Association of biological sex with clinical outcomes and biomarkers of Alzheimer's disease in adults with Down syndrome

M Florencia Iulita^{1

2

3}, Alexandre Bejanin^{1

2}, Eduard Vilaplana^{1

2}, Maria Carmona-Iragui^{1

2

4}, Bessy Benejam^{2

4}, Laura Videla^{1

2

4}, Isabel Barroeta^{1

2}, Susana Fernández⁴, Miren Altuna^{1

2}, Jordi Pegueroles^{1

2}, Victor Montal^{1

2}, Silvia Valldeneu^{1

2}, Sandra Giménez⁵, Sofía González-Ortiz⁶, Soraya Torres^{1

2}, Shaimaa El Bounasri El Bennadi^{1

2}, Concepcion Padilla^{1

2}, Mateus Rozalem Aranha^{1

2}, Teresa Estellés^{1

2}, Ignacio Illán-Gala^{1

2}, Olivia Belbin^{1

2}, Natalia Valle-Tamayo^{1

2}, Valle Camacho⁷, Esther Blessing⁸, Ricardo S Osorio⁸, Sebastian Videla⁹, Sylvain Lehmann¹⁰, Anthony J Holland^{11

12}, Henrik Zetterberg^{13

14

15

16

17}, Kaj Blennow^{13

14}, Daniel Alcolea^{1

2}, Jordi Clarimón^{1

2}, Shahid H Zaman^{11

12}, Rafael Blesa^{1

2}, Alberto Lleó^{1

2}, Juan Fortea^{1

2

4}

Affiliations

¹ Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona 08025, Spain.
² Center of Biomedical Investigation Network for Neurodegenerative Diseases (CIBERNED), Madrid 28031, Spain.
³ Women's Brain Project, Guntershausen 8357, Switzerland.
⁴ Barcelona Down Medical Center, Fundació Catalana Síndrome de Down, Barcelona 08029, Spain.
⁵ Multidisciplinary Sleep Unit, Hospital de la Santa Creu i Sant Pau, Barcelona 08041, Spain.
⁶ Hospital del Mar, Barcelona 08003, Spain.
⁷ Nuclear Medicine Department, Hospital de la Santa Creu i Sant Pau, Barcelona 08041, Spain.
⁸ Department of Psychiatry, NYU Grossman School of Medicine, New York, NY 10016, USA.
⁹ Clinical Research Support Unit, Bellvitge Biomedical Research Institute (IDIBELL), Department of Clinical Pharmacology, University of Barcelona, Barcelona 08908, Spain.
¹⁰ Institute for Neurosciences of Montpellier, Institute for Regenerative Medicine and Biotherapy, Université de Montpellier, CHU de Montpellier, INSERM, Montpellier 34295, France.
¹¹ Department of Psychiatry, Cambridge Intellectual and Developmental Disabilities Research Group, University of Cambridge, Douglas House, Cambridge CB2 8AH, United Kingdom.
¹² Cambridgeshire & Peterborough NHS Foundation Trust, Fulbourn Hospital, Cambridge CB21 5EF, United Kingdom.
¹³ Department of Psychiatry and Neurochemistry, University of Gothenburg, Möndal 40530, Sweden.
¹⁴ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal 40530, Sweden.
¹⁵ UK Dementia Research Institute, University College London, London WC1E 6BT, United Kingdom.
¹⁶ Department of Neurodegenerative Disease, University College London Institute of Neurology, London WC1E 6BT, United Kingdom.
¹⁷ Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong 1512-1518, China.

PMID: 37056479
PMCID: PMC10088472
DOI: 10.1093/braincomms/fcad074

Association of biological sex with clinical outcomes and biomarkers of Alzheimer's disease in adults with Down syndrome

M Florencia Iulita et al. Brain Commun. 2023.

. 2023 Mar 17;5(2):fcad074.

doi: 10.1093/braincomms/fcad074. eCollection 2023.

