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. 2023 Jan-Feb;120(1):70–78.

Complementary and Alternative Medicine Approaches in Alzheimer Disease and Other Neurocognitive Disorders

David Q Beversdorf 1, Haley W Crosby 2, Joel I Shenker 3
PMCID: PMC9970340  PMID: 36860601

Abstract

As our population ages, there is interest in delaying or intervening in cognitive decline. While newer agents are under development, agents in mainstream use do not impact the course of diseases that cause cognitive decline. This increases interest in alternative strategies. Even as we welcome possible new disease-modifying agents, they are likely to remain costly. Herein, we review the evidence behind other complementary and alternative strategies for cognitive enhancement and prevention of cognitive decline.

Background

Dementia from Alzheimer disease (AD) and other causes has a major impact on patients and their families, resulting in a loss of quality of life for the patient, and at times devastating the lives of families and others that care for patients. Current approved therapies offer limited help, such as AD treatments, cholinesterase inhibitors, and NMDA antagonists. These agents have some impact on functional ability, but do not impact disease trajectory. Newer approaches target pathogenesis of diseases such as AD, but decades of work along these lines have struggled to yield definitive clinical results for any agent. Therefore, families, desperate for other options, often ask about complementary and alternative treatment approaches. Herein, we review evidence for such approaches.

Alternative Approaches for Treatment

Any discussion of this type should consider prevention. Substantial evidence supports strategies that might prevent dementia. A recent report by the Lancet Commission,1 identified a 12 factor life-course model for modifiable factors that may affect dementia outcomes. In this study, less education, hypertension, hearing impairment, smoking, obesity, depression, physical inactivity, diabetes, infrequent social contact, excessive alcohol consumption, head injury, and air pollution exposure collectively contributed about 40% risk for dementia. Referring to ways to promote good cognitive outcomes, an extensive review of “successful aging” strategies2 supported regular physical activity, treatment of cardiovascular risk factors (hypertension, diabetes, hyperlipidemia, obesity, metabolic syndrome), cognitively stimulating activities, social engagement, a heart healthy diet, smoking cessation, managing stress and depression, getting adequate sleep, avoiding anticholinergics, assessing sensory deficits, limiting alcohol use, and avoiding physical and toxin-related brain damage. A very recent study also showed that greater adherence to Healthy Lifestyle Factors (no current smoking, moderate alcohol consumption, regular physical activity, healthy diet, adequate sleep, less sedentary behavior, and frequent social contact) is associated with decreased incidence of dementia in patients with type 2 diabetes. 3 However, in the case of AD dementia, when it is already in place, the most consistent data argue that outcomes are most affected by a more narrow set of risk factors, including malnutrition, genetic variants, altered gene regulation, baseline cognitive level, neuropsychiatric symptoms, and extrapyramidal signs.4 Therefore, a discussion of complementary and alternative treatments regarding dementia should emphasize that there is likely a vastly greater preventative role rather than a way to treat extant neurocognitive impairment.

Dietary Interventions

One of the most consistent findings in complementary and alternative approaches to dementia has been decreased risk of Alzheimer disease dementia or neurocognitive decline more generally in people who follow a “Mediterranean diet.”5–8 This type of diet consists of high intake of vegetables, legumes, fruits, nuts, cereals, and unsaturated fatty acids (mostly olive oil), moderate to high fish intake, low to moderate intake of dairy, low intake of meat and saturated fatty acids, and regular but limited alcohol use.8 The Mediterranean diet has been found to be associated with less accumulation of cerebral beta-amyloid, an AD biomarker, in the Australian Imaging, Biomarkers, and Lifestyle Study of Ageing9 and in a study based at New York University School of Medicine/Weill Cornell Medical College,10 and mitigated decreases in total brain volume over three years from age 73 to 76 in a Scottish cohort.11 When the Mediterranean is blended with the “DASH” (Dietary Approaches to Stop Hypertension) diet, the resultant catchy-named MIND (Mediterranean – DASH Intervention for Neurodegenerative Delay) diet is associated with less emergence of dementia.12–13 The MIND diet modifies the Mediterranean diet by allocating separate categories for green leafy vegetables and berries, fruit is not included, and fish consumption is reduced from daily to two to three times a week.14 One study suggested similar future cognitive benefits from either MIND or Mediterranean diets,15 while a more recent study suggested the 12-year risk of cognitive decline was better for the MIND diet than the Mediterranean diet.14 Trials of the Mediterranean diet with additional olive oil or nuts had better cognitive results in patients with cardiovascular risk.16 Clear evidence of the benefits of dietary interventions in patients with existing cognitive decline is lacking: whereas one pilot study found a beneficial effect of a coconut oil enriched Mediterranean diet on cognitive performance in people already diagnosed with AD,17 a large Swedish population-based study did not find a protective effect from a Mediterranean diet.18 As for other dietary regimens, a decreased risk of incident dementia has been found to correlate with a greater adherence to a Japanese diet.19 Elsewhere, adherence to a healthy diet as assessed by a modified version of the Alternative Healthy Eating Index was associated with a decreased risk of a three or more point decline in the Mini-Mental State Examination Score.20 Further, the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) study found that among 1,260 healthy older adults there was a significantly positive association between adherence to a healthy diet on global cognition and executive function.21

