Category: Publications

“Hormone replacement therapy is associated with improved cognition and larger brain volumes in at-risk APOE4 women: results from the European Prevention of Alzheimer’s Disease (EPAD) cohort”

Authors: Rasha N. M. Saleh, Michael Hornberger, Craig W. Ritchie and Anne Marie Minihan

Abstract:

Background: The risk of dementia is higher in women than men. The metabolic consequences of estrogen decline during menopause accelerate neuropathology in women. The use of hormone replacement therapy (HRT) in the prevention of cognitive decline has shown conflicting results. Here we investigate the modulating role of APOE genotype and age at HRT initiation on the heterogeneity in cognitive response to HRT.

Methods: The analysis used baseline data from participants in the European Prevention of Alzheimer’s Dementia (EPAD) cohort (total n= 1906, women= 1178, 61.8%). Analysis of covariate (ANCOVA) models were employed to test the independent and interactive impact of APOE genotype and HRT on select cognitive tests, such as MMSE, RBANS, dot counting, Four Mountain Test (FMT), and the supermarket trolley test (SMT), together with volumes of the medial temporal lobe (MTL) regions by MRI. Multiple linear regression models were used to examine the impact of age of HRT initiation according to APOE4 carrier status on these cognitive and MRI outcomes.

Results: APOE4 HRT users had the highest RBANS delayed memory index score (P-APOE*HRT interaction = 0.009) compared to APOE4 non-users and to non-APOE4 carriers, with 6–10% larger entorhinal (left) and amygdala (right and left) volumes (P-interaction= 0.002, 0.003, and 0.005 respectively). Earlier introduction of HRT was associated with larger right (standardized β= −0.555, p=0.035) and left hippocampal volumes (standardized β= −0.577, p=0.028) only in APOE4 carriers.

Conclusion: HRT introduction is associated with improved delayed memory and larger entorhinal and amygdala volumes in APOE4 carriers only. This may represent an effective targeted strategy to mitigate the higher life-time risk of AD in this large at-risk population subgroup. Confirmation of findings in a fit for purpose RCT with prospective recruitment based on APOE genotype is needed to establish causality.

DOI: 10.1186/s13195-022-01121-5

Published online: 9 January 2023 in the Journal Alzheimer’s Research Therapy

“Identification of preclinical dementia according to ATN classification for stratified trial recruitment A machine learning approach“

Authors: Ivan Koychev, Evgeniy Marinov, Simon Young, Sophia Lazarova, Denitsa Grigorova, Dean Palejev

Abstract:

Introduction: The Amyloid/Tau/Neurodegeneration (ATN) framework was proposed to identify the preclinical biological state of Alzheimer’s disease (AD). We investigated whether ATN phenotype can be predicted using routinely collected research cohort data.

Methods: 927 EPAD LCS cohort participants free of dementia or Mild Cognitive Impairment were separated into 5 ATN categories. We used machine learning (ML) methods to identify a set of significant features separating each neurodegeneration-related group from controls (A-T-(N)-). Random Forest and linear-kernel SVM with stratified 5-fold cross validations were used to optimize model whose performance was then tested in the ADNI database.

Results: Our optimal results outperformed ATN cross-validated logistic regression models by between 2.2% and 8.3%. The optimal feature sets were not consistent across the 4 models with the AD pathologic change vs controls set differing the most from the rest. Because of that we have identified a subset of 10 features that yield results very close or identical to the optimal.

Discussion: Our study demonstrates the gains offered by ML in generating ATN risk prediction over logistic regression models among pre-dementia individuals.

DOI: 10.1371/journal.pone.0288039

Published online: 19 October 2023 in the Journal PlosOne

“Interactions between apolipoprotein E, sex, and amyloid-beta on cerebrospinal fluid p-tau levels in the European prevention of Alzheimer’s dementia longitudinal cohort study (EPAD LCS)”

Authors: Tyler S. Saunders, Natalie Jenkins, Kaj Blennow, Craig Ritchieand Graciela Muniz-Terrera

Abstract:

Background: Alzheimer’s Disease, the leading cause of dementia, is over-represented in females. The apolipoprotein E (APOE)ε4 allele is the strongest genetic risk factor for late-onset AD and is associated with aberrant cerebrospinal fluid levels (CSF) of total tau (t-tau), phosphorylated tau (p-tau), and amyloid-β (Aβ). There is some evidence that sex may mediate the relationship between APOE status and CSF tau, however, evidence is mixed.