Authors

Affiliations

¹ Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona 08025, Spain.
² Center of Biomedical Investigation Network for Neurodegenerative Diseases (CIBERNED), Madrid 28031, Spain.
³ Women's Brain Project, Guntershausen 8357, Switzerland.
⁴ Barcelona Down Medical Center, Fundació Catalana Síndrome de Down, Barcelona 08029, Spain.
⁵ Multidisciplinary Sleep Unit, Hospital de la Santa Creu i Sant Pau, Barcelona 08041, Spain.
⁶ Hospital del Mar, Barcelona 08003, Spain.
⁷ Nuclear Medicine Department, Hospital de la Santa Creu i Sant Pau, Barcelona 08041, Spain.
⁸ Department of Psychiatry, NYU Grossman School of Medicine, New York, NY 10016, USA.
⁹ Clinical Research Support Unit, Bellvitge Biomedical Research Institute (IDIBELL), Department of Clinical Pharmacology, University of Barcelona, Barcelona 08908, Spain.
¹⁰ Institute for Neurosciences of Montpellier, Institute for Regenerative Medicine and Biotherapy, Université de Montpellier, CHU de Montpellier, INSERM, Montpellier 34295, France.
¹¹ Department of Psychiatry, Cambridge Intellectual and Developmental Disabilities Research Group, University of Cambridge, Douglas House, Cambridge CB2 8AH, United Kingdom.
¹² Cambridgeshire & Peterborough NHS Foundation Trust, Fulbourn Hospital, Cambridge CB21 5EF, United Kingdom.
¹³ Department of Psychiatry and Neurochemistry, University of Gothenburg, Möndal 40530, Sweden.
¹⁴ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal 40530, Sweden.
¹⁵ UK Dementia Research Institute, University College London, London WC1E 6BT, United Kingdom.
¹⁶ Department of Neurodegenerative Disease, University College London Institute of Neurology, London WC1E 6BT, United Kingdom.
¹⁷ Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong 1512-1518, China.

PMID: 37056479
PMCID: PMC10088472
DOI: 10.1093/braincomms/fcad074

Abstract

The study of sex differences in Alzheimer's disease is increasingly recognized as a key priority in research and clinical development. People with Down syndrome represent the largest population with a genetic link to Alzheimer's disease (>90% in the 7th decade). Yet, sex differences in Alzheimer's disease manifestations have not been fully investigated in these individuals, who are key candidates for preventive clinical trials. In this double-centre, cross-sectional study of 628 adults with Down syndrome [46% female, 44.4 (34.6; 50.7) years], we compared Alzheimer's disease prevalence, as well as cognitive outcomes and AT(N) biomarkers across age and sex. Participants were recruited from a population-based health plan in Barcelona, Spain, and from a convenience sample recruited via services for people with intellectual disabilities in England and Scotland. They underwent assessment with the Cambridge Cognitive Examination for Older Adults with Down Syndrome, modified cued recall test and determinations of brain amyloidosis (CSF amyloid-β 42 / 40 and amyloid-PET), tau pathology (CSF and plasma phosphorylated-tau181) and neurodegeneration biomarkers (CSF and plasma neurofilament light, total-tau, fluorodeoxyglucose-PET and MRI). We used within-group locally estimated scatterplot smoothing models to compare the trajectory of biomarker changes with age in females versus males, as well as by apolipoprotein ɛ4 carriership. Our work revealed similar prevalence, age at diagnosis and Cambridge Cognitive Examination for Older Adults with Down Syndrome scores by sex, but males showed lower modified cued recall test scores from age 45 compared with females. AT(N) biomarkers were comparable in males and females. When considering apolipoprotein ɛ4, female ɛ4 carriers showed a 3-year earlier age at diagnosis compared with female non-carriers (50.5 versus 53.2 years, P = 0.01). This difference was not seen in males (52.2 versus 52.5 years, P = 0.76). Our exploratory analyses considering sex, apolipoprotein ɛ4 and biomarkers showed that female ɛ4 carriers tended to exhibit lower CSF amyloid-β 42/amyloid-β 40 ratios and lower hippocampal volume compared with females without this allele, in line with the clinical difference. This work showed that biological sex did not influence clinical and biomarker profiles of Alzheimer's disease in adults with Down syndrome. Consideration of apolipoprotein ɛ4 haplotype, particularly in females, may be important for clinical research and clinical trials that consider this population. Accounting for, reporting and publishing sex-stratified data, even when no sex differences are found, is central to helping advance precision medicine.

Keywords: Alzheimer’s disease; Down syndrome; gender; precision medicine; sex.

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Conflict of interest statement

O.B. reported receiving personal fees from ADx NeuroSciences outside the submitted work. H.Z. declares that he has served on scientific advisory boards and/or as a consultant for Abbvie, Alector, Annexon, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Pinteon Therapeutics, Red Abbey Labs, Passage Bio, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen and Roche and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, which is a part of the GU Ventures Incubator Program, outside the submitted work. K.B. declares that he has served as a consultant, on advisory boards, or data monitoring committees for Abcam, Axon, BioArctic, Biogen, JOMDD/Shimadzu, Julius Clinical, Lilly, MagQu, Novartis, Pharmatrophix, Prothena, Roche Diagnostics and Siemens Healthineers and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, which is a part of the GU Ventures Incubator Program, outside the submitted work. D.A. reported receiving personal fees for advisory board services and/or speaker honoraria from Fujirebio-Europe, Roche, Nutricia, Krka Farmacéutica and Esteve, outside the submitted work. A.L. has served as a consultant or on advisory boards for Fujirebio-Europe, Roche, Biogen and Nutricia, outside the submitted work. J.F. reported receiving personal fees for service on the advisory boards, adjudication committees or speaker honoraria from AC Immune, Novartis, Lundbeck, Roche, Fujirebio and Biogen, outside the submitted work. 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Figures

