Grit against cognitive decline in aging and preclinical Alzheimer Disease

In most older adults, memory and other cognitive abilities decline with advancing age. This decline is not inevitable, however. Recent studies from our laboratory and others indicate that some older adults maintain youthful cognitive function at advanced age. This cognitive resilience may be related to motivational factors, as

successful agers show a stronger tendency to maintain effort in the face of challenging tasks than their peers. This quality is sometimes called grit (i.e., persistence of effort, perseverance). Recent findings also indicate that high-grit successful agers are resilient to memory decline even when they exhibit neuropathologic changes

associated with Alzheimer’s disease, such as the accumulation of beta amyloid. This suggests that higher levels of grit may convey cognitive resilience in cognitively normal amyloid positive adults who are at elevated risk to develop AD (preclinical AD). The neural underpinnings of this resilience are not presently well understood.

However, a number of limbic and paralimbic structures associated with motivation have been found to be relatively preserved in successful agers. The most notable of these structures is the anterior mid-cingulate cortex (MCC). The activity and connectivity of this region predicts persistence on difficult tasks, and stimulation of this

region produces “the will to persevere”, suggesting a central role for this region in representing grit in the brain. In this proposal we will expand on prior research which has relied solely on correlative designs and propose a novel model – The Neural Grit Model of Cognitive Aging – to test the relationships between grit, MCC function

and memory in a causal way. Our central hypothesis is that MCC functional and structural integrity mediates the protective role of grit against age-related cognitive decline. To test this central hypothesis, we propose to modulate the functional connectivity of the MCC using repetitive transcranial magnetic stimulation (rTMS). We

will assess the effects of rTMS-induced MCC connectivity on grit and memory in 40 amyloid-positive (Aβ+) cognitively normal older adults (preclinical AD) and 40 healthy cognitively normal older adults who are amyloid negative (Aβ-). All older adults will undergo behavioral testing and brain imaging (structural and functional

connectivity MRI) before and after 2 weeks of brain stimulation using rTMS. We predict that: 1) Higher levels of grit will predict more persistent effort and better memory function, 2) Greater structural integrity and functional connectivity of the MCC will be associated with higher levels of grit and will mediate the relationship between grit

and memory, 3) MCC-targeted rTMS will enhance MCC connectivity, grit and memory performance, particularly in amyloid-negative individuals. This proposal is innovative in that it represents the first attempt to demonstrate a causal relationship between MCC function, grit, and memory. It is significant, as establishing this relationship

points to MCC function as a biomarker for cognitive resilience in aging. Additionally, if enhancing MCC connectivity does augment grit, this research could lead to the development of interventions targeting the MCC to enhance motivation and potentially protect against age-related cognitive decline.