Social Cognition Deficits: The Key to Discriminate Behavioral Variant Frontotemporal Dementia from Alzheimer’s Disease Regardless of Amnesia?

Abstract

Relative sparing of episodic memory is a diagnostic criterion of behavioral variant frontotemporal dementia (bvFTD). However, increasing evidence suggests that bvFTD patients can show episodic memory deficits at a similar level as Alzheimer’s disease (AD). Social cognition tasks have been proposed to distinguish bvFTD, but no study to date has explored the utility of such tasks for the diagnosis of amnestic bvFTD. Here, we contrasted social cognition performance of amnestic and non-amnestic bvFTD from AD, with a subgroup having confirmed in vivo pathology markers. Ninety-six participants (38 bvFTD and 28 AD patients as well as 30 controls) performed the short Social-cognition and Emotional Assessment (mini-SEA). BvFTD patients were divided into amnestic versus non-amnestic presentation using the validated Free and Cued Selective Reminding Test (FCSRT) assessing episodic memory. As expected, the accuracy of the FCSRT to distinguish the overall bvFTD group from AD was low (69.7% ) with ∼50% of bvFTD patients being amnestic. By contrast, the diagnostic accuracy of the mini-SEA was high (87.9% ). When bvFTD patients were split on the level of amnesia, mini-SEA diagnostic accuracy remained high (85.1% ) for amnestic bvFTD versus AD and increased to very high (93.9% ) for non-amnestic bvFTD versus AD. Social cognition deficits can distinguish bvFTD and AD regardless of amnesia to a high degree and provide a simple way to distinguish both diseases at presentation. These findings have clear implications for the diagnostic criteria of bvFTD. They suggest that the emphasis should be on social cognition deficits with episodic memory deficits not being a helpful diagnostic criterion in bvFTD.

Keywords

Alzheimer’s disease amnesia differential diagnosis frontotemporal dementia episodic memory neuropsychology social-cognition

INTRODUCTION

Relative sparing of episodic memory remains a diagnostic feature of behavioral variant frontotemporal dementia (bvFTD) and is heralded as the neuropsychological gold standard to distinguish bvFTD from Alzheimer’s disease at presentation [1, 2]. However, increasing evidence suggest that bvFTD patients can show episodic memory deficits [3], with a subgroup of bvFTD patients being impaired to a similar level as Alzheimer’s disease, even in biologically and pathologically confirmed cases [4, 5]. Similarly, on a neural level, memory-related structures of the limbic system are found to be affected up to a similar degree as Alzheimer’s disease in bvFTD [3 , 6–8].

By contrast, social cognition assessments have emerged as powerful new tools to distinguish both diseases in a clinical setting, when cerebrospinal fluid (CSF) biomarkers or amyloid imaging are not available [9 –11]. However, it is currently not clear whether the high sensitivity and specificity for social cognition deficits in bvFTD holds regardless of their amnestic impairment when compared to Alzheimer’s disease as previous study only investigated social cognition in non-amnestic bvFTD. In others words, in case of severe episodic memory deficits, is assessment of social cognition able to discriminate between the two diseases? The current study addresses this question by contrasting social cognition performance of biologically confirmed amnestic versus non-amnestic bvFTD as well as Alzheimer’s disease patients and healthy controls. We hypothesized that social cognition deficits can distinguish bvFTD from Alzheimer’s disease regardless of amnesia.

MATERIALS AND METHODS

Participants

Ninety-six subjects were selected from the database of the Memory and Alzheimer Institute of the Pitié-Salpêtrière Hospital from September 2005 to June 2012. Twenty-eight typical Alzheimer’s disease patients were selected according to the revised NINCDS-ADRDA criteria [1]. Among them, thirteen Alzheimer’s disease patients underwent a lumbar puncture (LP) showing biological evidence of the Alzheimer’s disease pathophysiological process from their CSF biomarker profile defined by a p-Tau/Aβ₄₂ ratio greater than 0.21 [12].

Thirty-eight bvFTD patients met the following inclusion criteria: prominent changes in personality and social behavior according to the core clinical diagnostic criteria for probable FTD [13], clinical progression consistent with the diagnosis of bvFTD (therefore excluding so-called “FTD phenocopies”), frontal/fronto-temporal atrophy at MRI scan, and/or frontal/fronto-temporal hypoperfusion at SPECT scan and normal CSF biomarker profile as defined by p-Tau/Aβ₄₂ ratio lower than 0.21 when a LP was performed (n = 17/38, 45% ). We included patients with memory impairment if the other core diagnostic criteria of bvFTD were present. Two patients had a genetic mutation (1 GRN, 1 MAPT).

