Different Trajectories of Apathy and Depression Among Subjective Cognitive Impairment Individuals with or without Conversion to Dementia: Results from the Memento Cohort in France

Abstract

Background:

Apathy and depression are two early behavioral symptoms in Alzheimer’s disease (AD) and related disorders that often occur prior to the onset of cognitive decline and memory disturbances. Both have been associated with an increased risk of conversion to dementia, with a distinct neuropathology.

Objective:

The assessment of the trajectories of apathy and depression and their independent impact on dementia conversion.

Methods:

Apathy and Depression were measured using the Neuropsychiatric Inventory for caregiver (NPI) and clinician (NPI-C), among the nondemented individuals reporting subjective cognitive decline (SCD) at baseline. They were followed up over a 60-month period. Some converted to dementia, according to the methodology carried out by the French Memento Cohort.

Results:

Among individuals with SCD (n = 2,323), the levels of apathy and depression were low and did not evolve significantly over the 60-month period, despite a trend in apathy increasing as of month 24. Regarding SCD individuals who converted to dementia within the 60-month period (n = 27), the prevalence of depression remained globally steady, while the levels of apathy increased over time.

Conclusion:

Apathy and depression have different trajectories among individuals with SCD and apathy alone is more likely—compared to depression—to be associated with conversion to dementia.

Keywords

Alzheimer’s disease apathy behavioral and psychological symptoms dementia depression

INTRODUCTION

Apathy and depression are both neuropsychiatric symptoms with a high incidence rate of minor and major neurocognitive disorders. 35 to 75% of individuals with minor neurocognitive disorders have at least one neuropsychiatric symptom [1]. In a meta-analysis, Ismail et al. found a 32% depression rate for subjects with mild cognitive impairment (MCI) [2], with a statistically significantly higher occurrence in clinical settings compared to community dwelling individuals. In addition, subjects with depression had a higher incidence of MCI than those without [3].

Apathy is defined as a quantitative reduction of goal-directed activities in comparison to the patient’s previous level of functioning [4]. In a meta-analysis carried out by Van Dalen et al., the report stated an occurrence of 20.1% of apathy in the early stages of neurocognitive disorders [5] and the variation of prevalence varying between 25% in minor neurocognitive disorders up to 77% in Major Neurocognitive Disorders [6]. While cerebral networks are not strictly identical, [7 –9], apathy and depression share similar symptoms such as diminished interests, psychomotor retardation, and diminished decision-making and initiative. Differentiating apathy from depression is challenging due to a symptom overlap (loss of interest, anhedonia, psychomotor retardation). The mimicking factors are challenging for clinicians to identify. However, a key differentiator between depression and apathy is the presence of a depressed mood.

More recently, the concept of Mild Behavior Impairment (MBI) has been proposed [10]. It describes a syndrome, in which late-life onset of psychiatric symptoms (mood disorders, anxiety, apathy, delusions, etc.) that are not described in other classifications, become early manifestations of a neurodegenerative disease [10]. Subjective cognitive decline (SCD) was defined as the subjective feeling of cognitive decline compared to the normal state, with no abnormalities on the neuropsychiatric tests [11]. Furthermore, subjective memory decline rather than a decline in other cognitive domains increases the likelihood of a preclinical Alzheimer’s disease [12]. MBI has a high prevalence in MCI and SCD and is associated with a significantly higher caregiver burden, independent of the MCI [13].

In some developed countries, a decrease in the occurrence of dementia among elderly individuals has been reported [14], suggesting that there are protective interventions for patients with MCI or SCD that may reduce the rate of dementia. Apathy and depression have been reported as risk factors for dementia conversion in previous studies [3 , 15–19]. The prognosis is currently informed by longitudinal trajectories rather than cross-sectional analyses and evaluations of apathy and depression [20]. Behavior and psychological symptoms of dementia (BPSD) can co-occur in the same individual and the coexistence is associated with a more rapid cognitive decline. The independent impact of each symptom on the dementia conversion remains difficult to evaluate [21].

Our hypothesis is that apathy and depression are early signs on a dementia continuum. Their presence increases the risk of conversion, but they both have different and independent impacts in terms of conversion risk.

In this study, we investigate the trajectories of apathy, depression (as well as anxiety that is often associated with depression) having been assessed with NPI-C. Moreover, the study discusses the impact on dementia conversion over a 5-year period in a large French cohort of participants presenting either isolated cognitive complaints or recently diagnoses of MCI (Memento Cohort).

