# Longitudinal Cognitive Changes in Genetic Frontotemporal Dementia Within the GENFI Cohort

Jackie M Poos, Amy Macdougall, Esther van den Berg, Lize C Jiskoot, Janne M Papma, Emma L van der Ende, Harro Seelaar, Lucy L Russell, Georgia Peakman, Rhian Convery, et al.

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Jackie M Poos, Amy Macdougall, Esther van den Berg, Lize C Jiskoot, Janne M Papma, et al. Longitudinal Cognitive Changes in Genetic Frontotemporal Dementia Within the GENFI Cohort. Neurology, 2022, 99 (3), pp.e281-e295. 10.1212/WNL.0000000000200384. hal-04423209

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# Longitudinal Cognitive Changes in Genetic Frontotemporal Dementia Within the GENFI Cohort

Jackie M. Poos, MSc, Amy MacDougall, PhD, Esther van den Berg, PhD, Lize C. Jiskoot, PhD, Janne M. Papma, PhD, Emma L. van der Ende, MD, PhD, Harro Seelaar, MD, PhD, Lucy L. Russell, PhD, Georgia Peakman, MSc, Rhian Convery, MSc, Yolande A.L. Pijnenburg, MD, PhD, Fermin Moreno, MD, PhD, Raquel Sanchez-Valle, PhD, Barbara Borroni, MD, Robert Laforce, Jr., MD, PhD, Marie-Claire Doré, PhD, Mario Masellis, MD, PhD, Maria Carmela Taraglia, MD, Caroline Graff, MD, PhD, Daniela Galimberti, PhD, James B. Rowe, FCRCP, PhD, Elizabeth Finger, MD, Matthis Synofzik, MD, Rik Vandenberghe, MD, PhD, Alexandre Mendonça, MD, PhD, Pietro Tiraboschi, MD, Isabel Santana, MD, PhD, Simon Ducharme, MD, Christopher Butler, FRCP, PhD, Alexander Gerhard, MRCP, MD, Johannes Levin, MD, Adrian Danek, MD, Markus Otto, MD, Isabelle Le Ber, MD, PhD, Florence Pasquier, MD, PhD, John van Swieten, MD, PhD, and Jonathan D. Rohrer, FRCP, PhD, on behalf of the Genetic FTD Initiative (GENFI)

*Neurology®* 2022;99:e281-e295. doi:10.1212/WNL.0000000000200384

**Correspondence**

Dr. Rohrer
j.rohrer@ucl.ac.uk

## Abstract

### Background and Objectives

Disease-modifying therapeutic trials for genetic frontotemporal dementia (FTD) are underway, but sensitive cognitive outcome measures are lacking. The aim of this study was to identify such cognitive tests in early stage FTD by investigating cognitive decline in a large cohort of genetic FTD pathogenic variant carriers and by investigating whether gene-specific differences are moderated by disease stage (asymptomatic, prodromal, and symptomatic).

### Methods

C9orf72, GRN, and MAPT pathogenic variant carriers as well as controls underwent a yearly neuropsychological assessment covering 8 cognitive domains as part of the Genetic FTD Initiative, a prospective multicenter cohort study. Pathogenic variant carriers were stratified according to disease stage using the global Clinical Dementia Rating (CDR) plus National Alzheimer's Coordinating Center (NACC) FTLD score (0, 0.5, or ≥1). Linear mixed-effects models were used to investigate differences between genetic groups and disease stages as well as the 3-way interaction between time, genetic group, and disease stage.

## Results

A total of 207 C9orf72, 206 GRN, and 86 MAPT pathogenic variant carriers and 255 controls were included. C9orf72 pathogenic variant carriers performed lower on attention, executive function, and verbal fluency from CDR plus NACC FTLD 0 onwards, with

From the Department of Neurology (J.M. Poos, E.v.d.B., L.C.J., J.M. Papma, E.L.v.d.E., H.S., J.v.S.), Erasmus MC University Medical Center, Rotterdam, the Netherlands; Dementia Research Centre (J.M. Poos, L.C.J., L.L.R., G.P., R.C., J.D.R.), Department of Neurodegenerative Disease, UCL Institute of Neurology; Department of Medical Statistics (A.M.), London School of Hygiene and Tropical Medicine, UK; Department of Neurology (Y.A.L.P.), Alzheimer Center, Amsterdam University Medical Center, Amsterdam Neuroscience, the Netherlands; Cognitive Disorders Unit (F.M.), Department of Neurology, Donostia University Hospital, San Sebastian, Gipuzkoa; Alzheimer's Disease and Other Cognitive Disorders Unit (R.S.-V.), Neurology Service, Hospital Clinic, Institut d'Investigacions Biomédiques August Pi I Sunyer, University of Barcelona, Spain; Centre for Neurodegenerative Disorders (B.B.), Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Italy; Clinique Interdisciplinaire de Mémoire (R.L., M.-C.D.), Département des Sciences Neurologiques, Université Laval, Québec; Sunnybrook Health Sciences Centre (M.M.), Sunnybrook Research Institute and Tanz Centre for Research in Neurodegenerative Diseases (M.C.T.), University of Toronto, Ontario, Canada; Department of Geriatric Medicine (C.G.), Karolinska University Hospital-Huddinge, Stockholm, Sweden; Centro Dino Ferrari (D.G.), University of Milan; Fondazione IRCCS Ca' Granda (D.G.), Ospedale Policlinico, Neurodegenerative Diseases Unit, Milan, Italy; Department of Clinical Neurosciences (J.B.R.), University of Cambridge, UK; Department of Clinical Neurological Sciences (E.F.), University of Western Ontario, London, Canada; Department of Neurodegenerative Diseases (M.S.), Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen; German Center for Neurodegenerative Diseases (DZNE) (M.S.), Tübingen, Germany; Laboratory for Cognitive Neurology (R.V.), Department of Neurosciences, KU Leuven, Belgium; Faculty of Medicine (A.M.), University of Lisbon, Portugal; Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Neurologica Carlo Besta (P.T.), Milan, Italy; Faculty of Medicine (I.S.), University of Coimbra, Portugal; Department of Psychiatry (S.D.), McGill University Health Centre, McGill University, Montreal, Québec, Canada; Department of Clinical Neurology (C.B.), University of Oxford; Divison of Neuroscience & Experimental Psychology (A.G.), Faculty of Medicine, Biology and Health, University of Manchester, UK; Departments of Geriatric Medicine and Nuclear Medicine (A.G.), Essen University Hospital, Germany; Department of Neurology (J.L., A.D.), Ludwig-Maximilians-University, Munich; German Center for Neurodegenerative Diseases (DZNE) (J.L.), Munich; Munich Cluster for Systems Neurology (SyNergy) (J.L.); Department of Neurology (M.O.), University of Ulm, Germany; Sorbonne Université (I.L.B.), Paris Brain Institute-Institut du Cerveau-ICM, Inserm U1127, CNRS UMR 7225, AP-HP-Hôpital Pitié-Salpêtrière; Centre de Référence des Démences Rares ou Précoces (I.L.B.), IM2A, Département de Neurologie, AP-HP-Hôpital Pitié-Salpêtrière; Univ Lille (F.P.); Inserm 1172 (F.P.); and CHU (F.P.), CNR-MAJ, Labex Distalz, LiCEND, Lille, France.

Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

Coinvestigators are listed at links.lww.com/WNL/B988.

The Article Processing Charge was funded by the authors.

This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
# Glossary

**bvFTD** = behavioral variant frontotemporal dementia; **C9orf72** = chromosome 9 open reading frame 72; **CDR plus NACC FTLD** = Clinical Dementia Rating (CDR) scale plus National Alzheimer's Coordinating Center (NACC) frontotemporal lobar degeneration; **D-KEFS** = Delis-Kaplan Executive Function System; **FCSRT** = Free and Cued Selective Reminding Test; **FTD** = frontotemporal dementia; **GENFI** = Genetic FTD Initiative; **GRN** = progranulin; **MAPT** = microtubule-associated protein tau; **MMSE** = Mini-Mental State Examination; **PPA** = primary progressive aphasia; **TMT** = Trail-Making Test; **WMS-R** = Wechsler Memory Scale-Revised.

relatively minimal decline over time regardless of the CDR plus NACC FTLD score (i.e., disease progression). The cognitive profile in MAPT pathogenic variant carriers was characterized by lower memory performance at CDR plus NACC FTLD 0.5, with decline over time in language from the CDR plus NACC FTLD 0.5 stage onwards, and executive dysfunction rapidly developing at CDR plus NACC FTLD ≥1. GRN pathogenic variant carriers declined on verbal fluency and visuoconstruction in the CDR plus NACC FTLD 0.5 stage, with progressive decline in other cognitive domains starting at CDR plus NACC FTLD ≥1.

