorbidities mentioned and incident YOD.

5. Abstract: Conclusions:Line 45-46: Please revise to “...higher YOD frequency in men may be partly explained by higher prevalence…”

6. Author summary: Why was this study done?: We suggest changing the second point to: “To the best of our knowledge, there is a lack of data regarding the frequency of young onset dementia…”

7. Author summary: What do these findings mean?: Please revise the final point to: “YOD incidence was higher in men than women, and this could possibly be due, at least in part, to the higher prevalence of…” or similar.

8. In-text citations: Please place the reference bracket before the sentence punctuation, rather than after.

9. Introduction: Line 74: We suggest noting here that young-onset dementia can also be referred to as early-onset dementia.

10. Introduction: Line 101: Here and throughout, please replace the term “subjects” with “individuals” or similar.

11. Methods: Ethical approval: Please state in the Methods that the relevant institutional review board(s) waived the need for ethical approval for the study.

12. Methods: Analysis plan: Please make sure that the Methods section transparently describes when the described analyses were planned, and when/why any data-driven changes to analyses took place. Changes in the analysis-- including those made in response to peer review comments-- should be identified as such in the Methods section of the paper, with rationale. For example, please note whether the prevalence, incidence and comorbidities analyses were preplanned, and please note that the analysis of comorbidities in the context of sex differences was planned after observing differences in YOD between sexes. Please also note that the analysis of TBI was also added after the main analyses were completed.

13. Methods: Line 111: We suggest “Data on hospitalizations in short stay departments....and at home are available.”

14. Methods: Line 134, Line 153 and Line 159: Please replace “subjects” with “individuals” in these sentences.

15. Methods: Line 143-151: Please provide more details, or a list in the Supporting Information files, of the specific comorbidities assessed, unless this is described in supplementary table S1.

16. Methods: Line 168-169: Please provide a reference to the National Institute of Statistics and Economic Studies data used here.

17. Methods: Line 180-181: Please include the reference to the STROBE Checklist in the Supporting Information file (S1 Checklist, or similar).

18. Results: Line 187-188: Please revise this sentence to clarify: “Women (12.7%) more often met all three criteria for inclusion compared to men (7.9%)...” or similar.

19. Results: Line 209: Please report p values as <0.001 where applicable.

20. Results: Line 219: Please clarify if “delusional disorders” is meant, or if psychotic disorder was intended.

21. Discussion: Line 227: We suggest removing the word “robust” from the sentence.

22. Discussion: Line 231-232: We suggest revising to: “Rates of YOD were higher in men compared to women, and we identified that this association was attenuated by 55% after adjustment for all comorbid conditions considered, suggesting a potential role for comorbid conditions in the relationship between sex and YOD.” or similar.

23. Discussion: Line 241: Please change to “...four catchment areas of eastern Sydney, Australia…”

24. Discussion: Line 264: Please change “overestimate” to “overestimation” if accurate.

25. Discussion: Line 267-270: Please revise this sentence to clarify, as the meaning is unclear: “A recent review on the accuracy of dementia diagnosis in routinely collected datasets reported good specificity and positive predictive value with moderate sensitivity,[24] comprised between 21%-86%, with only 3 of 12 studies reporting estimates ≥60%; however, sensitivity was higher at younger ages.[25, 26].”

26. Discussion: Line 277: Please replace the term “subject” with “individuals” or similar.

27. Discussion: Line 313: Please clarify “inclusions of all persons <65 years” as your study seemed to consider adults less than 65 yrs of age but at least 40 years.

28. Discussion: Line 322: Please replace “subject” with “individual” or similar.

29. Discussion: Line 324: Please replace “subject” with “individual” or similar. We suggest clarifying “overestimate” in this sentence by rephrasing “...which could be delayed relative to the actual age at incidence, leading to misclassification of some individuals with YOD as having LOD.” or similar.

30. Discussion: Line 343: Limitations: Please comment on whether it is possible that people with Parkinson’s disease but not dementia are included in your study because they are receiving donepezil, for example?

31. Discussion: Line 344 and Line 348: Please replace the term “subject” with “individual” or similar.

32. Discussion: Line 360: We suggest revising to “Our results may suggest that preventive approaches targeting cardiovascular risk factors in mid-life, substance-abuse disorders, and prevention and managing traumatic brain injury could be further investigated as strategies for reducing or postponing young onset of dementia.” or similar, to make it clear that these results cannot demonstrate causal relationships between comorbidities and young onset dementia.

33. Sections “Disclosure of potential conflicts of interest” “Funding” and “Availability of data and material” in the main manuscript text: Please remove these from the manuscript body, and please make sure all information is accurately entered with the manuscript submission metadata.

