When I was a kid, my Grandma was diagnosed with Alzheimer's Dementia. As her mental state deteriorated, I witnessed the ravages that this disease can do to someone. Over the course of a decade or so (I don't remember the exact timeline), she went from being a capable, independent woman to someone who became totally dependent on others for all of her care and struggled to remember the names of her own grandchildren.
It is estimated that approximately 6.7 million adults over the age 65 have Alzheimer's Dementia.[1] According to the CDC, Alzheimer's dementia is the 7th leading cause of death in the United States in 2022.[2] The cost of providing health and long-term care to individuals with Alzheimer’s is project to be $360 billion in 2024 and rising to $1 trillion in 2050.[3]
In his book, Outlive, Peter Attia discusses the concept of longevity in the context of modern medicine and seeks to find ways to increase not just our lifespan but also our healthspan. Early in the book he describes what he calls four horsemen that contribute to morbidity and mortality. These are heart disease, cancer, neurodegenerative disease, and metabolic disease. Each of these, in their own way, erode both quantity and quality of life.[4]
Unfortunately, by the time that dementia is confirmed, there is little that can be done to modify the trajectory of the disease. There are a few medications available that are marketed to patients with dementia, but their effect is modest at best and do not turn back the hands of time. As such, it seems that the best offense for dementia is a good defense. That is, the best way to combat dementia is to identify modifiable risk factors before dementia develops and target these.
Cardiorespiratory fitness (CRF) has been proposed as one such modifiable factor. Poor fitness level is the risk factor with exercise as the antidote. As we peruse the medical literature, there are a myriad of studies that look at the effects of physical activity and fitness on dementia and other neurocognitive disorders. For the purposes of this analysis, we will look at four studies in particular.
The first study was published in 2018 in the Journal of Age and Aging by Kurl and colleagues.[5] This study is a population-based cohort study of over 2000 Finish men enrolled between the ages of 42-61 and followed for over 20 years. The broader study was designed to investigate risk factors for cardiovascular disease, carotid atherosclerosis and other related outcomes. This particular study was set up to assess the association between VO2max and the development of dementia.
VO2max was used in this study as an objective measure of physical activity and fitness. As a functional biometric measurement, VO2max assesses the maximal oxygen consumption during vigorous exercise. For reference, the average VO2max for a sedentary adult male is generally between 35-40 ml/kg/min and 27-30 ml/kg/min for the average sedentary adult female. These values vary by age and sex, but a VO2max over 40 is generally considered good for anybody.[6]
In this particular study, the authors categorized individuals by VO2max into five different quintiles. The worst quintile was <23 ml/kg/min and the best quintile was >36.5 ml/kg/min. The risk for development of dementia was calculated for each quintile using an age adjusted model and a multivariate adjusted model. In both models, the authors demonstrated a statistically significant increased relative risk of dementia for the bottom quintile compared with the top. For the age adjusted model the bottom quintile had a 1.92 increased relative risk of dementia compared with the top. And the multivariate adjusted model demonstrated a 1.95 increased relative risk compare with the top quintile.
This study demonstrates a robust decrease in the risk of developing dementia with increasing levels of fitness. Specifically, the authors report that a 1 standard deviation increase on VO2max correlated with a 20% reduction in dementia.
The next study was published in 2023 in the journal of Alzheimer’s Dementia by Cheng and colleagues.[7] This study is a retrospective chart review of over 600,000 American veterans between the ages of 30-95 years using data abstracted from the Veterans Affairs (VA) electronic health records. Using natural language processing tools and ICD 9 & 10 codes, the authors examined the association between cardiorespiratory fitness as assessed by metabolic equivalents (METs) and the risk of developing Alzheimer’s dementia or related dementias over a 20 year period.
A MET is a measurement of degree of physical exertion for a particular activity. 1 MET is defined as 3.5 ml O2 consumed per kg of body weight per minute when at rest. Activities are then graded based on the maximum METs for the activity. A casual walk is approximately 3 METs. A brisk walk or hiking is generally around 6 METs. And jogging at a 10 minute/mile pace is approximately 10 METs.[8]
In this study, the authors stratified study subjects in to 5 groups based on maximum METs that they were able to achieve as documented in the medical records. The least fit group achieved 3.8±0.6 METs and the most fit achieved 11.7±2.1 METS. The rate of developing dementia in each cohort was calculated over 20 years. Additionally, a hazard ratio was calculated for each cohort with the least fit being the reference standard.
The authors reported that the rate of developing dementia decreased across cohorts from 9.5 per 1000 person/years in the least fit group to 6.4 in the most fit group. Additionally with the hazard ratio for developing dementia in each of the progressively more fit groups declined compared with the least fit group. For the most fit group, the hazard ratio was reported as 0.61 with p<0.0001.
This study showed that there is a significant and progressively lower risk of developing dementia for individuals with increasing levels of fitness across a wide cohort of individuals - even using age and sex adjusted modeling.
