Abstract
Alzheimer's disease (AD) manifests with progressive memory loss and spatial disorientation. Neuropathological studies suggest early AD pathology in the entorhinal cortex (EC) of young adults at genetic risk for AD (APOE ε4-carriers). Because the EC harbors grid cells, a likely neural substrate of path integration (PI), we examined PI performance in APOE ε4-carriers during a virtual navigation task. We report a selective impairment in APOE ε4-carriers specifically when recruitment of compensatory navigational strategies via supportive spatial cues was disabled. A separate fMRI study revealed that PI performance was associated with the strength of entorhinal grid-like representations when no compensatory strategies were available, suggesting grid cell dysfunction as a mechanistic explanation for PI deficits in APOE ε4-carriers. Furthermore, posterior cingulate/retrosplenial cortex was involved in the recruitment of compensatory navigational strategies via supportive spatial cues. Our results provide evidence for selective PI deficits in AD risk carriers, decades before potential disease onset.
Highlights
Alzheimer’s disease (AD), by far the most common form of dementia, is characterized by a progressive deterioration of cognitive functions, starting with episodic memory loss and spatial disorientation [1]
Participants navigated toward a variable number of trees (“outgoing phase”), systematically varying outgoing distance, until they found a tree with an apple (“retrieval location”)
We found that the adverse effect of apolipoprotein E (APOE) 4 on pure PI” (PPI) performance was present in the older subsample only, suggesting that this APOE effect may be mediated by age-dependent accumulation of preclinical AD pathology
Summary
Alzheimer’s disease (AD), by far the most common form of dementia, is characterized by a progressive deterioration of cognitive functions, starting with episodic memory loss and spatial disorientation [1]. No causal therapies for AD are currently available, possibly because drugs that would otherwise be effective are applied too late [2]. The 4 allele of the apolipoprotein E (APOE) gene is the most important genetic risk factor for late-onset AD [3]. It may provide an opportunity for assessing subclinical alterations of behavior, brain structure, and brain function at very early disease stages [1, 4]. Previous studies and meta-analyses on APOE-behavior relationships in young and middle-aged healthy participants showed divergent results: While some described cognitive impairments [e.g., [5]], others reported improved functioning [e.g., [6]]—suggesting antagonistic pleiotropy—or no effects [e.g., [4, 5, 7]]
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