34. References: Please check the formatting of each reference in the list. Please use the "Vancouver" style for reference formatting, and see our website for other reference guidelines https://journals.plos.org/plosmedicine/s/submission-guidelines#loc-references

Specifically, please check the NLM abbreviations of journal titles; for example, “The Lancet Neurology” should be “Lancet Neurol” in references 1 and 2. Please also check capitalization (e.g. “Bmj” in reference 18).

35. Table 1 and Figure 1: Please define the abbreviation YOD in the legend.

36. Figure 1: Please clarify that the shaded region represents the 95% CIs.

37. Figure 2: Please clarify that the bars represent the 95% CIs. Please define IRR and PRR in the legend.

38. Table 1: Please report p values as <.001 where relevant rather than <.0001.

39. Table 2 and Table 3: We suggest replacing “psychiatric diseases” with “disorders” and “delusional diseases” with “delusional disorders” in the tables.

40. Table 2: In the footnote, please clarify the source of the comparison group “Overall French Population without YOD (2016). Please also report p values as <.001 where applicable.

41. Supplementary table 1: We suggest “psychiatric disorders” instead of “diseases” in the table. We suggest changing “delusional diseases” to “psychotic disorders” or similar, as the ICD-10 codes seem to include disorders related to psychosis, in addition to including delusional disorders. In the legend, please briefly explain “t” and “t-4” as used in the study.

42. Supplementary table 2: Please define YOD in the legend. Please clarify “(Rniam)” in the legend. Here and for supplementary table 3, please provide a reference for the number of persons/ person-years affiliated to the general scheme of the social security in 2016.

43. Supplementary table 4: We suggest “psychiatric disorders” instead of “diseases” in the table. We suggest changing “delusional diseases” to “psychotic disorders” or similar, as the ICD-10 codes seem to include disorders related to psychosis, in addition to including delusional disorders. Please also report p values as <.001 where applicable.

44. STROBE Checklist: We suggest renaming the file as S1 Checklist or S1 Strobe Checklist, or similar.

Comments from Reviewers:

Reviewer #1: The authors have responded to each comment in turn.

Can the authors please re-visit the following conclusion, and change the tone from 'likely' to 'possibly' due to insufficient statistical power?

"Age-specific IRRM/W were similar to corresponding age-specific PRRM/W, and there was a similar trend of decreasing IRRM/W with continuous age but it was not statistically significant (p-interaction=0.494),

likely due to insufficient statistical power as the number of incident cases in each age group was considerably smaller than the number of prevalent cases."

Reviewer #2: The authors have sold all my comments addressing them clearly and correctly.

Reviewer #3: Thank you for sending a revision of this paper and for giving such a clear account of changes made. I have four minor points arising and have also listed a equally small number of spelling/grammatical changes to address.

1. I noted the new title but would like to suggest streamlining to:

"Young onset dementia in France: prevalence, incidence and role of comorbidities."

2. The editors asked that, in the abstract, you should quantify the main results (with 95% CIs and p values) - please check you have done this.

3. I also noted the request for you to include the (completed) STROBE checklist. I did not see the checklist in the supplementary materials, despite a heading on p.45.

4. Lines 246-251. Can you hypothesise the reason for the lower rates in then Scottish, English and Japanese studies?

Errors of spelling or grammar:

1. Line 112: "After each hospital stay, a discharge summary is filled." - was this intended to say 'filed'?

2. Line 234 - add two words: 'Previous Field studies have provided inconsistent results regarding YOD prevalence

3. Line 264: which may have led to overestimation of YOD frequency.

4. Lines 267-270 sentence beginning 'A recent review on the accuracy of dementia diagnosis …' would be better broken into two.

5. Line 309: 'However, these findings ….'

Reviewer #4: I have read the response to mine and to the other Reviews with great interest and appreciation. All my comments have been addressed and my questions answered properly. I strongly recommend publication.

Any attachments provided with reviews can be seen via the following link:

[LINK]

PLoS Med. 2021 Sep 23;18(9):e1003801. doi: 10.1371/journal.pmed.1003801.r005

Author response to Decision Letter 2

2 Sep 2021

Attachment

Submitted filename: Point by point response to reviewers and editor R2_VF.docx

Click here for additional data file.^{(36.8KB, docx)}

PLoS Med. doi: 10.1371/journal.pmed.1003801.r006

Decision Letter 3

Caitlin Moyer

8 Sep 2021

Dear Dr Carcaillon-Bentata,

On behalf of my colleagues and the Academic Editor, Perminder Singh Sachdev, I am pleased to inform you that we have agreed to publish your manuscript "Prevalence and incidence of young-onset dementia and associations with comorbidities: A study of data from the French national health data system" (PMEDICINE-D-21-00532R3) in PLOS Medicine.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. Please be aware that it may take several days for you to receive this email; during this time no action is required by you. Once you have received these formatting requests, please note that your manuscript will not be scheduled for publication until you have made the required changes.

