Neuropsychological tests are central to the detection of Alzheimer’s disease (AD), but currently
available tests are not sufficiently sensitive to AD neuropathology until the disease has progressed for
years. We recently introduced and provided preliminary support for an episodic autobiographical
memory (EAM) hypothesis of preclinical AD. This hypothesis states that because EAM places high
demands on a neural network that is targeted by the initial stages of AD, EAM testing can improve
“preclinical” (i.e., early) cognitive detection of AD. This R03 proposal builds on our novel hypothesis
and seeks to advance the development of EAM tests for preclinical AD by filling two gaps in current
knowledge. Specifically, our objectives for this proposal are to better understand (1) the cognitive sub-
components of EAM that are sensitive to preclinical AD and (2) at what stage of preclinical AD (mild
versus severe) EAM disruption is detectable. To achieve these objectives, we formed a team of
researchers with expertise in the neuropsychology of autobiographical memory and aging (PI Grilli),
the default mode network (DMN) and resting state functional connectivity (RSFC) (Co-I Andrews-
Hanna), and the neuroimaging of cognitive aging (Co-I Ryan). Our approach is to study EAM and
investigate the relation of EAM to DMN RSFC in cognitively normal older adults, half of whom are
carriers of the apolipoprotein E e4 allele, which increases risk for preclinical AD. We have two specific
aims: (1) to reveal that core EAM sub-components are disrupted in cognitively normal older e4 carriers
and (2) to demonstrate that EAM disruption is associated with altered DMN RSFC. Under the first aim,
we will investigate established and novel behavioral tasks, each emphasizing a different EAM cognitive
sub-component that we hypothesize is compromised in preclinical AD. Under the second aim, we will
investigate whether poorer performance on any of the EAM tasks studied under Aim 1 is associated
with hyper- and/or hypo-RSFC in regions of the DMN that have been identified as particularly sensitive
to preclinical AD. Our reasoning is that if cognitively normal e4 carriers exhibit worse EAM performance
on the behavioral tasks relative to non-carriers, we have gained insight into EAM cognitive sub-
components that are vulnerable to preclinical AD. Also, by studying the relation of EAM to DMN RSFC,
we can shed light on whether disrupted EAM is sensitive to mild or severe preclinical AD, and by
extension, the sensitivity of EAM to two key AD processes. This research is significant because it
ultimately could lead to the development of neuropsychological tests and cognitive outcome measures
that can detect preclinical AD, which currently do not exist. This research is innovative because the
EAM hypothesis is a novel idea for cognitive detection of preclinical AD, and this project will be the
first to test whether EAM is related to RSFC signatures of mild or severe preclinical AD.