Thirty healthy controls were selected according to the following criteria: normal scores at the MMSE and the FAB, no depression, and no history of psychiatric or neurological conditions. Controls were matched to patients on age and education.

Importantly, all patients were followed-up over at least three years. The clinical progression of every patient was in favor of the initial diagnosis. We did not include participants who presented with the following: (1) clinical or neuroimaging evidence of focal lesions, (2) severe cortical or subcortical vascular lesions on brain MRI, (3) severe depression, or (4) motor neuron disease.

Measurement of CSF biomarkers

CSF samples were collected by LP and analyzed for total tau, tau phosphorylated at threonine 181 (p-Tau), and Aβ₄₂ using a double-sandwich enzyme-linked immunosorbent assay (ELISA) method (Innogenetics, Gent, Belgium). Assays were conducted at the Metabolic Biochemistry Department of the Pitié-Salpêtrière Hospital, as described elsewhere [12].

Neuropsychological assessment

All patients underwent a neuropsychological assessment that included the Mini-Mental State Exam (MMSE) [14], the Frontal Assessment Battery (FAB) [15], the Free and Cued Selective Reminding Test (FCSRT) [16], the mini-SEA [9], semantic and morphologic verbal fluencies, digit spans, and a picture-naming task in order to identify semantic memory deficits. In addition, bvFTD patients were tested with the Mattis Dementia Rating Scale (MDRS) and the modified Wisconsin Card Sorting Task (WCST) [17, 18].

Assessment of episodic memory (FCSRT)

The FCSRT is based on a semantic cueing method that controls for effective encoding of the list of words and facilitates retrieval by semantic cueing [16]. Immediate cued recall was tested in a first phase in order to control for encoding (16 written words presented in groups of 4 × 4, maximum score = 16). Then, the memory phase was performed in three successive recall trials. Each recall trial included (1) a free recall attempt consisting of spontaneous recall of as many items as possible, then (2) a cued recall attempt using an orally presented semantic category for items that were not spontaneously retrieved by the patient. The same semantic cues given in the initial encoding stage were used. This provided (1) a free recall score and (2) a total (free + cued) recall score (/48). Then, after an interval of 30 minutes, a last recall trial was performed, providing (3) a delayed total recall score (/16).

Social cognition & Emotional Assessment (mini-SEA)

The mini-SEA taps into social cognition and emotion disturbances. It consists of two subtests and provides two weighted composite scores: (1) a facial emotion recognition test, scored from 0 to 15, in which participants must identify the emotion expressed in a photograph of a face (happiness, surprise, neutral, sadness, disgust, anger, and fear); (2) a shortened version of the Faux-Pas Recognition Test [19], scored from 0 to 15, which evaluates theory of mind, where participants must detect and explain social faux-pas through short stories. The overall mini-SEA composite score is calculated by adding the two subscores, and scored from 0 to 30. More details about the administration procedure were presented before in a previous study [39].

Standard protocol approvals, registrations, and patient consent

Controls were included in the INSERM RBM-05-15 study, which was approved by the Ethics Committee of the Pitié-Salpêtrière hospital. Participants provided written informed consent before participating. For all patients, the biological and clinical data were generated during routine clinical work-ups and were retrospectively extracted for the purpose of this work. According to French legislation, explicit informed consent was waived as patients and their relatives were informed that individual data might be used in retrospective clinical research studies.

Definition of bvFTD subgroups

In order to test the ability of the mini-SEA to distinguish amnestic bvFTD patients from Alzheimer’s disease, the bvFTD group was divided in two subgroups based on the total recall score of the FCSRT, resulting in A-bvFTD (amnesic bvFTD; n = 19; 50% ) and nonA-bvFTD (non-amnesic bvFTD; n = 19; 50% ). The normative data of the FCSRT were employed to compare the total recall score of each patient to its age and educational matched normative group and, consecutively, abnormal scores were defined as scores below the 10th percentile [20]. Data of the FCSRT for the bvFTD group and result of this analysis are presented in the Supplementary Material 1.

