Awareness of episodic memory and meta-cognitive profiles: associations with cerebrospinal fluid biomarkers at the preclinical stage of the Alzheimer's continuum

David López-Martos; Marc Suárez-Calvet; Marta Milà-Alomà; Juan Domingo Gispert; Carolina Minguillon; Clara Quijano-Rubio; Gwendlyn Kollmorgen; Henrik Zetterberg; Kaj Blennow; Oriol Grau-Rivera; Gonzalo Sánchez-Benavides

doi:10.3389/fnagi.2024.1394460

Awareness of episodic memory and meta-cognitive profiles: associations with cerebrospinal fluid biomarkers at the preclinical stage of the Alzheimer's continuum

Front Aging Neurosci. 2024 May 30:16:1394460. doi: 10.3389/fnagi.2024.1394460. eCollection 2024.

Authors

David López-Martos^{1

2}, Marc Suárez-Calvet^{1

2

3

4}, Marta Milà-Alomà^{1

5

6}, Juan Domingo Gispert^{1

2

7}, Carolina Minguillon^{1

2

3}, Clara Quijano-Rubio⁸, Gwendlyn Kollmorgen⁹, Henrik Zetterberg^{10

11

12

13

14

15}, Kaj Blennow^{10

11

16

17}, Oriol Grau-Rivera^{1

2

3

4}, Gonzalo Sánchez-Benavides^{1

2

3}

Affiliations

¹ Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.
² Hospital del Mar Research Institute (IMIM), Barcelona, Spain.
³ Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable, Instituto de Salud Carlos III, Madrid, Spain.
⁴ Servei de Neurologia, Hospital del Mar, Barcelona, Spain.
⁵ Department of Veterans Affairs Medical Center, Northern California Institute for Research and Education (NCIRE), San Francisco, CA, United States.
⁶ Department of Radiology, University of California San Francisco, San Francisco, CA, United States.
⁷ Centro de Investigación Biomédica en Red Bioingeniería, Biomateriales y Nanomedicina, Madrid, Spain.
⁸ Roche Diagnostics International Ltd, Rotkreutz, Switzerland.
⁹ Roche Diagnostics GmbH, Penzberg, Germany.
¹⁰ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, Mölndal, Sweden.
¹¹ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
¹² Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom.
¹³ UK Dementia Research Institute at UCL, London, United Kingdom.
¹⁴ Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, Hong Kong SAR, China.
¹⁵ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States.
¹⁶ Paris Brain Institute, ICM, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France.
¹⁷ Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, and Department of Neurology, Institute on Aging and Brain Disorders, University of Science and Technology of China and First Affiliated Hospital of USTC, Hefei, China.

Abstract

Introduction: The lack of cognitive awareness, anosognosia, is a clinical deficit in Alzheimer's disease (AD) dementia. However, an increased awareness of cognitive function, hypernosognosia, may serve as a marker in the preclinical stage. Subjective cognitive decline (SCD) might correspond to the initial symptom in the dynamic trajectory of awareness, but SCD might be absent along with low awareness of actual cognitive performance in the preclinical stage. We hypothesized that distinct meta-cognitive profiles, both hypernosognosia and anosognosia, might be identified in preclinical-AD. This research evaluated the association between cerebrospinal fluid (CSF) AD biomarkers and the awareness of episodic memory, further exploring dyadic (participant-partner) SCD reports, in the preclinical Alzheimer's continuum.

Methods: We analyzed 314 cognitively unimpaired (CU) middle-aged individuals (mean age: 60, SD: 4) from the ALFA+ cohort study. Episodic memory was evaluated with the delayed recall from the Memory Binding Test (MBT). Awareness of episodic memory, meta-memory, was defined as the normalized discrepancy between objective and subjective performance. SCD was defined using self-report, and dyadic SCD profiles incorporated the study partner's report using parallel SCD-Questionnaires. The relationship between CSF Aβ42/40 and CSF p-tau181 with meta-memory was evaluated with multivariable regression models. The role of SCD and the dyadic contingency was explored with the corresponding stratified analysis.

