Structural and metabolic brain correlates of excess Aβ accumulation at the earliest AD continuum

Abstract Background The discrepancy between the expected and actual level of cerebral amyloid (Aβ) deposition for any given level of soluble Alzheimer’s disease (AD) core biomarkers, has been proposed as a proxy measure of factors promoting fibrillar Aβ accumulation in the brain. However, the impact of these factors on brain structure and function in cognitively unimpaired (CU) individuals has not been reported. Here, we assessed the impact on brain structure and metabolism of the excess cortical Aβ deposition for a given level of CSF pTau/Aβ42 ratio, a marker of pathophysiological progression along the Alzheimer’s continuum . Furthermore, we analyzed whether this association is modulated by the APOE ‐ε4 risk allele. Method We included 243 CU participants from the ALFA study (mean age=61.68 years) who underwent a lumbar puncture, magnetic resonance imaging (MRI), 18 F‐Fluorodeoxyglucose (FDG) and 18 F‐Flutemetamol positron emission tomography (PET) scans. CSF Aβ42 and pTau181 were measured with the Elecsys® immunoassay (Roche Diagnostics International Ltd). The centiloid pipeline was applied to Aβ PET and a general linear model (GLM) was implemented to regress out the effects of CSF pTau/Aβ42 ratio from centiloid values. These residualized centiloids (resCent) were used in subsequent GLMs to predict whole‐brain gray matter volume (GMv) as well as metabolism. Statistical significance threshold was set to p<0.005, with a cluster extent correction of 100 voxels. Result Negative associations between resCent and GMv were observed in the dorsolateral prefrontal cortex (Fig. 1a), while for FDG, positive associations were found in the inferior frontal and superior temporal gyrus, as well as the anterior cingulate and inferior temporal cortices (Fig. 1b). The associations for GMv were further modulated by the APOE ‐ε4 risk allele in a dose‐dependent manner, indicating a lower GMv in ε4‐carriers, in the inferior and middle frontal gyrus, subgenual cingulate cortex and the insula (Fig. 2). Conclusion Our results suggest that, factors associated with excessive Aβ deposition are associated with structural and metabolic brain alterations already in the earliest stages of preclinical Alzheimer’s continuum . The associations for GMv were modulated by APOE ‐ε4 indicating a higher structural vulnerability to these factors for carriers of the risk allele all along the preclinical stages of AD.