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Ethical issues in the development of readiness
cohorts in Alzheimer’s disease research

European Prevention of Alzheimer’s Dementia Registry:
Recruitment and prescreening approach for a longitudinal
cohort and prevention trials

European Prevention of Alzheimer’s Dementia
Longitudinal Cohort Study (EPAD LCS): study
protocol

Evaluating the Alzheimer’s disease data landscape

Evolution and future directions for the concept of mild
cognitive impairment

“Gray matter network properties show distinct associations with CSF p-tau 181 levels and amyloid status in individuals without dementia”

Authors: Lorenzini Luigi, Ingala Silvia, Wottschel Viktor, Alle Meije WinkHenk JMM Mutsaerts, Haller Sven, Blennow Kaj, John T. O’Brien, Frisoni B. Giovanni, Chételat Gael, Payoux Pierre, Martinez-Lage Pablo, Waldman Adam, Wardlaw Joanna, Ritchie Craig, Juan Domingo Gispert, Pieter Jelle Visser, Scheltens Philip, Barkhof Frederik, Betty M. Tijms

Abstract: Gray matter networks are altered with amyloid accumulation in the earliest stage of AD, and are associated with decline throughout the AD spectrum. It remains unclear to what extent gray matter network abnormalities are associated with hyperphosphorylated-tau (p-tau). We studied the relationship of cerebrospinal fluid (CSF) p-tau181 with gray matter networks in non-demented participants from the European Prevention of Alzheimer’s Dementia (EPAD) cohort, and studied dependencies on amyloid and cognitive status. Gray matter networks were extracted from baseline structural 3D T1w MRI. P-tau181 and abeta were measured with the Roche cobas Elecsys System. We studied the associations of CSF biomarkers levels with several network’s graph properties. We further studied whether the relationships of p-tau 181 and network measures were dependent on amyloid status and cognitive stage (CDR). We repeated these analyses for network properties at a regional level, where we averaged local network values across cubes within each of 116 areas as defined by the automated anatomical labeling (AAL) atlas. Amyloid positivity was associated with higher network size and betweenness centrality, and lower gamma, clustering and small-world coefficients. Higher CSF p-tau 181 levels were related to lower betweenness centrality, path length and lambda coefficients (all p < 0.01). Three-way interactions between p-tau181, amyloid status and CDR were found for path length, lambda and clustering (all p < 0.05): Cognitively unimpaired amyloid-negative participants showed lower path length and lambda values with higher CSF p-tau181 levels. Amyloid-positive participants with impaired cognition demonstrated lower clustering coefficients in association to higher CSF p-tau181 levels. Our results suggest that alterations in gray matter network clustering coefficient is an early and specific event in AD.

DOI: 10.1016/j.nbas.2022.100054

Published online: 23 October 2022 in the Journal Aging Brain

“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