# Discussion

We confirmed cognitive decline in the asymptomatic and prodromal stage of genetic FTD. Specifically, tests for attention, executive function, language, and memory showed clear differences between genetic groups and controls at baseline, but the speed of change over time differed depending on genetic group and disease stage. This confirms the value of neuropsychological assessment in tracking clinical onset and progression and could inform clinical trials in selecting sensitive end points for measuring treatment effects as well as characterizing the best time window for starting treatment.

Frontotemporal dementia (FTD) is a common cause of dementia, often presenting at a young age, with devastating effects on daily living.¹ The typical cause of FTD is neurodegeneration of the frontal and temporal lobes resulting in behavioral disturbances (behavioral variant FTD [bvFTD]) or language impairment (primary progressive aphasia [PPA]).²,³ FTD is highly heritable and is autosomal dominantly inherited in up to ~30% of cases. The most common causes are pathogenic variants in the microtubule-associated protein tau (MAPT), progranulin (GRN), or chromosome 9 open reading frame 72 (C9orf72) genes.⁴ Deficits in executive function, language, and social cognition are often predominant, but may vary in severity and progression due to the heterogeneous nature of the disease.¹⁻³,⁵

Research into genetic FTD has shown that disease pathology emerges years before symptom onset.⁶⁻¹³ Initiating disease-modifying interventions at this early stage of the disease may have the most profound effect because neuronal loss is minimal and cognitive functions are preserved.¹⁴ It is therefore important to identify sensitive clinical instruments that can signal disease onset and track disease progression. Identifying such instruments for this early stage of the disease is also important because they can be used as clinical end points in therapeutic trials.

Gene-specific cognitive decline during the presymptomatic period has been demonstrated by both cross-sectional and longitudinal studies.⁶,¹⁰,¹⁵⁻²⁶ For example, previous reports have shown decline in memory,¹⁷,¹⁹,²⁰,²⁶ language,¹⁷,²⁰,²³ and social cognition¹⁷,¹⁹,²⁰ in MAPT pathogenic variant carriers, decline in attention¹⁵,¹⁶,¹⁹,²⁰

and executive function¹⁵,¹⁶,¹⁸,²⁰ in GRN pathogenic variant carriers, and a decline in social cognition in C9orf72 pathogenic variant carriers.²²,²⁴,²⁵ However, other studies on genetic FTD failed to find these results.¹³,²¹,²⁶,²⁷

Most studies investigating cognitive decline in presymptomatic genetic FTD have had a small sample size, a limited number of yearly follow-ups, or did not include all 3 major causes of genetic FTD. Furthermore, most studies split their sample of pathogenic variant carriers either according to the artificial boundary of presymptomatic vs symptomatic or according to estimated years to symptomatic onset. As a result, none of the studies fully highlights the complexity of the disease trajectory.²⁸

Larger international cohort studies with longer follow-up time are crucial to identify cognitive markers that signify disease onset at the earliest stage and can measure changes during disease progression. In addition, clinical instruments for disease severity, such as the Clinical Dementia Rating scale plus National Alzheimer's Coordinating Center frontotemporal lobar degeneration module,²⁹ could stratify pathogenic variant carriers and provide valuable insight into cognitive decline during the different stages of the disease per genetic group.

This study aims to investigate longitudinal cognitive decline in genetic FTD pathogenic variant carriers. We performed a 5-year follow-up study in which we investigated baseline and longitudinal differences on neuropsychological test performance between C9orf72, GRN, and MAPT pathogenic variant carriers and control participants and stratified pathogenic variant carriers according to the CDR NACC FTLD global score.
# Methods

## Participants

Data were included from the fifth Genetic FTD Initiative (GENFI) data freeze, in which participants from confirmed genetic FTD families were recruited in 24 centers across Europe and Canada between January 30, 2012, and May 31, 2019. Pathogenic variant carriers were included in this study if they performed at least 1 or more neuropsychological assessments. A total of 207 C9orf72, 206 GRN, and 86 MAPT pathogenic variant carriers and 255 pathogenic variant negative family members (who served as control group) were included. A total of 109 C9orf72, 112 GRN, and 60 MAPT pathogenic variant carriers and 154 controls had completed at least 1 follow-up visit (Table 1). Pathogenic variant carriers were divided into 3 categories based on the CDR plus NACC FTLD global score at baseline: 0, 0.5, or ≥1. Of those with a CDR plus NACC FTLD global score of ≥1, 51 C9orf72, 27 GRN, and 21 MAPT pathogenic variant carriers met diagnostic criteria for bvFTD,² 16 GRN and 3 C9orf72 pathogenic variant carriers met criteria for PPA,³ and 8 C9orf72 pathogenic variant carriers met criteria for FTD with amyotrophic lateral sclerosis.³⁰ Ten percent of C9orf72, 8% of GRN, and 8% of MAPT pathogenic variant carriers progressed from CDR category 0 to 0.5, and 4% of C9orf72, 2% of GRN, and 4% of MAPT pathogenic variant carriers progressed to ≥1. Six percent of C9orf72, 16% of GRN, and 20% of MAPT pathogenic variant carriers progressed from CDR category 0.5 to ≥1 (eTable 1, links.lww.com/WNL/B987).

## Standard Protocol Approvals, Registrations, and Patient Consents

All GENFI sites had local ethical approval for the study and all participants gave written informed consent.

## Procedures

Participants underwent a yearly standardized clinical assessment including the CDR plus NACC FTLD and a comprehensive neuropsychological test battery covering attention and processing speed (Wechsler Memory Scale-Revised [WMS-R] digit span forward³¹; Trail-Making Test [TMT] part A³²; Wechsler Adult Intelligence Scale-Revised Digit Symbol test³¹; Delis-Kaplan Executive Function System [D-KEFS] Color-Word Interference Test color and word naming³³), executive function (WMS-R Digit span backward³¹; TMT part B³²; D-KEFS Color-Word Interference Test ink naming³³), language (modified Camel and Cactus Test²³; Boston Naming Test [short 30-item version]³¹), verbal fluency (category fluency³¹; phonemic fluency³⁴), memory encoding (Free and Cued Selective Reminding Test [FCSRT] immediate free and total recall²⁶), memory recall (FCSRT delayed free and total recall; Benson Complex Figure recall), social cognition (Facial Emotion Recognition Test²⁴), and visuoconstruction (Benson Complex Figure copy). Previous studies have shown that verbal fluency can involve both language and executive function processes and therefore we included it as a separate domain.³⁵,³⁶

<table><caption>**Table 1** Number of Participants at Each Yearly Follow-up</caption><thead><tr><th></th><th colspan="5">Year</th></tr><tr><th></th><th>1</th><th>2</th><th>3</th><th>4</th><th>5</th></tr></thead><tbody><tr><th>C9orf72</th><td>207</td><td>109</td><td>105</td><td>34</td><td>0</td></tr><tr><th>GRN</th><td>206</td><td>112</td><td>72</td><td>31</td><td>3</td></tr><tr><th>MAPT</th><td>86</td><td>60</td><td>40</td><td>11</td><td>1</td></tr><tr><th>Controls</th><td>255</td><td>154</td><td>105</td><td>34</td><td>1</td></tr></tbody></table>

Abbreviations: C9orf72 = chromosome 9 open reading frame 72; GRN = progranulin; MAPT = microtubule-associated protein tau.

Mental State Examination (MMSE)³⁷ measured global cognitive functioning.

## Statistical Analysis

Statistical analyses were performed using Stata version 14.2 and R version 4.0.4. We compared continuous demographic data between groups with 2-way analyses of variance and a $\chi^2$ test for sex. The significance level was set at $p < 0.05$ (2-tailed) across all comparisons.

All neuropsychological data were standardized to z scores (i.e., raw score - mean score controls at baseline/SD controls at baseline). z scores for tests with reaction times (i.e., TMT and D-KEFS Color-Word Interference Test) were inversed so that lower z scores indicate worse performance. Cognitive domains were calculated by averaging the mean z scores of the neuropsychological tests in that domain. Only the FCSRT total recall was included in the memory domains, as the free recall scores are a part of the total recall scores. The memory, social cognition, and visuoconstruction domains are represented by only 1 test.

