Rush Religious Orders Study

The Religious Orders Study enrolls nuns, priests, and brothers without known dementia, from across the United States. Participants must agree to an annual detailed clinical evaluation and brain donation at the time of death. Each subject signs a consent form and an Anatomical Gift Act. The study was approved by the Institutional Review Board of Rush University Medical Center. The study primarily recruits clergy living in more than 40 communities, including three predominantly African American communities, and Hispanic sisters primarily from communities in San Antonio. Clinical data collection began in January of 1994. The study has a rolling admission with participants enrolling each year. To date, more than 1150 participants have enrolled, approximately 30% are men and approximately 90% are white, non-Hispanic. The mean age at entry is approximately 75 years with an average education of approximately 18 years. Follow-up clinical evaluations are conducted annually with a 95% follow-up rate of survivors. More than 500 brain autopsies have been performed with an autopsy rate nearly 95%.

Rush Memory and Aging Project

The Memory and Aging Project enrolls older lay persons from across northeastern Illinois (Bennett, Buchman, et al., 2005). Participants must agree to an annual detailed clinical evaluation and donation of brain, spinal cord, nerve, and muscle at the time of death. Each subject signs a consent form and an Anatomical Gift Act. The study was approved by the Institutional Review Board of Rush University Medical Center. The study primarily recruits from more than 40 communities. It also recruits from Section 8 and Section 202 housing, retirement homes, and through local Churches and social service agencies serving minorities and low-income elderly. Clinical data collection began in the fall of 1997. The study has a rolling admission with participants enrolling each year. To date, more than 1450 participants have enrolled, approximately 30% are men and approximately 90% are white, non-Hispanic. The mean age at entry is approximately 80 years with an average education of approximately 14 years with more than a third with 12 or fewer years of education. Follow-up clinical evaluations are conducted annually with a follow-up rate in excess of 90% of survivors. More than 375 autopsies have been performed with an autopsy rate over 80%.

Rush Minority Aging Research Study

The Minority Aging Research Study recruits older African Americans from the Chicago area using the same methodology as used by the Rush Memory and Aging Project. Each subject signs a consent form agreeing to an annual detailed clinical evaluation and participation in an organ donation component is encouraged but not required. The study was approved by the Institutional Review Board of Rush University Medical Center. Clinical data collection began in 2004. The study has a rolling admission with participants enrolling each year. To date, more than 350 participants have enrolled, approximately 30% are men. The mean age at entry is approximately 73 years with an average education of approximately 14 years with more than a third with 12 or fewer years of education. Follow-up clinical evaluations are conducted annually with a follow-up rate in excess of 90% of survivors.

Demographics, Indicators of Reserve, and Clinical Diagnoses

Sex, race, and ethnicity are ascertained using the 1990 U.S. Census questions.

Indicators of reserve included direct and indirect measures. Direct measures included years of formal education, and early, mid-, and late life cognitive activities (Barnes, Wilson, Mendes de Leon, & Bennett, Reference Barnes, Wilson, Mendes de Leon and Bennett2006; Bennett, Schneider, Wilson, Bienias, & Arnold, Reference Bennett, Schneider, Wilson, Bienias and Arnold2005; Bennett, Wilson, et al., Reference Bennett, Wilson, Schneider, Evans, Aggarwal, Arnold and Bienias2003; Wilson, Mendes de Leon, et al., Reference Wilson, Mendes de Leon, Barnes, Schneider, Bienias, Evans and Bennett2002; Wilson, Scherr, Schneider, Tang, & Bennett, Reference Wilson, Scherr, Schneider, Tang and Bennett2007). We also measure height (Buchman, Schneider, Wilson, Bienias, & Bennett, Reference Buchman, Schneider, Wilson, Bienias and Bennett2006). Indirect measures included parental education, income, occupation, and father's occupation; in addition, birth addresses were linked to 1920 census data to determine early-life socioeconomic status including literacy rates and Duncan socioeconomic status of head of household for county or census track (Wilson et al., Reference Wilson, Scherr, Hoganson, Bienias, Evans and Bennett2005; Wilson, Scherr, Schneider, Tang, & Bennett, Reference Wilson, Scherr, Schneider, Tang and Bennett2007).

