Principal Investigator: Clifford G, Andrew, M.D., Ph.D., Assistant Professor (Part-Time)

Principal Investigator: Clifford G, Andrew, M.D., Ph.D., Assistant Professor (Part-time) Neurology,

Staff: Madeleine Price Ball, Ph.D., Open Humans, and Personal Genome Project

Pete Estep, Ph.D., Mind First Foundation, and Personal Genome Project

Application: Genomic Longitudinal Environmental Aging Memory Study

Pilot Protocol

Genomic Longitudinal Environmental Aging Memory (GLEAM) Project

I. Abstract

1. Overview:

This is a 1-2 year protocol for the Genomic Longitudinal Environmental Aging Memory (GLEAM) Project a pilot for the eventual prospective longitudinal study that aspires to survey and record metrics of cognitive function over time along with demographic, behavioral and health history, andassociate these with individual genome and genetic data, with the goal of discovering how these factors relate to cognitive impairment during the aging process. It plans to build off existing genetic data resources. The pilot phase of this projectwill engage individuals participating in projects in which they already publicly share their genome, genetic, demographic, and medical data. In particular, we plan to engage participants enrolled in the Harvard Personal Genome Project as of March 2016 has 4,874 participants, with 260 who have publicly shared whole genome data and 747who have shared genotyping data. We focus on this cohort as a set of highly engaged individuals interested in making ongoing contributions to research, which makes them an ideal group for longitudinal study. By engaging individuals with public data we reduce security risks for them in our data management. We also anticipate that at a later date longitudinal data thatGLEAMS generates could become publicly shared as joint public data set combined with the individuals’ existing public genetic data.

1. The Problem:

Alzheimer’s disease and other forms of cognitive impairment of aging are a major and growing problem in our country and in the world at large as populations age. There are currently no reliable treatments to cure, reverse or significantly slow the mental impairment, and physical disability they inflict. This is in large part due to the fact that the underlying causes are poorly understood. These disorders are thought to result from a complex interaction between combinations of underlying gene sets and various external environmental factors.

C. Research Hypotheses:

1. A large and growing number of individuals are currently having their genomic, medical and phenotypic traits characterized and are openly sharing this information publiclyin effort to advance scientific knowledge.

2. Comprehensive ICD-10based epidemiologic surveys can be developed to characterize, record and analyze these individuals’ environmental exposures.

3. Standardized and validated methodsare available to safely and accurately quantify cognitive function longitudinally as these individuals age.

D. Importance of the Research:

Analysis of whole genome sequences, lifetime environmental factors and exposures; andmeasurements in cognitive function in significant numbers of subjects over a sufficient period of time should reveal important causal relationships underlying Alzheimer’s disease and other forms of cognitive impairment of aging. Thisshould lead to important recommendations for lifestyle changes for prevention of the disease in individuals with specific genomic compositions, as well as specific treatments to slow the progression, reverse the severity, and eventually eliminate the morbidity and mortalityassociated with these diseases.

II. Objectives

1. Primary:

This pilot project’s objectives are to recruit 100-500participants from a set of already highly engaged and consented individuals interested in making ongoing contributions to research, and who have completed and are publicly sharinggenetic information including whole genome sequencing, into a longitudinal study of cognitive function; todevelop reproducible, verifiable online methods for recording epidemiologic data on relevant environmental factors, and to accurately measure cognitive function changes over time using existing standardized techniques; and to compile and securely store this data in aformat that is readily available to integration, analysis, and correlation; eventually leading to completion of the secondary objective.

1. Secondary:

The study’s eventual objectives are to expand numbers to several thousand subjects in effort to identify specific combinations of genetic and environmental factors leading to Alzheimer’s disease and other forms of cognitive impairment and dementia of aging; and to come up with recommendations of lifestyle changes and treatments for prevention and reversal of disease.

