The CSF p-tau/β-amyloid 42 ratio correlates with brain structure and fibrillary β-amyloid deposition in cognitively unimpaired individuals at the earliest stages of pre-clinical Alzheimer’s disease

CSF concentrations of β-amyloid 42 (Aβ42) and phosphorylated tau (p-tau) are well-established biomarkers of Alzheimer's disease and have been studied in relation to several neuropathological features both in patients and in cognitively unimpaired individuals. The CSF p-tau/Aβ42 ratio, a biomarker combining information from both pathophysiological processes, has emerged as a promising tool for monitoring disease progression, even at pre-clinical stages. Here, we studied the association between the CSF p-tau/Aβ42 ratio with downstream markers of pre-clinical Alzheimer's disease progression including brain structure, glucose metabolism, fibrillary Aβ deposition and cognitive performance in 234 cognitively unimpaired individuals, who underwent cognitive testing, a lumbar puncture, MRI, 18F-fluorodeoxyglucose and 18F-flutemetamol PET scanning. We evaluated both main effects and interactions with Alzheimer's disease risk factors, such as older age, female sex and the apoliporoptein E (<i>APOE</i>)-ɛ4 allele, in <i>a priori</i> defined regions of interest and further examined the associations on the whole-brain using voxel-wise regressions. In addition, as the association between CSF Alzheimer's disease biomarkers and brain structure and function may be non-linear, we tested the interaction between the CSF p-tau/Aβ42 ratio and stages of pre-clinical Alzheimer's disease defined using the amyloid (A) and tau (T) classification. We found significantly positive associations between CSF p-tau/Aβ42 and both cortical Aβ deposition and regional grey matter volume while no effect was observed for brain metabolism. A significant interaction with age indicated that, for the same level of CSF p-tau/Aβ42, older individuals displayed both increased Aβ deposition and lower grey matter volume, in widespread cortical areas. In addition, we found that women compared with men had a greater Aβ fibrillary accumulation in midline cortical areas and inferior temporal regions, for the same level of the CSF biomarker. The impact of CSF p-tau/Aβ42 on grey matter volume was modulated by AT stages, with A+T+ individuals displaying significantly less positive associations in areas of early atrophy in the Alzheimer's continuum. Finally, we found that sex and <i>APOE</i>-ɛ4 modulated the association between the CSF biomarker and episodic memory as well as abstract reasoning, respectively. Our data indicate that the CSF p-tau/Aβ42 ratio is strongly associated with multiple downstream neuropathological events in cognitively unimpaired individuals and may thus serve as a potent biomarker to investigate the earliest changes in pre-clinical Alzheimer's disease. Given that its impact on both Aβ deposition and grey matter volume is modulated by specific risk factors, our results highlight the need to take into account such predisposing variables in both clinical practice and prevention trials.

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Journal
Brain Communications
Published
2024-12-13
DOI
https://doi.org/10.1093/braincomms/fcae451
Citations
6
Primary Topic
Alzheimer's disease research and treatments
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article
Field-Weighted Citation Impact
1.96

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article

The CSF p-tau/β-amyloid 42 ratio correlates with brain structure and fibrillary β-amyloid deposition in cognitively unimpaired individuals at the earliest stages of pre-clinical Alzheimer’s disease

Marta Milà‐Alomà, Karine Fauria, Annabella Beteta, Alba Cañas et al.
6 citations
Brain Communications
Alzheimer's disease research and treatments
1.96
article

The CSF p-tau/β-amyloid 42 ratio correlates with brain structure and fibrillary β-amyloid deposition in cognitively unimpaired individuals at the earliest stages of pre-clinical Alzheimer’s disease

Marta Milà‐Alomà, Karine Fauria, Annabella Beteta, Alba Cañas, Anna Brugulat Serrat, María Pascual, Albina Polo, Gonzalo Sánchez‐Benavides, Kaj Blennow, Sherezade Fuentes, Irene Cumplido, Anna Soteras, Carles Falcón, N. Tejedor, Sandra Pradas, Eva Palacios, José Luís Molinuevo, Laura Ros Freixedes, Marc Suárez Calvet, Marta del Campo, Iva Knezevic, Paula Marne, Armand González Escalante, Raffaele Cacciaglia, Mahnaz Shekari, Jordi Huguet, Gemma Salvadó, Marc Vilanova, Laura L. Hernandez, Juan Domingo Gispert, Frances‐Catherine Quevenco, Marie E F Karine, Maria Emilio, Ruth Dominguez, Oriol Grau‐Rivera, Gema Huesa, Henrik Zetterberg, Laura S Stankeviciute, Tania Menchón, Marc Suárez‐Calvet, Carolina Minguillón, Carme Deulofeu, Annabella B Gorriti, Lidia C Gispert, Jordi H Ninou, Mahnaz S Mahnaz, Lluis S Harster, Anna S Prat, Blanca R Fernandez, Paula M Alvarez, A Ballester, Ruth D Iglesias, Laura H Penas, Sandra P Mendez, Ricardo A Aguilar, Marc V Jaramillo, P Serra, Tania M Diaz, Alba C Martinez, Carmen D Gomez, Sherezade F Julian, Laura I Gamez, Carolina M Gil, Irina A Radoi, Gonzalo A Sanchez Benavides, Omar Iván Vargas Rivera, Gema H Rodriguez, Aleix S Vila
article en
6 citations

