Unraveling the intersection of synaptic biology, lifestyle, and cognitive resilience

PROJECT SUMMARY / ABSTRACT
Brain pathology begins accumulating in early adulthood and is detectable in almost all brains by older age. Yet,
there is remarkable heterogeneity in cognitive aging, and most aged adults do not evidence cognitive
impairment or dementia. Uncovering the naturally occurring processes that support this cognitive resilience to
neuropathology burden may yield potent targets to prevent or slow Alzheimer's disease and related dementias
(ADRD). We hypothesize that maintained synaptic integrity and physical activity may represent two such
protective factors. Synaptic communication is the foundational underpinning of cognition. Increasing data
suggest that preserved synaptic integrity may support clinical functioning regardless of pathology presence or
etiology. Further, physical activity is a highly implicated resilience behavior that has also been linked to
synaptic maintenance in animals. Our goal is to determine the synaptic biology that may underlie cognitive
resilience and physical activity in humans. We will collaborate across two ADRC programs to leverage their
unique strengths. In the Rush Memory and Aging Project (R-MAP), brain tissue samples from autopsied adults
followed in life will be used to quantify >150 synaptic protein markers (n=869). In the UCSF Memory and Aging
Center (UC-MAC), cerebrospinal fluid samples from longitudinally followed living older adults will be used to
quantify seven synaptic protein markers (n=200). Both cohorts complete longitudinal actigraphy monitoring as
an index of physical activity levels, and comprehensive neurobehavioral assessments. Cognitive resilience will
be operationalized as the discrepancy between neuropathology markers and cognitive performances. Aim one
will identify the in-depth synaptic networks (R-MAP) and the longitudinal, dynamic nature (UC-MAC) between
synaptic markers and cognitive resilience. Aim two will apply innovative machine learning techniques to identify
precise actigraphy features that most robustly relate to in-depth synaptic networks (R-MAP), longitudinal
synaptic marker changes (UC-MAC), and cognitive resilience (both). Accomplishing these aims will
significantly impact the ADRD field. We are designed to carefully identify synaptic and exercise features that
support sustained cognitive resilience using cutting edge measurement technologies, analytics, and
exceptional collaborative expertise. This proposal represents a bridging between two national ADRCs to more
powerfully address high impact questions than could be answered by either individually.

Grant Number: 5R01AG072475-05
NIH Institute/Center: NIH
Principal Investigator: Kaitlin Casaletto