ABSTRACT
Given the aging of the population, Alzheimer's disease (AD) is a major public health issue. Because of the lack
of effective interventions to date, there is a need to identify new treatments. Emerging evidence has shown that
AD involves multiple pathological mechanisms, with combinations of various forms of vascular and AD pathology.
The renin angiotensin system (RAS) plays a key role in blood pressure (BP) regulation and there is
growing evidence about its likely involvement in the pathogenesis of AD, potentially through BP control and
associated improvement of cerebral blood flow (CBF) and vascular endothelial function, but also through other
mechanisms, including antioxidant, and anti-inflammatory effects, in addition to modulation of amyloid and tau
metabolism. There are very few studies, including our studies, evaluating the role of RAS in cognitively normal
at-risk population to evaluate associations between RAS peptides, structural brain changes and cognitive
function, and none following participants over long period of time. In this study we propose to extend our
previous research in cognitively normal participants
who are obese with T2DM, thus at increased risk
for AD
, from Look AHEAD (Action for Health in Diabetes) study by measuring RAS peptides to elucidate
the underlying mechanism by which the RAS may be involved in structural brain changes affecting
cognitive function over an 9-14-year period. The Look AHEAD study was a randomized clinical trial of a
lifestyle intervention that is now in an observational phase. Look AHEAD is ideal for the proposed study because
of the high prevalence of vascular risk factors (diabetes mellitus, obesity, hypertension, dyslipidemia) as well as
1) stored blood samples and 2) ancillary studies with detailed measures of cognitive function and structural MRI
imaging available. Our aims are to examine 1) change of blood RAS peptide and enzyme levels (ACE-1, ACE-
2, ANGII, ANGIII and ANG1-7) over time (collected at years 1 and 4); 2) associations between blood RAS
enzyme and peptide levels and
brain MRI structural measures related to AD signature regions and vascular
measures
(collected once through years 9-11); and 3) associations between blood RAS enzymes and peptide
levels and global and domain specific cognitive measures (collected longitudinally through years 8-14).
In this proposal we aim to elucidate the role of RAS during aging to understand its contribution in the development
of AD using cross-disciplinary approach. The results of this study will help understand the relationship between
RAS and brain biomarkers and guide future research to examine whether changes in these peptides could serve
as predictors of cognitive decline and/or cognitive impairment.
