Genetic risk for Alzheimer's disease alters the five-year trajectory of semantic memory activation in cognitively intact elders

Abstract

Healthy aging is associated with cognitive declines typically accompanied by increased task-related brain activity in comparison to younger counterparts. The Scaffolding Theory of Aging and Cognition (STAC) (Park and Reuter-Lorenz, 2009; Reuter-Lorenz and Park, 2014) posits that compensatory brain processes are responsible for maintaining normal cognitive performance in older adults, despite accumulation of aging-related neural damage. Cross-sectional studies indicate that cognitively intact elders at genetic risk for Alzheimer’s disease (AD) demonstrate patterns of increased brain activity compared to low risk elders, suggesting that compensation represents an early response to AD-associated pathology. Whether this compensatory response persists or declines with the onset of cognitive impairment can only be addressed using a longitudinal design. The current prospective, 5-year longitudinal study examined brain activation in APOE ε4 carriers (N=24) and non-carriers (N=21). All participants, ages 65–85 and cognitively intact at study entry, underwent task-activated fMRI, structural MRI, and neuropsychological assessments at baseline, 18, and 57 months. fMRI activation was measured in response to a semantic memory task requiring participants to discriminate famous from non-famous names. Results indicated that the trajectory of change in brain activation while performing this semantic memory task differed between APOE ε4 carriers and non-carriers. The APOE ε4 group exhibited greater activation than the Low Risk group at baseline, but they subsequently showed a progressive decline in activation during the follow-up periods with corresponding emergence of episodic memory loss and hippocampal atrophy. In contrast, the non-carriers demonstrated a gradual increase in activation over the 5-year period. Our results are consistent with the STAC model by demonstrating that compensation varies with the severity of underlying neural damage and can be exhausted with the onset of cognitive symptoms and increased structural brain pathology. Our fMRI results could not be attributed to changes in task performance, group differences in cerebral perfusion, or regional cortical atrophy.

Brain insulin resistance deteriorates cognition by altering the topological features of brain networks

“…The higher node degree identified a greater need for compensation, suggesting more severe disease. As the disease progressed, the abilities of the brain to provide effective compensation would eventually diminish, at which time patients show severe cognitive deficits (Rao et al, 2015). …”

Five-Year Longitudinal Brain Volume Change in Healthy Elders at Genetic Risk for Alzheimer’s Disease

“…Most of these studies focus on the hippocampus, due to its known relationship with early AD pathogenesis [6]. Some longitudinal studies have demonstrated that cognitively intact elders possessing the ε4 allele experience greater hippocampal atrophy over time compared to non-carriers [7–9], although these results have not been demonstrated in other studies [10–12]. Notably, most of these studies measured the rate of atrophy based on two MRI assessments.…”

Interactive effects of physical activity and APOE-ε4 on white matter tract diffusivity in healthy elders

“…Moreover, the physically active ε4 carriers had greater semantic memory-related activation compared to the group of physically inactive ε4 carriers (Smith et al, 2011), which we have shown to predict cognitive stability over 18 months (Woodard et al, 2010). This pattern of activation appears to reflect a successful neural compensatory response over 5 years (Rao et al, 2015). In contrast, the combination of being physically inactive and at increased genetic risk for AD, despite being cognitively intact with normal hippocampal volumes at baseline, resulted in greater probability of cognitive decline and hippocampal atrophy over 18-months (Smith et al, 2014; Woodard et al, 2012).…”

“…We recently published a series of papers that have examined the moderating effect of PA on indices of brain structure and brain function based on a cohort of healthy older adults who participated in a 5-year longitudinal observational study (Rao et al, 2015). We previously reported that over an 18-month period, greater levels of PA in APOE-ε4 allele carriers significantly reduced the risk for cognitive decline (Woodard et al, 2012) and preserved hippocampal volume (Smith et al, 2014) compared to physically inactive carriers.…”