Statistical analysis

Data were analyzed using SPSS20 (SPSS Inc., Chicago, IL). Prior to any analysis, variables were plotted and checked for normality of distribution using the Shapiro-Wilk test. Parametric data were compared across the four groups (controls, Alzheimer’s disease, A-bvFTD, nonA-bvFTD) via ANOVA, followed by Student’s t-test. Non-parametric data were analyzed by Kruskal-Wallis ANOVA followed by the Mann-Whitney test for two-by-two comparisons. Cohen’s d effect-size was computed for all comparisons. Correlations were analyzed using Spearman rank coefficient. Bonferroni’s correction for multiple measures was applied for all analyses. Logistic stepwise regression analysis (using the Enter method) and Area Under the Curve were processed in order to determine the accuracy of the mini-SEA to classify each patient in its correct (bvFTD or Alzheimer’s disease) group.

RESULTS

Demographics, clinical characteristics, and neuropsychological scores

The three groups (controls, Alzheimer’s disease, bvFTD) were not significantly different with regard to age, gender, and educational level (Table 1). Patient groups did not differ on duration of disease. Not surprisingly, MMSE and FAB scores were significantly lower in the bvFTD and Alzheimer’s disease groups compared to controls (p < 0.10⁻⁷). No difference in the MMSE score was observed between bvFTD and Alzheimer’s disease, as well as for digit spans (forward and backward), semantic fluency, and picture denomination task. FAB and morphological fluency scores were significantly lower in bvFTD compared to Alzheimer’s disease (p < 0.001). No difference was observed between bvFTD patients who underwent LP or had a genetic confirmation (n = 21/38) and those who did not (n = 17/38) for any clinical features andneuropsychological scores (Supplementary Material 2). The same result (i.e., no difference for any features or scores) was observed between Alzheimer’s disease patients who underwent LP (n = 13/28) and those who did not (n = 15/28) (Supplementary Material 4).

Demographics, clinical characteristics, and neuropsychological executive scores of A-bvFTD and nonA-bvFTD are presented in Table 2. There was no significant difference in age, gender, education, disease duration, MMSE, executive cognitive scores (MDRS, WCST, FAB, verbal fluency), language (picture naming), or working memory (forward/backward digit span) between A-bvFTD and nonA-bvFTD patients. A-bvFTD and nonA-bvFTD were, respectively, 9 and 12 to have a diagnosis confirmation (CSF excluding Alzheimer’s disease, or genetic mutation). Within bvFTD subgroups (A-bvFTD and nonA-bvFTD), there was no difference on any demographic, clinical, or cognitive measures between patients with and without LP (Supplementary Material 2 and 3).

Episodic memory scores

At the group level, bvFTD patients had significantly higher free recall (p = 0.10⁻⁴; d = 0.79), total recall (p < 10⁻⁴; d = 0.83), and delayed total recall scores (p < 10⁻⁵; d = 0.97) than Alzheimer’s disease patients (Fig. 1). bvFTD and Alzheimer’s disease patients did not differ on encoding score. Each FCSRT score of each patient was compared to its age and educational matched normative group. bvFTD patients were 47.4% (n = 18/38), 65.8% (n = 25/38), 50% (n = 19/38), and 42.1% (n = 16/38) to have a score below normative scores for, respectively, encoding, free recall, total (free+cued) recall and delayed total recall at the FCSRT. Alzheimer’s disease patients were 35.7% (n = 10/28, 1 missed data), 85.7% (n = 24/28), 85.7% (n = 24/28), and 75% (n = 21/28) to have a score below normative scores for, respectively, encoding, free recall, total (free+cued) recall, and delayed total recall at the FCSRT (Supplementary Material 1, Supplementary Table 1). Binary logistic regression using the Enter method using the FCSRT correctly classified bvFTD or Alzheimer’s disease with 69.7% of accuracy. AUC for this test (bvFTD versus Alzheimer’s disease) was 0.773. ROC curve for the FCSRT is displayed on Fig. 1. The overlap between bvFTD and AD on the FCSRT total recall score was 53% .

At the subgroup level, the ANOVA showed significant difference between the three patient groups for all memory scores. More precisely, as expected, A-bvFTD patients performed similarly to Alzheimer’s disease patients for each memory scores (Table 3, Fig. 2),although they had significantly lower encoding (p < 0.10⁻⁴; d = 1.58), free recall (p < 0.10⁻⁵; d = 0.88), total recall (p < 0.10⁻⁷; d = 1.21), and delayed total recall (p < 0.10⁻⁷; d = 0.87) scores than nonA-bvFTD patients. The nonA-bvFTD patients had higher encoding (p < 0.10⁻⁴; d = 1.40), free recall (p < 0.10⁻⁶; d = 1.48), total recall (p < 0.10⁻⁷; d = 1.67), and delayed total recall (p < 0.10⁻⁷; d = 1.51) than Alzheimer’s disease patients. Results were similar when analyses were restricted to bvFTD who underwent LP or had genetic mutation and there were also no differences in the results when contrasting bvFTD who underwent LP or had genetic mutation and bvFTD with clinical diagnosis only, or when the analyses were restricted to bvFTD with clinical diagnosis only (Supplementary Material 2 and 3).