METHODS

Participants

The MEMENTO Study enrolled 2,323 patients consecutively from 2011 to 2014 in 28 French expert memory clinics. Participant characteristics at baseline and study procedures are described elsewhere [22]. Participants selected in the study exhibited either isolated subjective cognitive complaints, assessed through visual analogue scale, without any objective deficits, or very mild to mild cognitive impairments. The definition is based on 1 standard deviation under the mean of age and education corresponding to a group in one or more cognitive domains. The objective for the deviation was to identify the neurocognitive tests performed less than 6 months prior to the screening phase with a Clinical Dementia Rating (CDR) of ≤0.5, therefore not demented [23]. Patients were excluded if they exhibited a contraindication or they refused to perform an MRI, if they were under guardianship, a resident at a skilled nursing facility, pregnant or breastfeeding (for women), having AD caused by gene mutations, having a history of intracranial surgery, a treated Parkinson’s disease, Huntington’s disease, a brain tumor, a subdural hematoma, progressive supranuclear palsy, or having a history of trauma to the brain followed by persistent neurological deficits, a stroke diagnosed in the past 3 months preceding an enrollment visit, a history of strokes followed by persistent neurological deficits, a history of schizophrenia (as defined by the Diagnostical and Statistical Manuel of Mental Disorders DSM –IV) or/and if they were illiterate (unable to count or read).

All participants signed a consent form to be a part of the study. This was approved by the French Ethics Committee “Comité de Protection des Personnes Sud-Ouest et Outre Mer III.” The study conducted followed the standards of the Good Clinical Practice and the Helsinki Declaration.

The Protocol for MEMENTO was registered in ClinicalTrials.gov (Identifier: NCT01926249, https://clinicaltrials.gov/ct2/show/NCT01926249).

Neuropsychiatric symptom evaluation

All subjects underwent neuropsychiatric symptom evaluation using the Neuropsychiatric Inventory [24]. The NPI was designed to assess behavior and psychiatric symptoms of dementia. The dysphoria subscale of the NPI assessed the potential for a depressed mood, and investigated the core symptoms including tearfulness, sadness, statements reflecting certain thoughts of worthlessness and hopelessness, verbalizations regarding feelings of helplessness, and statements about death and suicide.

Apathy, depression, and anxiety were analyzed and defined according to the NPI-clinician rating scale (NPI-C). The NPI-C is a revised and an expanded version of the NPI, with additional domains and items within various domains. It includes a clinician rated methodology [25]. There is a standardized evaluation that provides an interview with the caregiver as well as with the patient followed by a clinician’s evaluation. Every item presented in the subdomain is rated in terms of frequency, severity, and distress communicated by the caregiver. The clinician interviews the patient and delivers an overall severity rating for every subdomain item. The total subdomain score is the sum of the scores for each subdomain item [25].

For the NPI-C, training sessions were key to the optimization and standardization across the 28 centers.

The NPI-C was administered at each center, every 6 months from M0 to M60 (11 measures). The NPI-C maximum sub-score for each domain is 39 for depression, 36 for apathy and 42 for anxiety, respectively. The clinically significant threshold for each of the NPI-C subdomains was defined at 3. The analogy related to previous studies involving the NPI [26 –29] in order to define a clinically significant symptom. In this cohort, the Pearson correlation between NPI and NPI-C for apathy was 0.75 (p < 0.001) and for depression –0.70 (p < 0.001).

Conversion to dementia

The Cohort defined dementia using the DSM-IV criteria for dementia and the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s Disease and Related Disorders Association criteria for AD [30]. All incidences of dementia were reviewed by an independent committee [22].

APOE genotyping

KBiosciences (Hoddesdon, UK; http://www.kbioscience.co.uk) defined and determined Apolipoprotein E (APOE) ɛ2, ɛ3, or ɛ4 alleles for all participants, as described elsewhere [22].

Statistical analysis

Descriptive analyses conducted used percentages and frequency for qualitative variables and mean with SD for quantitative variables. Time to conversion to dementia was calculated using the dementia state when it was declared during a medical visit. Subjects who did not convert to dementia were censured at the last visit. Variables as apathy, depression, and Mini-Mental State Examination (MMSE) were time dependent. Variables such as age, sex, APOE ɛ4, being in a partnership, and the level of education followed the baseline measurement. Cox’s proportional hazard regression model identified factors associated with dementia conversion. A p value inferior to 0.20 in univariate analysis was used for multivariate analysis. A p value inferior to 0.05 was considered statistically significant in the multivariate analysis. Adjusted Hazard Ratios (HR) were presented with 95% CIs. All tests were performed bilaterally. Statistical analyses were carried out using the SAS Enterprise Guide software, version 5.1 (SAS Institute, Cary, NC, USA).

