Why do some people with a major genetic risk factor for Alzheimer’s disease remain cognitively healthy well into their 70s, 80s, and beyond?
That question drove a new study led by Stanford Medicine researchers that turns the usual approach to Alzheimer’s research on its head. Rather than focusing only on what goes wrong in people who develop the disease, the team studied people who appear to remain protected despite carrying genetic risk for late-onset Alzheimer’s disease.
We spoke with lead author Yann Le Guen, PhD, about what researchers can learn from people who remain healthy despite elevated genetic risk.
The Conversation
For someone who has never heard of APOE ε4, what is it, and why is it so important in Alzheimer’s research?
APOE is a gene that comes in several common forms, or variants. APOE ε4 is the variant with the strongest known effect on the risk of developing late-onset Alzheimer’s disease. Carrying one copy increases risk and tends to shift disease onset earlier, while carrying two copies generally confers still greater risk.
It is especially important for research because it is both relatively common and biologically influential. Studying APOE ε4 carriers gives us an opportunity to understand not only why some people develop Alzheimer’s disease, but also why others with the same major genetic risk factor remain cognitively healthy into late life.
If someone carries APOE ε4, does that mean they are destined to develop Alzheimer’s?
No. APOE ε4 changes a person’s probability of developing Alzheimer’s disease; it does not determine their future. Many ε4 carriers never develop dementia, and an individual’s risk also varies with age, sex, ancestry, other genetic factors, and health and environmental influences.
That uncertainty was central to our study. The fact that some people remain cognitively healthy despite carrying APOE ε4 tells us that there must be other biological factors that modify or counterbalance its effects.
Can you tell us more about the study you and your team carried out and why?
We usually learn about disease by studying people who become ill, but people who remain well despite high risk may be just as informative.
In this case, most Alzheimer’s studies compare people with and without disease. We approached the question from the opposite direction: Why do some people at high genetic risk remain healthy? These individuals represent a type of natural experiment. They carry a major genetic risk factor and have reached ages at which that risk would often have become clinically apparent, yet they remain cognitively unimpaired.
We compared blood samples from 456 older APOE ε4 carriers who remained cognitively unimpaired with samples from 1,096 APOE ε4 carriers who had developed Alzheimer’s disease. We measured thousands of plasma proteins and looked for differences between the two groups. We then used additional population-wide proteomic analyses and human genetic data to identify which signals were most likely to reflect biologically meaningful pathways, rather than simply the downstream consequences of having dementia.
The goal was not to develop an immediate clinical blood test. It was to identify candidate mechanisms that might help delay the clinical onset of Alzheimer’s disease.
You measured thousands of proteins. What differences did you see between people who remained cognitively healthy and those who developed Alzheimer’s?
We found 721 protein measures that differed between APOE ε4 carriers who remained cognitively healthy and those who developed Alzheimer’s disease. Some were higher in the protected group, while others were higher in people with Alzheimer’s.
More broadly, the protected group tended to have higher levels of proteins involved in the health, communication, and structure of brain cells. The Alzheimer’s group showed more proteins associated with inflammation, fats in the blood, and tissue injury.
That does not mean all 721 proteins are protective. Many could simply reflect changes that happen after Alzheimer’s develops. We therefore used additional genetic and statistical analyses to narrow the list to a smaller group of proteins that may be more directly involved in modifying risk.
Do the findings suggest there may be several different ways the body can protect the brain, rather than one single “protective factor”?
Yes. Our findings are more consistent with multiple interacting forms of protection than with one single protective switch.
The proteins we identified point to several systems that may be important, including the immune system, the health and communication of brain cells, metabolism, blood vessels, and the structures that support nerve cells.
These processes may protect the brain in different ways. Some might help slow the buildup of Alzheimer’s-related damage, while others may help the brain continue functioning despite that damage.
Is there one finding from the study that you find especially intriguing or that you most want to investigate next?
LILRA5 is particularly intriguing to me. It is an immune receptor that is much less established in Alzheimer’s research than other proteins, but it appeared across several complementary analyses.
LILRA5 differed between APOE ε4 carriers who remained cognitively healthy and those who developed Alzheimer’s. Several analyses also suggested that its relationship with Alzheimer’s may be particularly important in people who carry APOE ε4. Importantly, a separate large genetic study also found evidence linking the region containing LILRA5 to Alzheimer’s risk in APOE ε4 carriers.
That said, I would not yet call LILRA5 a proven protective target. What makes it compelling is the current evidence suggesting that it may be part of an APOE ε4-specific immune mechanism. The next question is how this receptor functions in particular immune cell types and whether altering its activity changes Alzheimer’s-related biology.
Could studying people who seem naturally protected eventually point researchers toward new drugs or prevention strategies?
People who remain healthy despite high inherited risk may reveal biological processes that could eventually be mimicked or strengthened with a therapy. Instead of focusing only on what goes wrong after Alzheimer’s develops, this approach asks whether we can identify biological pathways that help delay the onset of symptoms.
But there is an important distinction between a protein associated with protection and a validated drug target. Before considering a therapeutic strategy, researchers must establish directionality, relevant tissues and cell types, safety, and whether experimentally modifying the pathway actually improves disease-related outcomes
What needs to happen next before these findings could have implications for patients?
Several steps are essential.
First, the findings need to be confirmed in other groups of APOE ε4 carriers. We also need studies that follow people over time to see whether these proteins help predict who remains cognitively healthy and who develops problems with memory or thinking.
Studies that include biomarkers, measurable signs of disease in the body, could also help explain why some people remain protected. In Alzheimer’s disease, important biomarkers include amyloid and tau, two proteins that can build up abnormally in the brain. Measuring them could help researchers determine whether protected individuals develop less Alzheimer’s-related damage, or whether their brains are better able to tolerate that damage without developing symptoms.
Finally, laboratory studies are needed to test whether changing these proteins actually affects processes involved in Alzheimer’s disease. Before any of these findings could influence patient care, they would also need to be confirmed in diverse populations and carefully evaluated for safety.
Anything else you would like to add?
I would emphasize that this is a discovery and target-prioritization study, not a clinical test. The results do not mean that an individual should measure these proteins or make medical decisions based on them.
The broader message is that people who remain cognitively healthy despite high genetic risk are not simply exceptions to be set aside. They are scientifically informative and may reveal biological strategies that the brain and body already use to delay disease.
Acknowledgments:
This work was possible because many cohorts contributed samples and data through the Global Neurodegeneration Proteomics Consortium, and because participants and their families made those resources available to researchers. The study also benefited from the Alzheimer’s Disease Data Initiative’s AD Workbench and emerged from the ADDI-sponsored GNPC Data Challenge.
