Journal of Alzheimer's Disease - Volume 74, issue 4

Authors: Wang, Ya-Juan | Hu, Hao | Yang, Yu-Xiang | Zuo, Chuan-Tao | Tan, Lan | Yu, Jin-Tai | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Recent studies have shown that amyloid-β (Aβ) burden influenced white matter (WM) integrity before the onset of dementia. Objective: To assess whether the effects of Aβ burden on WM integrity in cognitively normal (CN) individuals were regionally specific. Methods: Our cohort consisted of 71 CNs from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database who underwent both AV45 amyloid-PET and diffusion tensor imaging. Standardized uptake value ratio (SUVR) was computed across four bilateral regions of interest (ROIs) corresponding to four stages of in vivo amyloid staging model (Amyloid stages I–IV). Linear regression models were conducted …in entire CN group and between APOE ɛ 4 carriers and non-carriers. Results: Our results indicated that higher global Aβ-SUVR was associated with higher mean diffusivity (MD) in the entire CN group (p  = 0.023), and with both higher MD (p  = 0.015) and lower fractional anisotropy (FA) (p  = 0.026) in APOE ɛ 4 carriers. Subregion analysis showed that higher Amyloid stage I-II Aβ-SUVRs were associated with higher MD (Stage-1: p  = 0.030; Stage-2: p  = 0.016) in the entire CN group, and with both higher MD (Stage-1: p  = 0.004; Stage-2: p  = 0.010) and lower FA (Stage-1: p  = 0.022; Stage-2: p  = 0.014) in APOE ɛ 4 carriers. No associations were found in APOE ɛ 4 non-carriers and in Amyloid stage III-IV ROIs. Conclusions: Our results indicated that the effects of Aβ burden on WM integrity in CNs might be regionally specific, particularly in Amyloid stage I-II ROIs, and modulated by APOE ɛ 4 status. Show more

Keywords: Amyloid PET, cognitively normal elders, diffusion tensor imaging, in vivo amyloid staging model, white matter integrity

DOI: 10.3233/JAD-191350

Citation: Journal of Alzheimer's Disease, vol. 74, no. 4, pp. 1261-1270, 2020

Authors: Harrison, Judith R. | Mistry, Sumit | Muskett, Natalie | Escott-Price, Valentina

Article Type: Research Article

Abstract: Background: Late-onset Alzheimer’s disease (AD) is highly heritable. The effect of many common genetic variants, single nucleotide polymorphisms (SNPs), confer risk. Variants are clustered in areas of biology, notably immunity and inflammation, cholesterol metabolism, endocytosis, and ubiquitination. Polygenic scores (PRS), which weight the sum of an individual’s risk alleles, have been used to draw inferences about the pathological processes underpinning AD. Objective: This paper aims to systematically review how AD PRS are being used to study a range of outcomes and phenotypes related to neurodegeneration. Methods: We searched the literature from July 2008–July 2018 following PRISMA …guidelines. Results: 57 studies met criteria. The AD PRS can distinguish AD cases from controls. The ability of AD PRS to predict conversion from mild cognitive impairment (MCI) to AD was less clear. There was strong evidence of association between AD PRS and cognitive impairment. AD PRS were correlated with a number of biological phenotypes associated with AD pathology, such as neuroimaging changes and amyloid and tau measures. Pathway-specific polygenic scores were also associated with AD-related biologically relevant phenotypes. Conclusion: PRS can predict AD effectively and are associated with cognitive impairment. There is also evidence of association between AD PRS and other phenotypes relevant to neurodegeneration. The associations between pathway specific polygenic scores and phenotypic changes may allow us to define the biology of the disease in individuals and indicate who may benefit from specific treatments. Longitudinal cohort studies are required to test the ability of PGS to delineate pathway-specific disease activity. Show more

Keywords: alleles, Alzheimer’s disease, amyloid-beta peptides, cognitive dysfunction, genome-wide association study, multifactorial inheritance, neuroimaging, phenotype, precision medicine, single nucleotide polymorphism

DOI: 10.3233/JAD-191233

Citation: Journal of Alzheimer's Disease, vol. 74, no. 4, pp. 1271-1283, 2020

Authors: Feinkohl, Insa | Schipke, Carola G. | Kruppa, Jochen | Menne, Felix | Winterer, Georg | Pischon, Tobias | Peters, Oliver