RESULTS

Overall, 2,323 individuals (age 70.86 (SD = 8.7); MMSE 27.91 (SD = 1.93)) were included in the final analysis (Table 1), comprising 61.9% women, with 41.3% of participants having received a high educational level, and 64.3% of individuals lived with a partner spouse while 31% were living alone in their own home. Among all participants, 26.6% and 3.4%, respectively, had one or two copies of APOE ɛ4. At the end of the 60-month follow-up, 272 individuals (11.8%) were diagnosed with a major cognitive disorder and 67 individuals (2.9%) had passed away.

Table 1

Population baseline characteristics—The Memento cohort

N = 2,323	Mean	[SD]
Age at inclusion	70.86	[8.72]
MMSE at M0 (n = 2,313)	27.91	[1.93]
	n	(%)
Gender
Male	885	(38.1)
Female	1,438	(61.9)
Education
No education	3	(0.1)
Primary	277	(12.1)
Middle school	521	(22.7)
Baccalaureate degree	549	(23.9)
Higher degree	949	(41.3)
Missing data	24
Civil status
Single	161	(7.0)
Divorced	331	(14.4)
Widowed	327	(14.2)
Married	1,478	(64.3)
Missing data	26
Living alone
No	1,583	(67.0)
Yes	712	(31.0)
Event
Non-Converters	1,971	(85.3)
Converters	272	(11.8)
Deceased	67	(2.9)
APOE ɛ4
0	1,538	(70.0)
1	584	(26.6)
2	74	(3.4)

The average NPI total score over the 60-month follow-up period was between 4 and 6 for a maximum of 144. The score was between 0 and 12 for each behavioral domain (Fig. 1).

Fig. 1

Trajectories of neuropsychiatric symptoms.

During an NPI-clinician assessment, scores for anxiety, dysphoria, and apathy were lower than 2, without any time-effect over the 60-month follow up period (Table 2).

Table 2

Mean apathy, anxiety, and dysphoria values (NPI-C)

Anxiety			Dysphoria			Apathy
	N	Mean	[SD]	N	Mean	[SD]	N	Mean	[SD]
M0	2,077	1.9	[3.3]	2,069	1.5	[3.1]	2,062	0.8	[2.4]
M6	1,577	1.8	[3.3]	1,572	1.5	[3.3]	1,578	0.8	[2.7]
M12	1,844	1.7	[3.2]	1,842	1.4	[3.1]	1,842	0.9	[2.9]
M18	1,172	1.5	[3.1]	1,168	1.4	[3.0]	1,169	1.0	[3.2]
M24	1,724	1.5	[3.1]	1,722	1.5	[3.4]	1,717	1.0	[3.4]
M30	883	1.6	[3.2]	878	1.4	[3.3]	871	1.1	[3.7]
M36	1,519	1.6	[3.2]	1,510	1.4	[3.4]	1,506	1.1	[3.5]
M42	776	1.6	[3.1]	774	1.3	[2.9]	770	1.5	[4.3]
M48	1,356	1.7	[3.2]	1,344	1.4	[3.3]	1,335	1.3	[4.0]
M54	626	1.8	[3.3]	623	1.6	[3.4]	612	1.8	[5.0]
M60	837	1.8	[3.3]	836	1.7	[3.7]	830	1.7	[4.6]

Considering the participants with a dull completion level of behavioral assessments during each visit, there was a statistically significant trend of an increase in apathy over time, yet not depression. The prevalence for a clinically significant apathy (NPI-C sub score for apathy >3) at M0 was at 11.1% and 15.5% at M60. The occurrence of clinically significant dysphoria: NPI-C sub score for dysphoria >3 at inclusion is 21.3% and 21.4% at M60 (Fig. 2).

Fig. 2

Prevalence of clinically significant apathy and dysphoria (NPI-C, sub score per domain >3).

In this cohort, more men (26.1%) than women (18.8%) exhibited apathy over the course of the study, with a statistically significant difference (p < 0.001). There was no difference for depression.

