Alzheimer Disease Prevention

In this exclusive blog, Psych Congress Network Geriatric Psychiatry Section Editor Marc Agronin, MD, provides expert clinical insights on helping patients reduce their risk for Alzheimer disease as well as how to delay onset and progression. Dr Agronin discusses modifiable risks and risk mitigation strategies.

The last year has brought highs and lows in the progression of our understanding and treatment of Alzheimer disease (AD). In 2021, the US Food and Drug Administration (FDA) approved the first disease-modifying therapy for AD in the form of aducanumab, an anti-amyloid immunotherapy. This decision appeared to herald a new era of Alzheimer treatment for millions of affected individuals. In 2022, after months of controversy over the FDA’s decision in light of the limited efficacy of aducanumab, Centers for Medicare and Medicaid (CMS) decided not to cover the costs of treatment outside of clinical trials, and the pharmaceutical company Biogen consequently decided to no longer promote its sales.¹ The pending FDA applications of several other immunotherapies will likely face similar challenges. The story of aducanumab is a microcosm of the entire saga of Alzheimer research, with tremendous progress in terms of understanding the disease and testing promising therapeutics, but limited yield towards a truly effective treatment. Not surprisingly, then, more and more clinicians are asking how we can prevent this disease in the first place.

Assessing Risk

Alzheimer disease prevention begins with understanding underlying risk factors. Genetics play a defining role for many individuals with early-onset AD (e.g., dominant transmission due to presenilin gene mutations on chromosomes 1 and 14) and a significant role for many individuals with late-onset AD (e.g., increased risk from the Apolipoprotein E (APOE) gene ε4 allele located on chromosome 19), but these factors constitute a relatively fixed risk.² In contrast, research has identified numerous modifiable risk factors that are estimated to account for 30% to 40% of all cases. According to a recent cross-sectional study³ as well as guidelines from the UK National Institute of Health and Care Excellence and the US National Institutes of Health⁴, the major modifiable risk factors include low educational attainment in early life; hearing loss, traumatic brain injury, hypertension, and obesity in mid-life; and smoking, depression, physical inactivity, social isolation, and diabetes in later life. These risk factors are described in Table 1.

Table 1 – Modifiable Risk Factors for Alzheimer’s Disease

Additional dementia risk factors may include visual impairment, sleep disorders (e.g., obstructive sleep apnea), and elevations in cholesterol and homocysteine levels.² In addition, post-menopausal women have an increased risk for AD.

The first step in disease prevention is to provide a comprehensive assessment to identify and quantify all of these risk factors, tailored to the individual’s family / genetic, medical, psychiatric, and social history. To this end, researchers at the Australian National University (ANU) College of Health and Medicine developed an online risk calculator called the ANU Alzheimer’s Disease Risk Index (ANU-ADRI) that reviews major risk factors and provides a current risk profile.⁵ This questionnaire takes 10 to 15 minutes to fill out and review 11 major risk factors and 4 protective factors. There are other risk calculators as well. In terms of in-person assessment, one excellent clinical model was developed by Isaacson and colleagues, and involves a comprehensive assessment of multiple risk factors, including detailed analysis of metabolic risk factors and neuropsychological testing to assess early, subtle neurocognitive changes.^6,7

Risk Mitigation

The goal of Alzheimer or dementia “prevention” may be to prevent the disease from occurring, but it may also involves slowing its premorbid pathological progression to delay and blunt its eventual clinical expression. The strategies involved may also improve the aging process and enable individuals to live better even when symptoms begin to develop. Contrary to lots of clever marketing and exaggerated claims, there are no pills, tonics, or other formulas that have been shown scientifically to improve neurocognitive function, treat AD or any other form of dementia, or prevent its development. The FDA-approved acetylcholinesterase inhibitors and memantine are not indicated for preclinical or early states of dementia, and have been found to be ineffective in mild cognitive impairment. Instead, individuals interested in reducing their risk for Alzheimer disease and other neurocognitive disorders (as well as delaying and blunting clinical onset) should adopt a brain healthy lifestyle.

