Medical and public health innovations in the 20th century resulted in unprecedented increases in longevity. With increased lifespan, however, the prevalence of age-related diseases also has increased. Chief among these illnesses is Alzheimer disease, by far the most common cause of dementia in late life. Although Alois Alzheimer first identified the disease that bears his name in 1906, little attention was given the disorder until the 1970s.
In that decade, clinicians and investigators at Washington University began to seek answers. Led by Leonard Berg, MD, a dementia research team eventually obtained funding from the National Institutes of Health (NIH) in 1979 and inaugurated the Memory and Aging Project (MAP). Since that time, the MAP has supported seminal studies and projects that have expanded the research understanding of Alzheimer disease and set worldwide standards for its diagnosis and treatment. The St. Louis Chapter of the National Alzheimer’s Association initially was founded in 1981 by Berg and family members of MAP participants. Major NIH-grants funded in 1984 and 1985 (see below) established the Alzheimer Disease research Center (ADRC) with Berg as Center Director.
Following Dr. Berg’s retirement in 1998, the Knight ADRC was co-directed by Eugene H. Johnson, PhD, Norman J. Stupp Professor of Neurology, and John C. Morris, MD, Harvey A. and Dorismae Hacker Friedman Distinguished Professor of Neurology, until 2003 when Morris assumed the title of ADRC Director. In 2010, Charles F. and Joanne Knight endowed the Center, which then became the Charles F. and Joanne Knight Alzheimer Disease Research Center (Knight ADRC). While advancing a high-power basic and clinical research agenda, the Knight ADRC also is an active center for therapeutic trials.
From its beginning, the Knight ADRC promoted collaborative research at Washington University and beyond by welcoming students, trainees and visiting scientists, both domestic and international. It provides a productive training environment for students in nursing, social work and medicine, residents in geriatrics, psychiatry and neurology, and postdoctoral fellows. The Knight ADRC supports junior faculty as well as regional, national and international scholars. Among others, investigators from Brazil, Canada, Chile, China, Croatia, France, Italy, Japan, the Netherlands, the Philippines, Saudi Arabia, Singapore, South Korea, Spain, Taiwan, and Turkey have completed visiting fellowships at the Knight ADRC.
The MAP evolved into two major grants that have been continuously funded by the National Institute on Aging of the NIH. The program project, Healthy Aging and Senile Dementia (HASD), awarded first in 1984, and then the Alzheimer Disease Research Center (Knight ADRC), awarded in 1985. In the 1990s clinical-neuropathological studies from these grants led by John C. Morris, MD, and ADRC colleague, Joseph L. Price, PhD, found evidence of AD lesions in brains of participants who were cognitively normal at death. This finding in conjunction with amyloid imaging of MAP participants developed the concept of preclinical AD, i.e. the hypothesis that AD pathology begins years before symptoms appear.
The study of preclinical AD was the foundation of the Adult Children Study (ACS) funded in 2005 with Morris as Principal Investigator. The ACS recruited cognitively normal, middle-aged adult children of individuals with and without AD for collection of biological markers of AD (fluid and imaging). Studying individuals with a family history of AD longitudinally from middle age permitted study of the critical preclinical period prior to symptom onset. This was one of the first major biomarker studies of healthy, middle-aged, participants at risk of AD by virtue of family history. One ACS project, entitled the Familial Adult Children Study (FACS), examined a very rare group of adult children: offspring of a parent afflicted with a causative mutation for AD.
The success of the ACS and FACS encouraged NIA program staff to issue a request for applications to establish an international registry of research participants from families with dominantly inherited AD. Dr. Morris successfully led an international team to establish the Dominantly Inherited Alzheimer Network (DIAN) in 2008. The DIAN participants, highly likely to develop AD at a predictable age, enabled the first-ever secondary prevention trials for AD. Randall J Bateman, MD established the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) and in 2012 enrolled the initial DIAN participant in the first-ever AD prevention trial using putative disease-modifying therapies.
Learn more about Knight ADRC funding.
Early Contributions and Principles
- Development of a clinical tool to determine the absence or presence of dementia, and where present to stage its severity. The Clinical Dementia Rating Scale or CDR®1,2 involves experienced clinicians who synthesize information regarding intraindividual cognitive and functional decline that is obtained from interviews with the participant and separately with an informant. The reliability of the CDR has been established and our protocol to obtain the information to derive the CDR is the basis for other standard dementia assessment batteries. The CDR has become the standard scale worldwide by which clinicians rate dementia severity for most all dementia research and therapeutic trials and has been translated 84 times. The ability to distinguish the early stages of Alzheimer disease from healthy aging has been a direct result of the Knight ADRC’s use of collateral source interviews in which information provided by an individual’s spouse, child, other relative, or friend is incorporated into the assessment.
- Independence of clinical evaluation from neuropsychological and biomarker assessments to enhance scientific rigor. The CDR is scored without reference to neuropsychological tests, biomarker results or even previous CDR determinations.1 The CDR is sensitive to even very mild impairment and accurately identifies symptomatic AD, often before objective cognitive deficits can be detected. This separation of clinical and other variables avoids confounding when dependent and independent variables are mixed.