Considering individuals who exhibited major cognitive decline over a 60-month follow-up period, there was no significant difference in the prevalence for depression, independently of an apathy status. The incidence of depression in the convertor group remained at 26.2% at M0 and 27.8% at M60 (Fig. 3).

Fig. 3

Trajectories of depression in converters and non-converters.

Non-converters and converters did not exhibit significant differences in trajectories of depression. Mean values of depression fluctuate over time, without any statistically significant increase over the 60-month follow-up. The prevalence for apathy in the converter sub-group increased significantly between M0 (21.6%) and M60 (52.3%). Furthermore, there was a significant increase in mean values, from 1.8 at baseline to 6.7 at M60 (Fig. 4).

Fig. 4

Trajectories of apathy in converters and non-converters.

Among the converters, the number of individuals with A+/D+ increased significantly over time, from 11.6% at M0 to 18.7% at M60 (Fig. 7).

Fig. 7

Evolution of the four groups over time in converters and non-converters.

Non-converters had a steady occurrence of apathy (∼9%). The prevalence of depression in non-converters was higher than that of apathy at baseline (20.6%) and at M60 (20.3%) but relatively stable over time. Mean values in non-converters were low for both apathy (∼0.7%) (Fig. 5) and depression (1.5 at baseline and 1.7 at M60) (Fig. 6).

Fig. 5

Mean values of apathy in converters and non-converters.

Fig. 6

Mean values of depression in converters and non-converters.

In terms of the association between apathy and depression, non-converters generally had an A-/D- status –steady at around 76% during the follow-up period (Fig. 7).

More men (14.6%) then women (10.1%) converted, with a statistically significant difference (p < 0.001).

Using the Cox model for the univariate analysis, all BPSD symptoms of interest (apathy, anxiety, and depression) had an association with an increased risk/incidence of conversion to dementia (for a cut-off score of ≥3). Other factors associated with an increased risk in the univariate model was gender (male), as well as a low level of education and the presence of APOE ɛ4 allele.

Table 3

Neuropsychiatric symptoms impact on dementia conversion

Univariate			Multivariate
	HR	[95% CI]	p	HR	[95% CI]	p
Age at inclusion	1.09	[1.07; 1.11]	<0.001	1.07	[1.05; 1.09]	<0.001
MMSE	0.76	[0.74; 0.77]	<0.001	0.78	[0.76; 0.81]	<0.001
Apathy and depression (cut-off > = 3)
Apathy –and depression –	1			1
Apathy + and depression –	8.50	[6.14; 11.77]	<0.001	2.09	[1.37; 3.19]	0.001
Apathy –and depression +	1.64	[1.13; 2.40]	0.010	1.01	[0.65; 1.56]	0.983
Apathy + and depression +	4.53	[3.24; 6.34]	<0.001	2.59	[1.73; 3.87]	<0.001
Anxiety (cut-off > = 3)
No	1			1
Yes	2.27	[1.77; 2.91]	<0.001	1.75	[1.28; 2.38]	<0.001
Gender
Male	1.54	[1.19; 1.94]	0.001	1.04	[0.79; 1.37]	0.783
Female	1			1
Education
No Education/ primary	2.07	[1.46; 2.95]	<0.001	1.37	[0.93; 2.02]	0.110
Middle School	1.39	[1.02; 1.90]	0.039	1.21	[0.86; 1.70]	0.267
Baccalaureate degree	0.85	[0.70; 1.35]	0.852	1.15	[0.80; 1.65]	0.452
Higher degree	1			1
APOE 4
0	1			1
1	2.32	[1.78; 3.02]	<0.001	2.30	[1.75; 30.2]	<0.001
2	4.80	[3.12; 7.39]	<0.001	4.65	[2.96; 7.32]	<0.001

In the multivariate model, after adjustments for previous predictors, only apathy (HR 2.09, p = 0.001), the co-existence of both apathy and depression (HR 2.59, p < 0.001) and anxiety (HR 1.75, p < 0.001) increased the risk for the conversion. Depression alone, in the multivariate model, was not associated with such a risk nor did a low level of education. With APOE ɛ4, the presence of one allele increased the risk by 2.30, p < 0.001. The presence of two increased conversion by 4.65, p < 0.001. A low MMSE level increased the risk of conversion in both univariate and multivariate models.