III. Background

1. Preclinical data:

The Harvard Personal Genome Project was launched in 2005 with the whole sequencing and public posting of ten individuals’ genomes along with health and trait data. Because it was assumed that the data would be highly identifiable and anonymity could not be guaranteed, the project has relied on an “open consent” format whereby participants are required to demonstrate comprehension prior to enrollment. Under this system as of March 2016,4874individuals have successfully enrolled;3042 participants have completed and posted online 14-part surveys on family history, general phenotype, traits, and medical conditions; and 660 have had whole genomes sequenced and posted online. In the analysis of 660 PGP participants with whole genome sequencing, 176 (20.6%) have been found to be heterozygous for the major genetic mutation in APOE-C130R associated with late onset Alzheimer’s disease (ApoE-4), while 12 (1.8%) individuals have been found to be homozygous for this allele.

B. Clinical data:

N/A. There is no clinical data. The GLEAM Project is not occurring within the clinical care context. Additionally, the study will not be receiving clinical data in any manner that would render it an entity covered by the Health Insurance Portability and Accountability Act (HIPAA).

C. Current experience with procedures (drug or device = N/A):

Assessment of cognitive function of individuals usingvalidated testing, such as the Johns Hopkins Mini Mental State Exam or MMSE (Folstein), the Montreal Cognitive Assessment or MoCA (Nasreddine), the Self-Administered Gerocognitive Exam or SAGE (Scharre), and the AD-8 Dementia Screening Interview of family members (Galvin) have been routinely and reproducibly performed in clinical neurology practices as testing for early signs of cognitive impairment.

D. Any other relevant information to justify the research:

Prior to 2009, the only identified genetic risk factor for Alzheimer’s disease was the aforementioned ApoE-C130R gene. Of the three alleles for this particular gene, one ApoE-3 was neutral, while the third ApoE-2 had a beneficial effect. One study (Khachaturian) has suggested the chance of developing AD by age 80 increased from 7% to 10% in individuals heterozygous for ApoE-4, shifting age of onset forward four years; while the incidence in those homozygous increased to 40% with shift forward 13 years. Clearly other factors (genetic and environmental) are involved as individuals homozygous for ApoE-4 still have a 60% chance of not developing the disease; and there are many other forms of age-related cognitive dysfunction. In the past six years over22 genes have been implicated in one form or another of dementia.

IV. Project Procedures

1. Project design including sequence and timing of project procedures:

The goal of this pilot protocol is to establish efficient techniques for recruitment of human subjects who are already sharing genomic data; to develop an ICD-10 based system and online technique to record in these individuals’relevant environmental exposures and to measure cognitive abilities that can then be reproducibly assessed over time; and to set up secure systems for digital storage of these three data sets that can eventually be analyzed and readily shared with other scientists and researchers around the world.

1.Recruitment will initially be online through the Harvard Personal Genome Project posted as a third party activity on their website well as in-person at gatherings which select for individuals that meet the inclusion criteria, including the Genome Environment Trait GET and MindEx Conferences.

2.Interested participants will register for the GLEAM Project, will complete informed consent, along with identification of third party family contact. We plan to eventually extend recruitment for the larger study outside of PGP to participants who have expressed interest in, or are already, sharing their genomic and genetic data online including on the Global Network of Personal Genome Projects in Canada, UK, and Austria as well as on Open SNP

3.Over the first year of this pilot project protocol, we plan to work on four phases of data gathering (developing and releasing one per quarter):

a. Registered and consented participants will initiallyundergocognitive testingwith either the Montreal Cognitive Assessment MoCA orthe Self-Administered Gerocognitive Exam SAGE in-person at GET Conferences or alternatively posted online at We may also over time enlist other such validated tests or develop alternativemethods for participants to reliably perform exams, record results online, and reliably and securely transmitthe data with or without assistance of third party family contact. This is projected to take place in the Spring of 2016.