Brain Healthy Lifestyle

A brain healthy lifestyle involves both avoidance and mitigation of risk factors as well as adopting certain positive habits. All together, there are 4 basic strategies:

• Physical exercise
• Brain-healthy diet
• Brain stimulation and soothing
• Physical health maintenance

Each of these strategies will be described below along with practical suggestions.

Physical Exercise

Multiple studies have shown positive correlations between physical exercise in older individuals and well-maintained, enhanced cognition, especially executive function, delayed cognitive impairment, and lower rates of dementia.⁸ This benefit appears to stem from how exercise improves cerebral blood flow, decreases loss of cortical tissue, and increases the release of neural growth factors that improve synaptogenesis and neuroplasticity.^9,10,11

Brain-Healthy Diet

Despite numerous claims about diets and dietary supplements that may enhance brain function or prevent dementia, the most robust data showing reduced cognitive decline and lowered Alzheimer risk has stemmed from the Mediterranean, Dietary Approaches to Stop Hypertension (DASH), and Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diets.¹² The MIND diet consists of eating regular portions of vegetables (especially green leafy ones), fruits (especially berries), nuts, olive oil, whole grains, fish, beans, poultry, and even a single glass of wine, while limiting servings of butter/margarine, cheese, red meat, fried food, and pastries / sweets. Individuals who did not drink alcohol in the past should not necessarily start, and those who have regular drinks should adhere strictly to the one-glass-a-day guideline. There is no evidence that any specific dietary supplements or vitamins can reduce risk.

Brain Stimulation and Soothing

Keeping the brain stimulated is an important part of building cognitive reserve, reducing Alzheimer risk, and delaying onset.¹³ This can take many forms, including reading, writing, games, hobbies, adult education classes, social activities, and volunteer work.¹⁴ Having a positive attitude and a sense of purpose in life can also reduce risk.^15,16 At the same time, the brain needs adequate sleep and hydration, augmented with stress-reducing activities such as spiritual experiences, exposure to nature, meditation, yoga, tai chi, and other similar pursuits.^17,18,19

Physical Health Maintenance

Reducing risk requires attention to key risk factors that injure the brain, including hypertension, elevated glucose and cholesterol levels, and infections. One study compared individuals reducing systolic blood pressure to below 140 and below 120, with the lower group demonstrating 19% fewer diagnoses of mild cognitive impairment and 15% fewer cases of dementia.²⁰ Another study suggests that bacteria associated with poor oral hygiene may increase the risk of amyloid protein in the brain.²¹ Seeing one’s doctor regularly and closely managing these and other factors that can affect brain health are important to avoiding unnecessary cerebral damage.

Put together, these lifestyle changes can make a big difference. Dhana and colleagues looked at 5 healthy lifestyle factors (e.g., physical exercise, MIND diet, cognitive exercises, not smoking, limited alcohol intake) and found that individuals who engaged in 2 or 3 of these had a 37% lower risk of Alzheimer’s disease, while those adhering to 4 or 5 factors had a 60% lower risk.²² This and other studies accentuates the key message that while we do not yet have an effective treatment to significantly slow or stop Alzheimer disease, there are evidence-based lifestyle factors that, alone but especially in aggregate, can have an significant, even life-saving, impact.

