Cognitive Health — Part 2
Understanding Non-Modifiable Risk of Cognitive Decline
If you had to choose just one, would you choose to keep physical or cognitive function throughout your life?
The vast majority of people choose the latter without much thought.
As I introduced last week in Cognitive Health - Part 1, cognitive function is so much more than memory.
It is identity.
It is independence.
Until recently, it seemed that the risk of cognitive decline and dementia (now more commonly called “neurocognitive decline”) was left to fate.
We are lucky to live in a time where we know more and can be proactive about understanding our risk.
Alzheimer's disease accounts for an estimated 60–80% of diagnosed dementias, making it by far the most studied and the primary focus of research on cognitive decline prevention.1
Alzheimer’s Disease risk is due to both non-modifiable and modifiable risk factors.
Let’s start with the risks you can’t change.
Non-Modifiable Risk Factors:
Age — risk of chronic diseases, including Alzheimer’s disease, goes up with age.
Biological sex2 — Women represent approximately two-thirds of all Alzheimer's cases, which we are still trying to understand.
This difference is not fully explained by longer lifespan, and research is actively exploring the roles of estrogen/menopause, depression, reproductive history, and historically lower access to education and cognitively stimulating work.
The vast majority of Alzheimer’s genetic research has focused on the APOE gene3, which accounts for an estimated 20–25% of population-level risk. Importantly, APOE risk is not deterministic, meaning even the highest-risk combination does not guarantee developing the disease.
The APOE gene comes in three forms:
APOE-2 — associated with decreased risk of Alzheimer’s disease
APOE-3 — associated with neutral risk (neither increased nor decreased)
APOE-4 — associated with increased risk of Alzheimer’s disease
Since we each inherit two copies of the gene (one from each biological parent), the six possible combinations are:
APOE 2/2, 2/3, 3/3, 2/4, 3/4, 4/4
APOE 3/3 is the most common combination
APOE 3/4 increases risk approximately 2–3x compared to APOE 3/3
APOE 4/4 increases risk approximately 8–12x compared to APOE 3/3
Ok, I know that went deep into the science for a moment. So let’s take a step back and put everything into perspective.
The vast majority of Alzheimer’s Disease and other dementias are related to both non-modifiable and modifiable risk factors.
Understanding each risk factor is important information as you figure out where you are and what you need to do to influence what happens going forward.
When it comes to genetic risk, I know it can be scary, and some people would rather not know. That’s ok.
For me, I choose to look at genetic risk as a motivator. I want to know all the cards on the table so I can make my next move.
Even if my genetic risk is high, remember it is not guaranteed that the disease will develop.
This is an important distinction.
Next week, for Cognitive Health — Part 3, we will dive into the important topic of modifiable risk factors. These are the risk factors that put you in the driver’s seat to decrease your risk of dementia and other chronic diseases.
Now that is inspiring and motivating.
As always, thanks for being here,
~Allison
Please remember that this information is meant to educate and inspire, but is not medical advice — please consult your healthcare team to determine what is most appropriate for you.
Many dementia cases are mixed, meaning Alzheimer's pathology co-exists with vascular dementia or other types. So the 60–80% figure includes cases where Alzheimer's is the primary or contributing diagnosis, not always the sole cause.
The role of gender identity and affirming hormone therapy remains understudied across most areas of health research, and Alzheimer's disease is no exception. What we do know is that chronic stress and experiences of discrimination are recognized contributors to cognitive decline, factors that may disproportionately affect transgender individuals.
While APOE dominates late-onset Alzheimer’s Disease research, early-onset Alzheimer’s (diagnosed before age 65) is more strongly linked to rare mutations in three genes: APP, PSEN1, and PSEN2. Unlike APOE, mutations in these genes — particularly PSEN1 — carry a more deterministic risk. However, they are rare, accounting for less than 1% of all Alzheimer’s Disease cases.