Alzheimer disease (AD) is the most common cause of dementia and represents the most frequently diagnosed neurodegenerative disease.1 In the United States, approximately 6.5 million people aged 65 years and older live with AD, and that number may rise to a projected 12.7 million by 2050.2

Nonmodifiable and Potentially Modifiable Risk Factors for AD

Pathologically, AD is defined by the presence of amyloid plaques, in addition to neurofibrillary tangles, as a result of the accumulation of amyloid beta peptide in the medial temporal lobe and neocortical structures.3 A genetic polymorphism in the APOE gene which encodes for apolipoprotein E, the ϵ4 allele, is an unmodifiable risk factor for sporadic AD, or AD that affects people without a family history of the condition.3


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Despite the strong genetic component, further investigation into AD has revealed certain modifiable risk factors for the condition. For instance, medical factors such as obesity and type 2 diabetes, cardiovascular disease, diet, and air pollution have been linked to AD, given that these factors may increase oxidative stress and inflammation.3

Some estimates suggest that 1 in 3 cases of AD and related dementia are associated with modifiable risk factors. In addition to obesity and diabetes, other potentially modifiable risk factors for AD and related dementia include physical inactivity, low educational attainment, depression, social isolation, and smoking.4,5

Ines Moreno-Gonzalez, PhD, who serves as an adjunct associate professor in the department of neurology at the University of Texas Health Science Center at Houston, explained that there are currently significant knowledge gaps regarding what triggers sporadic AD. “We don’t know the combination of risk factors, if any, that will ultimately initiate the pathologic cascade of events leading to dementia,” she said.

Dr Moreno-Gonzalez, who has previously published papers exploring the potential modifiable nature of AD, suggests that efforts can be made to try and control these modifiable risk factors. “Except in familial cases of AD, as genetic factors are also considered risk factors, modifiable risks may help us to reduce the chances of developing the disease, but we still do not know to what extent,” she said.6

Lifestyle Factors That Impact AD Risk

While aging is the strongest known nonmodifiable risk factor for developing AD, dementia isn’t considered a normal aspect of aging.7 Dr Moreno-Gonzalez noted that from the age of 65 years, individuals have a double chance every 5 years of developing the disease. “There is nothing we can do to prevent aging, but we can have healthy aging,” she said.

The production and intake of advanced glycation end products in highly cooked and processed foods, for instance, have been implicated in cognitive decline and AD risk and progression, suggesting nutrition may be an important modifiable lifestyle intervention for the disease.3,8,9 According to Dr Moreno-Gonzalez, strategies to support “healthy aging” include maintaining a healthy diet low in carbs, fats, salt, and red meat.

Additionally, she shared that increased aerobic exercise, good sleep habits, and controlling common disorders like diabetes and high blood pressure, represent key strategies to prevent age-related conditions like AD. “The role of clinicians is to advise patients to acquire healthy habits and follow their instructions to have their diseases under control,” she said.

A potentially modifiable risk factor for AD is vascular problems, including hypertension and heart diseases.10 These can lead to reduced brain blood flow or cerebral perfusion, Dr Moreno-Gonzalez noted, adding that these issues ultimately result in neuronal damage and cognitive impairment.

While age-related vascular changes can exert a deleterious effect on the brain, certain vascular conditions are linked to lifestyle habits. Hypertension, a main risk factor for stroke, is a condition that is largely associated with lifestyle, including diet, exercise, and stress management.10

According to Dr Moreno-Gonzalez, stroke related to hypertension can accelerate the development of brain disorders such as AD and vascular dementia.11 “After the reduction of blood supply, and therefore nutrients and oxygen, to neurons, there is an activation of the immune system,” she said. “The combination of reduced blood flow, neuroinflammation, and age-associated alterations in the cerebral vasculature can contribute to the development of AD.”

Dr Moreno-Gonzalez reiterated the potentially protective role of physical activity in AD risk, given that exercise can help maintain blood pressure and glucose levels.12 “It is well known that exercise can help maintain heart health, reduce body weight, and control obesity,” she added, “but it also contributes to improving memory performance and cognitive function.”