The third study was published in 2023 in the British Medical Journal by Gafni and colleagues.[9] This was a cohort study using data from the Cooper Clinic Longitudinal Study which is designed to study the effects of fitness and lifestyle decision on longevity. The authors examined over 6000 individuals with the goal of assessing midlife BMI with the risk of developing dementia. Study participants were assessed for fitness and weight and placed in one of four permutations of these factors (normal weight/fit, normal weight/unfit, overweight/fit, overweight/unfit). Baseline fitness and weight was assessed as well as development of dementia over a median follow up of 16 years.
When evaluating fitness and weight categorically, the authors found that both were risk factors for developing dementia. Like the previous study, the authors calculated hazard ratios but this time with the reference group being the normal weight/fit group. By comparison, the overweight/unfit group had a hazard ratio for developing dementia of 2.28.
Overall, this study demonstrated that both fitness and obesity are important risk factors for developing dementia. Interestingly between the two, fitness had the strongest effect.
The final study was published in the Journal of the Alzheimers Association in 2024 and examined a population of Swedish septuagenarians to assess for life factors and the association on brain age gap.[10] The brain age gap was defined as the predicted brain age as assessed by MRI compared with the individual's chronological age. An increased brain age gap was associated with poorer cognitive function. Of all of the life factors studied, physical activity was shown to have the greatest impact on brain age gap.
It seems from the literature that exercise plays a significant role in protecting an individual from developing dementia later in life. There are two questions that follow from this information. The first question is; why is exercise independently protective despite other potential risk factors? The second is: how much exercise do I need to get to receive neuroprotection?
Cheng suggests that some of this benefit comes from the suppression of inflammation and neurohormonal stress that results from cardiorespiratory fitness. Other factors include increase in growth factor expression in the brain and decreased amyloid deposition.[7] Gafni postulates that this effect comes from fitness related improvements in cerebral blood flow as well as improved neuroplasticity from increased brain-derived neurotrophic factor.[9]
In answer of the second question, the Cheng study defined physical fitness according to peak MET achieved during the physical assessment. The authors specifically indicate that they found neuroprotective effects of fitness at 6 METs and higher, the equivalent of doing a minimum of a brisk walk.
The US Department of Health and Human Services (HHS) in their recommended fitness guidelines define 6 METs as the cutoff between moderate and intense physical activity. In the same document, HHS recommends a minimum of 150-300 minutes of moderate physical activity or 75-150 minutes of vigorous physical activity per week. However, it is estimated that only 26% of adults men and 19% of adult women actually achieve these recommendations. [11]
Since the development of Alzheimer’s dementia or other similar dementias seems to be strongly linked with cardiorespiratory fitness, a good target for decreasing dementia risk, both at an individual and population level, would be to encourage improving fitness levels.
To improve your risk of dementia, targeting activities requiring 6 METs and do those for 30 minutes/day, 5 days/week seems like a good target. While discussing fitness may seem like something that sounds intimidating, painful or boring, there are many activities that fit within the 6METs/30min/5days framework. The easiest is take a brisk walk each evening after dinner. From there, the options are limitless.
References
1. 2023 Alzheimer’s disease facts and figures. Alzheimers Dement. 2023;19(4):1598-1695. doi:10.1002/alz.13016
2. FastStats. October 26, 2024. Accessed December 25, 2024. https://www.cdc.gov/nchs/fastats/leading-causes-of-death.htm
3. Alzheimer’s Disease Facts and Figures. Alzheimer’s Disease and Dementia. Accessed December 25, 2024. https://www.alz.org/alzheimers-dementia/facts-figures
4. Attia P, Gifford B. Outlive: The Science & Art of Longevity. First edition. Harmony; 2023.
5. Kurl S, Laukkanen JA, Lonnroos E, Remes AM, Soininen H. Cardiorespiratory fitness and risk of dementia: a prospective population-based cohort study. Age Ageing. 2018;47(4):611-614. doi:10.1093/ageing/afy060
6. VO2 Max: The Fitness Metric That Can Help You Run Faster and Work Out Harder. Accessed December 24, 2024. https://www.cnet.com/health/fitness/vo2-max-the-fitness-metric-that-can-help-you-run-faster-and-workout-harder/
7. Cheng Y, Zamrini E, Faselis C, et al. Cardiorespiratory fitness and risk of Alzheimer’s disease and related dementias among American veterans. Alzheimers Dement J Alzheimers Assoc. 2023;19(10):4325-4334. doi:10.1002/alz.12998
8. Jetté M, Sidney K, Blümchen G. Metabolic equivalents (METS) in exercise testing, exercise prescription, and evaluation of functional capacity. Clin Cardiol. 1990;13(8):555-565. doi:10.1002/clc.4960130809
9. Gafni T, Weinstein G, Leonard D, et al. Independent and joint associations of cardiorespiratory fitness and BMI with dementia risk: the Cooper Center Longitudinal Study. BMJ Open. 2023;13(12):e075571. doi:10.1136/bmjopen-2023-075571
10. Marseglia A, Dartora C, Samuelsson J, et al. Biological brain age and resilience in cognitively unimpaired 70-year-old individuals. Alzheimers Dement. n/a(n/a). doi:10.1002/alz.14435
11. Current Guidelines | odphp.health.gov. Accessed November 8, 2024. https://odphp.health.gov/our-work/nutrition-physical-activity/physical-activity-guidelines/current-guidelines
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