Results: CSF Aβ42/40 was non-linearly associated with meta-memory, showing an increased awareness up to Aβ-positivity and a decreased awareness beyond this threshold. In the non-SCD subset, the non-linear association between CSF Aβ42/40 and meta-memory persisted. In the SCD subset, higher Aβ-pathology was linearly associated with increased awareness. Individuals presenting only study partner's SCD, defined as unaware decliners, exhibited higher levels of CSF p-tau181 correlated with lower meta-memory performance.

Discussion: These results suggested that distinct meta-cognitive profiles can be identified in preclinical-AD. While most individuals might experience an increased awareness associated with the entrance in the AD continuum, hypernosognosia, some might be already losing insight and stepping into the anosognosic trajectory. This research reinforced that an early anosognosic profile, although at increased risk of AD-related decline, might be currently overlooked considering actual diagnostic criteria, and therefore its medical attention delayed.

Keywords: Alzheimer’s disease; awareness; biomarkers; episodic memory; preclinical.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The design and execution of the study were independent of any influence from funding sources. This includes data collection, analysis, interpretation, manuscript preparation, review, and approval. The research leading to these results has received funding from “la Caixa” Foundation (ID 100010434), under agreement LCF/PR/GN17/50300004, the Alzheimer’s Association, and an international anonymous charity foundation through the TriBEKa Imaging Platform project (TriBEKa-17-519007). Additional support has been received from the Universities and Research Secretariat, Ministry of Business and Knowledge of the Catalan Government under the grant no. 2021 SGR 00913. DL-M was supported by Instituto de Salud Carlos III through the project PI19/00117 (Co-funded by European Regional Development Fund/European Social Fund “A way to make Europe”/”Investing in your future”). MS-C receives funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Grant agreement No. 948677); ERA PerMed (ERAPERMED2021-184); Project “PI19/00155” and “PI22/00456, funded by Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union; and from a fellowship from “la Caixa” Foundation (ID 100010434) and from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 847648 (LCF/BQ/PR21/11840004). JG receives funding from the European Comission Innovative Health Initiative (Grant Agreement: 101112145), the BrightFocus Foundation (Grant Reference ID: A2022034S), and La Marató de TV3 (Project: 202318 30-31-32). HZ was a Wallenberg Scholar and a Distinguished Professor at the Swedish Research Council supported by grants from the Swedish Research Council (#2023-00356; #2022-01018 and #2019-02397), the European Union’s Horizon Europe research and innovation programme under grant agreement No 101053962, Swedish State Support for Clinical Research (#ALFGBG-71320), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer’s Association (#ADSF-21-831376-C, #ADSF-21-831381-C, #ADSF-21-831377-C, and #ADSF-24-1284328-C), the Bluefield Project, Cure Alzheimer’s Fund, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2022-0270), the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), the European Union Joint Programme – Neurodegenerative Disease Research (JPND2021-00694), the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, and the UK Dementia Research Institute at UCL (UKDRI-1003). KB was supported by the Swedish Research Council (#2017-00915 and #2022-00732), the Swedish Alzheimer Foundation (#AF-930351, #AF-939721 and #AF-968270), Hjärnfonden, Sweden (#FO2017-0243 and #ALZ2022-0006), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986 and #ALFGBG-965240), the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236), the Alzheimer’s Association 2021 Zenith Award (ZEN-21-848495), and the Alzheimer’s Association 2022-2025 Grant (SG-23-1038904 QC). OG-R was supported by the Spanish Ministry of Science and Innovation –State Research Agency (IJC2020-043417-I/MCIN/AEI/10.13039/501100011033) and the European Union laquoNextGenerationEUraquo/PRTR. GS-B was supported by the Agencia Estatal de Investigación AEI/10.13039/501100011033 through the project PID2020-119556RA-I00 and Instituto de Salud Carlos III (ISCIII) through the project CP23/00039 (Miguel Servet contract), co-funded by the European Union (FSE+).