What are the risk factors for Alzheimer’s disease?

Aging

One of the most important risk factors for Alzheimer’s disease is older age. The prevalence of Alzheimer’s disease is around 3% between ages 65 and 74, increases to 17% between 75 and 84, and reaches 32% at 85 or older.^[1]

Depression

Depression has long been linked to the disease, with a 2021 meta-analysis of 28 prospective cohort studies reporting that the presence of depression or depression symptoms was associated with a 54% higher risk of Alzheimer’s disease.^[2] Additionally, many genes that increase Alzheimer’s disease risk seem to do so by increasing the risk of depression.^[3]

Being female

The overall incidence of Alzheimer’s disease is higher among females than males.^[4] A major reason for this could simply be that women live longer than men and, as previously noted, risk increases with age.^[5] Another contributing factor could be depression, which occurs more often in women^[6] and, as covered, is associated with a higher risk of Alzheimer’s disease. Among females, the use of estrogen replacement therapy is associated with a lower risk of Alzheimer’s, but this has not been confirmed in clinical trials.^[7]

Head injuries

Head injuries, such as a traumatic brain injury (TBI), may increase the risk of neurodegenerative disorders. Evidence suggests people who have experienced a TBI have higher odds of developing dementia,^[8] but the evidence is somewhat mixed as to whether TBIs increase the risk of Alzheimer’s disease specifically.^[9][10] It’s possible that characteristics of the injury itself could determine its effect on Alzheimer’s risk, but more research is needed.

Limited cognitive reserve

Some people seem capable of experiencing a significant amount of the neuronal death and amyloid plaque accumulation that characterize Alzheimer’s disease without displaying cognitive symptoms of the disease itself.^[11][12] A major hypothesis used to explain these unusual cases is cognitive reserve.

Cognitive reserve refers to the capacity of the brain to compensate for damage and maintain function, and is believed to vary from person to person. The greater a person’s cognitive reserve, the longer it is believed to take for the underlying brain changes to induce cognitive impairment. In line with this, the risk of Alzheimer’s disease is lower in people with higher levels of education,^[13] a factor believed to increase cognitive reserve.

Another related concept, neuroplasticity, is a broad term for the brain’s ability to alter itself. This can involve rerouting neural pathways, in some cases as a way of replacing damaged ones. An extreme example of this was described in a case study of a 29-year-old woman who had a significant stroke that required the removal of the right hemisphere of her brain.^[14] This initially resulted in impairments in aspects of her cognitive function, including visuospatial ability, organization, and problem solving, but when examined around 5 years later, her cognitive function appeared to be normal, likely due in part to neuroplasticity.

Some factors that may promote neuroplasticity are adequate sleep, physical activity, and environmental enrichment.^[15]

Limited physical activity

A large number of prospective cohort studies have found that physical activity is associated with a lower risk of Alzheimer’s disease.^[16][16] In one meta-analysis of prospective cohort studies, compared with little or no physical activity, high amounts of physical activity was associated with a 38% lower risk of Alzheimer’s disease and moderate amounts, with a 29% lower risk.

Diabetes

Type 2 diabetes has frequently been associated with a higher risk of Alzheimer’s disease, with two meta-analyses finding an increase of about 55 to 57%.^[17][18] A number of mechanisms have been suggested to explain this finding, but confirmation has remained elusive. One theory is that the brain becomes insulin resistant, and the resulting reduction in neuronal insulin signaling increases the production of amyloid beta, the main component of amyloid plaques.^[19]

Of note, the relationship between diabetes and Alzheimer’s disease does not seem to be explained by differences in body weight, as the association remains after adjusting for body mass index(BMI).^[17]

Some evidence suggests people with type 1 diabetes may also be at higher risk of developing dementia.^[20][21] These studies did not differentiate dementia type, however, meaning more research is needed to determine whether type 1 diabetes is associated with a higher risk of Alzheimer’s disease or a different form of dementia (e.g., vascular dementia).

Elevated body weight

A 2020 meta-analysis of prospective cohort studies found that being overweight or obese at midlife was associated with a higher risk of Alzheimer’s disease.^[22] One possible explanation could be that elevated body fat promotes greater insulin resistance and a higher risk of type 2 diabetes, a risk factor for Alzheimer’s disease, as discussed. Interestingly, the prior meta-analysis also found being overweight (and, in high-quality studies, obese) during later life was associated with a lower risk of Alzheimer’s disease. It’s possible this merely reflects reverse confounding, as some research suggests people begin to lose weight in the years leading up to their dementia diagnosis.^[23]

Abnormal blood pressure

Meta-analyses of numerous prospective cohort studies have found that hypertension (high blood pressure) around midlife (ages 45 to 65) is associated with a higher risk of Alzheimer’s disease.^[24][13] Hypertension was not found to be associated with Alzheimer’s disease in later life (≥65 years old), although in one meta-analysis, use of antihypertensive medication during this time was nonetheless associated with a lower risk.^[24]

Several abnormal blood pressure patterns have also been associated with a higher risk of Alzheimer’s disease, including orthostatic hypotension (low blood pressure when rising from a sitting position);^[13] higher blood pressure in the evening, relative to the daytime;^[25] and increased fluctuations in blood pressure (i.e., throughout the day or from day to day).^[26]

Microbes in the brain

A growing body of evidence suggests amyloid beta may function as an antimicrobial peptide, binding to bacteria and viruses and preventing infection and disease.^[27]

The herpes virus (typically herpes simplex virus 1; HSV-1) is present more often in the brains of people with Alzheimer’s than those without the disease.^[28] This has led to the theory that amyloid beta is produced as a protective response to the herpes virus in the brain and inadvertently promotes Alzheimer’s disease.^[29]

Another microbe linked to Alzheimer’s disease, Porphyromonas gingivalis, is also associated with periodontal disease, which itself is linked to Alzheimer’s disease.^[30] Compounds called gingipains, produced by this bacteria, have been observed at higher rates in the brains of people with Alzheimer’s disease and these gingipains have been shown to produce neurotoxic effects in mice.^[31]

Poor sleep quality

The glymphatic system is a sort of biological drainage system that moves fluid into and out of the brain. This fluid has been shown to collect amyloid beta and clear some of it from the brain,^[32] and the rate of this clearance increases dramatically during sleep.^[33] As a result, it’s been theorized that inadequate sleep may promote Alzheimer’s disease by disrupting the removal of amyloid beta. However, the evidence for this hypothesis is mixed.

By and large, prospective cohort studies have not found an association between shorter sleep duration (about 6 hours or fewer per night) and a higher risk of Alzheimer’s disease, but they have found a higher risk with longer sleep duration (around 9 or more hours per night).^[34] Most of these studies relied on self-reported sleep times, however, and several studies have found that people often inaccurately assess how much they sleep.^[35]

Meanwhile, a number of observational studies have found that poor sleep quality is associated with a higher risk of Alzheimer’s disease, including when using objective measures of sleep efficiency (e.g., wrist actigraph, which records movement through a device worn on the wrist).^[36][37] Still, it’s important to note that neurodegenerative diseases can disrupt areas of the brain involved in sleep regulation, meaning it’s possible that poor sleep could simply be a consequence of early brain changes in the years leading up to a dementia diagnosis.