b. Participants’ identified third party family contacts will complete the Washington Univ.AD8 Dementia Screening Interview online. We may also over time enlist and develop additional methods for third party family informants to register such validated assessments of subjects’ cognitive function electronically with integrated instructions for administration, timing, scoring, and electronic transmission for storage, compilation, and analysis. This is projected to take place in the summer of 2016.

c. Over the first six months of this pilot project protocol we plan to develop an ICD-10 based Environmental Factors Survey EFS to reliably and reproducibly assess other non-genetic factors involved changes in cognitive function with aging. This survey will be made available place on participants to complete online similar to the PGP Trait & Disease Survey in Google Docs format. This is projected for release in the autumn of 2016.
d. During the last months of the first year of this pilot project protocol, subjects will complete an online Health and Safety QuestionnaireHSQ to assess for medical and emotional issues arising as result of the study. This is projected to occur in the winter of 2016.

4.We plan to develop secure systems for digital storage of these three data sets that can eventually be analyzed and readily shared with other scientists and researchers.

5.After the first year we plan to continue to recruit new participants online. Enrolled GLEAMS subjects will be expected to complete quarterly online updates including: validated variants of MoCA I-IV or SAGE I-III, AD8, EFS, and HSQ. Those attending GET Conference will have optional in-person validation testing with MoCA of SAGE or MMSE.

6.We will continue recruiting GLEAMS participantsfrom consented participants in theHarvard (US) and Global Network of Personal Genome Projects (Canada, UK, and Austria), OpenSNPs and other programs composed of participants who are already sharing their genomic and genetic data online, aiming for up to 750 new human subjects per year.

7.This GLEAMS pilot project protocol is intended for 1-2 years with goal of establishing a baseline cohort of 100-500participants in effort to establish sound techniques for obtaining and securely storing reliable, validated measurements of cognitive function and environmental exposures over several years.

8.Data availability and exportability: GLEAMS may allow participants to optionally receive access to their study data, including formatted or unformatted survey response data. If and when implemented, this access is optional and not required for participation.

9.The pilot project may eventually allow subjects to authorize secure sharing of their individual project data with third parties. At completion of the pilot GLEAM Project, subjects may be given the option upload link and post their own data on open public sites along with their genomic data such as:

a.Personal Genome Project

b.Open Humans

1. Project duration and number of study visits required of research participants: GLEAMS is planned to eventually be a prospective longitudinal study. Afterthe initial 1-2 year pilot project, we aspire to establish a long-term project with annual adjustments in surveys and testing that will last another 23-24 years. GLEAMS subjectswould be expected to complete quarterly assessments online includingMoCA or SAGE, AD-8, EFS, and HSQ. There will also be optional in-person validation cognitivetesting available at the annual GET Conference.

1. Blinding, including justification for or not blinding the trial: N/A.

Blinding is not necessary as no participant or tester bias or preference is anticipated to influence the outcome (analysis of data for statistical relationship between genomic status, environmental factors and cognitive function).

1. Justification of why participants will not receive routine care or will have current therapy stopped:

N/A. No medical care is anticipated and no change in current therapy is anticipated.

1. Justification for inclusion of placebo or non-treatment group:

N/A. There is no treatment involved as part of this study, and therefore no placebo or non-treatment group is necessary.

1. Definition of treatment failure:

N/A. No treatment is planned through this study.Participant removal criteria:

Participants may voluntarily withdraw from the study at any time. Participants would be removed by the researchers ifintentional fraud or deception were to be identified in any part of their participation.

1. Description of what happens to participants receiving therapy when project ends:

N/A. Description of what happens if participation in the project ends prematurely. We plan to follow the wishes of participants in terms of their continued activity and sharing of any personal data generated. Participants will need to understand before entering the study that upon withdrawal from the study, removal of any personal or anonymous data may still be able to be historically discoverable, identifiable, or re-identifiable.

