Episodic memory declines more steeply with increasing age than other types of memory, and is severely impaired in Alzheimer’s Disease. Even the modest memory impairment typical of healthy people in their 70’s can negatively impact quality of life. Moreover, changes in memory function that harbinger Alzheimer’s Disease (AD) onset years before the emergence of symptoms. This prodromal period provides a window for disease- modifying interventions and places a premium on early detection of trajectories of ‘unsuccessful’ brain aging. Thus, it is important to understand the neurocognitive bases of the effects of age on episodic memory. The aim of the present research is to elucidate the functional significance of age-related differences in neural activity underpinning episodic memory. We aim to determine which of these differences reflect processes that contribute to age-related memory decline, which reflect compensatory mechanisms that ameliorate decline, and which differences are indicative of memory pathology. The focus of the program is on the neural correlates of episodic encoding and retrieval as these are indexed by fMRI. In one strand of the research, subjects will be people in their 60s and 70s with amnestic mild cognitive impairment (aMCI), a significant risk factor for AD, along with healthy aged-matched controls aged around 70 yrs, and healthy adults in their 80s. The goal is to identify which of the neural correlates of successful episodic encoding and retrieval previously identified in healthy people are also evident in aMCI, which correlates are shared with healthy older individuals with broadly comparable memory abilities, and which are specific to aMCI, especially to individuals at high risk for AD. In two studies we will examine the neural correlates of associative encoding and retrieval, and recollection-related cortical reinstatement, respectively. We will also continue to advance our recent work on healthy aging and episodic encoding. We have described several neural measures of encoding that are predictive of memory performance in people aged around 65-75 yrs, but not in middle-aged (45-55 yrs) or younger people. One of these measures - the ‘right frontal subsequent memory effect’ – correlated positively with memory performance in a recent study, but correlated negatively with performance in an earlier study. We shall examine the hypothesis that the direction of the relationship depends upon the conditions under which memory is tested. In another experiment, we will investigate the effects of age on ‘pre-stimulus’ subsequent memory effects – neural activity predictive of subsequent memory performance that precedes a study event. We predict that pre-stimulus effects will be attenuated in older subjects. Should this be so, it will constitute a novel mechanism by which memory encoding is compromised in later life. In a final experiment, we will assess whether age-invariance in the neural correlates of successful retrieval extends to circumstances where retrieved information must be retained in working memory for a period prior to being used to guide response selection.

Decline in episodic memory – memory for unique events – is typical of healthy aging and, in a much more exaggerated fashion, of age-related neurodegenerative disorders such as Alzheimer’s Disease. The proposed research will contribute to the understanding of the changes in neural activity that accompany decline in episodic memory in healthy older people and in people with incipient Alzheimer’s Disease, and to differences in neural function that may ameliorate or exacerbate such decline.