Differential associations of APOE-ε2 and APOE-ε4 alleles with PET-measured amyloid-β and tau deposition in older individuals without dementia

Salvadó, Gemma; Grothe, Michel J.; Groot, Colin; Moscoso, Alexis; Schöll, Michael; Gispert, Juan Domingo; Ossenkoppele, Rik

doi:10.1007/s00259-021-05192-8

Cited by 36 publications

(39 citation statements)

References 86 publications

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“…Together, these results suggest that only one APOE ε4 allele is sufficient to increase tau accumulation in females, while two APOE ε4 alleles are needed to cause a similar effect in males. Consistent with previous studies, 29 , 30 we found that region of interest analysis of entorhinal cortex, amygdala and parahippocampal gyrus showed an amyloid-β-independent association between the APOE ε4 gene dosage and tau deposition in males but not females after controlling for global cortex 18 F-florbetapir SUVR. These findings have important clinical implications towards developing sex and genotype-guided therapeutics in Alzheimer’s disease and uncover a possible explanation underlying differential APOE ε4-associated Alzheimer’s risk in males and females.…”

Section: Discussionsupporting

confidence: 92%

Sex modifies APOE ε4 dose effect on brain tau deposition in cognitively impaired individuals

Yan

Zheng

Paranjpe

et al. 2021

Brain

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Recent studies in cognitively unimpaired elderly individuals suggest that the APOE ε4 allele exerts a dosage-dependent effect on brain tau deposition. The aim of this study was to investigate sex differences in APOE ε4 gene dosage effects on brain tau deposition in cognitively impaired individuals using quantitative 18F-flortaucipir PET. Preprocessed 18F-flortaucipir tau PET images, T1-weighted structural MRI images, demographic information, global cortical amyloid-β burden measured by 18F-florbetapir PET, CSF total tau and phosphorylated tau measurements were obtained from the Alzheimer’s Disease Neuroimaging Initiative database. Two hundred and sixty-eight cognitively impaired individuals with 146 APOE ε4 non-carriers and 122 carriers (85 heterozygotes and 37 homozygotes) were included in the study. An iterative reblurred Van Cittert iteration partial volume correction method was applied to all downloaded PET images. MRI images were used for PET spatial normalization. Twelve regional standardized uptake value ratios relative to the cerebellum were computed in standard space. APOE ε4 dosage by sex interaction effect on 18F-flortaucipir standardized uptake value ratios was assessed using generalized linear models and sex-stratified analysis. We observed a significant APOE ε4 dosage by sex interaction effect on tau deposition in the lateral temporal, posterior cingulate, medial temporal, inferior temporal, entorhinal cortex, amygdala, parahippocampal gyrus regions after adjusting for age and education level (P < 0.05). The medial temporal, entorhinal cortex, amygdala and parahippocampal gyrus regions retained a significant APOE ε4 dosage by sex interaction effect on tau deposition after adjusting for global cortical amyloid-β (P < 0.05). In sex-stratified analysis, there was no significant difference in tau deposition between female homozygotes and heterozygotes (P > 0.05). In contrast, male homozygotes standardized uptake value ratios were significantly greater than heterozygotes or non-carriers throughout all twelve regions of interest (P < 0.05). Female heterozygotes exhibited significantly increased tau deposition compared to male heterozygotes in the orbitofrontal, posterior cingulate, lateral temporal, inferior temporal, entorhinal cortex, amygdala and parahippocampal gyrus (P < 0.05). Results from voxelwise analysis were similar to the ones obtained from regions of interest analysis. Our findings suggest that an APOE ε4 dosage effect on brain region-specific tau deposition exists in males, but not females. These results have important clinical implications towards developing sex and genotype-guided therapeutics in Alzheimer’s disease and uncovers a potential explanation underlying differential apolipoprotein E ε4-associated Alzheimer’s risk in males and females.

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Section: Discussionsupporting

confidence: 92%

Sex modifies APOE ε4 dose effect on brain tau deposition in cognitively impaired individuals

Yan

Zheng

Paranjpe

et al. 2021

Brain

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“…Hence, our results suggest that APOE-ε4, by exacerbating cortical Aβ deposition in MTL areas, might facilitate the spread of tau in extra medial-temporal regions, plausibly promoting an earlier co-localization of Aβ and tau. In line with this, previous PET imaging studies have documented a higher tau deposition in APOE-ε4 carrier AD patients compared to noncarriers [29,[36][37][38]. Furthermore, our interaction effects may help to explain the faster disease progression [39][40][41] as well as the stronger relationship between Aβ and cognitive decline [42,43] in APOE-ε4 carriers compared to non-carriers.…”

Section: Discussionsupporting

confidence: 85%

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

et al. 2022

Self Cite

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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.

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“…Furthermore, in the Aβ+ individuals we observed a cross-talk between PGS and baseline levels of amyloid-PET on the rate of subsequent change in tau-PET, suggesting that the PGS affects the formation of tau pathology in cortical brain regions downstream of the abnormally elevated Aβ. In contrast, previous studies on APOE ε4 status reported that the effect of APOE ε4 on higher cortical tau-PET accumulation were due to the effect on increased levels of Aβ [45][46][47] .…”

Section: Discussioncontrasting

confidence: 70%

Polygenic effect on accelerated tau pathology accumulation in Alzheimer’s disease: implications for patient selection in clinical trials

Rubinski¹,

Frerich²,

Malik³

et al. 2021

Preprint

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Progression of fibrillar tau is a key driver of dementia symptoms in Alzheimer’s disease (AD), but predictors of the rate of tau accumulation at patient-level are missing. Here we combined the to-date largest number of genetic risk variants of AD (n=85 lead SNPs) from recent GWAS to generate a polygenic score (PGS) predicting the rate of change in fibrillar tau. We found that a higher PGS was associated with higher rates of PET-assessed fibrillar-tau accumulation over a mean of 1.8 yrs (range = 0.6 – 4 yrs). This, in turn, mediated effects of the PGS on faster rates of cognitive decline. Sensitivity analysis showed that the effects were similar for men and women but pronounced in individuals with elevated levels of beta-amyloid and strongest for lead SNPs expressed in microglia. Together, our results demonstrate that the PGS predicts tau progression in Alzheimer’s disease, which could afford sample size savings by up to 34% when used alone and up to 61% when combined with APOE ε4 genotype in clinical trials targeting tau pathology.

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Differential associations of APOE-ε2 and APOE-ε4 alleles with PET-measured amyloid-β and tau deposition in older individuals without dementia

Cited by 36 publications

References 86 publications

Sex modifies APOE ε4 dose effect on brain tau deposition in cognitively impaired individuals

Sex modifies APOE ε4 dose effect on brain tau deposition in cognitively impaired individuals

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

Polygenic effect on accelerated tau pathology accumulation in Alzheimer’s disease: implications for patient selection in clinical trials

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