One dietary intervention with intriguing recent support is a ketogenic diet. This diet allows the brain to use ketones to switch away from obligatory processing of glucose. One small study showed AD patients had improvement in daily function and quality of life with a ketogenic diet.22 Another study, using randomized assignments of a ketogenic drink, found that improved brain energy was associated with cognitive improvements in patients with mild cognitive impairment (MCI) from AD.23 Yet another study suggested benefit for memory from a modified Atkins diet for early AD dementia and MCI patients.24 A medium-chain triglyceride-based ketogenic formula was also found to be beneficial for cognition in patients with mild-to-moderate AD.25

Finally, diets emphasizing specific types of food have received attention. Consumption of green leafy vegetables has been associated with decreased cognitive decline with aging in the Memory and Aging Project26 and also a decreased risk of developing all-cause MCI was found in the China Longitudinal Aging Study.27 Diets rich in fruits and vegetables also resulted in better cognitive performance in older adults in a large European study,28 as well as in a study in the United States,29 further supported by a meta-analysis,30 and for subjective cognition as well.31 Diets rich in citrus have also been associated with decreased risk of all-cause dementia in a Japanese cohort study.32 Diets including a specific fibre supplementation targeting the microbiome has also been associated with improved cognitive performance in healthy adults.33

Specific Dietary Components

Numerous lines of evidence have argued that docosahexaenoic acid (DHA) and omega-3 fatty acids have a protective effect for dementia.34 Red blood cell DHA was associated with decreased risk of both AD dementia and all-cause dementia in the Framingham offspring study.35 A trial of polyunsaturated fatty acids in patients with AD showed a better profile of neurodegenerative markers (neurofilament light (NfL) and chitinase-2-like protein 1 (YKE-40) ) in the treated group as compared to the untreated group.36 The combination of omega-3 fatty acid and alpha lipoic acid was found to slow functional decline in AD in a small randomized trial.37 Additionally, DHA intake was associated with decreased structural changes on brain imaging in cognitively unimpaired individuals with two copies of the high AD risk APOE ɛ4 allele38. The protective effect of omega-3 fatty acids against development of AD dementia among those at greatest genetic risk is further supported by protection of memory function and lowered amyloid burden among the high risk APOE ɛ4 carriers,39 and decreased risk of cognitive decline in multiple domains was found with one meal per week of seafood and long chain n-3 fatty acids in APOE ɛ4 carriers.40 A measure of “fluid intelligence” was found to be associated with greater alpha-linolenic acid, stearidonic acid, and eicosatrienoic acid among omega-3 fatty acids in a population of healthy aging individuals,41 and higher alpha-linolenic acid intake was associated with slower cognitive decline in global cognition and memory in middle and older age individuals in the Doetinchem Cohort Study.42 However, in a clinical trial in diagnostically diverse sample of non-demented patients who already had memory complaints, neither omega-3 fatty acids nor a multidomain intervention, nor their combination, impacted cognitive function followed over a three-year epoch.43 Additionally, an earlier randomized, placebo-controlled trial of high dose omega-3 fatty acids including DHA did not show benefit in patients with Alzheimer disease44. Despite the negative studies in trials of patients with active cognitive decline, reviews suggest that supplementation in APOE ɛ4 carriers might be promising for prevention.45 Other ‘healthier’ fatty acids also have suggested benefits that may be relevant for dementia. Higher olive oil intake has also been associated with decreased risk of death associated with neurodegenerative diseases in the Nurses Health Study,46 and in a randomized prospective trial with MCI patients, high phenolic early harvest extra virgin olive oil resulted in better cognitive outcomes than seen with other dietary interventions.47 Virgin olive oil has also been shown to benefit cognition in a randomized trial in healthy older adults in primary care centers at the University of Navarra.48