As this is a prospective cohort study, not all pathogenic variant carriers had completed all study visits, which resulted in missing data. We used linear mixed-effects models for each cognitive domain to examine whether differences existed between C9orf72, GRN, and MAPT pathogenic variant carriers and controls in cognitive decline since baseline. This type of model allows for the analysis of longitudinal data with unbalanced time points and missing data.³⁸ Age and years of education were included in all models as covariates. In each model, a different cognitive outcome was used as the dependent variable and we specified the following fixed effects: time since baseline in years, gene group, CDR category at baseline, age at baseline, years of education, the 2-way interactions between time and group, time and CDR category, and gene group and CDR category, and the 3-way interaction between time, group, and CDR category. We included random intercepts for participants who were nested within families, but not random slopes as this did not improve model fit. A natural cubic splines model did not improve model fit. We performed post hoc pairwise comparisons in intercepts and slopes between genetic groups within CDR categories. Results are shown as a difference between pathogenic variant group and the control group or a different pathogenic variant group if stated.
<table><caption>**Table 2** Demographics and Neuropsychological Data per Genetic Group and CDR plus NACC FTLD Global Score Category at Baseline</caption><thead><tr><th></th><th>C9orf72</th><th>GRN</th><th>MAPT</th><th>Controls</th></tr></thead><tbody><tr><td><strong>Demographic data</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>CDR plus NACC FTLD category</td><td>0</td><td>0.5</td><td>≥1</td><td>0</td></tr><tr><td>N</td><td>109</td><td>32</td><td>66</td><td>129</td></tr><tr><td>Sex ratio, F:M</td><td>64:45</td><td>20:12</td><td>24:42</td><td>84:45</td></tr><tr><td>Age, y</td><td>44.0<br>(11.6)</td><td>47.7<br>(10.7)</td><td>62.2 (8.9)</td><td>45.9<br>(12.2)</td></tr><tr><td>Education, y</td><td>14.3 (3.0)</td><td>14.3 (2.6)</td><td>13.2 (3.7)</td><td>14.7 (3.4)</td></tr><tr><td>MMSE</td><td>28.9 (3.1)</td><td>28.8 (2.0)</td><td>23.7 (6.1)</td><td>29.0 (3.9)</td></tr><tr><td>CDR plus NACC FTLD sum of boxes</td><td>0.0 (0.0)</td><td>1.1 (0.8)</td><td>10.9 (5.5)</td><td>0.0 (0.0)</td></tr><tr><td><strong>Neuropsychological data</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Language</td><td>-0.2 (1.0)</td><td>-0.3 (1.3)</td><td>-3.1 (2.7)</td><td>0.1 (0.6)</td></tr><tr><td>Attention</td><td>-0.3 (0.8)</td><td>-0.3 (1.0)</td><td>-2.7 (1.7)</td><td>-0.0 (0.6)</td></tr><tr><td>Verbal fluency</td><td>-0.2 (0.8)</td><td>-0.3 (0.9)</td><td>-2.0 (0.9)</td><td>0.1 (0.8)</td></tr><tr><td>Executive function</td><td>-0.4 (1.1)</td><td>-0.4 (1.2)</td><td>-3.3 (1.9)</td><td>-0.0 (0.7)</td></tr><tr><td>Memory: immediate recall</td><td>-0.5 (1.8)</td><td>-0.8 (2.3)</td><td>-3.3 (4.0)</td><td>0.1 (0.7)</td></tr><tr><td>Memory: delayed recall</td><td>-0.3 (0.9)</td><td>-0.1 (1.2)</td><td>-2.6 (2.6)</td><td>-0.0 (0.7)</td></tr><tr><td>Social cognition</td><td>-0.1 (1.0)</td><td>-0.7 (1.3)</td><td>-3.1 (2.2)</td><td>0.1 (1.1)</td></tr><tr><td>Visuoconstruction</td><td>-0.1 (1.2)</td><td>-0.2 (1.6)</td><td>-2.3 (2.9)</td><td>0.2 (0.8)</td></tr></tbody></table>

Abbreviations: C9orf72 = chromosome 9 open reading frame 72; CDR plus NACC FTLD = Clinical Dementia Rating scale plus National Alzheimer's Coordinating Center Frontotemporal Lobar Degeneration; GRN = progranulin; MAPT = microtubule-associated protein tau; MMSE = Mini-Mental State Examination. Values are represented as mean z score compared with controls (SD) unless otherwise specified.

β indicates an estimated difference in z score at baseline; β₁ indicates a difference in change over time (slope). An example of the model and its outputs is shown in eAppendix 1 (links.lww.com/WNL/B987).

## Data Availability

Anonymized data not published within this article will be made available upon reasonable request from any qualified investigator.

## Results

### Demographics

There were more female participants in CDR categories 0 and 0.5 and more male participants in CDR category ≥1 for C9orf72 (χ²[2] = 9.8, *p* = 0.007) and MAPT (χ²[2] = 6.6, *p* = 0.036) pathogenic variant carriers (Table 2). We found differences in age at baseline between gene groups (*F*<sub>3,744</sub> = 5.6, *p* < 0.001) and between CDR categories (*F*<sub>2,744</sub> = 91.4, *p* < 0.001) (Table 2). Post hoc pairwise comparisons revealed that C9orf72 and GRN pathogenic variant carriers were older than MAPT pathogenic variant carriers (all *p* ≤ 0.02) and controls (all *p* < 0.001) and each CDR category represented older pathogenic variant carriers than the categories with a lower

CDR category (all *p* ≤ 0.008). We found differences between CDR categories in years of education at baseline (*F*<sub>2,744</sub> = 8.8, *p* < 0.001), with CDR category ≥1 having had fewer years of education than the other categories (all *p* < 0.03) (Table 2). There was an interaction effect between gene group and CDR category on MMSE at baseline (*F*<sub>4,742</sub> = 4.3, *p* = 0.002). Post hoc simple main effects illustrated a difference in MMSE at baseline between CDR categories in all 3 gene groups and a difference in MMSE at baseline between gene groups in CDR category ≥1. Descriptive and neuropsychological data at baseline are reported in Table 2 and eTable 2 (links.lww.com/WNL/B987).

Baseline and longitudinal results for each cognitive domain are discussed in the following sections (Tables 2 and 3, Figures 1 and 2, and summarized in Figure 3).