In this longitudinal study, we reported that SCD/incipient MCI patients with both apathy and depression had a significantly greater risk for conversion to dementia compared with patients without any clinically significant apathy and/or depression. Apathy alone is associated with a 2.09-increased risk of conversion compared to patients without BPSD symptoms and the association with both apathy and depression, which increased the risk by 2.59.

The impact of apathy on dementia conversion has been previously reported. Robert et al. discussed that lack of interest, a key component of Apathetic Syndrome, is associated with a higher risk of developing AD in amnestic MCI patients [31]. Vicini Chilovi et al. found a 7.07 risk of conversion from MCI to dementia for apathetic patients in a cohort of 124 patients [16]. Palmer et al. found a 6.9 risk of conversion for apathetic patients in a cohort of 131 MCI patients [17]. Ruthirakuhan et al. reported a 1.24 risk for apathetic patients and a 1.37 risk for patients with both apathy and depression, in a large (n = 4,932) cohort of MCI patients followed from inclusion to AD diagnosis, with a median follow-up of 23 months [15]. The discrepancy in the results can be partially explained by different methodologies used for the studies. Vicini Chilov et al. used Marin’s criteria to define apathy [32] and the DSM IV for depression while Palmer et al. used Starkstein’s criteria for apathy [33] and Olin’s criteria for depression in AD [34]. Ruthirakuhan et al. used the NPI-Q [35]. In addition, these studies included mostly MCI patients, not SCD. In SCD, apathy could increase the risk of conversion from 2 to 7 times, but data is sparse and at times ambiguous [5]. In our study, depression alone was not associated with an increased risk of conversion for the multivariate model. The evidence in the literature is conflicting. Depression is the most studied neuropsychiatric symptom in MCI [21], and it has been reported that depression is a significant risk factor for AD conversion [3 , 19]. A history of depression during an individual’s lifetime was not a risk factor for cognitive impairment. However, older individuals with a later life depression are at a higher risk of persistent cognitive deficits even after the affective episode went into remission, thus suggesting that later life depression represents a prodrome of future dementia [36]. It may also suggest a higher risk of vascular dementia compared to AD [37]. Other studies did not report an increased risk of conversion for subjects exhibiting depression, without significant apathy [15, 17]. Studies reporting a greater risk of conversion disorder for depressed patients did not consider apathy independently.

In our study, anxiety was associated with a 1.75% risk of conversion in the multivariate model, in line with previous studies. Anxiety is a suggested predictor for incipient cognitive impairment and for dementia in community samples [38]. The prevalence for anxiety varied between 11.6% in population-based samples and 26.3% in clinical based samples of MCI patients, and the relationship between anxiety and MCI could potentially be circular due to MCI patients experiencing anxiety as a result of their cognitive impairment and anxiety interfering with cognitive resources, thus increasing cognitive impairment [21]. The severity of anxiety was also associated with an amyloid deposition in MCI patients [39].

With regard to the BPSD trajectories of our cohort, the prevalence of apathy alone increased from 11.1% to 15.5% with different trajectories between converters (from 21.6% to 52.3%). The non-convertors remained at around 9.5%, which was consistent with previous studies [40]. Although the intensity of the symptoms in this cohort is low, an increase in apathy over a period of time predicted conversion, suggesting that the prognosis depends not only on a cross-sectional evaluation of the NPS but also on the patient’s trajectory to NPS over time [20].

Gonfrier et al. reported an increase in NPS prevalence from 66% at baseline to 88% over 4 years among community dwelling AD individuals, with affective symptoms being stable at a prevalence of 35%, whereas apathy showed a higher prevalence at baseline (49%) and an increase at 65% [41].

This study demonstrated the prevalence of depression being higher than the level of apathy at baseline (21.3%), which remained stable over time. The trajectories did not differ between converters and non-convertors. At the same time converters had a higher frequency at baseline and at M60. Apathy and depression can co-occur. The prevalence was at 6.1% at baseline in non-converters, stable over time, and at 11.6% in converter terms, with an increase of 7.7% over 60 months. The presence of both apathy and depression increases the risk of conversion by 2.59, in the multivariate model. This may be linked to underlying neuro-degenerative processes. Apathy and depression exhibit diverse neuronal pathways. Apathy has been linked to dopaminergic transmission in imaging studies [42] and dopaminergic agents (methylphenidate and bupropion, that inhibit the recapture of dopamine, dopamine agonists, L-Dopa) demonstrate a reduction of apathy in different neurodegenerative disorders [43].