Article Type: Research Article

Abstract: Background: Collection of cerebrospinal fluid (CSF) for measurement of amyloid-β (Aβ) species is a gold standard in Alzheimer’s disease (AD) diagnosis, but has risks. Thus, establishing a low-risk blood Aβ test with high AD sensitivity and specificity is of outmost interest. Objective: We evaluated the ability of a commercially available plasma Aβ assay to distinguish AD patients from biomarker-healthy controls. Method: In a case-control design, we examined plasma samples from 44 AD patients (A + N+) and 49 controls (A–N–) from a memory clinic. AD was diagnosed using a combination of neuropsychological examination, CSF biomarker analysis and brain …imaging. Total Aβ40 and total Aβ42 in plasma were measured through enzyme-linked immunosorbent assay (ELISA) technology using ABtest40 and ABtest42 test kits (Araclon Biotech Ltd.). Receiver operating characteristic (ROC) analyses with outcome AD were performed, and sensitivity and specificity were calculated. Results: Plasma Aβ42/40 was weakly positively correlated with CSF Aβ42/40 (Spearman’s rho 0.22; p  = 0.037). Plasma Aβ42/40 alone was not able to statistically significantly distinguish between AD patients and controls (AUC 0.58; 95% CI 0.46, 0.70). At a cut-point of 0.076 maximizing sensitivity and specificity, plasma Aβ42/40 had a sensitivity of 61.2% and a specificity of 63.6%. Conclusion: In this sample, the high-throughput blood Aβ assay was not able to distinguish well between AD patients and controls. Whether or not the assay may be useful in large-scale epidemiological settings remains to be seen. Show more

Keywords: Alzheimer’s disease, amyloid, diagnosis, high-throughput assay, plasma

DOI: 10.3233/JAD-200046

Citation: Journal of Alzheimer's Disease, vol. 74, no. 4, pp. 1285-1294, 2020

Authors: Li, Lily | Cavuoto, Marina | Biddiscombe, Karen | Pike, Kerryn E.

Article Type: Research Article

Abstract: Background: Dementia is a devastating condition for older adults, with both modifiable (e.g., diabetes mellitus) and unmodifiable risk factors (e.g., APOE ɛ 4 allele). It remains unclear how, and to what extent, diabetes impacts dementia risk via both cerebrovascular and amyloid-β pathways. Objective: We conducted a quantitative meta-analysis to investigate the contribution of diabetes to incident dementia risk in people with ɛ 4 and, based on the vascular-related neuropathology of diabetes, whether the combination of these factors increases risk for vascular dementia versus Alzheimer’s disease (AD). Methods: Systematic literature searches were conducted using EMBASE, MEDLINE, …PsycINFO, and CINAHL databases. Pooled relative risk (RR) estimates were calculated using a random effects model, and subgroup analyses conducted across dementia subtypes. Results: Twelve studies were included, with a total of 16,200 participants. Considered concurrently, diabetes increased incident dementia risk an additional 35% for those with ɛ 4 (RR = 1.35, 95% CI = 1.13–1.63). Similar patterns were observed for AD and vascular dementia. Conclusion: Interventions to prevent co-morbid diabetes, and diabetes-related complications and neuropathological changes, may be one way of modifying dementia risk in the vulnerable ɛ 4 population. Show more

Keywords: Alzheimer’s disease, Apolipoproteins E, dementia, diabetes mellitus, risk factors, vascular dementia

DOI: 10.3233/JAD-191068

Citation: Journal of Alzheimer's Disease, vol. 74, no. 4, pp. 1295-1308, 2020

Authors: Daly, Timothy | Houot, Marion | Barberousse, Anouk | Agid, Yves | Epelbaum, Stéphane

Article Type: Research Article

Abstract: The amyloid cascade hypothesis (ACH) has dominated contemporary biomedical research into Alzheimer’s disease (AD) since the 1990 s but still lacks definitive confirmation by successful clinical trials of anti-amyloid medicines in human AD. In this uncertain period regarding the centrality of amyloid-β (Aβ) in AD pathophysiology, and with the community apparently divided about the ACH’s validity, we used citation practices as a proxy for measuring how researchers have invested their belief in the hypothesis between 1992 and 2019. We sampled 445 articles citing Hardy & Higgins (1992, “HH92”) and classified the polarity of their HH92 citation according to Greenberg (2009)’s citation …taxonomy of positive, neutral, and negative citations, and then tested four hypotheses. We identified two major attitudes towards HH92: a majority (62%) of neutral attitudes with consistent properties across the time period, and a positive attitude (35%), tending to cite HH92 earlier on within the bibliography as time went by, tending to take HH92 as an established authority. Despite the majority of neutral HH92 citations, there was a positive majority of attitudes toward different versions of the ACH and anti-amyloid therapeutic strategies (65%), suggesting that the ACH has been dominant and has undergone significant refinement since 1992. Finally, of those 110 original articles within the sample also testing the ACH empirically, an overwhelming majority (89%) returned a pro-ACH test result, suggesting that the ACH’s central claim is reproducible. Further studies will quantify the extent to which results from different methods within such original studies convergence to provide a robust conclusion vis-à-vis Aβ’s pathogenicity in AD. Show more

Keywords: Alzheimer’s disease, amyloid cascade hypothesis, amyloid-β, belief, bibliometrics, citations, confirmation, Karl Popper, reproducibility, scientific bias

DOI: 10.3233/JAD-191321

Citation: Journal of Alzheimer's Disease, vol. 74, no. 4, pp. 1309-1317, 2020