This post was co-authored by Jillian H. Graham, B.S., Justin M. Palmer, Ph.D., & Scott M. Hayes, Ph.D.

What is the hippocampus?

The hippocampus is an area of the brain that is central to forming some of our most important memories that come from our daily experiences. These memories range from landmark life events, such as your best friend’s wedding ceremony, to more mundane events, such as running errands around town.

The hippocampus is vulnerable to age-related structural and functional decline, which contributes to memory difficulties in older adulthood. For example, previous studies have shown that hippocampal volume declines with age (Wolf et al., 2015), which may be associated with greater difficulties on memory tasks (O’Shea et al., 2016). The hippocampus is also one of the first regions to accumulate Alzheimer’s disease pathology, which can further exacerbate hippocampal decline and cognitive impairment.

Additionally, sex differences in hippocampal volumes are often not examined, leading to a lack of understanding of how these structures may vary by biological sex. This lack of knowledge is important to consider given that females are at a higher risk for Alzheimer’s disease compared to males. Therefore, understanding potential sex differences in hippocampal volume may have implications for early detection and intervention of age-related cognitive decline or Alzheimer’s disease.

Segmenting the hippocampus

The hippocampus is not a uniform structure. It consists of several key subregions, called “subfields,” that play unique roles in memory functioning. Limitations in the resolution of magnetic resonance imaging (MRI) scans often impede characterization of hippocampal subfields. Think of this problem as needing a higher-resolution microscope to see small objects in daily life. Fortunately, improvements in neuroimaging technology now allow researchers to measure these different hippocampal subfields. A recently published study with over 200 participants across the adult lifespan (21-87 years old) has demonstrated novel findings on how different areas of the hippocampus are associated with age and biological sex.

Study participants underwent an ultra-high-resolution MRI scan. This may sound invasive, but undergoing these types of scans is harmless! The participant lies on the table, and the scanner takes pictures of the brain. Participants also completed several cognitive tests to measure memory, attention, processing speed, and executive functions. A subgroup of females completed a reproductive questionnaire to measure age of first menstrual cycle, age of menopause, and reproductive span.

This study had several important findings:

• There were different ages at which the volume began to be significantly lower for each hippocampal subregion. Most areas show significantly lower volume around age 50, but an area referred to as CA2/3 may begin to decline slightly later in life, closer to age 57.
• Lower volume began earlier for females in the dentate gyrus, a region that is important for separating similar memories, and the CA1 region. However, once lower volume reduction was observed in older males, the age-related volume loss appeared more accelerated relative to females
• Volumes of the CA1 and dentate gyrus were positively associated with attention scores. However, this same relationship was not observed with memory scores.
• In females, a younger age of first menstrual cycle was associated with a larger volume in the presubiculum, a region referred to as the “navigation and map-making” hub of the brain.

What are the implications of this research?

The study by Hall and colleagues improves our understanding of age- and sex-related differences in the hippocampus. Their findings may be useful in establishing the age at which hippocampal subfields begin to shrink, which appears to be closer to middle age.

The authors suggested that lower volumes within the hippocampus among females may be related to decreases in estradiol levels, the most potent type of estrogen found in the body. Estrogen is known to directly interact with the hippocampus and can benefit its functioning. However, compared to males, females have a more rapid decline. Males generally have a gradual, slight decline in estradiol as they age, whereas females have a more rapid decline in estradiol during the onset of menopause, which is around the same age at which declines in hippocampal volume were observed. Therefore, the loss of estrogen at these ages may diminish its neuroprotective effects on the hippocampus for females.

Volume within certain areas of the hippocampus predicted performance on attention tasks, but not on memory tasks. This was somewhat surprising, given that the hippocampus is well-known to support memory function. The authors explained this finding by noting that attention may help facilitate adequate memory functioning. In other words, attention skills can impact the ability to learn and remember information.

Even though it is easy to think about lower brain volume in older adults relative to younger adults as a decline, it’s important to note that this research study was not longitudinal. Longitudinal studies evaluate the same participants over time, which allows scientists to measure true change in brain structure. Studies such as the one from Hall and colleagues took a snapshot of hippocampal volumes at one point in time across individuals of different ages, which limits the ability to conclude that there was actual decline over time.

Overall, these findings highlight that hippocampal subfields may have differential sensitivity to the effects of aging. While more research is needed to determine potential interventions, such as hormone-based treatments, and how they could help preserve hippocampal structure, these findings emphasize the importance of considering biological sex in aging research for early detection and prevention of decline.