### Attention

We found strong evidence for differences in the attention domain between CDR categories (χ²[2] = 23.2, *p* < 0.001) and between gene groups (χ²[3] = 26.0, *p* < 0.001) at baseline. C9orf72 (β = -2.2, SE 0.14, *p* < 0.001), GRN (β = -2.2, SE 0.16, *p* < 0.001), and MAPT (β = -1.1, SE 0.21, *p* < 0.001)
<table><caption>**Table 3** Slopes and CIs Stratified by Genetic Group and CDR Plus NACC FTLD Global Score for Each Cognitive Domain</caption><thead><tr><th rowspan="2">CDR plus NACC FTLD</th><th colspan="2">0</th><th colspan="2">0.5</th><th colspan="2">≥1</th></tr><tr><th>β</th><th>95% CI</th><th>β</th><th>95% CI</th><th>β</th><th>95% CI</th></tr></thead><tbody><tr><td colspan="7"><strong>C9orf72</strong></td></tr><tr><td>Language</td><td>0.02</td><td>-0.09 to 0.14</td><td>-0.03</td><td>-0.37 to 0.32</td><td>-0.50</td><td>-0.70 to -0.30</td></tr><tr><td>Attention</td><td>-0.03</td><td>-0.10 to 0.05</td><td>0.07</td><td>-0.15 to 0.29</td><td>-0.24</td><td>-0.36 to -0.11</td></tr><tr><td>Verbal fluency</td><td>-0.01</td><td>-0.07 to 0.04</td><td>0.03</td><td>-0.14 to 0.19</td><td>-0.13</td><td>-0.22 to -0.04</td></tr><tr><td>Executive function</td><td>-0.07</td><td>-0.16 to 0.02</td><td>-0.04</td><td>-0.31 to 0.23</td><td>-0.03</td><td>-0.20 to 0.14</td></tr><tr><td>Memory: immediate recall</td><td>0.26</td><td>0.11 to 0.40</td><td>0.45</td><td>0.06 to 0.84</td><td>-0.01</td><td>-0.25 to 0.24</td></tr><tr><td>Memory: delayed recall</td><td>0.14</td><td>0.05 to 0.23</td><td>0.14</td><td>-0.09 to 0.37</td><td>0.00</td><td>-0.16 to 0.16</td></tr><tr><td>Social cognition</td><td>0.06</td><td>-0.06 to 0.17</td><td>0.14</td><td>-0.15 to 0.43</td><td>0.20</td><td>0.00 to 0.40</td></tr><tr><td>Visuoconstruction</td><td>-0.07</td><td>-0.25 to 0.11</td><td>-0.13</td><td>-0.58 to 0.32</td><td>0.02</td><td>-0.25 to 0.28</td></tr><tr><td colspan="7"><strong>GRN</strong></td></tr><tr><td>Language</td><td>0.05</td><td>-0.04 to 0.14</td><td>-0.08</td><td>-0.39 to 0.23</td><td>-1.24</td><td>-1.51 to -0.97</td></tr><tr><td>Attention</td><td>0.02</td><td>-0.04 to 0.07</td><td>-0.03</td><td>-0.22 to 0.17</td><td>-0.34</td><td>-0.52 to -0.16</td></tr><tr><td>Verbal fluency</td><td>0.00</td><td>0.04 to 0.05</td><td>-0.18</td><td>-0.33 to -0.03</td><td>-0.15</td><td>-0.28 to -0.02</td></tr><tr><td>Executive function</td><td>-0.01</td><td>-0.08 to 0.06</td><td>0.09</td><td>-0.16 to 0.33</td><td>-0.09</td><td>-0.32 to 0.15</td></tr><tr><td>Memory: immediate recall</td><td>0.06</td><td>-0.05 to 0.17</td><td>0.17</td><td>-0.17 to 0.52</td><td>-0.24</td><td>-0.64 to 0.17</td></tr><tr><td>Memory: delayed recall</td><td>0.05</td><td>-0.02 to 0.12</td><td>-0.03</td><td>-0.24 to 0.18</td><td>-0.06</td><td>-0.32 to 0.20</td></tr><tr><td>Social cognition</td><td>0.09</td><td>0.00 to 0.18</td><td>0.11</td><td>-0.16 to 0.39</td><td>-0.47</td><td>-0.70 to -0.23</td></tr><tr><td>Visuoconstruction</td><td>-0.09</td><td>-0.23 to 0.05</td><td>-0.45</td><td>-0.88 to -0.02</td><td>-0.13</td><td>-0.48 to 0.23</td></tr><tr><td colspan="7"><strong>MAPT</strong></td></tr><tr><td>Language</td><td>0.08</td><td>-0.06 to 0.22</td><td>-0.43</td><td>-0.76 to -0.10</td><td>-0.39</td><td>-0.67 to -0.10</td></tr><tr><td>Attention</td><td>-0.01</td><td>-0.09 to 0.08</td><td>-0.08</td><td>-0.28 to 0.13</td><td>-0.21</td><td>-0.39 to -0.04</td></tr><tr><td>Verbal fluency</td><td>0.00</td><td>-0.07 to 0.07</td><td>0.05</td><td>-0.10 to 0.21</td><td>-0.09</td><td>-0.23 to 0.04</td></tr><tr><td>Executive function</td><td>0.07</td><td>-0.04 to 0.17</td><td>0.14</td><td>-0.12 to 0.41</td><td>-0.55</td><td>-0.77 to -0.33</td></tr><tr><td>Memory: immediate recall</td><td>0.02</td><td>-0.15 to 0.18</td><td>0.19</td><td>-0.20 to 0.57</td><td>-0.06</td><td>-0.46 to 0.34</td></tr><tr><td>Memory: delayed recall</td><td>0.03</td><td>-0.07 to 0.13</td><td>0.07</td><td>-0.16 to 0.31</td><td>-0.16</td><td>-0.41 to 0.09</td></tr><tr><td>Social cognition</td><td>0.08</td><td>-0.05 to 0.21</td><td>0.20</td><td>-0.12 to 0.52</td><td>-0.13</td><td>-0.37 to 0.12</td></tr><tr><td>Visuoconstruction</td><td>0.04</td><td>-0.17 to 0.25</td><td>0.11</td><td>-0.36 to 0.58</td><td>0.20</td><td>-0.17 to 0.58</td></tr><tr><td colspan="7"><strong>Controls</strong></td></tr><tr><td>Language</td><td>0.06</td><td>-0.02 to 0.13</td><td></td><td></td><td></td><td></td></tr><tr><td>Attention</td><td>0.05</td><td>0.00 to 0.10</td><td></td><td></td><td></td><td></td></tr><tr><td>Verbal fluency</td><td>0.02</td><td>-0.02 to 0.05</td><td></td><td></td><td></td><td></td></tr><tr><td>Executive function</td><td>0.02</td><td>-0.03 to 0.08</td><td></td><td></td><td></td><td></td></tr><tr><td>Memory: immediate recall</td><td>0.00</td><td>-0.11 to 0.22</td><td></td><td></td><td></td><td></td></tr><tr><td>Memory: delayed recall</td><td>0.05</td><td>-0.01 to 0.10</td><td></td><td></td><td></td><td></td></tr><tr><td>Social cognition</td><td>0.04</td><td>-0.03 to 0.12</td><td></td><td></td><td></td><td></td></tr><tr><td>Visuoconstruction</td><td>0.13</td><td>0.04 to 0.12</td><td></td><td></td><td></td><td></td></tr></tbody></table>

Abbreviations: C9orf72 = chromosome 9 open reading frame 72; CDR plus NACC FTLD = Clinical Dementia Rating scale plus National Alzheimer's Coordinating Center Frontotemporal Lobar Degeneration; GRN = progranulin; MAPT = microtubule-associated protein tau.
pathogenic variant carriers with CDR category ≥1 all per-
formed worse than controls, with both C9orf72 (β = -1.1, SE
0.23, *p* < 0.001) and GRN (β = -1.2, SE 0.25, *p* < 0.001)
pathogenic variant carriers performing worse than MAPT
pathogenic variant carriers. C9orf72 pathogenic variant car-
riers with CDR category 0 also performed worse at baseline
than GRN (β = -0.3, SE 0.13, *p* = 0.010) and MAPT (β = -0.4,
SE 0.16, *p* = 0.030) pathogenic variant carriers and controls
(β = -0.4, SE 0.11, *p* < 0.001; Figure 1A). In addition, we
found an interaction effect between time and gene group
(χ²[3] = 37.1, *p* < 0.001). All gene groups with CDR category
≥1 declined over time compared with controls (C9orf72:
β₁ = -0.3, SE 0.07, *p* < 0.001; GRN: β₁ = -0.4, SE 0.10,
*p* < 0.001; MAPT: β₁ = -0.3, SE 0.09, *p* = 0.004). There was
some weak evidence that C9orf72 pathogenic variant carriers
with CDR category 0 declined over time compared with
controls (β₁ = -0.4, SE 0.11, *p* = 0.086; Figure 1A).

Executive Function

We found strong evidence for differences on the executive
function domain between CDR categories (χ²[2] = 27.2, *p* <
0.001) and between gene groups (χ²[3] = 23.3, *p* < 0.001) at
baseline. A similar profile was seen in all gene groups with
CDR category ≥1 performing worse at baseline than controls
(C9orf72: β = -3.1, SE 0.25, *p* < 0.001; GRN: β = -3.2, SE
0.23, *p* < 0.001; MAPT: β = -1.7, SE 0.29, *p* < 0.001), and
C9orf72 (β = -1.0, SE 0.32, *p* = 0.003) and GRN (β = -1.1, SE
0.35, *p* = 0.002) pathogenic variant carriers performing worse
than MAPT pathogenic variant carriers (Figure 1B). C9orf72
pathogenic variant carriers with CDR category 0 also per-
formed worse than GRN (β = -0.4, SE 0.17, *p* = 0.016) and
MAPT (β = -0.6, SE 0.23, *p* = 0.012) pathogenic variant
carriers, and controls (β = -0.5, SE 0.15, *p* < 0.001) and GRN
pathogenic variant carriers with CDR category 0.5 performed
worse than controls (β = -0.7, SE 0.25, *p* = 0.006). We found
interaction effects between time and gene group (χ²[3] =
24.7, *p* < 0.001), time and CDR category (χ²[2] = 25.8, *p* <
0.001), and time, gene group, and CDR category (χ²[4] =
18.6, *p* = 0.001). MAPT pathogenic variant carriers with CDR
category ≥1 demonstrated steeper decline over time than
C9orf72 (β₁ = -0.5, SE 0.14, *p* = 0.002) and GRN pathogenic
variant carriers (β₁ = -0.5, SE 0.17, *p* = 0.005) and controls
(β₁ = -0.6, SE 0.12, *p* < 0.001) (Figure 1B).

Language

Language differed between CDR categories (χ²[2] = 96.7,
p < 0.001) and between gene groups (χ²[3] = 21.5, p < 0.001)
at baseline. Again, all gene groups with CDR category ≥1
performed worse than controls (C9orf72: β = -3.2, SE 0.28,
p < 0.001; GRN: β = -2.9, SE 0.31, p < 0.001; MAPT: β = -5.0.
SE 0.41, p < 0.001) at baseline, but in this case MAPT
pathogenic variant carriers performed worse than C9orf72
(β = -1.7, SE 0.34, p = 0.002) and GRN (β = -1.3, SE 0.33,
p = 0.009) pathogenic variant carriers (Figure 1C). We also found
interaction effects between time and gene group (χ²[3] = 104.8,
p < 0.001), time and CDR category (χ²[2] = 14.0, p = 0.001), and
time, gene group, and CDR category (χ²[4] = 25.5, p < 0.001).

