Research Project
9976632
There is no simple test to detect early Alzheimer?s disease (AD) or predict when symptoms will start, but evidence of presymptomatic AD comes from expensive imaging or invasive cerebrospinal fluid (CSF) detection of amyloid. Our goal is to identify biomarkers that fill this gap with simple tests that detect the presymptomatic stage of AD pathology benchmarked to amyloid biomarkers. Our early studies defined presymptomatic AD based on CSF testing: elderly study participants (60-100 yr) were classified as cognitively healthy (CH) when they did not deviate from age, sex, and education norms in a multi-domain, neuropsychometric battery. CH participants were next classified based on a regression-derived Aß42/Tau ratio cutoff that diagnosed >85% of clinically probably AD: CH individuals with pathological CSF ratio were CH-PAT; those with normal CSF amyloid/tau ratios were CH-NAT. After 3-4 years, 40% of CH-PAT but none of CH-NAT declined cognitively. This confirms that CH individuals provide a strong cohort to evaluate simple biomarkers to identify presymptomatic AD (CH-PATs) from normal aging (CH-NATs). Executive function measured by Stroop interference was less good in CH-PATs, consistent with known age- related decline. We hypothesized that this apparent subtle decline in executive function in CH-PAT might be objectively unmasked with cognitive challenge, analogous to the Treadmill test to unmask incipient coronary insufficiency. We confirmed this during simple (zero-back) working memory testing, revealed by EEG biomarkers of spectral entropy and alpha event-related desynchronization. Since executive functions are consciously motivated and are heavily influenced by subliminal sensory and autonomic input, we postulate that subliminal and autonomic measures might combine to provide a more complete set of biomarkers of the early presymptomatic stage of AD. This conscious, subliminal, and autonomic (CSA) system is altered in the symptomatic stage of AD, but has not been examined in presymptomatic AD. We detect changes in CH-PATs in conscious and autonomic biomarkers, and developed a method for sensitive subliminal testing under cognitive challenge. We hypothesize that cognitive challenge in CH individuals will expose latent impairment of CSA system biomarkers in CH-PATs (presymptomatic AD), and predict biochemical and cognitive decline. Our Specific Aims will test our hypothesis in a new cohort and test the ability of CSA biomarkers to predict decline in a 3-year longitudinal study. This CSA systems approach provides multiple novel translational biomarkers to characterize presymptomatic AD (CH-PATs) based on simple executive function challenge. The biomarkers are non-invasive, yet are validated with their benchmark to established CSF biomarkers. Our research addresses an important current gap in identifying presymptomatic AD biomarkers.