The diagnostic process for Alzheimer's disease and mild cognitive impairment included a decision tree designed to mimic expert clinical judgment, implemented by computer (Bennett, Schneider, Aggarwal, et al., Reference Bennett, Schneider, Aggarwal, Arvanitakis, Shah, Kelly and Wilson2006). It combines data reduction techniques for the cognitive performance testing (see below) with a series of discrete clinical judgments made in series by a neuropsychologist and a clinician. The evaluation is designed to reduce costs and enhance uniformity of diagnostic decisions over time and space (Weir et al., Reference Weir, Wallace, Langa, Plassman, Wilson, Bennett and Sano2011).

Apolipoprotein E allele status was performed by Agencourt Bioscience Corporation (Beverly, MA) using high throughput sequencing (Bennett, De Jager, Leurgans, & Schneider, Reference Bennett, De Jager, Leurgans and Schneider2009).

Measures of Cognition

A battery of cognitive performance tests is administered each year (Barnes et al., Reference Barnes, Wilson, Mendes de Leon and Bennett2006; Boyle, Barnes, Buchman, & Bennett, Reference Boyle, Barnes, Buchman and Bennett2009; Wilson, Beckett, et al., Reference Wilson, Beckett, Barnes, Schneider, Bach, Evans and Bennett2002). The Mini-Mental State Examination (MMSE) is primarily used to describe the cohort. Eleven tests are used for diagnostic classification, including complex ideational material. The remaining tests assess a range of cognitive abilities and are used to construct separate summary measures of five cognitive domains, including episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability. Semantic memory can be separated into word knowledge and word generation (fluency). There are nineteen tests in common across the three studies. Seven tests can be administered by telephone. This version yields composites for episodic memory, semantic memory, and working memory (Wilson & Bennett, Reference Wilson and Bennett2005).

Measures of Neuropathology

The brain is removed and weighed. The post-mortem neuropathologic evaluation includes a uniform structured assessment of AD pathology, cerebral infarcts, Lewy body disease, and other pathologies common in aging and dementia. Brain tissue stained with modified Bielschowky is used to count neuritic plaques, diffuse plaques, and neurofibrillary tangles in five brain regions, including the mesial temporal lobe (hippocampal formation and entorhinal cortex) and neocortex (superior frontal and middle temporal gyri, and parietal lobe) (Bennett, Schneider, Arnold, Tang, & Wilson, Reference Bennett, Schneider, Arnold, Tang and Wilson2006; Bennett et al., Reference Bennett, Wilson, Schneider, Evans, Aggarwal, Arnold and Bienias2003). The location, size, and age of each macroscopic infarct are recorded as described (Schneider et al., Reference Schneider, Wilson, Bienias, Evans and Bennett2004; Schneider, Boyle, et al., Reference Schneider, Boyle, Arvanitakis, Bienias and Bennett2007). Microscopic infarctions are identified on H&E stained sections (Arvanitakis et al., Reference Arvanitakis, Leurgans, Barnes, Bennett and Schneider2011). Lewy bodies are identified on alpha-synuclein immunostained sections from six brain regions (Bennett, Schneider, et al, Reference Bennett, Schneider, Wilson, Bienias and Arnold2005; Schneider, Arvanitakis, et al, Reference Schneider, Boyle, Arvanitakis, Bienias and Bennett2007; Schneider, Arvanitakis, et al., Reference Schneider, Arvanitakis, Bang and Bennett2007).

Advantages of These Cohort Studies for Examining Cognitive Reserve

The neurobiologic basis of cognitive reserve is not well understood. Although there is evidence to suggest that the modest association between cognition and neuropathology may reflect the inter-individual variability of cognitive reserve, it has been challenging to operationalize or measure reserve directly. As noted by Jones et al. (this issue), if reserve is defined as the difference between expected and observed impairment for a given level of pathology, then good measures of performance and pathology are needed to measure reserve. The observational studies used in three of the current papers have several advantages that advance the study of reserve and the sophisticated latent variable modeling techniques used by the authors allow a better understanding of both the neural underpinnings of reserve and the experiential factors that may influence reserve. The combination of large, clinically well-characterized older adults with high rates of follow-up participation, comprehensive well-established cognitive performance measures, and a wide spectrum of neuropathology in prospective longitudinal studies provide a unique opportunity to directly link common indicators of reserve (e.g., education, occupation, cognitive activities) to measures of neuropathology. Furthermore, the substantial overlap in clinical and cognitive measures across the three epidemiologic studies allows investigators to pool data across studies increasing power to not only examine clinical–pathologic correlations but to address issues across race and ethnicity as well. Together, the set of papers in this special series represents an important contribution to the study of cognitive reserve.