Increased consumption of dietary flavonoids have also been associated with decreased risk of cognitive decline49 as well as subjective cognitive decline in the Nurses Health Study,50 and is associated with a decreased risk of AD in the Rush Memory and Aging Project51 as well as the Framingham Offspring Cohort52 and the French Three-City (3C) Study cohort.53 Consumption of cocoa-based flavanols was associated with better performance on hippocampal-dependent list-learning in a trail of healthy aging adults.54 Consumption of blueberries in individuals with subjective cognitive impairment in midlife has been associated with an increased lexical access and decreased memory interference as well as decreased self-reported encoding difficulties in daily activities.55 Blueberry intake was also found to alter circulating phenolic compounds and improve aspects of cognition on healthy older adults.56–57 Increased neuronal activation was also observed with blueberries in MCI patients.58 Such improvement with blueberries is supported in systematic reviews, but a conclusion was limited by methodological heterogeneity.59 Consumption of cranberries for 12 weeks was also found to improve episodic memory and regional perfusion in the brain.60 Concord grape juice was also found to improve memory in MCI patients.61 Montmorency tart cherry juice was found to improve memory in a randomized controlled trial of older adults with normal cognitive function.62 One postmortem study of a large population suggested that strawberry and pelargonidin intake was associated with fewer phosphorylated tau tangles.63 A meta-analysis of the cognitive benefits for polyphenols, though, supported only a tentative positive effect, a finding also limited by methodological heterogeneity.64 Citrus consumption has also been associated with decreased risk of developing all-cause dementia in the Ohsaki Cohort Study.32

Coffee and tea might also have neuroprotective effects. Higher coffee consumption was found to be associated with slower cognitive decline and decreased amyloid beta accumulation in a population of healthy older adults in Australia.65 A significant decrease in risk for dementia was also observed among those consuming two to three cups of coffee or two to three cups of tea in the UK Biobank cohort study.66 Another meta-analysis argued that the risk of cognitive disorders was lowest with the daily consumption of one to two cups of coffee daily, compared to no coffee drinking or more than three cups a day.67 Data from the Women’s Health Initiative Memory Study showed that caffeine intake was associated with a lower risk of cognitive impairment.68 Regular tea consumption was also found to be associated with decreased risk of neurocognitive disorders among Chinese elderly in the Singapore Longitudinal Aging Study.69 Tea consumption was also associated with better performance in attention and psychomotor speed in the Newcastle 85+ longitudinal study.70 Green tea consumption has also been associated with significantly decreased risk of all-cause dementia in the Ohsaki Cohort Study,71 and associated with decreased AD biomarkers in healthy older adults in the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) study.72 Chocolate has also been associated with better overall cognitive function in a community based sample in the Maine-Syracuse Longitudinal Study.73 Decreased risk of developing all-cause MCI has also been associated with greater consumption of mushrooms,74 and a decreased risk of developing all-cause dementia has also been associated with mushroom consumption.75 An 18-month double-blind, placebo-controlled trial of curcumin was found to result in improved memory and attention as well as decreased amyloid and tau accumulation on PET in non-demented adults.76 A large study of community-dwelling elders in Korea found that lifetime consumption of ginseng was associated with better cognitive function.77

Additionally, avoiding ultraprocessed foods appears to be protective against risk of all-cause dementia,78 and greater consumption of ultraprocessed foods is associated with greater cognitive decline in a large community sample from six Brazilian cities.79 A higher dietary inflammatory index was also found to be associated with MRI markers of brain aging in the Framingham Heart Study Offspring Cohort.80

