The ALFA project: A research platform to identify early pathophysiological features of Alzheimer's disease

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Abstract

Introduction

The preclinical phase of Alzheimer's disease (AD) is optimal for identifying early pathophysiological events and developing prevention programs, which are shared aims of the ALFA project, including the ALFA registry and parent cohort and the nested ALFA+ cohort study.

Methods

The ALFA parent cohort baseline visit included full cognitive evaluation, lifestyle habits questionnaires, DNA extraction, and MRI. The nested ALFA+ study adds wet and imaging biomarkers for deeper phenotyping.

Results

A total of 2743 participants aged 45 to 74 years were included in the ALFA parent cohort. We show that this cohort, mostly composed of cognitively normal offspring of AD patients, is enriched for AD genetic risk factors.

Discussion

The ALFA project represents a valuable infrastructure that will leverage with different studies and trials to prevent AD. The longitudinal ALFA+ cohort will serve to untangle the natural history of the disease and to model the preclinical stages to develop successful trials.

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Most cited references 27

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EuroQol: the current state of play.

R. Brooks (1996)

The EuroQol Group first met in 1987 to test the feasibility of jointly developing a standardised non-disease-specific instrument for describing and valuing health-related quality of life. From the outset the Group has been multi-country, multi-centre, and multi-disciplinary. The EuroQol instrument is intended to complement other forms of quality of life measures, and it has been purposefully developed to generate a cardinal index of health, thus giving it considerable potential for use in economic evaluation. Considerable effort has been invested by the Group in the development and valuation aspects of health status measurement. Earlier work was reported upon in 1990; this paper is a second 'corporate' effort detailing subsequent developments. The concepts underlying the EuroQol framework are explored with particular reference to the generic nature of the instrument. The valuation task is reviewed and some evidence on the methodological requirements for measurement is presented. A number of special issues of considerable interest and concern to the Group are discussed: the modelling of data, the duration of health states and the problems surrounding the state 'dead'. An outline of some of the applications of the EuroQol instrument is presented and a brief commentary on the Group's ongoing programme of work concludes the paper.

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Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer's disease in the presenilin 1 E280A kindred: a case-control study.

Eric M. Reiman, Yakeel T. Quiroz, Adam Fleisher … (2012)

We have previously characterised functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's disease. To gain further knowledge on the preclinical phase of Alzheimer's disease, we sought to characterise structural and functional MRI, CSF, and plasma biomarkers in a cohort of young adults carrying a high-penetrance autosomal dominant mutation that causes early-onset Alzheimer's disease. Between January and August, 2010, 18-26-year-old presenilin 1 (PSEN1) E280A mutation carriers and non-carriers from the Colombian Alzheimer's Prevention Initiative Registry in Medellín Antioquia, Colombia, had structural MRI, functional MRI during associative memory encoding and novel viewing and control tasks, and cognitive assessments. Consenting participants also had lumbar punctures and venepunctures. Outcome measures were task-dependent hippocampal or parahippocampal activations and precuneus or posterior cingulate deactivations, regional grey matter reductions, CSF Aβ(1-42), total tau and phospho-tau(181) concentrations, and plasma Aβ(1-42) concentrations and Aβ(1-42):Aβ(1-40) ratios. Structural and functional MRI data were compared using automated brain mapping algorithms and search regions related to Alzheimer's disease. Cognitive and fluid biomarkers were compared using Mann-Whitney tests. 44 participants were included: 20 PSEN1 E280A mutation carriers and 24 non-carriers. The carrier and non-carrier groups did not differ significantly in their dementia ratings, neuropsychological test scores, or proportion of apolipoprotein E (APOE) ɛ4 carriers. Compared with non-carriers, carriers had greater right hippocampal and parahippocampal activation (p=0·001 and p<0·014, respectively, after correction for multiple comparisons), less precuneus and posterior cingulate deactivation (all p<0·010 after correction), and less grey matter in several parietal regions (all p<0·002 uncorrected and corrected p=0·009 in the right parietal search region). In the 20 participants (ten PSEN1 E280A mutation carriers and ten non-carriers) who had lumbar punctures and venepunctures, mutation carriers had higher CSF Aβ(1-42) concentrations (p=0·008) and plasma Aβ(1-42) concentrations (p=0·01) than non-carriers. Young adults at genetic risk for autosomal dominant Alzheimer's disease have functional and structural MRI findings and CSF and plasma biomarker findings consistent with Aβ(1-42) overproduction. Although the extent to which the underlying brain changes are either neurodegenerative or developmental remain to be determined, this study shows the earliest known biomarker changes in cognitively normal people at genetic risk for autosomal dominant Alzheimer's disease. Banner Alzheimer's Foundation, Nomis Foundation, Anonymous Foundation, Forget Me Not Initiative, Boston University Department of Psychology, Colciencias, National Institute on Aging, National Institute of Neurological Disorders and Stroke, and the State of Arizona. Copyright © 2012 Elsevier Ltd. All rights reserved.

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Detecting anxiety and depression in general medical settings.

D R Grayson, K Bridges, Rebecca Duncan … (1988)

To aid general practitioners and other non-psychiatrists in the better recognition of mental illness short scales measuring anxiety and depression were derived by latent trait analysis from a standardised psychiatric research interview. Designed to be used by non-psychiatrists, they provide dimensional measures of the severity of each disorder. The full set of nine questions need to be administered only if there are positive answers to the first four. When assessed against the full set of 60 questions contained in the psychiatric assessment schedule they had a specificity of 91% and a sensitivity of 86%. The scales would be used by non-psychiatrists in clinical investigations and possibly also by medical students to familiarise them with the common forms of psychiatric illness, which are often unrecognised in general medical settings.

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Author and article information

Contributors

José Luis Molinuevo

Jordi Camí

Journal

Journal ID (nlm-ta): Alzheimers Dement (N Y)

Journal ID (iso-abbrev): Alzheimers Dement (N Y)

Title: Alzheimer's & Dementia : Translational Research & Clinical Interventions

Publisher: Elsevier

ISSN (Electronic): 2352-8737

Publication date PMC-release: 03 March 2016

Publication date Collection: June 2016

Publication date (Electronic): 03 March 2016

Volume: 2

Issue: 2

Pages: 82-92

Affiliations

[a ]Barcelonaβeta Brain Research Center, Barcelona, Spain

[b ]Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain

[c ]Department of Physiological Sciences II, School of Medicine, University of Barcelona (UB), Barcelona, Spain

[d ]Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain

[e ]Pasqual Maragall Foundation, Barcelona, Spain

[f ]Universitat Pompeu Fabra, Barcelona, Spain

Author notes

[∗ ]Corresponding author. Tel.: (+34) 93 316 0990; Fax: (+34) 93 316 0996 . jlmolinuevo@ 123456fpmaragall.org jordicami@ 123456fpmaragall.org

Article

Publisher ID: S2352-8737(16)00006-8

DOI: 10.1016/j.trci.2016.02.003

PMC ID: 5644283

PubMed ID: 29067295

SO-VID: 03a49de7-6026-4fa5-b7d5-9bcdce45dfa6

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

The ALFA project: A research platform to identify early pathophysiological features of Alzheimer's disease

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Abstract

Introduction

Methods

Results

Discussion

Related collections

Alternative approaches to Alzheimer's Disease

Most cited references 27

EuroQol: the current state of play.

Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer's disease in the presenilin 1 E280A kindred: a case-control study.

Detecting anxiety and depression in general medical settings.

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