Brain imaging studies associate apathy with several areas such as anterior cingulate cortex, dorsolateral cortex and an inferior frontal gyrus [44, 45]. In MCI individuals, apathy was correlated with a hypometabolism in the posterior cingulate that matches the pattern of prodromal AD [46]. Depression in MCI was associated with glucose hypometabolism in frontal regions [47]. In depression serotoninergic transmission is reduced in the posterior cingulate and amygdala-hippocampus complex [44]. Furthermore, selective serotonin reuptake inhibitor (SSRI) treatment slows the progression of grey matter and atrophy in the frontal lobe in depressed MCI subjects, with beneficial effects on longitudinal cognitive performance, independent of amyloid-β status [48]. This also delays the progression from MCI to AD dementia by approximately 3 years with a long-term treatment [49]. The common pathophysiological events in depression and AD dementia presented involved amyloid-β accumulation, neuroinflammation, aberrant TNF-α signalization, and a deficit of BDNF and TGF-β1. SSRIs possess anti-inflammatory properties, contributing to a treatment response in Major Depressive Disorder and provide protective effects against neurodegeneration [50, 51]. Nevertheless, when prescribing an antidepressant, apathy requires a thorough prior assessment and evaluation, due to the potential of SSRI increasing the severity of apathy, when inappropriately prescribed [43, 52]. In our study, the prevalence of apathy was higher in men then in women, in line with other studies [53]. Furthermore, male gender has been associated with an increased severity of apathy in AD dementia [54]. There was no difference in the prevalence of depression. More males than females converted, and male gender was associated with an increased risk of conversion in the univariate model but not in the multivariate. Dementia has been reported to have a higher prevalence in females compared to males except for vascular dementia in younger individuals [55]. The population enrolled in MEMENTO was relatively young, which may explain this difference.

Limitations and strengths of the present study

MEMENTO is a large longitudinal cohort with extensive and frequent follow-ups examining cognitive and behavioral states. It covers patients with SCI and recently diagnosed MCI. The data acquired uses highly standardized methods. Apathy and depression were investigated using the NPI-C rate scale (a revised version of the NPI), which can now be utilized as a domain-specific measure [25]. It can now be considered independently in such analyses.

With all the study strengths included, the results require reviewal due to study limitations. Patients were recruited via Memory Clinics. The subjects underwent a selection bias, which may not be representative of the general population. The study involved 28 Memory Clinics across the country in total. The age of onset of neuropsychiatric symptoms is unknown. In addition, the analysis did not consider the patient’s previous psychiatric history (e.g., chronic depression) nor the current medication (antidepressants, beta-blockers, antipsychotics, medication that could modify apathy, anxiety, and depression).

The objective was to explore the impact of apathy and depression on dementia conversion. There are, however, other risk factors, such as anxiety, which may interfere with certain factors not considered independently of apathy and depression.

Perspectives

MEMENTO cohort permits the evaluation of patients with cognitive disturbances at an early stage. Some of them are rapid converters to dementia. In the population encompassing rapid converters, the impact of BPSD requires carefully assessment and evaluation, with due consideration for anxiety and sleep disturbances as independent variables. This is fundamental in order to identify high risk patients, and to predict how long it would take before conversion to dementia takes place.

During the MEMENTO cohort, patients underwent extensive evaluations, including neuroimaging, which allowed for an in-depth investigation into the neuroanatomical correlation of apathy with depression during follow-up sessions.

Conclusion

Apathy and depression have different trajectories among individuals with SCD and apathy alone being more likely, compared to depression when associated with conversion to dementia.

ETHICAL APPROVAL AND CONSENT TO PARTICIPATE

The study was conducted in accordance with the Declaration of Helsinki. According to French law, no consent was required since this study was based on an anonymous database. The draft was based on an example of the STROBE statement [56].

Footnotes

ACKNOWLEDGMENTS

We thank all the centers for their participation in the Memento Cohort.

FUNDING

The Memento Cohort was funded by the French Ministry of Health as part of the French Alzheimer plan 2008–2012 as a more personalized approach to patient care.

CONFLICT OF INTEREST

Isabelle Rouch is an Editorial Board Member of this journal but was not involved in the peer-review process nor had access to any information regarding its peer-review.

All other authors have no conflict of interest to report.

DATA AVAILABILITY

The data supporting the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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