Potential Impact of Individual Agents

Dietary interventions involve a large number of individual nutrients. Additionally, individual food items also involve a large number of individual nutrients. Therefore, dietary advice may involve synergistic effects of individual nutrients. Nonetheless, there is evidence specific to individual nutrients as well. Resveratrol was found to preserve hippocampal volume, improve hippocampal connectivity, but without differential effects on memory, in a randomized controlled trial in MCI patients,81 and improved memory performance, hippocampal connectivity, and glucose metabolism in healthy older adults.82 Oroxylum indicum extract, a traditional Ayurvedic medicine, was found to increase episodic memory among older adults with cognitive complaints in a double-blind, placebo-controlled, randomized trial.83 Decreased zinc levels have also been associated with greater amyloid PET deposition in cognitively normal older adults in study in Korea.84 Animal model evidence also suggests potential dementia-associated neuroprotection for some specific nutrients: astaxanthins, derived from marine mircoorganisms;85 centella asiatica, an herb used in Ayurvedic and traditional Chinese medicine;86 epigallocatechin-gallate (EGCG), a polyphenol found in green tea;87–88 quercetin, a bioflavonoid common in fruits and vegetables;89 yokukansan, a traditional Japanese herbal medicine;90 N-acetylcysteine, a widely used antioxidant;91 berberine, a protoberberine alkaloid used in Chinese medicine;92 dietary supplementation with walnuts93; β-lactolin, a whey-derived lacto-tetrapeptide;94 royal jelly, a secretion of honeybee hypopharyngeal and mandibular glands;95 and boldine, an alkaloid derived from the bark and leaves of the Chilean tree Peumus boldus.96 There is also growing evidence in support of curcumin, also known as turmeric, a spice also used as a remedy in India and China.97 Electroacupuncture was also found to impact cognition by regulating tau phosphorylation in an AD mouse model.98 Intermittent fasting has been shown to alleviate the increase of lipoprotein lipase in the brains of an AD model of mice.99 Resveratrol, the polyphenol found in red wine and other fruit sources, was found to reverse cognitive disturbances induced by a high fat diet in aged mice,100 and also reverses the effects of cholesterol and isoprenoid-mediated amyloidogenic processing in AD mouse models.101

A study using data from the National Health and Nutrition Examination Surveys exploring the effects of serum antioxidants and carotenoids found that incidence all-cause dementia was inversely associated with serum lutein+zeaxanthin and β-cryptoxanthin levels.102 Examination of this dataset also demonstrated better cognitive performance with higher dietary intake of B9 and B12.103 A randomized controlled trial of B vitamins to lower homocysteine was found to slow the rate of brain atrophy in MCI patient in a recent study.104 Others have reported that elevated homocysteine levels are associated with an increased incidence of all-cause dementia105, and in the Czech Brain Aging Study are also associated with worsened memory performance in older adults with subjective cognitive decline or amnestic MCI.106 In yet another study of Korean patients with and without cognitive impairment, a putative protective effect of folate was found.107 A meta-analysis also has concluded that B vitamin supplementation may play a preventative role in cognitive decline in older adults,108 and similarly for homocysteine and folic acid.109 Greater vitamin C levels have been associated with better cognitive function,110 with similar findings in the Boston Puerto Rican Health Study for vitamin B-6.111 A meta-analysis has continued to support the association between vitamin E levels and risk of developing dementia,112 but long double-blind randomized clinical trials did not show benefit for prevention of AD from vitamin E,113 while others did report benefit over two years.114 Additionally, serum 25-hydroxyvitamin D concentrations were inversely associated with risk of dementia among individuals with type 2 diabetes in the UK Biobank115 as well as in the Washington Heights-Inwood Columbia Aging Project.116 Serum vitamin D levels were also associated with cognitive function in a community sample of older adults in the Cooper Center Longitudinal Study.117 Genetically decreased vitamin D has also been associated with AD risk.118 Furthermore one study did suggest better cognition and Alzheimer biomarker profile among AD patients in a randomized double-blind placebo-controlled trial of vitamin D.119 However, one 18-year follow-up study in community living older males in Sweden found no association with vitamin D levels and incident dementia or cognitive impairment.120 In a randomized single-blinded placebo controlled trial of patients with symptomatic AD, cognitive outcomes were better in individuals who got folic acid and vitamin B12.121 One study suggested improvement in cognition and blood-based amyloid-beta related biomarkers with folate in a randomized controlled trial using MCI patients.122 The Cochrane Database of Systematic Reviews, though, concluded that evidence in support of vitamin or mineral supplementation was insufficient to conclude a meaningful effect for preventing decline123 or for intervening once people have MCI.124 Better outcomes were reported for Salvia officinalis extract, derived from sage, in double blind placebo controlled trials in mild to moderate AD patients.125–126

