The CSF p-tau/ß-amyloid 42 ratio correlates with brain structure and fibrillary ß-amyloid deposition in cognitively unimpaired individuals at the earliest stages of pre-clinical Alzheimer's disease.
Por:
Cacciaglia R, Shekari M, Salvadó G, Milà-Alomà M, Falcon C, Sánchez-Benavides G, Minguillón C, Fauria K, Grau-Rivera O, Molinuevo JL, Blennow K, Zetterberg H, Quevenco FC, Suárez-Calvet M and Gispert JD
Publicada:
1 ene 2025
Ahead of Print:
13 dic 2024
Resumen:
CSF concentrations of ß-amyloid 42 (Aß42) 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/Aß42 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/Aß42 ratio with downstream markers of pre-clinical Alzheimer's disease progression including brain structure, glucose metabolism, fibrillary Aß 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 (APOE)-?4 allele, in a priori 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/Aß42 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/Aß42 and both cortical Aß 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/Aß42, older individuals displayed both increased Aß deposition and lower grey matter volume, in widespread cortical areas. In addition, we found that women compared with men had a greater Aß fibrillary accumulation in midline cortical areas and inferior temporal regions, for the same level of the CSF biomarker. The impact of CSF p-tau/Aß42 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 APOE-?4 modulated the association between the CSF biomarker and episodic memory as well as abstract reasoning, respectively. Our data indicate that the CSF p-tau/Aß42 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 Aß 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.
Filiaciones:
Cacciaglia R:
Barcelonaßeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona 08005, Spain
Hospital del Mar Medical Research Institute (IMIM), Barcelona 08005, Spain
Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid 28089, Spain
Shekari M:
Barcelonaßeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona 08005, Spain
Hospital del Mar Medical Research Institute (IMIM), Barcelona 08005, Spain
Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid 28089, Spain
Salvadó G:
Barcelonaßeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona 08005, Spain
Hospital del Mar Medical Research Institute (IMIM), Barcelona 08005, Spain
Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid 28089, Spain
Department of Clinical Sciences, Clinical Memory Research Unit, Lund University, Box 117, SE-221 00 Lund, Sweden
Milà-Alomà M:
Barcelonaßeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona 08005, Spain
Hospital del Mar Medical Research Institute (IMIM), Barcelona 08005, Spain
Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid 28089, Spain
Falcon C:
Barcelonaßeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona 08005, Spain
Hospital del Mar Medical Research Institute (IMIM), Barcelona 08005, Spain
Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBERBBN), Madrid 28089, Spain
Sánchez-Benavides G:
Barcelonaßeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona 08005, Spain
Hospital del Mar Medical Research Institute (IMIM), Barcelona 08005, Spain
Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid 28089, Spain
Minguillón C:
Barcelonaßeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona 08005, Spain
Hospital del Mar Medical Research Institute (IMIM), Barcelona 08005, Spain
Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid 28089, Spain
Fauria K:
Barcelonaßeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona 08005, Spain
Hospital del Mar Medical Research Institute (IMIM), Barcelona 08005, Spain
Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid 28089, Spain
Grau-Rivera O:
Barcelonaßeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona 08005, Spain
Hospital del Mar Medical Research Institute (IMIM), Barcelona 08005, Spain
Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid 28089, Spain
Servei de Neurologia, Hospital del Mar, 08005 Barcelona, Spain
Molinuevo JL:
Lundbeck A/S, 2500 Copenhagen, Denmark
Blennow K:
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal 43180, Sweden
Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal 43180, Sweden
Zetterberg H:
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal 43180, Sweden
Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal 43180, Sweden
UK Dementia Research Institute at University College London, London WC1E 6BT, UK
Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK
Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China
UW Department of Medicine, School of Medicine and Public Health, Madison, WI 53705-2281, USA
Quevenco FC:
Roche Diagnostics International Ltd, 6343 Rotkreuz, Switzerland
Suárez-Calvet M:
Barcelonaßeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona 08005, Spain
Hospital del Mar Medical Research Institute (IMIM), Barcelona 08005, Spain
Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid 28089, Spain
Servei de Neurologia, Hospital del Mar, 08005 Barcelona, Spain
Gispert JD:
Barcelonaßeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona 08005, Spain
Hospital del Mar Medical Research Institute (IMIM), Barcelona 08005, Spain
Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBERBBN), Madrid 28089, Spain
Departament de Medicina i Ciències de la Vida, Universitat Pompeu Fabra, Barcelona 08002, Spain
Open Access
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