All these analyses were replicated using gender, age then duration of disease as covariates. No effect of these variables was observed and therefore, results did not change. In addition, gender effect was specifically assessed using direct comparison between males and females in each group and no differences were observed.

Social cognition and emotional assessment

At a group level, compared to controls, bvFTD patients had significantly lower scores in both the reduced Faux-pas test and the emotion recognition subtests (all p’s < 0.10⁻⁷, with respectively d = 2.27 and d = 2.61) and therefore a lower total mini-SEA total score (p < 0.10⁻⁷; d = 3.27). Alzheimer’s disease patients had a lower emotions recognition score (p < 0.10⁻⁴; d = 0.91) but showed no significant difference with controls on the Faux-pas test score and on the total mini-SEA score, although a trend was observed for the later (Fig. 1; Supplementary Table 2). Compared to bvFTD, Alzheimer’s disease patients had higher total mini-SEA (p < 10⁻⁷; d = 2.41), Faux-pas (p < 10⁻⁷; d = 2.09), and emotions recognition (p < 10⁻⁷; d = 1.90) scores. Logistic regression was able to classify patients into bvFTD or Alzheimer’s disease in 87.9% of cases when using the mini-SEA total score and in 89.2% or 76.9% in using either the reduced Faux-pas or the emotions recognition score. The results were similar when the analyses were restricted to the patients with CSF/genetic data (Supplementary Material 2 and 3). The overlap between bvFTD and AD on the mini-SEA score was inferior to 11% .

AUC for the mini-SEA (Alzheimer’s disease versus bvFTD) was 0.949. ROC curve for the mini-SEA is displayed on Fig. 1.

At the subgroup level (Table 3), ANOVA showed significant differences between the groups. Compared to controls, A-bvFTD and nonA-bvFTD groups had significantly lower scores in both the Faux-pas component (all p values <0.10⁻⁷; respectively, d = 2.37 and d = 2.60) and the Emotion recognition component (all p values <0.10⁻⁷; respectively, d = 2.71 and d = 2.56) and therefore a lower total mini-SEA score (all p values <0.10⁻⁷; respectively, d = 3.25 and d = 3.22). Alzheimer’s disease patients had a lower emotions recognition score (p < 0.10⁻⁴; d = 0.91) but showed no significant difference with controls on the Faux-pas test score and on the total mini-SEA score, although a trend was observed for the later. A-bvFTD and nonA-bvFTD patients also had significantly lower Faux-pas (respectively, p < 0.10⁻⁶; d = 2.10 and p < 0.10⁻⁶; d = 2.15) and emotions recognition scores than Alzheimer’s disease patients (respectively, p < 0.10⁻⁶; d = 1.92 and p < 0.10⁻⁵; d = 1.65), as well as a lower mini-SEA total score (respectively, p < 0.10⁻⁷; d = 2.40 and p < 0.10⁻⁷; d = 2.38). A-bvFTD and nonA-bvFTD did not significantly differ on these measures. Results were similar when analyses were restricted to bvFTD who underwent LP or had genetic mutation and there were also no differences in the results when contrasting bvFTD who underwent LP or had genetic mutation and bvFTD with clinical diagnosis only, or when the analyses were restricted to bvFTD with clinical diagnosis only (Supplementary Material 2 and 3).

Similarly to the analyses conducted on FCSRT scores, analyses for the mini-SEA were replicated using gender, age, then duration of disease as covariates. No effect of these variables was observed and therefore, results did not change. In addition, gender effect was specifically assessed using direct comparison between males and females in each group and no differences were observed.

Accuracy of the mini-SEA to distinguish A-bvFTD or nonA-bvFTD from Alzheimer’s disease

When bvFTD patients were divided on the basis of the presence of episodic amnesia, the mini-SEA has an accuracy of 85.1% to distinguish A-bvFTD patients from Alzheimer’s disease and 93.9% to distinguish nonA-bvFTD from Alzheimer’s disease.