**Figure 1**
**Association of biological sex with Alzheimer’s disease prevalence and cognitive decline in adults with Down syndrome.** (A) Point prevalence of symptomatic Alzheimer’s disease by 5-year age intervals. Group differences were assessed with Pearson's chi-squared analysis (for details, see Supplementary Table 2). (B) Survival analysis showing the probability of developing symptomatic Alzheimer’s disease by age and sex. The P-value refers to log-rank test analysis. (C) Scatterplots illustrating the distribution of age at diagnosis of symptomatic Alzheimer’s disease. The graph shows the individual data points, the means and the nonparametric bootstrapped 95% confidence intervals. The P-value refers to a t-test (for details, see Supplementary Table 2). (D–F) Neuropsychological performance by age and sex at the CAMCOG-DS (D), immediate (E), and delayed (F) recall at the mCRT, with bands representing the 95% confidence intervals. A significant difference between LOESS curves was defined as the age at which the curves diverged visually and the 95% confidence intervals did not overlap (P < 0.05). CAMCOG-DS, Cambridge Cognitive Examination for Older Adults with Down Syndrome; mCRT, modified cued recall test; F, female; M, male.

**Figure 2**
**Association of biological sex with Alzheimer’s disease biomarkers in adults with Down syndrome.** Shading represents 95% confidence intervals. The dotted lines represent the age-related changes in euploid individuals (healthy controls) for visual reference. A significant difference between LOESS curves was defined as the age at which the curves diverged visually, and the 95% confidence intervals did not overlap (P < 0.05). The scatterplots display, for males and females separately, the relationship between age and CSF Aβ42/40 (A), amyloid-PET (B), CSF and plasma p-tau181 (C, D), CSF and plasma NfL (E, F), FDG-PET (G) and hippocampal volume (H). Aβ40, amyloid β peptide 40; Aβ42, amyloid β peptide 42; CSF, cerebrospinal fluid; FDG, ¹¹⁸F-fluorodeoxyglucose; NfL, neurofilament light chain; SUVR, standardized uptake value ratio; TIV, total intracranial volume; F, female; M, male.

**Figure 3**
**Association of *APOE* ɛ4 haplotype and biological sex with Alzheimer’s disease prevalence and cognitive decline.** (A) Point prevalence of symptomatic Alzheimer’s disease by sex and *APOE* ɛ4 haplotype across 5-year age intervals. Group differences were assessed with Pearson's chi-squared analysis (for details, see Supplementary Table 4). (B) Survival analysis showing the probability to develop symptomatic Alzheimer’s disease by sex and *APOE* haplotype across age. The P-value refers to log-rank test analysis. (C) Scatterplots illustrating the distribution of age at diagnosis of Alzheimer’s disease and showing the individual data points, the means and the nonparametric bootstrapped 95% confidence intervals. The P-values refer to t-tests (for details, see Supplementary Table 4). (D–I) Age-related changes in neuropsychological performance at the CAMCOG-DS (D, G), immediate (E, H) and delayed recall (F, I) at the mCRT, with bands representing the 95% confidence intervals in male and female separately. A significant difference between LOESS curves was defined as the age at which the curves diverged visually and the 95% confidence intervals did not overlap (P < 0.05). CAMCOG-DS, Cambridge Cognitive Examination for Older Adults with Down Syndrome; mCRT, modified cued recall test; F, female; M, male; ɛ4, *APOE* ɛ4 carriers.

**Figure 4**
**Association of *APOE* ɛ4 haplotype and sex with Alzheimer’s disease biomarkers in adults with Down syndrome.** Shading represents 95% confidence intervals. The dotted lines represent the age-related changes in euploid individuals for visual reference. The dashed line without confidence intervals was used in groups with a sample size inferior to 20 participants. A significant difference between LOESS curves was defined as the age at which the curves diverged visually and the 95% confidence intervals did not overlap (P < 0.05). The scatterplots display, for males and females separately, the relationship between age and APOE ε4 carriership with CSF Aβ42/40 (A), amyloid-PET (B), CSF and plasma p-tau181 (**C, D**), CSF and plasma NfL (**E, F**), FDG-PET (G) and hippocampal volume (H). Aβ40, amyloid β peptide 40; Aβ42, amyloid β peptide 42; *APOE*, apolipoprotein E; CSF, cerebrospinal fluid; FDG, ¹¹⁸F-fluorodeoxyglucose; NfL, neurofilament light chain; SUVR, standardized uptake value ratio; TIV, total intracranial volume; F, female; M, male; ɛ4, *APOE* ɛ4 carriers.

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References

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Association of biological sex with clinical outcomes and biomarkers of Alzheimer's disease in adults with Down syndrome

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Association of biological sex with clinical outcomes and biomarkers of Alzheimer's disease in adults with Down syndrome

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