Please also address the following editorial requests:

-Where multiple references are included within brackets, please do not include spaces. For example, at line 86, this should be [6,7].

-Results: Line 231 and Line 235: Please also include the p values for these results in the text (it seems they would both be p<0.001).

In the meantime, please log into Editorial Manager at http://www.editorialmanager.com/pmedicine/, click the "Update My Information" link at the top of the page, and update your user information to ensure an efficient production process.

PRESS

We frequently collaborate with press offices. If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximise its impact. If the press office is planning to promote your findings, we would be grateful if they could coordinate with medicinepress@plos.org. If you have not yet opted out of the early version process, we ask that you notify us immediately of any press plans so that we may do so on your behalf.

We also ask that you take this opportunity to read our Embargo Policy regarding the discussion, promotion and media coverage of work that is yet to be published by PLOS. As your manuscript is not yet published, it is bound by the conditions of our Embargo Policy. Please be aware that this policy is in place both to ensure that any press coverage of your article is fully substantiated and to provide a direct link between such coverage and the published work. For full details of our Embargo Policy, please visit http://www.plos.org/about/media-inquiries/embargo-policy/.

Thank you again for submitting to PLOS Medicine. We look forward to publishing your paper.

Sincerely,

Caitlin Moyer, Ph.D.

Associate Editor

PLOS Medicine

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 STROBE Checklist. Checklist of items that should be included in reports of cross-sectional studies.

STROBE, Strengthening the Reporting of Observational Studies in Epidemiology.

(DOCX)

Click here for additional data file.^{(31.5KB, docx)}

S1 Table. Algorithms for the identification of comorbidities and treatments of interest in the SNDS.

SNDS, Système National des Données de Santé.

(DOCX)

Click here for additional data file.^{(16.5KB, docx)}

S2 Table. PRs (per 100,000 persons) of YOD in France on December 31, 2016.

PR, prevalence rate; YOD, young onset dementia.

(DOCX)

Click here for additional data file.^{(14.8KB, docx)}

S3 Table. IRs (per 100,000 person-years) of YOD in France in 2016.

IR, incidence rate; YOD, young onset dementia.

(DOCX)

Click here for additional data file.^{(14.4KB, docx)}

S4 Table. Association between comorbidities and sex in persons without YOD from the French population in 2016 (40 to 64 years).

YOD, young onset dementia.

(DOCX)

Click here for additional data file.^{(20.1KB, docx)}

Attachment

Submitted filename: Point by point response.docx

Click here for additional data file.^{(89.8KB, docx)}

Attachment

Submitted filename: Point by point response to reviewers and editor R2_VF.docx

Click here for additional data file.^{(36.8KB, docx)}

Data Availability Statement

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PERMALINK

Prevalence and incidence of young onset dementia and associations with comorbidities: A study of data from the French national health data system

Laure Carcaillon-Bentata

Cécile Quintin

Marjorie Boussac-Zarebska

Alexis Elbaz

Roles

Abstract

Background

Methods and findings

Conclusions

Author summary

Why was this study done?

What did the researchers do and find?

What do these findings mean?

Introduction

Methods

Data sources

Identification of persons with YOD

Comorbidities ascertainment

Statistical analysis

Results

Table 1. Characteristics of prevalent and incident YOD, overall and by sex, in France (2016).

PR and IR

Fig 1.

Fig 2. Male-to-female PR (PRRM/W) and IR (IRRM/W) rate ratios, overall and by age.

Contribution of comorbidities to YOD

Table 2. Prevalence of comorbidities in incident YOD and in persons without YOD from the French population (40 to 64 years) in 2016.

Table 3. Percentage reduction of the association between male sex and YOD incidence due to comorbidities.

Discussion

Burden of YOD in France and comparison with other studies

Sex differences in YOD incidence and role of comorbidities

Strengths and limitations of the study

Policy and research implications

Supporting information

Abbreviations

Data Availability

Funding Statement

References

Decision Letter 0

Caitlin Moyer

Roles

Decision Letter 1

Caitlin Moyer

Roles

Author response to Decision Letter 1

Decision Letter 2

Caitlin Moyer

Roles

Author response to Decision Letter 2

Decision Letter 3

Caitlin Moyer

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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Fig 2. Male-to-female PR (PRR_M/W) and IR (IRR_M/W) rate ratios, overall and by age.