GenADA/LONG/Imaging (Genetic Alzheimer's Disease Associations)

GenADA is a multi-site collaborative study, involving GlaxoSmithKline Inc and nine medical centres in Canada, to develop a dataset

containing 1000 Alzheimer's disease patients and 1000 ethnically-matched controls in order to associate DNA sequence (allelic) variations

in candidate genes with Alzheimer's disease phenotypes. The study consists of both retrospective and prospective components, that is,

patients with an existing diagnosis of Alzheimer's disease as well as newly diagnosed patients were enrolled in the study. Thus, clinical

data was retrospectively or prospectively obtained on Day 1 of entry into GenADA. Where possible, biological relatives with

Alzheimer's (up to third degree relationship such as cousins) and unaffected siblings of AD cases were also recruited. Note

that recruitment numbers for biological relatives were lower than expected and genotypic data has not been submitted to

dbGap for these subjects.

The purpose of this study is:

To identify DNA sequence variations (genotype) in candidate genes that are associated with the clinical symptoms and

behavioural features of Alzheimer's disease (phenotype), which differ between study participants with and without the

disease.

To identify other genotype-phenotype associations in cognitively impaired study participants such as age of onset, family

history, rate of cognitive decline, patterns of behavioural/psychiatric non-cognitive symptoms factors, response to treatment

co-morbid conditions, and risks/exposure.

The final subject recruitment for this study included 875 Alzheimer's disease patients, 850 ethnically-matched controls,

and 37 family members.

GenADA LONG is a longitudinal assessment to the original GenADA study. Eligible subjects were recruited from five of the

nine memory clinics that participated in the GenADA study. Mild to moderate AD participants, a matched subset of controls, and

biological related siblings (both affected and unaffected) or other blood relatives affected with AD, were initially examined a

minimum of 12 months from recruitment into the original GenADA study, then at two further intervals of 12 and 18 months after

time of entry into GenADA LONG. This enables an evaluation of the disease progression in AD patients and a determination of

whether controls show evidence of cognitive decline. The overall goal of this extension study is to identify genetic differences

and environmental influences that modulate the age of onset of the disease, the course of the disease, and/or biomarkers for

neurodegenerative processes.

Three of the five memory clinics that participated in the GenADA LONG study recruited eligible patients into GenADA Imaging.

A concurrent neuroimaging sub-study was conducted at three of the five memory clinics participating in GenADA LONG. Eligible AD

cases with mild to moderate AD, who were recruited into the original GenADA study and participated in the GenADA LONG extension study,

were enrolled. Additionally, controls that showed signs of cognitive decline, as part of the assessment in GenADA LONG, were imaged

at baseline, 12 and 18 month scanning intervals. The objective of this study is to find genes that: affect changes in AD brain volume

measure by magnetic resonance in order to investigate how well change in brain volume predicts other key clinical measures in AD,

such as neurodegenerative scales; that correlate changes in brain volume for other genotype-phenotype associations in cognitively

impaired study participants; and that correlate with other clinically applicable magnetic resonance measures of pathology that can

be conducted at the same time as structural volume measures, and are complementary to the volume measures.

The ultimate aim of this research is to obtain a better understanding and definition of Alzheimer's Disease in order to develop

new improved medicines.]]>
Multi-Site Collaborative Study for Genotype-Phenotype Associations in Alzheimer’s disease, Longitudinal follow up (Genetic Alzheimer’s Disease Associations – GenADA LONG)Multi-Site Collaborative Study for Genotype-Phenotype Associations in Alzheimer’s diseaseNeuroimaging component of Genotype-Phenotype Associations in Alzheimer’s diseaseNormal RangesAD PATIENTS, Part 1CONTROL PATIENTS, Part 1AD PATIENTS, Part 2AD PATIENTS, Part 3CONTROL PATIENTS, Part 2CONTROL PATIENTS, Part 3For GenADA:

All study participants voluntarily provided an informed and signed consent by self and/or legal representative.

Alzheimer Patient

AD Patient Inclusion Criteria

An Alzheimer patient was eligible for inclusion in this study only if all of the following criteria applied:

Met ADRDA/NINCDS criteria for diagnosis of probable Alzheimer's disease

Positive diagnosis of Dementia of the Alzheimer's Type (DAT) on the DSM-IV check list, with a diagnostic

code based on age of onset (to be determined by first symptoms noted by friends and family) and predominant clinical

features: early onset (age 65 or less) uncomplicated (290.10), with delirium as mode of presentation (290.11), with

delusions as mode of presentation (290.12), with depressed mood as mode of presentation (290.13), versus late onset

(after age 65) uncomplicated (290.0), with delirium as mode of presentation (290.3), with delusions as mode of

presentation (290.20), with depressed mood as mode of presentation (290.21)

Global Deterioration Scale of Reisberg et al., score of 3 to 7

Have clinical data available confirming Alzheimer diagnosis

Patient Exclusion Criteria

An Alzheimer's patient was not eligible for inclusion in this study if any of the following criteria applied:

Was currently in a Major Depressive Episode, psychosis, acute manic or depressive episode of Bipolar Disorder

Control

A control was ethnically matched, and when feasible gender- and age- matched (or older) to the cases and eligible for inclusion in

this study only if all of the following criteria applied:

Control Inclusion Criteria

No history of memory problems

MMSE higher than the appropriate cut-off dementia score taking into account age and education level

DRS -2 AEMSS (Age and Education adjusted MOANS scale score) of 9 or higher (after adjustment for age and education)

Clock test (11:10) with a score > or = 14.

