Multiple Effect of APOE Genotype on Clinical and Neuroimaging Biomarkers Across Alzheimer’s Disease Spectrum

Liu, Ying; Tan, Lan; Wang, Hui-Fu; Liu, Yong; Hao, Xiaoke; Tan, Cheng; Jiang, Teng; Liu, Bing; Zhang, Daoqiang; Yu, Jin‐Tai; Initiative, Alzheimer’s Disease Neuroimaging

doi:10.1007/s12035-015-9388-7

Cited by 47 publications

(42 citation statements)

References 42 publications

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“…The progression of cognitive impairment is consistently found to correlate closely with AD pathology . Insel and colleagues report that Aβ positivity with cognitive information yielded a higher positive predictive value for the pre‐clinical AD stage .…”

Section: Discussionmentioning

confidence: 99%

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The combination of apolipoprotein E4, age and Alzheimer's Disease Assessment Scale – Cognitive Subscale improves the prediction of amyloid positron emission tomography status in clinically diagnosed mild cognitive impairment

Gao

et al. 2019

Euro J of Neurology

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Background and purpose Randomized clinical trials involving anti‐amyloid interventions focus on the early stages of Alzheimer's disease (AD) with proven amyloid pathology, using amyloid positron emission tomography (amyloid‐PET) imaging or cerebrospinal fluid analysis. However, these investigations are either expensive or invasive and are not readily available in resource‐limited centres. Hence, the identification of cost‐effective clinical alternatives to amyloid‐PET is highly desirable. This study aimed to investigate the accuracy of combined clinical markers in predicting amyloid‐PET status in mild cognitive impairment (MCI) individuals. Methods In all, 406 MCI participants from the Alzheimer's Disease Neuroimaging Initiative database were dichotomized into amyloid‐PET(+) and amyloid‐PET(−) using a cut‐off of >1.11. The accuracies of single clinical markers [apolipoprotein E4 (ApoE4) genotype, demographics, cognitive measures and cerebrospinal fluid analysis] in predicting amyloid‐PET status were evaluated using receiver operating characteristic curve analysis. A logistic regression model was then used to determine the optimal model with combined clinical markers to predict amyloid‐PET status. Results Cerebrospinal fluid amyloid‐β (Aβ) showed the best predictive accuracy of amyloid‐PET status [area under the curve (AUC) = 0.927]. Whilst ApoE4 genotype (AUC = 0.737) and Alzheimer's Disease Assessment Scale – Cognitive Subscale (ADAS‐Cog) 13 (AUC = 0.724) independently discriminated amyloid‐PET(+) and amyloid‐PET(−) MCI individuals, the combination of clinical markers (ApoE4 carrier, age >60 years and ADAS‐Cog 13 > 13.5) improved the predictive accuracy of amyloid‐PET status (AUC = 0.827, P < 0.001). Conclusions Cerebrospinal fluid Aβ, which is an invasive procedure, is most accurate in predicting amyloid‐PET status in MCI individuals. The combination of ApoE4, age and ADAS‐Cog 13 also accurately predicts amyloid‐PET status. As this combination of clinical markers is cheap, non‐invasive and readily available, it offers an attractive surrogate assessment for amyloid status amongst MCI individuals in resource‐limited settings.

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Section: Discussionmentioning

confidence: 99%

“…Demographics, the genetic carrier status of AD risk genes and cognitive performances have consistently been shown to be associated with stages of the AD spectrum . Apolipoprotein E4 (ApoE4) carrier, which is involved in Aβ deposition, is one of the most important and best‐established genetic risk factors for sporadic AD .…”

Section: Introductionmentioning

confidence: 99%

The combination of apolipoprotein E4, age and Alzheimer's Disease Assessment Scale – Cognitive Subscale improves the prediction of amyloid positron emission tomography status in clinically diagnosed mild cognitive impairment

Gao

et al. 2019

Euro J of Neurology

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“…Reduced amyloid beta‐42 levels in CSF are strongly correlated with Alzheimer's disease, but have been associated with the APOE ϵ4 genotype regardless of the presence of Alzheimer's disease [Liu et al, ], and with several other brain diseases, such as CADASIL, neuroinflammation, and Creutzfeldt‐Jakob Disease [Otto et al, ; Formichi et al, ; Krut et al, ]. No studies have been published on CSF profiles in FCCM patients [Morrison and Akers, ].…”

Section: Discussionmentioning

confidence: 99%

A novel CCM2 variant in a family with non‐progressive cognitive complaints and cerebral microbleeds