- The principal of intraindividual change guides the clinician’s judgment about the presence or absence of dementia where the individual serves as his or her own control. Impairment is defined as decline from previously attained levels of function due to cognitive change.1
- Establishing partnerships with the African American community through the African American Advisory Board (AAAB), the Memory and Aging Project Satellite (MAPS) and outreach efforts with the St. Louis Black Repertory Company, the Mound City Medical Forum and the Delta Sigma Theta Sorority to increase awareness of Alzheimer disease in the African American community. Importantly, the AAAB has been instrumental in raising the cultural competency of the Knight ADRC and its faculty and staff so that it is more welcoming to people of color, with the result that about 20% of the Knight ADRC’s cohort now identifies as African American.
More Recent Contributions
- The concept of preclinical disease emerged through examination of the brains of cognitively normal older adults individuals3 and molecular biomarker studies of middle-aged, cognitively normal individuals.4,5 These studies and the DIAN established that the presence of AD pathology first occurs some 20 years before symptom onset. This knowledge has improved understanding of how AD is initiated in the brain and also sets the stage for prevention trials, both primary and secondary.
- The routine collection of multiple biomarker modalities for correlation with clinical and cognitive data was accomplished by major investment of resource in amyloid and tau imaging and biofluid technology.6-10 The Knight ADRC has perhaps the largest collection of carefully characterized research participants (many beginning in middle-age) who undergo longitudinal clinical evaluations, neuropsychological tests, lumbar punctures, MRI, and amyloid and tau PET imaging. Need now to add blood biomarkers.
- Examination of race and its effects, social and biological, on AD risk, clinical and biological manifestations, and neuropathology. The ADRC was one of the first centers to engage the African American population in oversight, cooperation, and participation. Through these partnerships, the Knight ADRC has been successful in including African Americans in research participation, including biomarker and neuropathological studies.11-19
- Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology. 1993;43(11):2412-2414.
- Berg L. Clinical Dementia Rating (CDR). Psychopharmacol Bull. 1988;24(4):637-639.
- Morris JC, Price JL. Pathologic correlates of nondemented aging, mild cognitive impairment, and early-stage Alzheimer’s disease. J Mol Neurosci. 2001;17(2):101-118.
- Mintun MA, Larossa GN, Sheline YI, et al. [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease. Neurology. 2006;67(3):446-452.
- Mintun MA, Vlassenko A, Xiong C, Sheline Y, Goate A, Morris JC. The natural history of amyloid-beta plaque appearance and growth in cognitively normal adults as quantified with longitudinal [11C] PIB PET imaging. PNAS. 2010.
- Fagan AM, Csernansky CA, Morris JC, Holtzman DM. The search for antecedent biomarkers of Alzheimer’s disease. J Alzheimers Dis. 2005;8(4):347-358.
- Coats M, Morris JC. Antecedent biomarkers of Alzheimer’s disease: the adult children study. J Geriatr Psychiatry Neurol. 2005;18(4):242-244.
- Sutphen CL, Jasielec MS, Shah AR, et al. Longitudinal CSF biomarker changes in preclinical Alzheimer disease during middle-age. JAMA Neurol. 2015;72:1029-1042.
- Sutphen CL, McCue L, Herries EM, et al. Longitudinal decreases in multiple cerebrospinal fluid biomarkers of neuronal injury in symptomatic late onset Alzheimer’s disease. Alzheimers Dement. 2018;14(7):869-879.
- Bateman RJ, Xiong C, Benzinger TL, et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med. 2012;367(9):795-804.
- Wilkins CH, Grant EA, Schmitt SE, McKeel DW, Morris JC. The neuropathology of dementia of Alzheimer disease in African American and White individuals. Arch Neurol. 2006;63:87-90.
- Wilkins CH, Birge SJ, Sheline YI, Morris JC. Vitamin D Deficiency Is Associated With Worse Cognitive Performance and Lower Bone Density in Older African Americans. Journal of the National Medical Association. 2009;101(4):349-354.
- Malmstrom TK, Miller DK, Coats MA, Jackson P, Miller JP, Morris JC. Informant-based dementia screening in a population-based sample of African Americans. Alzheimer Dis Assoc Disord. 2009;23(2):117-123.
- Williams MM, Scharff DP, Mathews KJ, et al. Barriers and facilitators of African American participation in Alzheimer disease biomarker research. Alzheimer Dis Assoc Disord. 2010;24 Suppl:S24-29.
- Williams MM, Meisel MM, Williams J, Morris JC. An interdisciplinary outreach model of African American recruitment for Alzheimer’s disease research. Gerontologist. 2011;51 Suppl 1:S134-141.
- Morris JC, Schindler SE, McCue LM, et al. Assessment of Racial Disparities in Biomarkers for Alzheimer Disease. JAMA Neurol. 2019;76(3):264-273.
- Xiong C, Luo J, Coble D, Agboola F, Kukull W, Morris JC. Complex interactions underlie racial disparity in the risk of developing Alzheimer’s disease dementia. Alzheimers Dement. 2020;16(4):589-597.
- Meeker KL, Wisch JK, Hudson D, et al. Socioeconomic Status Mediates Racial Differences Seen Using the AT(N) Framework. Ann Neurol. 2021;89(2):254-265.
- Schindler SE, Cruchaga C, Joseph A, et al. African Americans Have Differences in CSF Soluble TREM2 and Associated Genetic Variants. Neurology Genetics. 2021;7(2):e571.