Blood plasma metrics as disease biomarkers in atypical Alzheimer's disease - PROJECT SUMMARY Alzheimer's disease (AD) is a major public health problem affecting an estimated 6.7 million Americans. However, ~25% AD patients present with atypical non-amnestic clinical features such as visual, language, behavioral, executive, or motor difficulties. Furthermore, not all patients that present with these clinical phenotypes show evidence of amyloid and tau on positron emission tomography (PET). To date, there have been no reports on the diagnostic utility and performance of blood plasma biomarkers in atypical AD patients. There is an urgent need to address this to allow blood plasma biomarkers to be incorporated into clinical practice to improve diagnosis and reduce diagnostic delays, and in clinical trials to aid patient selection and provide disease outcome measures. The overall goal of this R03 is, therefore, to determine the diagnostic utility of plasma biomarkers and their relation to aspects of pathophysiology in atypical AD. This R03 will leverage existing blood samples, and clinical and neuroimaging data from 210 patients recruited into R01-AG50603 (PI Whitwell) to address the following specific aims: 1) To assess the value of blood plasma measures as diagnostic biomarkers in atypical AD. Here we will assess whether plasma biomarkers would be useful diagnostic biomarkers in atypical AD patients, if they could differentiate atypical AD patients from healthy controls and from patients that present with these clinical syndromes but do not have AD. 2) To assess the value of blood plasma measures as useful disease biomarkers/outcome measures in atypical AD. Here we will assess whether plasma biomarkers could be useful disease markers and whether they are related to clinical outcomes and other aspects of brain pathophysiology, including amyloid and tau burden, brain metabolism and brain volume. This research proposal is innovative because it investigates the utility and performance of these plasma biomarkers in atypical AD patients, who, despite being a part of the AD continuum do not present with memory loss but presents with deficits in non-memory domains and distinct neuroimaging signatures. This is important because current AD trials typically emphasize memory dysfunction as key criteria, which atypical AD patients do not fulfil. Hence the inclusion of plasma biomarkers as pre- selection tools in AD treatment trials will allow the inclusion of these patients. Another regard in which this research proposal is innovative is its focus on identifying the relationship between plasma markers, neuroimaging biomarkers and aspects of brain pathophysiology in atypical AD patients. This is important as it will establish how plasma biomarkers relate to meaningful outcomes in atypical AD patients during clinical trials. Ultimately, this R03 will have a significant impact on public health as atypical AD affects ~1 million Americans.
