Dissociable effects of APOE-ε4 and β-amyloid pathology on visual working memory
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ABSTRACT:
SUBMITTER: Lu K
PROVIDER: S-EPMC7612005 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe ε4 allele of apolipoprotein E (APOE ε4) is the strongest known genetic risk factor for late-onset Alzheimer's disease (AD), associated with amyloid pathogenesis. However, it is not clear how APOE ε4 accelerates amyloid-beta (Aβ) deposition during the seeding stage of amyloid development in AD patient neurons.MethodsAD patient induced neurons (iNs) with an APOE ε4 inducible system were prepared from skin fibroblasts of AD patients. Transcriptome analysis was performed using RNA isolated from the AD patient iNs expressing APOE ε4 at amyloid-seeding and amyloid-aggregation stages. Knockdown of IGFBP3 was applied in the iNs to investigate the role of IGFBP3 in the APOE ε4-mediated amyloidosis.ResultsWe optimized amyloid seeding stage in the iNs of AD patients that transiently expressed APOE ε4. Remarkably, we demonstrated that Aβ pathology was aggravated by the induction of APOE ε4 gene expression at the amyloid early-seeding stage in the iNs of AD patients. Moreover, transcriptome analysis in the early-seeding stage revealed that IGFBP3 was functionally important in the molecular pathology of APOE ε4-associated AD.ConclusionsOur findings suggest that the presence of APOE ε4 at the early Aβ-seeding stage in patient iNs is critical for aggravation of sporadic AD pathology. These results provide insights into the importance of APOE ε4 expression for the progression and pathogenesis of sporadic AD.
| S-EPMC9594913 | biostudies-literature
Project description:BackgroundTo assess the effects of apolipoprotein E (ApoE) ε4 genotype on amyloid-β (Aβ) and tau burden and their longitudinal changes in Alzheimer's disease (AD) spectrum.MethodsAmong 272 individuals who underwent PET scans (18F-florbetaben for Aβ and 18F-flortaucipir for tau) and ApoE genotyping, 187 individuals completed 2-year follow-up PET scans. After correcting for the partial volume effect, we compared the standardized uptake value ratio (SUVR) for Aβ and tau burden between the ε4+ and ε4- groups. By using a linear mixed-effect model, we measured changes in SUVR in the ApoE ε4+ and ε4- groups.ResultsThe ε4+ group showed greater baseline Aβ burden in the diffuse cortical regions and greater tau burden in the lateral, and medial temporal, cingulate, and insula cortices. Tau accumulation rate was higher in the parietal, occipital, lateral, and medial temporal cortices in the ε4+ group. In Aβ+ individuals, baseline tau burden was greater in the medial temporal cortex, while Aβ burden was conversely greater in the ε4- group. Tau accumulation rate was higher in the ε4+ group in a small region in the lateral temporal cortex. The effect of ApoE ε4 on enhanced tau accumulation persisted even after adjusting for the global cortical Aβ burden.ConclusionsProgressive tau accumulation may be more prominent in ε4 carriers, particularly in the medial and lateral temporal cortices. ApoE ε4 allele has differential effects on the Aβ burden depending on the existing amyloidosis and may enhance vulnerability to progressive tau accumulation in the AD spectrum independent of Aβ.
| S-EPMC7603688 | biostudies-literature
Project description:PurposeTo examine associations between the APOE-ε2 and APOE-ε4 alleles and core Alzheimer's disease (AD) pathological hallmarks as measured by amyloid-β (Aβ) and tau PET in older individuals without dementia.MethodsWe analyzed data from 462 ADNI participants without dementia who underwent Aβ ([18F]florbetapir or [18F]florbetaben) and tau ([18F]flortaucipir) PET, structural MRI, and cognitive testing. Employing APOE-ε3 homozygotes as the reference group, associations between APOE-ε2 and APOE-ε4 carriership with global Aβ PET and regional tau PET measures (entorhinal cortex (ERC), inferior temporal cortex, and Braak-V/VI neocortical composite regions) were investigated using linear regression models. In a subset of 156 participants, we also investigated associations between APOE genotype and regional tau accumulation over time using linear mixed models. Finally, we assessed whether Aβ mediated the cross-sectional and longitudinal associations between APOE genotype and tau.ResultsCompared to APOE-ε3 homozygotes, APOE-ε2 carriers had lower global Aβ burden (βstd [95% confidence interval (CI)]: - 0.31 [- 0.45, - 0.16], p = 0.034) but did not differ on regional tau burden or tau accumulation over time. APOE-ε4 participants showed higher Aβ (βstd [95%CI]: 0.64 [0.42, 0.82], p < 0.001) and tau burden (βstd range: 0.27-0.51, all p < 0.006). In mediation analyses, APOE-ε4 only retained an Aβ-independent effect on tau in the ERC. APOE-ε4 showed a trend towards increased tau accumulation over time in Braak-V/VI compared to APOE-ε3 homozygotes (βstd [95%CI]: 0.10 [- 0.02, 0.18], p = 0.11), and this association was fully mediated by baseline Aβ.ConclusionOur data suggest that the established protective effect of the APOE-ε2 allele against developing clinical AD is primarily linked to resistance against Aβ deposition rather than tau pathology.