References

1. Loftus P: Alzheimer’s Patients Now Less Likely to Receive Biogen’s Aduhelm Treatment. Wall Street Journal. May 3, 2022. Accessed July 7, 2022 at: https://www.wsj.com/articles/alzheimers-patients-now-less-likely-to-receive-biogens-aduhelm-treatment-11651611189?st=vq2hijrigteyb9n&reflink=desktopwebshare_permalink
2. Silva MVF, Loures CMG, Alves LCV, et al.: Alzheimer's disease: risk factors and potentially protective measures. J Biomed Sci. 2019 May 9;26(1):33.
3. Nianogo RA, Rosenwohl-Mack A, Yaffe K, et al.: Risk Factors Associated With Alzheimer Disease and Related Dementias by Sex and Race and Ethnicity in the US. JAMA Neurol. Published online May 09, 2022.
4. Livingston G, Huntley J, Sommerland A, et al.: Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet 396, Aug 8, 2020, 413 – 446.
5. Australian National University: Alzheimer’s Disease Risk Index. 2013. Accessed July 7, 2022 at: https://anuadri.anu.edu.au
6. Isaacson RS, Ganzer CA, Hristov H, et al.: The clinical practice of risk reduction for Alzheimer's disease: A precision medicine approach. Alzheimers Dement. 2018 Dec;14(12):1663-1673.
7. Isaacson RS, Hristov H, Saif N, et al.: Individualized clinical management of patients at risk for Alzheimer's dementia. Alzheimers Dement. 2019 Dec;15(12):1588-1602.
8. Carvalho A, Rea IM, Parimon T, Cusack BJ. Physical activity and cognitive function in individuals over 60 years of age: a systematic review. Clin Interv Aging. 2014 Apr 12;9:661-82.
9. Colcombe SJ, Erickson KI, Scalf PE, et al.: Aerobic exercise training increases brain volume in aging humans. J Gerontol A Biol Sci Med Sci. 2006 Nov;61(11):1166-70.
10. Colcombe SJ, Kramer AF, Erickson KI, et al.: Cardiovascular fitness, cortical plasticity, and aging. Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):3316-21.
11. Pickersgill JW, Turco CV, Ramdeo K, et al.: The Combined Influences of Exercise, Diet and Sleep on Neuroplasticity. Front Psychol. 2022 Apr 26;13:831819.
12. van den Brink AC, Brouwer-Brolsma EM, Berendsen AAM, van de Rest O: The Mediterranean, Dietary Approaches to Stop Hypertension (DASH), and Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) Diets Are Associated with Less Cognitive Decline and a Lower Risk of Alzheimer's Disease-A Review. Adv Nutr. 2019 Nov 1;10(6):1040-1065.
13. Wilson RS, Wang T, Yu L, Grodstein F, et al.: Cognitive Activity and Onset Age of Incident Alzheimer Disease Dementia. Neurology. 2021 Aug 31;97(9):e922-e929.
14. Marioni RE, Proust-Lima C, Amieva H, Brayne C, et al. : Social activity, cognitive decline and dementia risk: a 20-year prospective cohort study. BMC Public Health. 2015 Oct 24;15:1089.
15. Levy BR, Slade MD, Pietrzak RH, Ferrucci L. Positive age beliefs protect against dementia even among elders with high-risk gene. PLoS One. 2018 Feb 7;13(2):e0191004.
16. Sutin AR, Aschwanden D, Luchetti M, et al.: Sense of Purpose in Life Is Associated with Lower Risk of Incident Dementia: A Meta-Analysis. J Alzheimers Dis. 2021;83(1):249-258.
17. Bratman GN, Hamilton JP, Daily GC. The impacts of nature experience on human cognitive function and mental health. Ann N Y Acad Sci. 2012 Feb;1249:118-36.
18. Khalsa DS, Newberg AB. Spiritual Fitness: A New Dimension in Alzheimer's Disease Prevention. J Alzheimers Dis. 2021;80(2):505-519. 
19. Wayne PM, Walsh JN, Taylor-Piliae RE, et al.: Effect of tai chi on cognitive performance in older adults: systematic review and meta-analysis. J Am Geriatr Soc. 2014 Jan;62(1):25-39.
20. The SPRINT MIND Investigators for the SPRINT Research Group. Association of intensive versus standard blood pressure control with cerebral white matter lesions. JAMA. Published online August 13, 2019 
21. Beydoun MA, Beydoun HA, Hossain S, et al.: Clinical and Bacterial Markers of Periodontitis and Their Association with Incident All-Cause and Alzheimer's Disease Dementia in a Large National Survey. J Alzheimers Dis. 2020;75(1):157-172.
22. Dhana K, et al. Healthy lifestyle and the risk of Alzheimer’s dementia: Findings from two longitudinal studies. Neurology. 2020;95:1-10.
23. De la Rosa A, Olaso-Gonzalez G, Arc-Chagnaud C, et al.: Physical exercise in the prevention and treatment of Alzheimer's disease. J Sport Health Sci. 2020 Sep;9(5):394-404.

Marc Agronin, MD, is a geriatric psychiatrist in Miami at Miami Jewish Health, and the author of The End of Old Age: Living a Longer, More Purposeful Life