MAPT pathogenic variant carriers with CDR category 0.5 (β₁ = -0.5, SE 0.17, *p* = 0.004) or ≥1 (β₁ = -0.5, SE 0.15, *p* = 0.003) as well as C9orf72 (β₁ = -0.6, SE 0.11, *p* < 0.001) and GRN (β₁ = -1.3, SE 0.14, *p* < 0.001) pathogenic variant carriers with CDR category ≥1 declined over time compared with controls. In CDR category ≥1, GRN pathogenic variant carriers demonstrated steeper decline over time than C9orf72 (β₁ = -0.7, SE 0.17, *p* < 0.001) and MAPT (β₁ = -0.9, SE 0.20, *p* < 0.001) pathogenic variant carriers (Figure 1C).

Verbal Fluency

For verbal fluency, we found strong evidence for differences be-
tween CDR categories (χ²[2] = 40.0, *p* < 0.001) at baseline. All
gene groups with CDR category ≥1 performed worse than con-
trols (C9orf72: β = -1.8, SE 0.12, *p* < 0.001; GRN: β = -1.6, SE
0.14, *p* < 0.001; MAPT: β = -1.3, SE 0.18, *p* < 0.001), with C9orf72
performing worse than MAPT pathogenic variant carriers (β =
-0.5, SE 0.19, *p* = 0.018; Figure 1D). In CDR category 0, C9orf72
pathogenic variant carriers performed worse than controls (β =
-0.3, SE 0.09, *p* = 0.003) and GRN pathogenic variant
carriers (β = -0.3, SE 0.11, *p* = 0.002). We found an interaction effect
between time and gene group (χ²[3] = 14.5, *p* < 0.002).
C9orf72 pathogenic variant carriers with CDR category ≥1
(β₁ = -0.2, SE 0.05, *p* = 0.004) and GRN pathogenic variant
carriers with CDR categories 0.5 (β₁ = -0.2, SE 0.08, *p* =
0.013) and ≥1 (β₁ = -0.2, SE 0.07, *p* = 0.015) declined over
time compared with controls (Figure 1D).

Memory: Immediate Recall

For immediate recall, we found strong evidence for differ-
ences between CDR categories (χ²[2] = 51.4, *p* < 0.001) and
between gene groups (χ²[3] = 40.2, *p* < 0.001) at baseline.
All gene groups with CDR category ≥1 performed worse
than controls (C9orf72: β = -2.7, SE 0.32, *p* < 0.001; GRN:
β = -5.5, SE 0.40, *p* < 0.001; MAPT: β = -4.3, SE 0.51,
*p* < 0.001), with MAPT performing worse than C9orf72
pathogenic variant carriers (β = -1.7, SE 0.56, *p* = 0.003) and
GRN pathogenic variant carriers performing worse than
C9orf72 (β = -3.0, SE 0.47, *p* < 0.001) and MAPT pathogenic
variant carriers (β = -1.2, SE 0.62, *p* = 0.032; Figure 2A).

Memory: Delayed Recall

For delayed recall, we also found evidence for differences be-
tween CDR categories (χ²[2] = 36.9, *p* < 0.001) and between
gene groups (χ²[3] = 10.4, *p* = 0.015) at baseline. Again, all gene
groups with CDR category ≥1 performed worse than controls
(C9orf72: β = -2.0, SE 0.21, *p* < 0.001; GRN: β = -2.8, SE 0.27,
*p* < 0.001; MAPT: β = -2.7, SE 0.35, *p* < 0.001), with GRN
(β = -0.9, SE 0.32, *p* = 0.007) and MAPT (β = -0.8, SE 0.38, *p* =
0.033) performing worse than C9orf72 pathogenic variant car-
riers. MAPT pathogenic variant carriers with CDR category 0.5
(β = -0.8, SE 0.36, *p* = 0.021) performed worse than controls
and C9orf72 pathogenic variant carriers (β = -0.9, SE 0.42, *p* =
0.023). There was some weak evidence indicating that MAPT
pathogenic variant carriers with CDR category 0 performed
worse than controls (β = -0.4, SE 0.21, *p* = 0.081; Figure 2B).
None of the groups declined significantly over time.
<figure><img src="image_2.png" /><figcaption>**Figure 1** Linear Mixed Effects Models Displaying Longitudinal Trajectories in Composite Domain Z Score Stratified by the CDR Plus NACC FTLD for C9orf72, GRN, and MAPT Pathogenic Variant Carriers and Healthy Controls</figcaption></figure>

Models are displayed per cognitive domain: (A) attention, (B) executive function, (C) language, and (D) verbal fluency. C9orf72 = chromosome 9 open reading frame 72; CDR = Clinical Dementia Rating scale plus National Alzheimer's Coordinating Center Frontotemporal Lobar Degeneration; GRN = progranulin; MAPT = microtubule-associated protein tau.

## Social Cognition

We found strong evidence for differences between CDR categories ($\chi^2[2] = 35.7, p < 0.001$) at baseline on social cognition. All gene groups with CDR category $\ge 1$ performed worse than controls (C9orf72: $\beta = -2.6, \text{SE } 0.19, p < 0.001$; GRN: $\beta = -2.3, \text{SE } 0.23, p < 0.001$; MAPT: $\beta = -1.9, \text{SE } 0.28, p < 0.001$), with GRN performing worse than MAPT pathogenic variant carriers ($\beta = -0.7, \text{SE } 0.33, p = 0.033$; Figure 2C). C9orf72 ($\beta = -0.7, \text{SE } 0.24, p = 0.001$) and GRN ($\beta = -0.7, \text{SE } 0.25, p = 0.001$) pathogenic variant carriers with CDR category 0.5 also performed worse at baseline than controls. We found interaction effects between time and gene group ($\chi^2[3] = 21.3, p < 0.001$) and time, CDR category, and gene group ($\chi^2[4] = 16.3, p < 0.003$). GRN pathogenic variant carriers with CDR category $\ge 1$ showed steeper decline over time compared with controls ($\beta_1 = -0.5, \text{SE } 0.13, p < 0.001$), C9orf72 ($\beta_1 = -0.7, \text{SE } 0.16, p < 0.001$), and MAPT ($\beta_1 = -0.3, \text{SE } 0.17, p = 0.049$) pathogenic variant carriers and MAPT pathogenic variant carriers with CDR category $\ge 1$ showed steeper decline over time compared to C9orf72 pathogenic variant carriers ($\beta_1 = -0.3, \text{SE } 0.16, p = 0.047$; Figure 2C).

## Visuoconstruction

We found differences between gene groups on visuoconstruction ($\chi^2[3] = 11.0, p = 0.012$) at baseline. All gene groups with CDR category $\ge 1$ performed worse than controls (C9orf72: $\beta = -2.0, \text{SE } 0.22, p < 0.001$; GRN: $\beta = -1.6, \text{SE } 0.26, p < 0.001$; MAPT: $\beta = -0.9, \text{SE } 0.32, p = 0.004$), with C9orf72 ($\beta = -1.2, \text{SE } 0.33, p = 0.002$) and GRN ($\beta = -1.0, \text{SE } 0.36, p = 0.008$) performing worse than MAPT pathogenic variant carriers. GRN pathogenic variant carriers with CDR
<figure><img src="image_3.png" /><figcaption>**Figure 2** Linear Mixed Effects Models Displaying Longitudinal Trajectories in Composite Domain Z Score Stratified by the CDR Plus NACC FTLD for C9orf72, GRN, and MAPT Pathogenic Variant Carriers and Healthy Controls</figcaption></figure>

Models are displayed per cognitive domain: (A) memory–immediate recall, (B) memory–delayed recall, (C) social cognition, and (D) visuoconstruction. *C9orf72* = chromosome 9 open reading frame 72; CDR = Clinical Dementia Rating scale plus National Alzheimer's Coordinating Center Frontotemporal Lobar Degeneration; GRN = progranulin; MAPT = microtubule-associated protein tau.

category 0.5 ($\beta_1$ = -0.5, SE 0.23, *p* = 0.050) showed steeper decline over time than controls (Figure 2D).

