People aged 90 and older (the oldest-old) comprise the fastest growing segment of the population and have the highest rates of dementia. Nonetheless, little is known about the causes of dementia in this age group. Approximately half of demented of oldest-old individuals do not appear to have significant pathology to explain cognitive loss, while a similar proportion of non-demented oldest-old have high levels of Alzheimer's disease (AD) and other pathologies while maintaining good cognition. Moreover, risk factors are largely unknown in this age group and appear paradoxical, with traditional risk factors such as hypertension appearing to be protective for dementia. The primary goal of our proposal is a better understanding of the risk factors and biological substrates for the expression of dementia in the oldest-old. Focusing our studies on the clinical pathological discordance for dementia and the paucity of knowledge of risk factors in this age group, we hypothesize that AD, vascular, and other pathologies represent preclinical disease in non-demented oldest-old (significant pathology without dementia) and thus will be associated with greater rates of cognitive decline and dementia in prospective studies (Aim1). In contrast, individuals who have dementia without significant pathology will, in fact, have low levels of multiple pathologies that contribute additively to cognitive impairment (Aim 2). Because multiple dementing pathologies, not just AD, appear to contribute to cognitive loss in people with advanced age, we will investigate risk factors in relation to specific pathologies, identified on autopsy or imaging (Aim 3). Risk factor data collected in the Leisure World Cohort Study (1980s) and The 90+ Study (2003-present) will provide our investigations with a rich dataset spanning several decades, and can contribute to our understanding of the changing relationship of risk factors with age. In addition to traditional risk factors, such as APOE, exercise, and physical performance, we will study novel factors (fluctuations in blood pressure and O2 saturation). For these investigations, new procedures have been added to our epidemiological study, including neuroimaging (structural MRI and florbetapir amyloid PET) and ambulatory 24-hour monitoring of blood pressure (BP) and O2 saturation. We hypothesize that normal BP is a risk factor for dementia because daytime and nocturnal BP fluctuations lead to hypotension increasing the risk of microinfarcts and vascular cognitive impairment. Hypoxia in the oldest-old will be associated with increased amyloid deposition and AD related pathologies, as well as with microinfarcts, thereby increasing the risk of dementia. We anticipate more than 2/3 of our subjects will participate in The 90+ Autopsy Study, adding further value to our clinical, genetic, and imaging studies in these well characterized population-based subjects. On completion of The 90+ Study, we anticipate making all of our data publicly available for research (Aim 4). The 90+ Study will provide a wealth of information about the oldest-old, an important and growing segment of our population. The knowledge obtained from these investigations can have profound public health impact.

Public Health Relevance

People over 90 (the Oldest Old) are the fastest growing segment of our population and have the highest rates of dementia, although causes and risk factors are largely unknown. With clinical, imaging and pathological investigations, the primary goal of this proposal is to better understand the risk factors and biological substrates for dementia in a population-based sample of our oldest citizens. Information from these investigations has the potential for enormous public health impact in ameliorating the burden of dementia in our oldest citizens.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG021055-12
Application #
8709957
Study Section
Special Emphasis Panel (ZRG1-PSE-P (02))
Program Officer
Anderson, Dallas
Project Start
2002-09-15
Project End
2018-05-31
Budget Start
2014-08-15
Budget End
2015-05-31
Support Year
12
Fiscal Year
2014
Total Cost
$2,063,256
Indirect Cost
$304,436
Name
University of California Irvine
Department
Neurology
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Robinson, John L; Molina-Porcel, Laura; Corrada, Maria M et al. (2014) Perforant path synaptic loss correlates with cognitive impairment and Alzheimer's disease in the oldest-old. Brain 137:2578-87
Pensalfini, Anna; Albay 3rd, Ricardo; Rasool, Suhail et al. (2014) Intracellular amyloid and the neuronal origin of Alzheimer neuritic plaques. Neurobiol Dis 71:53-61
Guay, Manon; Dubois, Marie-France; Corrada, MarĂ­a et al. (2014) Exponential increases in the prevalence of disability in the oldest old: a Canadian national survey. Gerontology 60:395-401
Nelson, Peter T; Estus, Steven; Abner, Erin L et al. (2014) ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology. Acta Neuropathol 127:825-43
Yasar, Sevil; Xia, Jin; Yao, Wenliang et al. (2013) Antihypertensive drugs decrease risk of Alzheimer disease: Ginkgo Evaluation of Memory Study. Neurology 81:896-903
Corrada, Maria M; Paganini-Hill, Annlia; Berlau, Daniel J et al. (2013) Apolipoprotein E genotype, dementia, and mortality in the oldest old: the 90+ Study. Alzheimers Dement 9:12-8
Berlau, Daniel J; Corrada, Maria M; Robinson, John L et al. (2013) Neocortical *-amyloid area is associated with dementia and APOE in the oldest-old. Alzheimers Dement 9:699-705
Kawas, Claudia H; Greenia, Dana E; Bullain, Szofia S et al. (2013) Amyloid imaging and cognitive decline in nondemented oldest-old: the 90+ Study. Alzheimers Dement 9:199-203
Bullain, Szofia S; Corrada, Maria M; Shah, Barbara Agee et al. (2013) Poor physical performance and dementia in the oldest old: the 90+ study. JAMA Neurol 70:107-13
Berlau, Daniel J; Corrada, Maria M; Peltz, Carrie B et al. (2012) Disability in the oldest-old: incidence and risk factors in the 90+ study. Am J Geriatr Psychiatry 20:159-68

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