| S-EPMC8175302 | biostudies-literature
Project description:BackgroundSubjective cognitive concerns may represent a simple method to assess likelihood of memory decline among apolipoprotein E (APOE) ε4 carriers.MethodsWe examined the relationship of self-reported subjective cognitive concerns, using seven specific cognitive concerns, with memory and memory decline over 6 years among APOE ε4 carriers and non-carriers from the Nurses' Health Study.ResultsIn both groups, increasing subjective cognitive concern score predicted worse baseline memory and faster rates of subsequent memory decline, after adjustment for age, education and depression. The relation with baseline memory appeared statistically stronger in APOE ε4 carriers (P-interaction = 0.03). For memory decline, mean differences in slopes of episodic memory (95% CI) for 4 to 7 versus no concern = -0.05 (-0.10, 0.01) standard units in APOE ε4 carriers, and -0.04 (-0.08, -0.01) standard units in non-carriers.ConclusionsAPOE ε4 carriers with self-assessed cognitive concerns appear to have worse memory, and possibly accelerated memory decline.
| S-EPMC4253880 | biostudies-literature
Project description:To examine interactions of apolipoprotein E (APOE) genotype with age and with in vivo measures of preclinical Alzheimer disease (AD) in cognitively normal aging.Two hundred forty-one cognitively normal individuals, aged 45-88 years, had cerebral amyloid imaging studies with Pittsburgh Compound-B (PIB). Of the 241 individuals, 168 (70%) also had cerebrospinal fluid (CSF) assays of amyloid-beta(42) (Abeta(42)), tau, and phosphorylated tau (ptau(181)). All individuals were genotyped for APOE.The frequency of individuals with elevated mean cortical binding potential (MCBP) for PIB rose in an age-dependent manner from 0% at ages 45-49 years to 30.3% at 80-88 years. Reduced levels of CSF Abeta(42) appeared to begin earlier (18.2% of those aged 45-49 years) and increase with age in higher frequencies (50% at age 80-88 years) than elevations of MCBP. There was a gene dose effect for the APOE4 genotype, with greater MCBP increases and greater reductions in CSF Abeta(42) with increased numbers of APOE4 alleles. Individuals with an APOE2 allele had no increase in MCBP with age and had higher CSF Abeta(42) levels than individuals without an APOE2 allele. There was no APOE4 or APOE2 effect on CSF tau or ptau(181).Increasing cerebral Abeta deposition with age is the pathobiological phenotype of APOE4. The biomarker sequence that detects Abeta deposition may first be lowered CSF Abeta(42), followed by elevated MCBP for PIB. A substantial proportion of cognitively normal individuals have presumptive preclinical AD.
| S-EPMC2830375 | biostudies-literature
Project description:Although the contents of working memory can be decoded from visual cortex activity, these representations may play a limited role if they are not robust to distraction. We used model-based fMRI to estimate the impact of distracting visual tasks on working memory representations in several visual field maps in visual and frontoparietal association cortex. Here, we show distraction causes the fidelity of working memory representations to briefly dip when both the memorandum and distractor are jointly encoded by the population activities. Distraction induces small biases in memory errors which can be predicted by biases in neural decoding in early visual cortex, but not other regions. Although distraction briefly disrupts working memory representations, the widespread redundancy with which working memory information is encoded may protect against catastrophic loss. In early visual cortex, the neural representation of information in working memory and behavioral performance are intertwined, solidifying its importance in visual memory.
| S-EPMC8342709 | biostudies-literature
Project description:ObjectiveTo evaluate whether APOE ε4 is associated with severity of Lewy body (LB) pathology, independently of Alzheimer disease (AD) pathology.MethodsSix hundred fifty-two autopsy-confirmed LB disease (LBD) cases and 660 clinical controls were genotyped for APOE. In case-control analysis, LBD cases were classified into 9 different groups according to severity of both LB pathology (brainstem, transitional, diffuse) and AD pathology (low, moderate, high) to assess associations between APOE ε4 and risk of different neuropathologically defined LBD subgroups in comparison to controls. In LBD cases only, we also measured LB counts from 5 cortical regions and evaluated associations with ε4 according to severity of AD pathology.ResultsAs expected, APOE ε4 was associated with an increased risk of transitional and diffuse LBD in cases with moderate or high AD pathology (all odds ratios ≥3.42, all p ≤ 0.004). Of note, ε4 was also associated with an increased risk of diffuse LBD with low AD pathology (odds ratio = 3.46, p = 0.001). In the low AD pathology LBD subgroup, ε4 was associated with significantly more LB counts in the 5 cortical regions, independently of Braak stage and Thal phase (all p ≤ 0.002).ConclusionsOur results indicate that APOE ε4 is independently associated with a greater severity of LB pathology. These findings increase our understanding of the mechanism behind reported associations of ε4 with risk of dementia with Lewy bodies and Parkinson disease with dementia, and suggest that ε4 may function as a modifier of processes that favor LB spread rather than acting directly to initiate LB pathology.