Discussion

This study demonstrated gene-specific baseline differences and decline over a 5-year time period in a large cohort of genetic FTD pathogenic variant carriers that was moderated by the CDR plus NACC FTLD global score. C9orf72 pathogenic variant carriers performed lower on attention, executive function, and verbal fluency from CDR plus NACC FTLD 0 onwards, with relatively minimal decline over time compared with other genetic groups regardless of the CDR plus NACC FTLD score (i.e., disease progression). The cognitive profile in MAPT pathogenic variant carriers was characterized by early impaired

memory (already at CDR plus NACC FTLD 0.5), with language decline starting at CDR plus NACC FTLD 0.5, and executive dysfunction developing rapidly at CDR plus NACC FTLD $\ge$1. GRN pathogenic variant carriers showed no differences or decline compared with controls at CDR plus NACC FTLD 0, but verbal fluency and visuoconstruction started to decline at CDR plus NACC FTLD 0.5. GRN pathogenic variant carriers showed the most rapid decline compared with the other groups in language and social cognition from CDR plus NACC FTLD $\ge$1 onwards. The results from this study confirm cognitive decline in the asymptomatic and prodromal stages of genetic FTD and hold potential for upcoming therapeutic trials by identifying (1) the most sensitive cognitive measures to track disease progression and treatment effects and (2) the speed of change over time, thereby providing insight into the best time window to start disease-modifying treatment.
<figure><img src="image_4.png" /><figcaption>**Figure 3** Summary of Cross-Sectional and Longitudinal Differences Between Each Genetic Group and Controls</figcaption></figure>

Asymptomatic *C9orf72* pathogenic variant carriers performed worse at baseline than controls on attention/mental processing speed, executive function, and verbal fluency. In the prodromal stage, social cognition was also lower at baseline, whereas at the fully symptomatic stage, all cognitive domains were lower at baseline. There was no decline over time in the asymptomatic stage or prodromal stage, but attention/mental processing speed, language, and verbal fluency declined over time in the symptomatic stage, although less rapidly than in other gene groups. The other cognitive domains remained relatively stable, and there were signs of possible practice effects for memory and social cognition. This is largely in line with previous studies demonstrating widespread cognitive impairment in *C9orf72* pathogenic variant carriers with relatively minimal decline over time.⁵,³⁹,⁴⁰ It is further corroborated by the fact that the neurodegenerative process associated with the *C9orf72* pathogenic variant is widespread, with neurodegeneration in the frontal and temporal cortices but also in more posterior cortical, subcortical, and cerebellar regions.³⁹,⁴¹ This group performed lowest compared with the other groups on a wide range of neuropsychological tests, specifically tests for attention/mental processing speed and executive function, at the asymptomatic stage. Although these

performances were not at an “impaired” level (i.e., z score ≤−2), these deficits might represent the earliest signs of neurodegeneration with very slow decline over time. Alternatively, the lack of decline over time in all 3 disease stages raises the intriguing possibility that these deficits are not merely preclinical signs of FTD as a result of early neurodegeneration, but might be indicative of a neurodevelopmental disorder in *C9orf72*, which at a certain age is superimposed by additional neurodegeneration. This hypothesis has been suggested by several previous studies that found gray and white matter deficits and connectivity disruption as well as psychiatric conditions and cognitive deficits many years before the estimated age at symptom onset without evidence of disease progression over time.⁴²,⁴³ Future studies should focus on ascertaining early-life radiologic and clinical assessments to test this hypothesis.

In MAPT pathogenic variant carriers, there was a trend towards lower memory performance than in controls at baseline in the asymptomatic stage, which became significant at the prodromal stage. All cognitive domains were lower than in controls at baseline in the symptomatic stage. There was no decline over time in the asymptomatic stage, but language
declined from the prodromal stage onwards. In addition, attention/mental processing speed, executive function, and social cognition declined progressively during the symptomatic stage. These results confirm that the first changes for this group occur in cognitive functions that are strongly associated with the temporal lobe, an area that already shows early degeneration in presymptomatic MAPT pathogenic variant carriers.⁶ Several previous studies have demonstrated that episodic memory impairment is a distinct feature in MAPT-related FTD, even in presymptomatic pathogenic variant carriers.¹⁹,²⁰,²⁶ Strikingly, we demonstrated lower memory performance in prodromal pathogenic variant carriers but with practice effects over time that disappeared at the fully symptomatic stage only. A likely explanation for these practice effects is that the same items for memory tests were used at all time points, stressing the need for the use of tests that have multiple versions with different stimuli in longitudinal cohort studies. The lower performance and decline seen in the language domain was largely driven by the Boston Naming Test, a test that strongly depends on the semantic memory system.⁴⁴ This is unsurprising given that semantic memory is strongly associated with the anteromedial temporal lobe, an area known to deteriorate early and progressively in MAPT-associated FTD.²⁶ Deficits in semantic memory have been described as a key symptom in MAPT pathogenic variant carriers in a more progressed disease stage,⁵ but our results illustrate that the first changes occur at a much earlier stage, suggesting that semantic tests might be a good candidate to serve as a sensitive end point in upcoming therapeutic trials of MAPT-associated FTD. Only at a later progressed stage, when atrophy spreads from the temporal to frontal areas of the brain, does impairment in cognitive functions that are typically associated with bvFTD develop, such as executive function and social cognition.²²,⁴⁵

There were no cross-sectional differences between asymptomatic GRN pathogenic variant carriers and controls at baseline and there was no decline over time in this stage. In the prodromal stage, pathogenic variant carriers performed worse than controls on executive function and social cognition, and they declined over time on verbal fluency and visuoconstruction. All cognitive domains were lower than in controls at baseline in the symptomatic stage, and they showed progressive decline over time on attention/mental processing speed, verbal fluency, language, and social cognition. This is in line with previous studies showing minimal changes in gray and white matter but also cognition in presymptomatic GRN pathogenic variant carriers, often with fast progressive decline after symptom onset.⁵,²⁰ Although in our study no change over time was detected in the asymptomatic stage, GRN pathogenic variant carriers performed worse on executive function and social cognitive tasks at the prodromal stage, suggesting some decline between these stages. Possible explanations could be that the asymptomatic pathogenic variant carriers were too far from symptom onset or that the time window between these stages where these changes occur is relatively short. Interestingly, verbal fluency declined

progressively in the prodromal period, indicating an early deficit in specifically verbal fluency. This could be interpreted as an early sign of pathogenic variant carriers developing nonfluent variant PPA, a clinical phenotype that is often seen in GRN pathogenic variant carriers.⁴¹ However, verbal fluency measures are also known to strongly depend on executive function,³⁶ a cognitive domain known to deteriorate in bvFTD.⁴⁵ Surprisingly, visuoconstruction also declined in the prodromal stage, whereas this is considered to be relatively spared in FTD.² However, most visuoconstructive tasks also strongly depend on executive functions such as planning, organizing, and keeping overview.⁴⁶ It seems, therefore, more likely that these tasks were influenced by impaired executive function rather than a pure impairment in language and visuoconstruction per se.

This is the first study to longitudinally investigate a large cohort of all 3 major causes of genetic FTD over a 5-year period. A major strength of this study is the use of the CDR plus NACC FTLD to stratify pathogenic variant carriers from asymptomatic to prodromal and fully symptomatic (i.e., 0, 0.5, ≥1). Most previous studies have stratified pathogenic variant carriers as either presymptomatic or symptomatic according to whether they fulfilled diagnostic criteria for FTD syndromes, but this does not fully grasp the clinical trajectory of FTD. The cognitive profile between the presymptomatic and symptomatic phase has not been well-characterized. Some other studies have used estimated years to symptom onset based on mean family age at onset, but a recent article demonstrated that the correlations between age at symptom onset and mean family age at symptom onset were weak for C9orf72 and GRN pathogenic variant carriers, indicating that this might not be a reliable proxy.²⁸ By stratifying according to CDR plus NACC FTLD, we have provided insight into cognitive decline during different disease stages.

