Are there sex differences in older adults at high risk of Alzheimer’s disease?
By Alex Samson
This week marks our return in-person to the Society for Neuroscience meeting. Over the next few days, we’re giving you a sneak peek of what we’ll be presenting in San Diego.
In today’s sneak peek, I’ll be covering my poster titled “Longitudinal sex differences in episodic memory-related brain activity and behaviour in older adults with a family history of Alzheimer’s disease” on Tuesday November 15th at 11am-12pm (Poster #YY50).
Late-onset Alzheimer’s disease (AD) is a brain disease that develops around the age of 65 years and is characterized by the loss of neurons in the brain. According to the World Health Organization, around 35 million people have AD worldwide but women make up almost 70% of the patient population. Thus, a disproportionate amount of females are diagnosed with AD compared to their male counterparts. However, why this remains the case is still unknown.
To fill this gap in AD research, I led a research project that looked at sex differences in brain activity during an episodic memory task and cognition in older adults at risk of AD over two years. Episodic memory was chosen because this is a prominent feature that declines in the early stages of AD. Further, we chose to assess healthy participants at high risk of AD because these individuals provide the unique opportunity to potentially pinpoint where these sex differences emerge in AD progression.
The Study
Our sample population included healthy older adults with a family history of AD (~65 years at baseline) because these individuals have a greater risk of developing the disease themselves. The participants were recruited for the PREVENT-AD program in Montreal, Canada. At both visits, participants completed an object-location episodic memory task while inside a magnetic resonance imaging (MRI) scanner, to measure their brain activity during the task, as well as they completed cognitive tests. In terms of brain activity, we were most interested in the brain activity patterns during the retrieval of successful object-location associations and successful correct rejection (identifying a new object as new). See Figure 1 for more information on the episodic memory task.
Figure 1. Object-location episodic memory task. This task was completed inside a magnetic resonance imaging scanner and the participants' brain activity was measured throughout. Forty eight everyday objects were presented left or right of the fixation cross during the encoding phase. Participants were asked to passively watch and remember the object and its location. There was a 20 minute break after the encoding phase when participants' brain structure was measured. During the retrieval phase, participants were presented with 96 objects in the middle of the screen; 48 of them old (presented in the encoding phase) and 48 of them new. Participants were required to make a response to each object presentation: i) the object is familiar; ii) I recognize the object and it was previously on the left; iii) I recognized the object and it was previously on the right; iv) the object is new.
The results
We found that males and females with a family history of AD demonstrated a general cognitive decline over two years however, they differed across the measures in which they showed this decline. For example, females illustrated a significant decline in language scores over time while the males demonstrated a significant decline across different episodic memory domains (see Figure 2). Moreover, a significant sex difference emerged in the brain activity patterns during the retrieval phase of the episodic memory task; different brain regions were activated at baseline compared to follow-up in males but this was not seen in females. Specifically, males demonstrated similar brain activity patterns during both retrieval conditions (successful object-location associations and successful correct rejections) at baseline compared to both retrieval conditions at follow-up (see Figure 3). Furthermore, the males that demonstrated a greater change in brain activity from baseline to follow-up, performed better on the episodic memory task at follow-up.
Figure 2. Significant sex differences across cognitive and behavioural scores. Left: Demonstrates the significant decrease in language scores within females from visit 1 to visit 2 and the significant difference in scores between males and females at visit 2. The language scores are based on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Males are in blue and females are in pink. The x-axis represents time (Month 0 is the first visit and Month 24 is the follow-up visit). The y-axis represents the average RBANS language scores. Right: Illustrates the significant decrease in episodic memory correct rejection rate in males compared to females from visit 1 to visit 2. Correct rejections is the ability to correctly identify a new object as new during the episodic memory task. The x-axis represents time (Month 0 is the first visit and Month 24 is the follow-up visit). The y-axis represents the average episodic memory correct rejection rate.
Figure 3. Average brain activity patterns for males during retrieval of the episodic memory task. The brain areas depicted in darker colours (green and blue) were activated at baseline during both successful retrieval of object-location associations and correct rejections. While the brain areas depicted in warmer colours (orange and yellow) were activated at follow-up during both successful retrieval of object-location associations and correct rejections. A = anterior; S = superior; P = posterior; I = inferior ; R = right; L = left.
What does this all mean?
Because males and females with a family history of AD demonstrated general declines across different measures, this illustrates the need for sex-specific AD diagnostic tools because males and females seem to cognitively decline in different cognitive areas. However, it is important to note that even though there were declines in cognition overtime, all the participants in the study remained cognitively intact at the follow-up visit. Furthermore, the time effect seen in brain activity seen across the male participants suggested potential “functional compensation”. Functional compensation is the recruitment of an additional or different brain area(s) to maintain performance on a similar task that would have previously used a different brain area. Similar to our study, males that demonstrated different brain activation at follow-up compared to baseline had maintained their episodic memory performance compared to males who did not show a change in brain activation over time.
Future research is required to assess these individuals over a longer period of time (e.g., 5 years) to see how many of these individuals do develop AD. Nonetheless, these findings provide a new perspective on sex differences in brain activity and cognition in people at high risk of developing AD.