Methods: We aimed to examine the interaction between sex, APOE ε4 status, CSF Aβ on t-tau and p-tau in 1599 mid-to-late life individuals without a diagnosis of dementia in the European Prevention of Alzheimer’s Dementia (EPAD) longitudinal cohort study.

Findings: We found a significant interaction between APOE status, sex, and CSF Aβ on CSF p-tau levels (β = 0·18, p = 0·04). Specifically, there was a stronger association between APOE status and CSF Aβ₄₂ on CSF p-tau in males compared to females. Further, in females with high Aβ levels (reflecting less cortical deposition), ε4 carriers had significantly elevated p-tau levels relative to non-carriers (W = 39663, p = 0·01). However, there were no significant differences in p-tau between male ε4 carriers and non-carriers with high Aβ (W = 23523, p = 0·64).

Interpretation: An interaction between sex and cerebrospinal fluid Aβ may mediate the relationship between APOE status and CSF p-tau. These data suggest tau accumulation may be independent of Aβ in females, but not males.

DOI: 10.1016/j.ebiom.2022.104241

Published online: 27 August 2022 in the journal EBioMedicine

Involving research participants in a pan-European
research initiative: the EPAD participant panel
experience

Lived time and the affordances of clinical research participation

Medial temporal lobe atrophy and posterior atrophy
scales normative values

“Memory performance mediates subjective sleep quality associations with cerebrospinal fluid Alzheimer’s disease biomarker levels and hippocampal volume among individuals with mild cognitive symptoms”

Authors: Laura Stankeviciute, Jonathan Blackman, Núria Tort-Colet, Ana Fernández-Arcos, Gonzalo Sánchez-Benavides, Marc Suárez-Calvet, Álex Iranzo, José Luis Molinuevo, Juan Domingo Gispert, Elizabeth Coulthard, Oriol Grau-Rivera

Abstract:

Sleep disturbances are prevalent in Alzheimer’s disease (AD), affecting individuals during its early stages. We investigated associations between subjective sleep measures and cerebrospinal fluid (CSF) biomarkers of AD in adults with mild cognitive symptoms from the European Prevention of Alzheimer’s Dementia Longitudinal Cohort Study, considering the influence of memory performance. A total of 442 participants aged >50 years with a Clinical Dementia Rating (CDR) score of 0.5 completed the Pittsburgh Sleep Quality Index questionnaire and underwent neuropsychological assessment, magnetic resonance imaging acquisition, and CSF sampling. We analysed the relationship of sleep quality with CSF AD biomarkers and cognitive performance in separated multivariate linear regression models, adjusting for covariates. Poorer cross-sectional sleep quality was associated with lower CSF levels of phosphorylated tau and total tau alongside better immediate and delayed memory performance. After adjustment for delayed memory scores, associations between CSF biomarkers and sleep quality became non-significant, and further analysis revealed that memory performance mediated this relationship. In post hoc analyses, poorer subjective sleep quality was associated with lesser hippocampal atrophy, with memory performance also mediating this association. In conclusion, worse subjective sleep quality is associated with less altered AD biomarkers in adults with mild cognitive symptoms (CDR score 0.5). These results could be explained by a systematic recall bias affecting subjective sleep assessment in individuals with incipient memory impairment. Caution should therefore be exercised when interpreting subjective sleep quality measures in memory-impaired populations, emphasising the importance of complementing subjective measures with objective assessments.

DOI: doi.org/10.1111/jsr.14108

Published online: 30 November 2023 in the Journal of Sleep Research

Multi-study validation of data-driven disease
progression models to characterize evolution of
biomarkers in Alzheimer’s disease

On the personal utility of Alzheimer’s disease-related
biomarker testing in the research context

Perspectives on Communicating Biomarker-Based
Assessments of Alzheimer’s Disease to Cognitively
Healthy Individuals