Genetics of Mendelian Forms of Young Onset Alzheimer Disease (GMAJ)

April 13, 2026 updated by: University Hospital, Rouen

Genetics of Mendelian Forms of Young Onset Alzheimer Disease. Identification of Novel Genetic Causes of AD Are of Importance in Completing the Mechanisms of the Amyloid Hypothesis. This Project is Useful to Promote the Guidelines on the Genetic Diagnosis of AD in France.

Genetics of mendelian forms of young onset Alzheimer Disease (GMAJ project)

Introduction : Autosomal dominant forms of Alzheimer disease (AD) are characterized by young age of onset. In France the prevalence was estimated at around 1000 cases. The Phenotypical Expression: There is diversity in phenotypical expression, associating dementia, spastic paraplegia, early extrapyramidal syndrome, ataxia or stroke caused by severe cerebral amyloid angiopathy. Diversity in neuropathological expression is demonstrated by the presence of cotton wool plaques, Lewy bodies with Lewy neurites and severe cerebral amyloid angiopathy.

The study of mendelian forms is decisive in the physiopathological comprehension of AD and related diseases, since the alteration of those genes involved is sufficient to cause the disease. In AD, identification of these genetic causes allows the formulation of the amyloid hypothesis, which is the basis of current therapeutic developments concerning the Ab peptide. Currently three genes (APP, PSEN1, PSEN2) are identified in early onset mendelian forms and their mutations are involved in 80% of the 139 French families, studied since 1993 within the framework of U614 and the National Reference Centre for Alzheimer Disease in young subjects (CNR-MAJ).These results are arguments in favor of the GMAJ project and have two main objectives:

(i) to identify new genes in mendelian AD forms without detectable alteration on known genes.

(ii) to correlate phenotypes and genotypes within families associated with known mutations and extend the description of the phenotypical spectrum.

Population: Families eligible for this study are those with at least 2 individuals with AD criteria (clinical or neuropathological) with onset before 65 years of age. Duration of inclusion is 3 years. This multicentre study groups 23 clinical centres. The inclusion number is 50 new families per year.

Method: Extension and description of families with unknown genetic causes, inclusion of novel families with autosomal dominant AD. The successive steps of the project are the following:

(i) Thorough phenotypical characterization in order to document family history and characterize the probands and affected related subjects according to standardized protocol for clinical, neuropsychological, biological (biomarker determination in plasma and cerebrospinal fluid) and imaging data (MRI, TEMP).

(ii) Identify known genetic causes (PSEN1/2, APP) with novel autosomal dominant families.

(iii) Extend analysis of the pedigrees of families with unknown genetic causes.

(iv) Identify novel genetic causes within these families which are negative for known mutations.

This study uses 3 methods:

  • pangenomic search is performed for microalterations (Copy Number Variants or CNV) by Comparative Genomic Hybridization (CGH) with high resolution (10 kb on average).
  • potential targets are then validated by the study of large control populations, intrafamilial cosegregation and functional validation.

  • the remaining families at the end of this stage will be characterized by means of high throughput sequencing of all exonic areas.

    (v) Follow up study of patients and siblings with 2 goals:

  • evaluation of the disease course and consequences (individual, familial and social);
  • occurrence of novel AD cases within the family.

(vi) Neuropathological description with potential novel description of atypical AD cases.

Results and consequences: Identification of novel genetic causes of AD are of importance in completing the mechanisms of the amyloidergic hypothesis. This project is useful to promote the guidelines on the genetic diagnosis of AD in France.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

150

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
      • Rouen, France, 76031
        • CMRR Rouen University Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Study Population

cases of familial Alzheimer disease with age of onset under 65

Description

Inclusion Criteria:

  • > in one family 2 cases of Alzheimer disease with age of onset under 65

Exclusion Criteria:

  • other cases of young onset dementia

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Other
  • Masking: Single

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospital, Rouen

Investigators

  • Principal Investigator: Didier HANNEQUIN, Pr, University Hospital, Rouen

Publications and helpful links

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General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 15, 2009

Primary Completion (Actual)

December 15, 2018

Study Completion (Actual)

December 15, 2018

Study Registration Dates

First Submitted

June 14, 2012

First Submitted That Met QC Criteria

June 18, 2012

First Posted (Estimated)

June 19, 2012

Study Record Updates

Last Update Posted (Actual)

April 17, 2026

Last Update Submitted That Met QC Criteria

April 13, 2026

Last Verified

April 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2008/067/HP
  • 2009-010884-18

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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