V. Inclusion/Exclusion Criteria

1. Inclusion:

1. Cohort Age:

a.Pilot Project: Age 21 years and above.

b.Long-term Study: Individuals born between January 1, 1941 and December 31, 1970(inclusive); or aged 46-80 years old in 2016-202.

2. Currently participating in or planning to enroll in an open study sharing genomic data online

c.Tested for understanding of ethical issues involved and having signed informed consent for this, including but not restricted to:

d.Harvard Personal Genome Project (US)

c.Global Network of Personal Genome Projects (Canada, UK, Austria)

d.OpenSNPs, etc.

1. Understanding that extension of this study beyond this pilot program will likely encourage, but not require, participants to openly sharetheGLEAMS data generated on Open Humans, PGP websites, etc.

1. Exclusion:
   

1. Initial cognitive impairment jeopardizing mental competency for informed consent.

VI. Drugs/Substances/Devices: N/A

1. Rationale for choosing drug and dose or for choosing the device to be used: N/A.

1. Justification and safety information if FDA approved drugs will be administered for non-FDA approved indications or if dose or routes of administration or participant populations are changed: N/A.

1. Justification and safety information if non-FDA approved drugs without an IND will be administered: N/A.

VII. Study Statistics

1. Primary outcome variables:

This pilot pilot will recruit a cohort of human subjects from a set of already engaged and consented individuals highly motivated in making ongoing contributions to research, who have completed and are publicly sharing whole genome sequencing, into a longitudinal study of underlying causative factors of cognitive dysfunction of aging. It will develop reproducible, verifiable online methods for gathering epidemiologic data on relevant environmental factors, and for accurately measuring cognitive function changes over time using existing validated methods. It will develop efficient methods of compiling and securely storing this data in a format that is readily available for eventual integration, analysis, and correlation; leading to completion of the secondary objectives:

1. Statistical plan including sample size justification and interim data analysis:

The primary objectives of this pilot project are achievable with small sample size. While GLEAMS is eventually projected to be a full-scale multi-decade longitudinal study, the GLEAM pilot project’s primary objectives are more limited and do not require large numbers of participants. Many of the techniques to be applied have already been developed and validated, and the pilot will consist of putting the various components together and have them work efficiently.This should be able to be accomplished with relatively small sample size, and are currently aiming to recruit 100-200 participants over 1-2 years for this purpose.

1. Secondary outcome variables:

Specific combinations of genetic and environmental factors will be identified that are associated with earlier onset, more rapid progression, and more severe mental and physical disability from Alzheimer’s disease and other specific forms of cognitive impairment and dementia of aging; while other combinations will prove to be protective; we will thereby be able to come up with specific recommendations for lifestyle modifications and treatments for prevention and reversal of these diseases.

1. Statistical plan including sample size justification and interim data analysis:

The secondary objectives of GLEAMS will eventually involve a multi-decade longitudinal study of individuals entering their 7th through 9th decades and is expected to require a significantly larger sample size.Subsequenttargets would be for1,000-2,000 subjects over 5 years, and eventually 5,000-10,000 subjects over 15-25 years, similar to that of the Physicians’ Health Study II (Gaziano).

1. Early stopping rules:

Participants will be notified on entry that if the study is terminatedthey will be notified, but that removal of any personal or anonymous data may still be able to be historically discoverable, identifiable, or re-identifiable.

VIII. Risks

1. Medical risks, listing all procedures, their major and minor risks and expected frequency:

1. GLEAM Project participants will be recruited from the Personal Genome Project and equivalent projects, and the risks associated with receiving genetic data and sharing it publicly are pre-existing.

1. Participants’risk of emotional stress, anxiety or depression which may result from discovery of genetic propensity for Alzheimer’s diseaseor otherforms of dementia is also pre-existing.

1. Risk of test results indicating cognitive impairment or dementia:

Risk of GLEAM project participants discovering dementia and other cognitive issues in the course of performing testing for this study is real, and could lead to emotional distress, anxiety or depression.