The study population and research site
The primary population under study consists of the retirement communities of northwest greater Phoenix, especially Sun City, Sun City West and Sun City Grand. A profile of these communities has been constructed using data from the US Census Bureau (2000) and from the files of the Sun Cities Area Historical Society. All of the communities have as residency requirements a minimum age of 55 years. The populations of Sun City, Sun City West and Sun City Grand, respectively, are 38,306, 26,344 and 9,270 (total of 73,920 as of 2000). Sun City, first established in 1960, was one of the first planned retirement communities in the United States. Sun City West and Sun City Grand followed, in 1978 and 1996, respectively. Due to a lack of new land availability, the populations of all three communities have stopped increasing. The population of Sun City has been maintained at about 40,000 for 3 decades, suggesting that a continued influx of new retirees will maintain the populations of all of the communities. Future new developments are already planned, with Sun City Festival Ranch now in its early stages. This latest community is expected to add another 12,000 residents by 2010. Additionally, surrounding areas contain a mix of retirees and young families.
Although migration of retirees to the region occurred initially in three major waves, coinciding with the establishment and marketing of housing developments in Sun City, Sun City West and Sun City Grand, the residents are all very similar, being composed overwhelmingly of elderly, well-educated, Caucasian, middle and upper income individuals originating most commonly from Midwestern US states. Initially there must have been some age differences between the communities due to the differences in their construction time, but continued replacement of initial residents with later migrants has almost erased the evidence of this, as the median ages of the residents are 75, 78 and 75, for Sun City, Sun City West and Sun City Grand, respectively. The average residency time in Sun City is 12.6 years. As there is very little outmigration, the turnover is mostly due to deaths. Of the original Sun City population, 90% were replaced by a second generation of retirees by 1990.

Sun Health Research Institute
Sun Health Research Institute (SHRI) is an affiliate of Sun Health Corporation, a non-profit, community owned and operated health care provider. What is now known as Sun Health was first conceived in 1965 and was intended to serve the needs of Sun City, Arizona, one of the first planned retirement communities. Sun Health now serves not only the original Sun City but also the adjacent retirement communities of Sun City West and Sun City Grand as well as northwest greater Phoenix in general, all of which have experienced rapid growth of both retirement and non-retirement populations. Services provided by Sun Health include medical insurance, two acute care hospitals, extended and hospice care, outpatient clinics and Alzheimer care residences. Sun Health has recently announced that it will merge with Banner Health, a larger not-for-profit health care provider with multiple facilities throughout greater Phoenix as well as California, Utah and Colorado.
Sun Health Research Institute was established in 1986 with funds from Sun Health operations revenue and charitable contributions to the Sun Health Foundation. Initially known as the Institute for Biogerontology Research, the Institute has grown into one of the world’s largest privately-funded research centers for age-related disorders. The focus of the Institute’s scientific work has been, since its inception, Alzheimer’s disease, with substantial Parkinson’s disease and arthritis research beginning in 1996. More recently there have been extensions into fibromyalgia, orthopedic and prostate cancer research. Since 1998, the Institute has been part of the Arizona Alzheimer’s Consortium (AAC), a state-funded alliance that includes Sun Health Research Institute, the University of Arizona, Tucson Veteran’s Administration Medical Center, Barrow Neurological Institute, the Arizona Mayo Clinic, Arizona State University and the Banner Health/Good Samaritan Hospital system. The same consortium was awarded a National Institutes on Aging Alzheimer’s Disease Core Center (ADCC) in 2001 and a state-funded Arizona Parkinson’s Disease Center in 2002. Both of these are headquartered at SHRI.