No impairment of the 7 instrumental ADL questions from the Duke Older American Resources and Services Procedures caused by

cognitive decline (allow for 'never did' or 'physical disability'): use the telephone, get to places, go shopping,

prepare meals, do housework, take own medicine, handle money)

Control Exclusion Criteria

A control was not eligible for inclusion in this study if any of the following criteria applied:

Was currently in a Major Depressive Episode, psychosis or acute manic or depressive episode of Bipolar Disorder

Had cognitive impairment on testing

Not ethnically matched to any of the target case cohorts

Unaffected Siblings of enrolled Alzheimer's patients

A sibling of an Alzheimer's patient was eligible for inclusion in this study only if all of the following criteria apply:

Is 65 years of age or older

Same as Control

Affected Biological (Blood) Relatives of enrolled Alzheimer's patients

Where feasible, affected biological relatives of up to third degree relationship were recruited and follow

the protocol as per a case (see above criteria for Alzheimer's patients).

For GenADA LONG:

Cases or Patients with Alzheimer's Disease (AD)

An Alzheimer's patient was eligible for inclusion in GenADA LONG only if all of the following criteria applied:

An informed and signed consent by self and/or appropriate representative.

They participated in the previous GenADA study. (The patients at this second time-point may have now progressed

to an atypical form of dementia and/or may not fulfill the inclusion criteria from the previous study.)

They have a Global Deterioration Scale (GDS) score of 3, 4 or 5 at the time of their GenADA visit

OR they have a GDS of 6 AND an Mini Mental State Examination (MMSE) of greater than or equal to 10 at the time of

their GenADA visit

An Alzheimer's patient was not eligible for inclusion in GenADA LONG if any of the following criteria applied:

Was currently in a Major Depressive episode, psychosis (excluding psychosis related to dementia), acute manic

depressive episode of Bipolar disorder.

In the investigator's opinion, was not able to be followed up (due to behaviour, ability to re-test, co-morbidities, etc)

Controls and Unaffected Biological Siblings

A control was eligible for inclusion in GenADA LONG if any of the following criteria applied:

They participated in the previous GenADA study.

They voluntarily provide an informed consent.

Controls were matched at site for age (+ 5 years) and gender or if assessed show signs of cognitive decline

A control was not eligible for inclusion in GenADA LONG if any of the following criteria applied:

Was currently in a Major Depressive episode, psychosis, acute manic depressive episode of Bipolar disorder

A control with change in cognitive status was eligible for inclusion into GenADA LONG if their DRS2 score has

declined ≥10% since their GenADA visit. These subjects were considered "controls with change in cognitive status".

Affected Biological (Blood) Relatives of enrolled Alzheimer patients

Where feasible, biological relatives with AD and who were recruited into the original GenADA were recalled for inclusion into

this longitudinal part. These study participants fall under the same study criteria as those for Cases or Patients with Alzheimer's.

For GenADA Imaging:

Cases and Controls Inclusion Criteria:

All participants from the original GenADA study who met the inclusion criteria below were invited to take part in this

optional sub-study.

All participants must have satisfied the minimum study inclusion of an informed and signed consent by self and/or

appropriate representative.

The participant must have been able to provide an adequate baseline scan acquisition. Two T1W scans were taken on

first baseline visit, with a repeat visit if necessary due to inadequate scan quality. If the scan was not fit for

purpose, participant was excluded from the study.

Cases:

Patients with probable AD were eligible for inclusion in this study if they participated in the previous GenADA study as

a case and were also participating in the GenADA LONG component. The patients at this second time-point may have

presented with a dementia which makes the diagnosis of probable AD less certain. These patients may have show

significant vascular pathology (e.g. > 25% white matter lesions), or have evolved clinical features suggestive of

an alternative diagnosis. They were included in the imaging study, but the change in diagnostic certainty were

recorded for the purpose of differential analysis.

All cases were at least mild to moderate at first scan as defined by a Global Deterioration Score (GDS) of 3-5 and

a Mini-Mental Status Examination (MMSE) greater than 15 out of 30.

Exclusion criteria for all participants:

Inability to tolerate MRI scanning or any contraindication to scanning such as pacemaker, certain ferrous metal implant, claustrophobia.

Participant suffers from uncontrolled epilepsy, seizures or blackouts etc.

Failure to obtain adequate baseline acquisition after 2 separate baseline visits.

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