Cognitive challenge to reveal systemic neurophysiology biomarkers in pre-symptomatic Alzheimer’s disease

The burden on Alzheimer’s disease (AD) is growing due to longer life span and lack of effective treatment. The
knowledge gap exists for early detection and prediction of symptom onset. AD pathology (amyloid/tau) and
synaptic dysfunction precedes symptoms by decades and offers a window of opportunity for early AD
detection. Current early AD diagnosis depends on expensive imaging or invasive cerebrospinal fluid (CSF)
detection of amyloid/tau. Our goal is to identify non-invasive biomarkers that fill this gap with simple tests
benchmarked to amyloid/tau biomarkers. Our early studies defined pre-symptomatic AD: elderly study
participants were classified as cognitively healthy (CH) in a multi-domain, neuropsychometric battery. We
classify CH participants into two groups based on a regression-derived CSF Aß42/Tau ratio cutoff: CH
individuals with pathological ratio (CH-PAT) or with normal ratio (CH-NAT). After 4 years, 40% of CH-PAT but
no CH-NAT individuals declined cognitively, providing a strong cohort to evaluate biomarkers for pre-
symptomatic AD (CH-PATs) from normal aging (CH-NATs).
AD affects multiple nervous systems. Tightly related to our health, the interactions between conscious
executive function, subliminal processing, and autonomic regulation (CSA system) respond to internal and
external stimuli with neural oscillations that are affected by synaptic dysfunctions. The CSA neural oscillations
can be detected by non-invasive electrophysiological methods: EEG and ECG, benchmarked to amyloid/tau.
Individual CSA dysfunctions have been reported in the mild cognitive impairment stage, while CSA has not
been studied in the pre-symptomatic AD.
We hypothesized that CSA system measurements combine to provide robust biomarkers for pre-symptomatic
AD. Analogous to the stress test to unmask coronary insufficiency, our cognitive challenge revealed CH-PATs
had frontal hyper-activities with low load challenge and insufficient cognitive resources with high load
challenges, hyperresponsivity to subliminal interference, and hyperactive autonomic regulation. Further,
combined CSA biomarkers improve detection of pre-symptomatic AD. Therefore, we hypothesize that neural
oscillations during cognitive challenge will reveal altered executive functions in pre-symptomatic AD,
correlate with compromised subliminal processing and autonomic nervous function, and their
combination will improve detection and prediction of pre-symptomatic AD.
Our Specific Aims will test our hypothesis in a new cohort and test the ability of CSA biomarkers to identify CH-
PATs and predict decline in a 2-year longitudinal study. Accomplishing this CSA approach will provide multiple
novel translational biomarkers to characterize pre-symptomatic AD. These biomarkers are non-invasive,
benchmarked to established CSF biomarkers. Our research addresses an important gap in pre-symptomatic
AD detection and prediction of AD symptom onset.

Grant Number: 5R01AG063857-05
NIH Institute/Center: NIH
Principal Investigator: Xianghong Arakaki