The Brain Donation Program at Sun Health Research Institute
The Brain Donation Program has been in existence since 1987 and has enrolled more than 2500 donors over that time, which constitutes about 2% of the current combined populations of the surrounding retirement communities. Of these, 1042 donors have expired and their brains have been collected and stored, while there are 1061 living donors. Donors have all volunteered specifically for the program and are highly motivated, with an annual drop-out rate of only 1.8%. Recruitment relied initially on hospital staff, who obtained consents from family members of individuals who died while admitted. Recruitment gradually became almost entirely done on a prospective basis, primarily by word-of-mouth, through interactions of the population with physicians and nursing staff belonging to the Sun Health provider network, and through public speaking events and tours of the Institute given by Institute staff to community groups and the general public. Institute staff give approximately 60 such public interactive events each year. Relatively frequent media releases also contribute to recruitment. Eligibility criteria for the Program are simple in that the subjects must be free of hazardous infectious diseases and must consent to annual clinical assessments at SHRI. Additionally, at least two years of the applicant’s private medical records must be received and reviewed by Brain Donation Program staff prior to acceptance. The medical records review is directed mainly at excluding hazardous infectious disease conditions. All enrolled subjects or legal representatives sign an Institutional Review Board-approved informed consent form allowing both clinical assessments during life and several options for brain and/or bodily organ donation after death. A separate section requests the subject to allow or disallow DNA isolation and storage as well as genetic testing. Donors are allowed to withdraw from the program at any time. When a donor loses his/her mental capability, ordinarily a family member will be appointed as the donor’s legal representative. That legal representative would then have the power to withdraw the donor from the program. The informed consent has a section that fully discloses the possible commercial use of our tissue, stating that SHRI, personnel from SHRI, personnel from other institutions, or other organizations that utilize our tissue may obtain monetary benefit from the use of the tissue.
Between 1987 and 1995 brain donors did not receive formal neuropsychological testing. Their mental status was determined by requisitioning medical records from their primary care physicians, neurologists, psychologists and psychiatrists, and through telephone interviews with family members and caregivers, both at the time of enrollment and in the immediate postmortem period. In 1996 a clinical psychologist was hired and from then onwards, a standardized neuropsychological screening assessment has been administered to most of the subjects enrolled in the Brain Donation Program. Also since 1996, most donors have received a standardized neurological evaluation tailored to detect overt and incipient movement disorders. In 2000, the clinical operations of the Program were greatly expanded, with the hiring of a neurologist, another neuropsychologist and associated support staff, allowing the administration of a full neuropsychological test battery. If a previously undetected medical abnormality is discovered in the course of the annual clinical assessment, the donor is informed and advised to visit their physician for further investigation and/or treatment. The SHRI physician will also ask the donor’s permission to inform their private physician of this finding.

Consideration of sampling issues
Subjects from the Sun Cities are not an accurate representative sample of the entire US elderly population, in that they lack racial diversity and are more highly educated, have higher incomes and live longer than the average US citizen. Although the study population lacks the diversity of the general US population, there are advantages of using a more homogeneous group. The use of homogeneous populations with minimal genetic and environmental variability decreases the subject number required to attain adequate statistical power. This has been recognized by many researchers and has been used, for example, by groups utilizing isolated populations to study inheritance (Adachi et al. 1992; Johanneson et al. 1999; Lio et al. 2003; Mathews et al. 2004; Peschken and Esdaile 1999). However, studying a homogeneous group allows the possibility of missing disease characteristics resulting from alleles that may be enriched in some ethnic groups but not in others.
The effect of selection bias on the study population must be considered, as autopsy studies do not represent random sampling. A recent study has shown that subjects selected for autopsy do not differ appreciably from those that are not autopsied (Lim et al. 1999) but this may differ with locale. The issue of “volunteer bias” has been raised, as some studies have suggested that volunteers generally come from a higher socioeconomic background than non-volunteers (Gustavsson et al. 1997; Mandel et al. 2000; Sofuoglu et al. 2000). Volunteer bias may apply differentially to normal and diseased subjects, as normal subjects are almost always true volunteers while diseased subjects are often enrolled by family members after they have lost independent decision-making capacity. Very elderly normal control subjects might even be regarded as “supernormals” possessing a general genetic resistance to disease. We have considered this possibility for our study population. Queries of our database have shown, however, that our Alzheimer’s disease and non-demented control subjects have generally similar prevalences of major disease conditions (Table 1). Control subjects have a substantially higher prevalence of cancer than AD subjects. Also, as the subjects had essentially the same age at death, the possibility of a “survivor bias” between the two groups is ruled out. The greater prevalence of a medical history of coronary atherosclerotic disease and stroke in AD subjects supports many previous similar reports.
Table 1 Comparison of AD and control subjects—age at death and disease class prevalence