Non-Nutrient Approaches

In addition to nutrient-based approaches, research has addressed other nonpharmacological interventions. Acupuncture was associated with decreased risk of dementia in migraine patients in a population study in Taiwan.127 An overview of systematic reviews suggested that support for the idea that acupuncture may be helpful in AD has been limited by the low quality of studies available.128 Yoga decreased gray matter atrophy in women at risk for AD in a randomized controlled trial.129 Tai chi was associated with improved memory as well as hippocampal structure and function in a cross sectional study of the elderly,130 and a trial of tai chi suggested benefits on cognition and activities of daily living in community dwelling MCI patients.131 Musical literacy was associated with a lower incidence of all-cause dementia in a Brazilian population.132 An 18-month meditation intervention study in healthy older adults revealed better performance on attention regulation but no effect on brain volume or perfusion in target areas.133 Postponing retirement was associated with decreased risk of dementia in a large population in the U.S. Health and Retirement Study.134 Cognitively engaging activity was associated with greater cortical and subcortical volumes in older adults,135 and playing analog games was associated with better cognitive performance with aging in a large study of community-dwelling individuals in Scotland.136 Integrated cognitive and physical fitness training, implemented by using a closed-loop, motion-capture video game, also improves attentional abilities in healthy older adults.137 A recent review and meta-analysis showed that leisure activities involving physical, social, and cognitive activity were associated with a decreased risk of dementia.138 One recent study also showed that greater physical activity was associated with decreased progression plasma neurofilament light chain in an observational study of patients who are carriers for autosomal dominant frontotemporal dementia.139 Additionally, one population study in Finland found that greater use of sauna bathing was associated with a lower risk of dementia140 and also in the Kuopio Ischaemic Heart Disease cohort study.141 ‘Positive age beliefs,’ or positive perceptions about various aspects of old age, were associated with decreased risk of dementia in patients at high risk for AD due to presence of the APOE ɛ4 allele, possibly because these beliefs helped reduce stress.142 Neighborhood greenness was associated with decreased risk of dementia in a large population of U.S. Medicare Beneficiaries.143 Neighborhood socioeconomic status, along with cardiovascular risk factors, are associated with higher dementia risk in the U.S. Health and Retirement study,144 and neighborhood level disadvantage was associated with Alzheimer pathology in a population study in Wisconsin and California.145 In the Rush Memory and Aging Project, people with early life cognitive enrichment had a lower risk of dementia.146

Turning to patients with memory impairment established, mindfulness-based training did not improve outcomes in one randomized controlled trial of MCI patients,147 but another small study of MCI patients did show cognition benefits with mindfulness-based stress reduction.148 One meta-analysis did find benefit for cognitive function from muscle resistance training among older adults with cognitive impairment as well as those that were cognitively healthy.149 A meta-analysis of MCI plus dementia patients showed modest benefit from music participation150 and similarly for acupuncture.151 One randomized study of a multi-component cognitive training intervention found that in AD MCI patients memory improved and in AD with mild to moderate dementia activities of daily living were improved.152 Acupuncture therapy resulted in better cognition in a randomized trial of AD patients in a small study in China,153 and Kundalini yoga produced better cognition in a randomized trial of MCI patients in a small study at UCLA.154

Conclusion

Current literature is replete with data addressing putative complementary and alternative approaches in AD and other causes of dementia and cognitive impairment. However, what we can state with certainty remains rather limited. The topic remains one of an emerging science. In general, the evidence for potential preventative roles is stronger than for intervention after cognitive impairment already exists. A very recent study further supports this, finding no effects of six months of a randomized clinical trial of mindfulness training and exercise on episodic memory or executive function in older adults with subjective cognitive complaints.155 Among specific diets, the evidence is strongest for preventative roles of the Mediterranean diet and MIND diet, and similarly, among specific dietary components, the evidence is strongest for a preventive role for omega-3 fatty acids. However, the data for this is also mixed, with no reduced risk of developing all-cause dementia, AD, or vascular dementia observed in 20 years of follow-up associated with adherence to a modified Mediterranean diet in the Swedish population-based Malmö Diet and Cancer Study.18 Intriguing data exist for interventions such as a ketotic diet, but trials with large populations are needed. Future work must examine interactions between factors that may have synergistic effects. More research is needed about how lifestyle modifications for known cardiovascular factors may also impact cognitive decline as an additional benefit, independent of cardiovascular benefits, and whether this can impact patients with emerging cognitive decline. Also needed is a better understanding of how prevention or interventions may affect cognitive decline generally, as distinguished specifically from that which occurs in particular diseases such as AD, the most common cause of dementia.

Footnotes

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David Q. Beversdorf, MD, (above), is in the Departments of Neurology, Radiology, and Psychological Sciences, and is the William and Nancy Thompson Endowed Chair in Radiology. Haley W. Crosby is a fourth-year medical student at the School of Medicine. Joel I. Shenker, MD, PhD, is in the Department of Neurology. All are at University of Missouri-Columbia School of Medicine, Columbia, Missouri.

Disclosure

DQB has received consultancy fees and/or honoararia for Biogen, YAMO Pharmaceuticals, Stalicla Biosciences, Scioto Biosciences, Impel Pharmaceuticals, Quadrant Bisociences, MA Pharmaceuticals, and Human Bioscience.

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