| S-EPMC6161556 | biostudies-literature
Project description:Failure of elimination of amyloid-β (Aβ) from the brain and vasculature appears to be a key factor in the etiology of sporadic Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). In addition to age, possession of an apolipoprotein E (APOE) ε4 allele is a strong risk factor for the development of sporadic AD. The present study tested the hypothesis that possession of the APOE ε4 allele is associated with disruption of perivascular drainage of Aβ from the brain and with changes in cerebrovascular basement membrane protein levels. Targeted replacement (TR) mice expressing the human APOE3 (TRE3) or APOE4 (TRE4) genes and wildtype mice received intracerebral injections of human Aβ(40). Aβ(40) aggregated in peri-arterial drainage pathways in TRE4 mice, but not in TRE3 or wildtype mice. The number of Aβ deposits was significantly higher in the hippocampi of TRE4 mice than in the TRE3 mice, at both 3- and 16-months of age, suggesting that clearance of Aβ was disrupted in the brains of TRE4 mice. Immunocytochemical and Western blot analysis of vascular basement membrane proteins demonstrated significantly raised levels of collagen IV in 3-month-old TRE4 mice compared with TRE3 and wild type mice. In 16-month-old mice, collagen IV and laminin levels were unchanged between wild type and TRE3 mice, but were lower in TRE4 mice. The results of this study suggest that APOE4 may increase the risk for AD through disruption and impedance of perivascular drainage of soluble Aβ from the brain. This effect may be mediated, in part, by changes in age-related expression of basement membrane proteins in the cerebral vasculature.
| S-EPMC3404985 | biostudies-literature
Project description:Lewy body (LB) pathology commonly occurs in individuals with Alzheimer's disease (AD) pathology. However, it remains unclear which genetic risk factors underlie AD pathology, LB pathology, or AD-LB co-pathology. Notably, whether APOE-ε4 affects risk of LB pathology independently from AD pathology is controversial. We adapted criteria from the literature to classify 4,985 subjects from the National Alzheimer's Coordinating Center (NACC) and the Rush University Medical Center as AD-LB co-pathology (AD+LB+), sole AD pathology (AD+LB-), sole LB pathology (AD-LB+), or no pathology (AD-LB-). We performed a meta-analysis of a genome-wide association study (GWAS) per subpopulation (NACC/Rush) for each disease phenotype compared to the control group (AD-LB-), and compared the AD+LB+ to AD+LB- groups. APOE-ε4 was significantly associated with risk of AD+LB- and AD+LB+ compared to AD-LB-. However, APOE-ε4 was not associated with risk of AD-LB+ compared to AD-LB- or risk of AD+LB+ compared to AD+LB-. Associations at the BIN1 locus exhibited qualitatively similar results. These results suggest that APOE-ε4 is a risk factor for AD pathology, but not for LB pathology when decoupled from AD pathology. The same holds for BIN1 risk variants. These findings, in the largest AD-LB neuropathology GWAS to date, distinguish the genetic risk factors for sole and dual AD-LB pathology phenotypes. Our GWAS meta-analysis summary statistics, derived from phenotypes based on postmortem pathologic evaluation, may provide more accurate disease-specific polygenic risk scores compared to GWAS based on clinical diagnoses, which are likely confounded by undetected dual pathology and clinical misdiagnoses of dementia type.
| S-EPMC10496176 | biostudies-literature
Project description:When we respond to a stimulus, our ability to quickly execute this response depends on how combinations of stimulus and response features match to previous combinations of stimulus and response features. Some kind of memory representations must be underlying these visuomotor repetition effects. In this paper, we tested the hypothesis that visual working memory stores the stimulus information that gives rise to these effects. Participants discriminated the colors of successive stimuli while holding either three locations or colors in visual working memory. If visual working memory maintains the information about a previous event that leads to visuomotor repetition effects, then occupying working memory with colors or locations should selectively disrupt color-response and location-response repetition effects. The results of two experiments showed that neither color nor spatial memory load eliminated visuomotor repetition effects. Since working memory load did not disrupt repetition effects, it is unlikely that visual working memory resources are used to store the information that underlies visuomotor repetitions effects. Instead, these results are consistent with the view that visuomotor repetition effects stem from automatic long-term memory retrieval, but can also be accommodated by supposing separate buffers for visual working memory and response selection.
| S-EPMC7018594 | biostudies-literature