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
Authors: Cacciaglia Raffaele , Shekari Mahnaz , Salvadó Gemma , Milà-Alomà Marta , Falcon Carles , Sánchez-Benavides Gonzalo , Minguillón Carolina , Fauria Karine , Grau-Rivera Oriol , Molinuevo José Luis , Blennow Kaj , Zetterberg Henrik , Quevenco Frances-Catherine , Suárez-Calvet Marc , Gispert Juan Domingo ,   the ALFA Study, Aguilar Ricardo A , Gorriti Annabella B , Serrat Anna B , Cacciaglia Raffaele , Gispert Lidia C , Martinez Alba C , Milan Marta D , Gomez Carmen D , Iglesias Ruth D , Karine Marie E F , Julian Sherezade F , Serra Patricia G , Gispert Juan D , Escalante Armand G , Rivera Oriol G , Penas Laura H , Rodriguez Gema H , Ninou Jordi H , Gamez Laura I , Knezevic Iva , Alvarez Paula M , Diaz Tania M , Gil Carolina M , Palacios Eva , Pascual Maria , Ballester Albina P , Mendez Sandra P , Radoi Irina A , Fernandez Blanca R , Freixedes Laura R , Vila Aleix S , Sanchez Benavides Gonzalo A , Mahnaz Mahnaz S , Harster Lluis S , Prat Anna S , Stankeviciute Laura S , Calvet Marc S , Jaramillo Marc V , Tejedor Natalia V , Beteta Annabella , Cañas Alba , Deulofeu Carme , Cumplido Irene , Dominguez Ruth , Emilio Maria , Fuentes Sherezade , Hernandez Laura , Huesa Gema , Huguet Jordi , Marne Paula , Menchón Tania , Polo Albina , Pradas Sandra , Soteras Anna , Vilanova Marc 
Published: December 2024

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 (APOE)-ɛ4 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/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 APOE-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.