Finally, in order to confirm the discriminative power of the mini-SEA, we conducted logistic regression analyses using independent random samples from the initial dataset for mini-SEA and FCSRT (Total recall) scores. They are presented in the Supplementary Material and showed very similar results, therefore confirming the sample-based results.

Correlation analyses

Age was set as a nuisance variable in correlations analyses. In Alzheimer’s disease, the FAB was significantly correlated to the total mini-SEA score (R = 0.60) and the FCSRT free recall (R = 0.51). The MMSE was also correlated to the FCSRT encoding score (R = 0.47) and the emotion recognition (R = 0.47). The digit-span (forward) was correlated to the emotion recognition (R = 0.51) and the mini-SEA scores (R = 0.64). In bvFTD, the MMSE was significantly correlated to the FAB (R = 0.62) and the digit-span (forward) (R = 0.48). No other significant correlation was observed.

DISCUSSION

Our results clearly show that social cognition can discriminate biologically confirmed bvFTD and Alzheimer’s disease to a high degree. More importantly, social cognition deficits are unrelated to the level of amnesia in bvFTD and thus may provide a uniquely sensitive and specific cognitive marker for the detection of the underlying pathology.

In more details, the preservation of episodic memory in bvFTD has been recently challenged by an increasing number of independent studies showing that bvFTD patients can present with similar levels of amnesia as Alzheimer’s disease [4, 5], with both manifesting a combination of frontally mediated and storage-based memory impairment. Although previous studies have suggested that prefrontal cortex degeneration might be the greatest determinant of amnesia in bvFTD [21, 22], more recent evidence suggest that bvFTD patients also show severe atrophy of the medial temporal lobes, including the hippocampus as well as the entire Papez circuit [4, 6] One of the only studies that cross-correlated episodic memory performance with grey matter intensity in bvFTD and Alzheimer’s disease showed that posterior parietal and cingulate regions were implicated exclusively in Alzheimer’s disease while temporal poles and medial frontal regions were involved specifically in bvFTD [8]. Although the profile of cortical involvement in episodic amnesia is different in bvFTD and Alzheimer’s disease, current available episodic memory assessments (i.e., words-list based) may lack of power to differentiate the amnestic form of bvFTD from Alzheimer’s disease [3, 5].

By contrast, during the last decade, there has been increasing evidence for the ability of social cognition assessment to distinguish bvFTD from other diseases and specifically from Alzheimer’s disease [23], as it taps into ventral and rostral parts of the medial prefrontal cortex [24, 25], which are specifically damaged in bvFTD [26], even at the early stages of the disease [27]. However, the utility of social cognition tasks to differentiate amnestic bvFTD from Alzheimer’s disease has not been investigated before. Our findings show that regardless of the presence of episodic amnesia, the mini-SEA can distinguish bvFTD from Alzheimer’s disease to a high degree, with a classification power of 87.9% at group level and, more precisely, an accuracy of 85.1% and 93.9% to respectively distinguish A-bvFTD and nonA-bvFTD from Alzheimer’s disease. By comparison, the FCSRT lacked of power to distinguish bvFTD from Alzheimer’s disease as it was able to classified only 69.7% of patients. The overlap between both groups (53% ) was too high to allow an accurate distinction, although bvFTD obtained better performances than AD. By contrast, the overlap between AD and bvFTD using the mini-SEA was low (11% ).

Research on social cognition benefits from the increasing recognition that social cognitive processes are crucial for human interactions and adequate social adaptation. A growing number of tests are available to assess the deficits in this domain, which all have different psychometric properties [28]. Theory of mind assessments are particularly useful for capturing the cognitive deficits related to the behavioral symptomatology of bvFTD [29], but a consensus is needed amidst the numerous available tests. Recently, Bora and colleagues provided crucial findings by conducting a meta-analysis across theory of mind studies in bvFTD and Alzheimer’s disease in order to determine the sensitivity and specificity of theory of mind tasks evaluating different processes such as faux-pas recognition, sarcasm detection, false belief, and reading the mind in the eyes [30]. Besides replicating previous findings by showing that theory of mind deficits could accurately differentiate bvFTD from Alzheimer’s disease, the results showed that faux-pas and sarcasm tests have the greatest discriminatory potential between both diseases [31]. Moreover, social adaptation also relies on the accurate recognition of other’s emotional expressions, a critical process that allows adjusting one’s behavior during a social interaction [32]. This process is also impaired in bvFTD and relatively spared in AD during the early stages of the diseases [33 –35]. This highlights the importance of assessing emotion recognition concurrently with theory of mind. Historically, neuropsychological testing of social cognition relied on long and experimental tasks, which are not always feasible in a clinical setting. The mini-SEA has been designed to provide a quick and easy way to assess theory of mind and emotional recognition through revised and shortened versions of the faux-pas and facial emotion recognition tests [19, 36]. This test has been linked, in bvFTD, to grey matter degeneration and perfusion decrease in rostral medial prefrontal cortex [37, 38], and has been shown to accurately distinguish bvFTD from Alzheimer’s disease and depression [9, 39].

