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.

Association of biological sex with clinical outcomes and biomarkers of Alzheimer’s disease in adults with Down syndrome

“…Indeed, a study by Cacciaglia et al . 65 recently showed that age, APOE ɛ4 and female sex were associated with higher amyloid-PET uptake in posterior middle cortical regions in cognitively unimpaired individuals. Likewise, APOE ɛ4 carriers in both sexes tended to show lower cerebral glucose metabolism compared with non-carriers, although the sample size of the subgroups was small to compare by sex.…”

APOE-ε4 modulates the association between regional amyloid deposition and cognitive performance in cognitively unimpaired middle-aged individuals

“…Regarding the temporal lobe, a recent study on the sample included here showed that APOE-ε4 carriers were more prone to Aβ aggregation in temporal areas for any given level of soluble Aβ dyshomeostasis. This finding suggests that APOE-ε4 facilitates the spread of Aβ in these regions, promoting an earlier co-localization with tau [ 42 ] to trigger AD-related neurodegeneration. Taken together, these studies suggest an interplay between patterns of Aβ and tau spread in determining cognitive decline, which would explain why positivity in regions of late Aβ accumulation is associated with cognitive decline in APOE-ε4 carriers in the present study.…”

Genetic characterization of the ALFA study: Uncovering genetic profiles in the Alzheimer’scontinuum

“…We also showed, as suggested in previous studies, that reversed the association between cognitive performance and brain morphology, similar to aging, suggesting that this risk allele leads to an accelerated biological phenotype of brain aging (Cacciaglia et al, 2019). Furthermore, ε4-homozygotes displayed reduced connectivity between networks in areas typically susceptible to amyloid deposition in the early AD continuum, and altered effects of amyloid on brain structure (Cacciaglia et al, 2020(Cacciaglia et al, , 2022.…”