There are limitations to this study. First, the sample size at the CDR plus NACC FTLD 0.5 stage was smaller than the other stages, which probably influenced the statistical power in this specific group. Second, due to ongoing recruitment within GENFI, participants varied in the number of completed visits, resulting in missing data at later time points. Therefore, we analyzed the data with linear mixed-effects models, as these models allow for unbalanced time points and missing data.³⁸ We could not use a nonlinear mixed effects model (e.g., natural cubic splines) due to the limited number of follow-up visits. However, similar to what has been performed in studies of familial AD,⁴⁷ nonlinear models might be more suitable for the analysis of clinical progression in FTD. Future studies with longer follow-up should therefore investigate the use of nonlinear models in analyzing clinical disease progression in FTD. Third, we did not take progression over time on the CDR plus NACC FTLD into account, but stratified groups according to their global score at baseline. Future research should investigate the cognitive trajectories of progressors compared with nonprogressors on the CDR plus NACC FTLD more in depth. Individual trajectories demonstrated
high variability between individuals in each group. A possible explanation for this interindividual variability could be that some individuals with a CDR plus NACC FTLD global score of 0 might be closer to symptom onset than others. Similarly, individuals with a CDR plus NACC FTLD score of 0.5 or ≥1 at baseline might vary in time since progression to that CDR category (i.e., individuals who had a global score of 0.5 for several years at inclusion will likely progress faster than individuals who progressed to a score of 0.5 more recently). Validation in other cohorts such as ALLFTD or DINAD is warranted. Fourth, practice effects were strikingly visible for the FCSRT and Facial Emotion Recognition Test, stressing the need for different test versions in the former, but more sensitive tasks for emotion recognition (e.g., the use of morphed facial expressions²²) and social cognition in general. Lastly, in the interpretation of memory-immediate recall, social cognition, and visuoconstruction results, it should be taken into account that they were represented by only a single cognitive test, and those individual tests might not be a representation of the entire cognitive domain.

We provide evidence for gene-specific cognitive decline in the prodromal stage of genetic FTD. Specifically, tests for attention/mental processing speed, executive function, language, and memory showed clear differences between gene groups and controls at baseline, but the speed and nature of change over time differed depending on (1) the gene group and (2) the CDR plus NACC FTLD global score. These results confirm the value of neuropsychological assessment in tracking disease progression and could inform upcoming clinical trials in selecting sensitive end points for measuring treatment effects as well as in characterizing the best time window for starting treatment.

## Acknowledgment

The authors thank the research participants and their families for their contribution to the study.

## Study Funding

Several authors of this publication are members of the European Reference Network for Rare Neurological Diseases (project ID 739510). J.D. Rohrer is supported by the Miriam Marks Brain Research UK Senior Fellowship, MRC Clinician Scientist Fellowship (MR/M008525/1), and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH) and both the MRC UK GENFI grant (MR/M023664/1) and the JPND GENFI-PROX grant (2019-02248). J.M. Poos, L. Jiskoot, E. van der Ende, J.M. Papma, H. Seelaar, and J. van Swieten's contributions to this work were supported by the Bluefield Project, the Dioraphte Foundation (grant 09-02-00), the Association for Frontotemporal Dementias Research Grant 2009, The Netherlands Organization for Scientific Research (NWO) (grant HCMI 056-13-018), ZonMw Memorabel (Deltaplan Dementie) (project numbers 733 050 103 and 733 050 813), and JPND PreFrontAls consortium (project number 733051042). J.M. Poos was supported by a Fellowship award

from Alzheimer Nederland (WE.15-2019.02). J.M. Papma received additional funding outside this submitted work from ZonMw and Alzheimer Nederland. F. Moreno's contributions to this work were supported by the Tau Consortium. R. Sanchez-Valle's contributions to this work were supported by the ISCIII grant (PI20/00448). B. Borroni received funding outside this submitted work in the past 36 months from the JPND consortium, the Italian Ministry of Health, and the Alzheimer's Drug Discovery Foundation (ADDF). M. Masellis' contribution to this work was funded by the Canadian Institutes of Health Research; in addition, he received funding outside the submitted work in the past 36 months from the Ontario Brain Institute, ADDF, Brain Canada, Weston Brain Institute, Roche, Washington University, Axovant, and Alector. M.C. Tartaglia has received funding from the NIH. C. Graff's contribution to this work was supported by (1) cofunding from the Swedish Research council and JPND grant GENFI-PROX (2019-02248), (2) cofunding from the Swedish Research Council and JPND grant PrefrontALS (2015-02926), (3) the Swedish Research Council (2018-02754), (4) the Schörling Foundation and Swedish FTD Initiative, (5) the Swedish Alzheimer Foundation, (6) the Swedish Brain Foundation, (7) the Region Stockholm ALF project, (8) Karolinska Institutet Doctoral and StratNeuro grants, and (9) the Swedish Dementia Foundation. J. Rowe's contribution to this work was supported by the National Institute for Health Research and the Medical Research Council (BRC-1215-20014) and the Medical Research Council (SUAG/051 G101400); he received additional funding outside the submitted work in the past 36 months from the Wellcome Trust (103838), Parkinsons UK, Alzheimer Research UK, PSP Association, Evelyn Trust, Janssen, Lilly, and AstraZeneca. E. Finger's contribution to this work was supported by the Canadian Institutes for Health Research; in addition, she received funding in the past 36 months from the Physician's Services Incorporated Foundation. M. Synofzik's contribution to this work was supported by the JPND GENFI-PROX grant via DLR/DFG 01ED2008B. R. Vandenberghe received funding outside this submitted work in the past 36 months from a clinical trial agreement with AbbVie, Roche, Alector, UCB, Johnson & Johnson, the Flemish Research Foundation, and Bijzonder Onderzoeksfonds KU Leuven. A. Mendonça received funding outside the submitted work for FMUL: BEYOND BETA-AMYLOID: Deciphering Early Pathogenic Changes in Alzheimer's Disease, FCT (2018-2022), and RADAR-AD: Remote Assessment of Disease And Relapse: Alzheimer's Disease (2020-2022). S. Ducharme received funding from the Canadian Institutes of Health Research: Neurosciences, Mental Health and Addiction, the FRQS Junior 2 Clinician Scientist Award, the Ministère de l'Économie et de l'Innovation (Brouillette Operational Grant), and JPND. C. Butler's contributions to this work were supported by the Medical Research Council. In addition, he received funding in the past 36 months from the Alzheimer's Association. A. Gerhard's contributions to this work were supported by the Medical Research Council UK. J. Levin's contributions to this work were supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)
under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy: ID 390857198). A. Danek received funding from Advocacy for Neuroacanthocytosis Patients. M. Otto received funding outside the submitted work in the past 36 months from BMBF, Boehringer Ingelheim, Alector, and Axon. I. Le Ber has received funding in the past 36 months from JPND.

## Disclosure

J.D. Rohrer has received consulting fees from UCB, AC Immune, Astex Pharmaceuticals, Biogen, Takeda, and Eisai and is part of the Medical Advisory Board for Alector, Arkuda Therapeutics, Wave Life Sciences, and Prevail Therapeutics. R. Sanchez-Valle has received consulting fees from Wave Pharmaceuticals and Ionis-Biogen and from Roche Diagnostics and Janssen for educational activities and is member of the Data Safety Monitoring Board for Wave Pharmaceuticals and Ionis-Biogen. B. Borroni has received consulting fees from Alector and Wave Pharmaceuticals and has a pending patent on noninvasive brain stimulation. M. Masellis has received compensation for royalties from Henry Stewart Talks Ltd.; consulting fees from Arkuda Therapeutics, Ionis, Alector, Biogen, and Wave Life Sciences; personal fees for educational activities from Alector and Arkuda Therapeutics; and travel fees from Alector Pharmaceuticals. M.C. Tartaglia has received consulting fees from Roche. C. Graff has received consulting fees from Studentlitteratur 238 SEK 2020 and reimbursement for travel and lodging from University of Pennsylvania for attending KOL-meeting in October 2019. J. Rowe has received consulting fees from Asceneuron, Biogen, UCB, SV Health, and Astex; has provided expert testimony in private noncommercial medicolegal case reports; is part of an Advisory Board for several noncommercial academic institutions; and is Chief Scientific Advisor to Alzheimers Research UK, Guarantor of Brain, Trustee PSP Association, Trustee Darwin College, and Associate Director of the Dementias Platform UK. E. Finger has received consulting fees for the AAN annual meeting speaker and course director honorariums; is member of the Data Safety Monitoring Board for the Lithium trial, PI E. Huey (trial funded by peer reviewed grants from ADDF); and is a scientific advisory board member for Vigil Neuroscience, Denali Therapeutics, and on an advisory panel for Biogen. M. Synofzik has received consulting fees from Janssen Pharmaceuticals, Ionis Pharmaceuticals, and Orphazyme Pharmaceuticals and received support from the Movement Disorder Society for travel. R. Vandenberghe has received consulting fees from CyTox and is a member of the Data Safety and Monitoring Board of AC Immune. I. Santana has received consulting fees from Biogen and Roche Biogen, personal fees for presentations from Biogen, and is part of the Data Safety Monitoring Board for Novo Nordisk. S. Ducharme has received consulting fees from Innodem Neurosciences and personal fees from Sunovion Eisai. J. Levin has received consulting fees from Bayer Vital, Roche, and Biogen; is part of the Advisory Board for Axon Neurosciences; has received compensation for duty as part-time

CMO from Modag; and has received author fees from Thieme medical publishers and W. Kohlhammer GmbH medical publishers as well as nonfinancial support from AbbVie. A. Danek has received consulting fees from 3 hospitals in Switzerland and personal fees from the German court of law for medico-legal opinion. M. Otto has received consulting fees from Biogen, Axon, and Roche and is part of the Advisory Board for Axon. I. Le Ber has received consulting fees from Alector Prevail Therapeutics and personal fees from MDS and is also part of the Data Safety Monitoring Board for Alector Prevail Therapeutics. Go to Neurology.org/N for full disclosures.