Our findings have strong implications on a biomarker level. Indeed, current diagnosis of sporadic bvFTD remains challenging, as no biomarkers exist to diagnose the disease. The episodic memory problems in bvFTD further complicate the picture. CSF biomarkers and amyloid imaging showed robust results for identifying Alzheimer’s disease relative to controls or patients suffering from FTD [40]. However these investigations rely either on a LP, an invasive exam for patients that requires a day of hospitalization, or expensive neuroimaging requiring the production of short-life radioisotopes which require a cyclotron and therefore cannot be performed outside of expert-centers. Similarly, radiological observations of hippocampal volumes have been proposed as a promising specific biomarker for Alzheimer’s disease, but recent studies challenged this finding, showing that bvFTD could present with a similar degree of atrophy [4, 6]. Short cognitive tests, such as the mini-SEA, could therefore provide a simple, inexpensive, non-invasive and efficient way to distinguish both diseases at presentation, when facing to a patient with an episodic amnesia that could be an indicator or Alzheimer’s disease or bvFTD. This might be in particular relevant for the detection of specific pathology (tau, TDP-43) in bvFTD. For example, a recent study by the Genetic Frontotemporal dementia Initiative (GENFI), a multi-center study on presymptomatic FTD, has shown that genetic predisposed tau patients (MAPT) show severe hippocampal atrophy already up to 10 years before diagnosis [41]. Thus, detection of memory problems in addition to social cognition deficits might be a potential cognitive marker for tau-bvFTD.

On the other hand, the present results raise the question about the specificity of the current framework for the diagnosis of bvFTD. The International consensus criteria for bvFTD proposes the presence of executive deficits with relative sparing of memory and visuospatial functions as neuropsychological features of bvFTD [13], without any reference to social cognition tests. Considering the increasing evidence of episodic memory impairment in bvFTD, and the diagnostic value of tests that tap into emotional and social abilities, it may be valuable to propose these tests as clinical markers for bvFTD diagnosis.

Although these results are in accordance with previous studies about the clinical relevancy to use social cognition tests to discriminate bvFTD from Alzheimer’s disease [23 , 30], it is important to consider that they could lack of power to distinguish the minority of bvFTD patients that have an Alzheimer’s disease underlying pathology. Because it taps into fronto-medial dysfunctions, the mini-SEA has shown to be impaired in those very specific cases [42]. Furthermore, social-cognition performance could be also lower in severe Alzheimer’s disease cases, as both theory of mind and emotion recognition performance have been shown to decrease over the course of Alzheimer’s disease as a consequence of a more general cognitive deterioration [30, 34], which was highlighted in this study by the correlation between general cognition and social-cognition performance in Alzheimer’s disease. However, we believe that these findings have critical implication on the clinical distinction of bvFTD and Alzheimer’s disease in bringing evidence that social cognition could accurately distinguish bvFTD from Alzheimer’s disease, regardless of amnesia.

Footnotes

ACKNOWLEDGMENTS

We are thankful to Aurélie Funkiewiez for her involvement in the acquisition of clinical data, as well as to Foudil Lamari for performing the CSF biomarkers measurements. We also thank Céline Chamayou, Virginie Czernecki, Richard Gnassounou, Elodie Guichart-Gomez, Valérie Hahn-Barma, Dalila Samri, and Christina Rogan as well as Marina Agen and Mary Rouillé from the Alzheimer Institute (Pitié-Salpêtrière) for their help in the acquisition of clinical data.

Maxime Bertoux is supported by a Marie Skłodowska-Curie Fellowship awarded by the European Commission. Claire O’Callaghan is supported by a National Health and Medical Research Council Neil Hamilton Fairley postdoctoral fellowship.

Authors’ disclosures available online ().

Appendix

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