Abstract

CSF concentrations of β-amyloid 42 (Aβ42) and phosphorylated tau (p-tau) are well-established biomarkers of Alzheimer's disease and have been studied in relation to several neuropathological features both in patients and in cognitively unimpaired individuals. The CSF p-tau/Aβ42 ratio, a biomarker combining information from both pathophysiological processes, has emerged as a promising tool for monitoring disease progression, even at pre-clinical stages. Here, we studied the association between the CSF p-tau/Aβ42 ratio with downstream markers of pre-clinical Alzheimer's disease progression including brain structure, glucose metabolism, fibrillary Aβ deposition and cognitive performance in 234 cognitively unimpaired individuals, who underwent cognitive testing, a lumbar puncture, MRI, 18F-fluorodeoxyglucose and 18F-flutemetamol PET scanning. We evaluated both main effects and interactions with Alzheimer's disease risk factors, such as older age, female sex and the apoliporoptein E (<i>APOE</i>)-ɛ4 allele, in <i>a priori</i> defined regions of interest and further examined the associations on the whole-brain using voxel-wise regressions. In addition, as the association between CSF Alzheimer's disease biomarkers and brain structure and function may be non-linear, we tested the interaction between the CSF p-tau/Aβ42 ratio and stages of pre-clinical Alzheimer's disease defined using the amyloid (A) and tau (T) classification. We found significantly positive associations between CSF p-tau/Aβ42 and both cortical Aβ deposition and regional grey matter volume while no effect was observed for brain metabolism. A significant interaction with age indicated that, for the same level of CSF p-tau/Aβ42, older individuals displayed both increased Aβ deposition and lower grey matter volume, in widespread cortical areas. In addition, we found that women compared with men had a greater Aβ fibrillary accumulation in midline cortical areas and inferior temporal regions, for the same level of the CSF biomarker. The impact of CSF p-tau/Aβ42 on grey matter volume was modulated by AT stages, with A+T+ individuals displaying significantly less positive associations in areas of early atrophy in the Alzheimer's continuum. Finally, we found that sex and <i>APOE</i>-ɛ4 modulated the association between the CSF biomarker and episodic memory as well as abstract reasoning, respectively. Our data indicate that the CSF p-tau/Aβ42 ratio is strongly associated with multiple downstream neuropathological events in cognitively unimpaired individuals and may thus serve as a potent biomarker to investigate the earliest changes in pre-clinical Alzheimer's disease. Given that its impact on both Aβ deposition and grey matter volume is modulated by specific risk factors, our results highlight the need to take into account such predisposing variables in both clinical practice and prevention trials.

Brain CommunicationsVol. 7(1)
Roche (Switzerland) (CH), Lundbeck (Denmark) (DK), Universitat Pompeu Fabra (ES), Lund University (SE), Sahlgrenska University Hospital (SE), Rotary International (US), Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (ES), Pasqual Maragall Foundation (ES), UK Dementia Research Institute (GB), Barcelonaβeta Brain Research Center (ES), Hospital Del Mar (ES), Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (ES), Hospital del Mar Research Institute (ES), University College London (GB), University of Gothenburg (SE)
Alzheimer's Association, Alzheimer's Drug Discovery Foundation, Familjen Erling-Perssons Stiftelse, Stiftelsen för Gamla Tjänarinnor, EU Joint Programme – Neurodegenerative Disease Research, Ministerio de Ciencia, Innovación y Universidades, University College London, European Commission, Hjärnfonden, Vetenskapsrådet, UK Dementia Research Institute, Fundación Bancaria Caixa d'Estalvis i Pensions de Barcelona, National Institutes of Health, HORIZON EUROPE Framework Programme, Instituto de Salud Carlos III, Agencia Estatal de Investigación
Good health and well-being
Openalex Percentile: Top 13%
Alzheimer's disease research and treatments
1.96
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