Age, sex and APOE-ε4 modify the balance between soluble and fibrillar β-amyloid in non-demented individuals: topographical patterns across two independent cohorts

Abstract

Amyloid (Aβ) pathology is the earliest detectable pathophysiological event along the Alzheimer's continuum, which can be measured both in the cerebrospinal fluid (CSF) and by Positron Emission Tomography (PET). Yet, these biomarkers identify two distinct Aβ pools, reflecting the clearance of soluble Aβ as opposed to the presence of Aβ fibrils in the brain. An open question is whether risk factors known to increase Alzheimer's' disease (AD) prevalence may promote an imbalance between soluble and deposited Aβ. Unveiling such interactions shall aid our understanding of the biological pathways underlying Aβ deposition and foster the design of effective prevention strategies. We assessed the impact of three major AD risk factors, such as age, APOE-ε4 and female sex, on the association between CSF and PET Aβ, in two independent samples of non-demented individuals (ALFA: n = 320, ADNI: n = 682). We tested our hypotheses both in candidate regions of interest and in the whole brain using voxel-wise non-parametric permutations. All of the assessed risk factors induced a higher Aβ deposition for any given level of CSF Aβ42/40, although in distinct cerebral topologies. While age and sex mapped onto neocortical areas, the effect of APOE-ε4 was prominent in the medial temporal lobe, which represents a target of early tau deposition. Further, we found that the effects of age and APOE-ε4 was stronger in women than in men. Our data indicate that specific AD risk factors affect the spatial patterns of cerebral Aβ aggregation, with APOE-ε4 possibly facilitating a co-localization between Aβ and tau along the disease continuum.

Fig. 1. APOE-ε4 significantly modified the spatial topography of Aβ PET as function of CSF Aβ42/40.

A, B Surface and volume rendering in ALFA participants of the Aβ PET statistical probability map resulting from the interaction model. Compared to non-carriers, APOE-ε4 carriers displayed higher SUVRs, for any given level of CSF Aβ42/40, in medial temporal regions including entorhinal cortex and hippocampus. C Group scatterplots in ALFA participants showing the significant interaction between APOE-ε4 and CSF Aβ42/40 in a priori defined progressive ROIs. D, E Surface and volume rendering in ADNI participants, of Aβ PET statistical probability map indicating that compared to non-carriers, APOE-ε4 carriers displayed higher SUVRs, for any given level of CSF Aβ42/40, in right inferior and middle temporal as well as right insula. F Group scatterplots in ADNI participants showing the significant interaction between APOE-ε4 and CSF Aβ42/40 in a priori defined progressive ROIs. LL Left lateral, LM Left medial, RL Right lateral, RM Right medial.

Fig. 2. Age significantly modified the association between of CSF Aβ42/40 and Aβ PET.

A, B In ALFA participants, older individuals displayed, for any given level of CSF Aβ42/40 concentration, a higher Aβ PET retention in distributed cerebral areas including inferior and superior temporal cortex as well as medial prefrontal and inferior parietal areas. Group scatterplot show these interactions in a priori defined progressive ROIs. C, D Interaction was replicated in the ADNI cohort, although in a less distributed topological pattern. For visualization purposes, age continuous variable was broken down in four subgroups. LL Left lateral, LM Left medial, RL Right lateral, RM Right medial.

Fig. 3. Sex significantly modified the association between CSF Aβ42/40 and Aβ PET.

A, B In ALFA participants, sex significantly modulated the association between CSF Aβ42/40 and Aβ PET uptake indicating higher SUVRs in females women compared to men, in posterior medial regions including the precuneus and the cuneus. Group scatterplot show these interactions in a priori defined progressive ROIs. C, D An overlapping cortical topology was found in ADNI participants indicating the same interaction effects as in ALFA. LL Left lateral, LM Left medial, RL Right lateral, RM Right medial.

Fig. 4. Analyses stratified by sex.

A Surface rendering of p value maps, for the interaction between CSF Aβ42/40 and APOE-ε4, as well as age, separately for women and men in the ALFA sample. B, C Group scatterplots, stratified by sex, of the assessed interactions in regions of interest. D Same as in A, in the ADNI sample. E, F Same as in B and C, in the ADNI sample. Wε4+ Women APOE-ε4 carriers, Wε4− Women APOE-ε4 non-carriers, Mε4+ Men APOE-ε4 carriers, Mε4− Men APOE-ε4 non-carriers.