Genetic architecture of declarative memory: implications for complex illnesses

Abstract

Why do memory abilities vary so greatly across individuals and cognitive domains? Although memory functions are highly heritable, what exactly is being genetically transmitted? Here we review evidence for the contribution of both common and partially independent inheritance of distinct aspects of memory function. We begin by discussing the assessment of long-term memory and its underlying neural and molecular basis. We then consider evidence for both specialist and generalist genes underlying individual variability in memory, indicating that carving memory into distinct subcomponents may yield important information regarding its genetic architecture. And finally we review evidence from both complex and single-gene disorders, which provide insight into the molecular mechanisms underlying the genetic basis of human memory function.

Figure 1

Long-term memory may be subdivided into categories and it differs structurally and functionally from working and short-term memory.

Figure 2

Information from multiple cortical association areas converge on areas that surround the hippocampus, namely, entorhinal, perirhinal and parahippocampal regions. These regions are interconnected and project to the hippocampus itself. Efferents from the hippocampus reach the surrounding areas and then project back to the same cortical regions from where the inputs were originated [adapted from (Eichenbaum, 2000)].

Figure 3

Schematic illustration of the main structures within and surrounding the hippocampus, as seen from a coronal slice through its anterior part.

Figure 4

Structural, functional and cognitive changes observed as a function of normal aging. Some cognitive functions are selectively preserved.

Figure 5

Long-term memory (LTM) deficits are a central feature of multiple disorders (both complex and Mendelian). LTM may serve as an endophenotype for these disorders, as the downstream expression of multiple underlying genetic, cellular, and neural systems abnormalities.

Figure 6

Patterns of hippocampal atrophy in AD patients with (left panel) and without the APOE ε4 allele (right panel) compared with demographically matched healthy controls. Top: statistical maps. White regions correspond to an uncorrected threshold of p<0.05. Comparisons were significant after correction for multiple testing by permutation testing, both in the ventral and dorsal hippocampal portions, bilaterally. Bottom: percentage hippocampal differences. Values are color-coded to express the percentage difference in radial size between AD patients and healthy controls. Values greater than 15% (yellow to red regions) denote statistically significant atrophic areas and red regions correspond to areas of severe hippocampal atrophy (differences greater than 25%) [from (Pievani et al., 2010)]

Figure 7

Mean hippocampal volumes and standard errors in subjects with diagnosis of schizophrenia (probands), compared to their monozygotic (MZ) or dizygotic (DZ) twins, concordant (CC) or not (DC) with the diagnosis, and compared with a group of healthy control twin pairs (MZ and DZ). Hippocampal volumes are reduced according to the putative genetic loading for the disorder [adapted from van Erp et al. (2004)].

Figure 8

Complex traits or disorders, such as memory or AD, which influence and are influenced in multiple ways, can only comprehensively be understood by disentangling their mechanisms at each expression level. Successful research at any level of analysis must build on discoveries on all other levels.

Figure 9

Relationships between keywords in published literature can expose interesting links between fields and highlight areas where important pieces may be missing, as well as evidence emergent patterns of research. In this figure, each point around the circle represents the relative quantity of publications of a given keyword in relation to the others, in logarithmic scale, as retrieved from PubMed in May/2011. The links represent the strength of the association, scaled by the natural logarithm of the Jaccard coefficient. The smaller numbers indicate stronger associations. See also the Supplemental Material for an interactive depiction of these relationships, and http://www.pubatlas.org/ for more literature mining and visualization tools.