## Publication History

Received by Neurology October 15, 2021. Accepted in final form February 25, 2022.

## Appendix 1 Authors

<table><thead><tr><td>Name</td><td>Location</td><td>Contribution</td></tr></thead><tbody><tr><td>Jackie M. Poos, MSc</td><td>Department of Neurology, Erasmus MC University Medical Center, Rotterdam, the Netherlands; Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, UK</td><td>Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data</td></tr><tr><td>Amy MacDougall, PhD</td><td>Department of Medical Statistics, London School of Hygiene and Tropical Medicine, UK</td><td>Analysis or interpretation of data</td></tr><tr><td>Esther van den Berg, PhD</td><td>Department of Neurology, Erasmus MC University Medical Center, Rotterdam, the Netherlands</td><td>Drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data</td></tr><tr><td>Lize C. Jiskoot, PhD</td><td>Department of Neurology, Erasmus MC University Medical Center, Rotterdam, the Netherlands; Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, UK</td><td>Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data</td></tr><tr><td>Janne M. Papma, PhD</td><td>Department of Neurology, Erasmus MC University Medical Center, Rotterdam, the Netherlands</td><td>Drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data</td></tr><tr><td>Emma L. van der Ende, PhD</td><td>Department of Neurology, Erasmus MC University Medical Center, Rotterdam, the Netherlands</td><td>Major role in the acquisition of data</td></tr><tr><td>Harro Seelaar, MD, PhD</td><td>Department of Neurology, Erasmus MC University Medical Center, Rotterdam, the Netherlands</td><td>Major role in the acquisition of data</td></tr></tbody></table>
Appendix 1 (continued)

<table><thead><tr><td>Name</td><td>Location</td><td>Contribution</td></tr></thead><tbody><tr><td>Lucy L. Russell, PhD</td><td>Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, UK</td><td>Major role in the acquisition of data; analysis or interpretation of data</td></tr><tr><td>Georgia Peakman, MSc</td><td>Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, UK</td><td>Major role in the acquisition of data</td></tr><tr><td>Rhian Convery, MSc</td><td>Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, UK</td><td>Major role in the acquisition of data</td></tr><tr><td>Yolande A.L. Pijnenburg, MD, PhD</td><td>Department of Neurology, Alzheimer Center, Amsterdam University Medical Center, Amsterdam Neuroscience, the Netherlands</td><td>Major role in the acquisition of data</td></tr><tr><td>Fermin Moreno, MD, PhD</td><td>Cognitive Disorders Unit, Department of Neurology, Donostia University Hospital, San Sebastian, Gipuzkoa, Spain</td><td>Major role in the acquisition of data</td></tr><tr><td>Raquel Sanchez-Valle, PhD</td><td>Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi I Sunyer, University of Barcelona, Spain</td><td>Major role in the acquisition of data</td></tr><tr><td>Barbara Borroni, MD</td><td>Centre for Neurodegenerative Disorders, Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Italy</td><td>Major role in the acquisition of data</td></tr><tr><td>Robert Laforce, Jr., MD, PhD</td><td>Clinique Interdisciplinaire de Mémoire, Département des Sciences Neurologiques, Université Laval, Québec, Canada</td><td>Major role in the acquisition of data</td></tr><tr><td>Marie-Claire Doré, PhD</td><td>Clinique Interdisciplinaire de Mémoire, Département des Sciences Neurologiques, Université Laval, Québec, Canada</td><td>Major role in the acquisition of data</td></tr><tr><td>Mario Masellis, MD, PhD</td><td>Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Ontario, Canada</td><td>Major role in the acquisition of data</td></tr><tr><td>Maria Carmela Tartaglia, MD</td><td>Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Ontario, Canada</td><td>Major role in the acquisition of data</td></tr><tr><td>Caroline Graff, MD, PhD</td><td>Department of Geriatric Medicine, Karolinska University Hospital-Huddinge, Stockholm, Sweden</td><td>Major role in the acquisition of data</td></tr></tbody></table>

Appendix 1 (continued)

<table><thead><tr><td>Name</td><td>Location</td><td>Contribution</td></tr></thead><tbody><tr><td>Daniela Galimberti, PhD</td><td>Centro Dino Ferrari, University of Milan; Fondazione IRCCS Ca' Granda, Ospedale Policlinico, Neurodegenerative Diseases Unit, Milan, Italy</td><td>Major role in the acquisition of data</td></tr><tr><td>James Rowe, FCRCP, PhD</td><td>Department of Clinical Neurosciences, University of Cambridge, UK</td><td>Major role in the acquisition of data</td></tr><tr><td>Elizabeth Finger, MD</td><td>Department of Clinical Neurological Sciences, University of Western Ontario, London, Canada</td><td>Major role in the acquisition of data</td></tr><tr><td>Matthis Synofzik, MD</td><td>Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany</td><td>Major role in the acquisition of data</td></tr><tr><td>Rik Vandenberghe, MD, PhD</td><td>Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Belgium</td><td>Major role in the acquisition of data</td></tr><tr><td>Alexandre Mendonça, MD, PhD</td><td>Faculty of Medicine, University of Lisbon, Portugal</td><td>Major role in the acquisition of data</td></tr><tr><td>Pietro Tiraboschi, MD</td><td>Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Neurologica Carlo Besta, Milan, Italy</td><td>Major role in the acquisition of data</td></tr><tr><td>Isabel Santana, MD, PhD</td><td>Faculty of Medicine, University of Coimbra, Portugal</td><td>Major role in the acquisition of data</td></tr><tr><td>Simon Ducharme, MD</td><td>Department of Psychiatry, McGill University Health Centre, McGill University, Montreal, Québec, Canada</td><td>Major role in the acquisition of data</td></tr><tr><td>Christopher Butler, FRCP, PhD</td><td>Department of Clinical Neurology, University of Oxford, UK</td><td>Major role in the acquisition of data</td></tr><tr><td>Alexander Gerhard, MRCP, MD</td><td>Division of Neuroscience & Experimental Psychology, Faculty of Medicine, Biology and Health, University of Manchester, UK; Departments of Geriatric Medicine and Nuclear Medicine, Essen University Hospital, Germany</td><td>Major role in the acquisition of data</td></tr><tr><td>Johannes Levin, MD</td><td>Department of Neurology, Ludwig-Maximilians-University; German Center for Neurodegenerative Diseases (DZNE); Munich Cluster for Systems Neurology (SyNergy), Germany</td><td>Major role in the acquisition of data</td></tr></tbody></table>

Continued
## Appendix 1 (continued)

<table><thead><tr><td>Name</td><td>Location</td><td>Contribution</td></tr></thead><tbody><tr><td>Adrian Danek, MD</td><td>Department of Neurology, Ludwig-Maximilians-University, Munich, Germany</td><td>Major role in the acquisition of data</td></tr><tr><td>Markus Otto, MD</td><td>Department of Neurology, University of Ulm, Germany</td><td>Major role in the acquisition of data</td></tr><tr><td>Isabelle Le Ber, MD, PhD</td><td>Sorbonne Université, Paris Brain Institute-Institut du Cerveau-ICM, Inserm U1127, CNRS UMR 7225, AP-HP-Hôpital Pitié-Salpetrière; Centre de Référence des Démences Rares ou Précoces, IM2A, Département de Neurologie, AP-HP-Hôpital Pitié-Salpetrière; Département de Neurologie, AP-HP-Hôpital Pitié-Salpetrière, France</td><td>Major role in the acquisition of data</td></tr><tr><td>Florence Pasquier, MD, PhD</td><td>Univ Lille, Inserm 1172, CHU, CNR-MAJ, Labex Distalz, LiCEND, Lille, France</td><td>Major role in the acquisition of data</td></tr><tr><td>John van Swieten, MD, PhD</td><td>Department of Neurology, Erasmus MC University Medical Center, Rotterdam, the Netherlands</td><td>Major role in the acquisition of data</td></tr><tr><td>Jonathan D. Rohrer, FRCP, PhD</td><td>Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, UK</td><td>Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data</td></tr></tbody></table>

## Appendix 2 Coinvestigators

Coinvestigators are listed at links.lww.com/WNL/B988.

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