Polygenic risk for Alzheimer's disease shapes hippocampal scene-selectivity

Abstract

Preclinical models of Alzheimer's disease (AD) suggest APOE modulates brain function in structures vulnerable to AD pathophysiology. However, genome-wide association studies now demonstrate that AD risk is shaped by a broader polygenic architecture, estimated via polygenic risk scoring (AD-PRS). Despite this breakthrough, the effect of AD-PRS on brain function in young individuals remains unknown. In a large sample (N = 608) of young, asymptomatic individuals, we measure the impact of both (i) APOE and (ii) AD-PRS on a vulnerable cortico-limbic scene-processing network heavily implicated in AD pathophysiology. Integrity of this network, which includes the hippocampus (HC), is fundamental for maintaining cognitive function during ageing. We show that AD-PRS, not APOE, selectively influences activity within the HC in response to scenes, while other perceptual nodes remained intact. This work highlights the impact of polygenic contributions to brain function beyond APOE, which could aid potential therapeutic/interventional strategies in the detection and prevention of AD.

Associations of Polygenic Risk Score for Late-Onset Alzheimer's Disease With Biomarkers

“…However, contrary research findings have been reported between the AD-PRS and hippocampal activation. Chandler et al ( 2020 ) found a significantly positive correlation and Xiao et al ( 2017 ) found a significantly negative correlation during the episodic memory. This divergence may be due to the different task codings and sample size of the studies.…”

APOE ɛ4, but not polygenic AD risk, is related to longitudinal decrease in hippocampal brain activity in non-demented individuals

“…fMRI studies of hippocampal activation during memory tasks have shown both hypo- (15)(16)(17) and hyper-activation (18-23) in individuals with mild cognitive impairment (MCI) or AD compared to controls. Hippocampal hyper-(24-28) and hypo-activation (29) have also been reported in cross-sectional studies of healthy APOE ε4 allele carriers relative to non-carriers, and as a function of increased AD PRS (30,31).…”

“…Based on previous studies showing effects of AD PRS on cognitive decline (9) and level of hippocampal functioning in healthy aging (30,31), we hypothesized that AD PRS would also predict decline in hippocampal activation. However, we did not observe such an effect for any of our three selected PRS pvalue thresholds.…”

Polygenic Score Models for Alzheimer’s Disease: From Research to Clinical Applications

“…The associations of polygenic scores with memory and cognitive function imply possible alterations of brain structure and functions. Several studies have examined the associations between AD polygenic risk and MRI findings ( Sabuncu et al, 2012 ; Habes et al, 2016 ; Harrison et al, 2016 ; Mormino et al, 2016 ; Nho et al, 2016 ; Desikan et al, 2017 ; Foley et al, 2017 ; Hayes et al, 2017 , 2020 ; Xiao et al, 2017 ; Ge et al, 2018 ; Kauppi et al, 2018 ; Li et al, 2018 ; Chandler et al, 2019 ; Tan et al, 2019 ; Wang et al, 2019 ; Altmann et al, 2020 ; Matloff et al, 2020 ; Zhou et al, 2020 ), fMRI findings ( Xiao et al, 2017 ; Axelrud et al, 2019 ; Chandler et al, 2020 ), and PET imaging findings ( Mormino et al, 2016 ; Darst et al, 2017 ; Ge et al, 2018 ; Porter et al, 2018a , b , c ; Tan et al, 2018 , 2019 ; Leonenko et al, 2019a ; Altmann et al, 2020 ).…”

“…In addition to structural changes, AD polygenic risk might be associated with brain Aβ load ( Mormino et al, 2016 ; Darst et al, 2017 ; Porter et al, 2018a , c ; Tan et al, 2018 , 2019 ; Leonenko et al, 2019a ; Altmann et al, 2020 ) as measured by PET imaging. Moreover, several studies discuss the possible effects of polygenic risk on brain functional changes including hippocampal activation ( Xiao et al, 2017 ; Chandler et al, 2020 ) and connectivity between specific brain regions ( Axelrud et al, 2019 ), providing additional evidence for the effects of AD polygenic risk on brain function. Meanwhile, Aβ measured by PET imaging has been introduced to stratify AD patients prior to PRS evaluation ( Porter et al, 2018b ).…”