In its ability to support memory and cognition, Dr Moreno-Gonzalez explained that exercise may increase hippocampal volume, a brain region associated with learning and memory and impacted by AD pathology.13 “Exercise also contributes to the production of neurotrophic factors, molecules that are key in the generation of new neurons and that are involved in memory formation,” she said.

Gaps in the Research

Dr Moreno-Gonzalez noted that few studies have evaluated the impact of a “multi-domain lifestyle intervention” to prevent dementia. These studies, she said, have shown that lifestyle interventions can prevent cognitive decline to some extent in older individuals who are at risk while “promoting brain health function and reducing the risk [for] dementia or even ameliorating the symptoms and advancement of the disease.” These lifestyle interventions, however, are still insufficient to cure this disease, underscoring the need for intensive research initiatives aimed at discovering potentially curative treatments for the disease.

References

1. Serrano-Pozo A, Growdon JH. Is Alzheimer’s disease risk modifiable? J Alzheimers Dis. Published online February 12, 2019. doi:10.3233/JAD181028

2. 2022 Alzheimer’s disease facts and figures. Alzheimers Dement. Published online March 14, 2022. doi:10.1002/alz.12638

3. Breijyeh Z, Karaman R. Comprehensive review on Alzheimer’s disease: Causes and treatment. Molecules. Published online December 8, 2020. doi:10.3390/molecules25245789

4. Nianogo RA, Rosenwohl-Mack A, Yaffe K, Carrasco A, Hoffmann CM, Barnes DE. Risk factors associated with Alzheimer disease and related dementias by sex and race and ethnicity in the US. JAMA Neurol. Published online May 9, 2022. doi:10.1001/jamaneurol.2022.0976

5. Ranson JM, Rittman T, Hayat S, et al. Modifiable risk factors for dementia and dementia risk profiling. A user manual for Brain Health Services-part 2 of 6. Alzheimers Res Ther. Published online October 11, 2021. doi:10.1186/s13195-021-00895-4

6. Edwards Iii GA, Gamez N, Escobedo G Jr, Calderon O, Moreno-Gonzalez I. Modifiable risk factors for Alzheimer’s disease. Front Aging Neurosci. Published online June 24, 2019. doi:10.3389/fnagi.2019.00146

7. Irwin K, Sexton C, Daniel T, Lawlor B, Naci L. Healthy aging and dementia: Two roads diverging in midlife? Front Aging Neurosci. Published online September 19, 2018. doi:10.3389/fnagi.2018.00275

8. Chou PS, Wu MN, Yang CC, Shen CT, Yang YH. Effect of advanced glycation end products on the progression of Alzheimer’s disease. J Alzheimers Dis. Published online October 29, 2019. doi:10.3233/JAD-190639

9. Lubitz I, Ricny J, Atrakchi-Baranes D, et al. High dietary advanced glycation end products are associated with poorer spatial learning and accelerated Aβ deposition in an Alzheimer mouse model. Aging Cell. Published online January 19, 2016. doi:10.1111/acel.12436

10. Cortes-Canteli M, Iadecola C. Alzheimer’s disease and vascular aging: JACC Focus seminar. J Am Coll Cardiol. Published online March 3, 2020. doi:10.1016/j.jacc.2019.10.062

11. Rolandi E, Zaccaria D, Vaccaro R, et al. Estimating the potential for dementia prevention through modifiable risk factors elimination in the real-world setting: a population-based study. Alzheimers Res Ther. Published online August 7, 2020. doi:10.1186/s13195-020-00661-y

12. Yu F, Vock DM, Zhang L, et al. Cognitive effects of aerobic exercise in Alzheimer’s disease: A pilot randomized controlled trial. J Alzheimers Dis. Published online March 9, 2021. doi:10.3233/JAD-201100

13. Yu F, Mathiason MA, Han S, et al. Mechanistic effects of aerobic exercise in Alzheimer’s disease: Imaging findings from the pilot FIT-AD trial. Front Aging Neurosci. Published online October 7, 2021. doi:10.3389/fnagi.2021.703691