Cohn-Hokke

Holstege

Weiss

et al. 2016

American J of Med Genetics Pt B

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Lobar cerebral microbleeds are most often sporadic and associated with Alzheimer's disease. The aim of our study was to identify the underlying genetic defect in a family with cognitive complaints and multiple lobar microbleeds and a positive family history for early onset Alzheimer's disease. We performed exome sequencing followed by Sanger sequencing for validation purposes on genomic DNA of three siblings with cognitive complaints, reduced amyloid‐beta‐42 in CSF and multiple cerebral lobar microbleeds. We checked for the occurrence of the variant in a cohort of 363 patients with early onset dementia and/or microbleeds. A novel frameshift variant (c.236_237delAC) generating a premature stop codon in the CCM2 gene shared by all three siblings was identified. Pathogenicity of the variant was supported by the presence of cerebral cavernous malformations in two of the siblings and by the absence of the variant exome variant databases. Two siblings were homozygous for APOE‐ϵ4; one heterozygous. The cognitive complaints, reduced amyloid‐beta‐42 in CSF and microbleeds suggest preclinical Alzheimer's disease, but the stability of the cognitive complaints does not. We hypothesize that the phenotype in this family may be due to a combination of the CCM2 variant and the APOE status. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.

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“…With the current shift in paradigm towards the investigation of preclinical AD cases (with or without cognitive complaints), the question arises whether genetic vulnerability (the APOE-ε4 allele), early amyloid deposition, or both, impact on the structural integrity of the hippocampus as recently suggested [13,14]. Such analysis should also consider the marked heterogeneity of cognitive trajectories within the normal range which includes healthy old people who remain stable over time as well as those displaying a continuous but subtle worsening of neuro-psychological performance.…”

Section: Introductionmentioning

confidence: 99%

Hippocampal Volume Loss, Brain Amyloid Accumulation, and APOE Status in Cognitively Intact Elderly Subjects

Haller¹,

Montandon

Rodriguez

et al. 2019

Neurodegener Dis

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Background: Hippocampal volume loss (HVL), PET-documented brain amyloid accumulation, and APOE-ε4 status are predictive biomarkers of the transition from mild cognitive impairment to Alzheimer disease (AD). In asymptomatic cases, the role of these biomarkers remains ambiguous. In contrast to the idea that HVL occurs in late phases of neurodegeneration, recent contributions indicate that it might occur before abnormal amyloid PET occurrence in elderly subjects and that its severity could be only marginally related to APOE variants. Using a longitudinal design, we examined the determinants of HVL in our sample, i.e., brain amyloid burden and the presence of APOE-ε4, and made a longitudinal assessment of cognitive functions. Methods: We performed a 4.5-year longitudinal study on 81 elderly community dwellers (all right-handed;, 48 (59.3%) women; mean age 73.7 ± 3.7 years) including MRI at baseline and follow-up, PET amyloid during follow-up, neuropsychological assessment at 18 and 54 months, and APOE genotyping. All cases were assessed using a continuous cognitive score (CCS) that took into account the global evolution of neuropsychological performance. Linear regression models were used to identify predictors of HVL. Results: There was a negative association between the CCS and HVL bilaterally. In multivariate models adjusting for demographic variables, the presence of APOE-ε4 was related to increased HVL bilaterally. A trend of significance was observed with respect to the impact of amyloid positivity on HVL in the left hemisphere. No significant interaction was found between amyloid positivity and the APOE-ε4 allele. Conclusion: The progressive decrement of neuropsychological performance is associated with HVL long before the emergence of clinically overt symptoms. In this cohort of healthy individuals, the presence of the APOE-ε4 allele was shown to be an independent predictor of worst hippocampal integrity in asymptomatic cases independently of amyloid positivity.

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Multiple Effect of APOE Genotype on Clinical and Neuroimaging Biomarkers Across Alzheimer’s Disease Spectrum

Cited by 47 publications

References 42 publications

The combination of apolipoprotein E4, age and Alzheimer's Disease Assessment Scale – Cognitive Subscale improves the prediction of amyloid positron emission tomography status in clinically diagnosed mild cognitive impairment

The combination of apolipoprotein E4, age and Alzheimer's Disease Assessment Scale – Cognitive Subscale improves the prediction of amyloid positron emission tomography status in clinically diagnosed mild cognitive impairment

A novel CCM2 variant in a family with non‐progressive cognitive complaints and cerebral microbleeds

Hippocampal Volume Loss, Brain Amyloid Accumulation, and APOE Status in Cognitively Intact Elderly Subjects

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