Understanding Studies that Link the Long-term Use of PPI's with Dementia in Context

Why Does the Habitual Use of PPI’s Increase the Risk for Dementia?

Evelyn Smith

M.S. in Library Science, University of North Texas (2012)

This week’s headlines that correlate the use of proton pump inhibitors with an increased risk for dementia should serve as a warning against reading medical reports in isolation and out of context, even though the information stems from a peer-reviewed JAMA Neurology article. 

Gomm, W., von Holt, K., Thomé, F.  (2016, February 16).  Association of proton pump inhibitors with risk of dementia:  A pharmacoepidemiological claims data analysis.  JAMA Neurology. doi:10.1001/jamaneurol.2015.4791. [Abstract only; published Online first].  Retrieved from http://archneur.jamanetwork.com/article.aspx?articleid=2487379

After conducting a longitudinal, cohort study using observational data from Germany’s statutory health insurer from 2004 to 2011, researchers found that out of the 73,679 participants free of Alzheimer’s at baseline, those regularly receiving proton pump inhibitor medications had a “significantly increased risk of incident dementia” (Gomm, 2016, February 16, Abstract only).

However, reading this abstract does not tell the whole story since the data only links the incidence of dementia with the habitual use of PPI’s--not the reasons why the dementia occurs:  One of which is a vitamin B₁₂ deficiency (Jameson, 2013, December 13), although taking PPI’s also meddles with beta and tau amyloid plaque levels (Badiola, 2013).  Of course, making permanent life style changes, such as losing access weight, might also decrease the need for taking PPI’s as well as decrease the risk for dementia.

See also:

Link between indigestion drugs and dementia ‘inconclusive’.  (2016, February 16).  NHS Choices.  Retrieved from http://www.nhs.uk/news/2016/02February/Pages/Link-between-indigestion-drugs-and-dementia-inconclusive.aspx

A peer-reviewed German study sensationalized in The Daily Mail and The Daily Telegraph  that associated a 44 percent higher risk of dementia with the habitual, long term use of PPI’s is accurate, although this risk might have other plausible causes (Link, 2016, February 16, para. 4-5).  Adults age 75 and older taking PPI’s ordinarily are in poorer health and are thus taking more medications than their peers not suffering from acid reflux (Link, 2016, February 16, para. 6).  The NHS therefore recommends that those currently taking PPI’s should not stop taking them without consulting a physician since this could acerbate their digestive problems (Link, 2016, February 16, para. 7). 

Adhering to a healthy [Mediterranean or DASH] diet, watching one’s weight, regularly exercising [30 minutes four or five days a week], consuming alcohol in moderation, not smoking, and controlling blood pressure all reduce the risk for dementia, according to the NHS (Link, 2016, February 16, para. 35).

The NHS article provides links to the original JAMA Neurology article as well as to the Daily Mail and Daily Telegraph articles.  All the same, while reassuring, the British give few details, so keep reading.

Locke, Tim. (2016, February 17).  Proton pump inhibitors linked to dementia.  Heartburn/GORD Health Center.  WebMD.  Retrieved from http://www.webmd.boots.com/heartburn-gord/news/20160217/proton-pump-inhibitors-linked-to-dementia

A new study has again confirmed a link between proton pump inhibitors taken for heartburn and acid reflux with an increased risk of Alzheimer’s; however, it does not determine whether PPI’s directly cause dementia in senior adults (Locke, 2016, February 17, para. 1-2). The study which looked at the medical data on 73,679 Germans age 75 and older between 2004 and 2011 found that those who used a PPI for at least 18 months had a “significantly higher risk” of dementia than those not taking these medications.

Researchers also took into account additional risk factors, like diabetes, depression, stroke, and being prescribed additional drugs, but they didn’t consider the participants’ educational levels, so critics claim that the study has only established a statistical link between PPI’s and Alzheimer’s (Locke, 2016, February 17, para. 6-9  & 14 & 16). The use of PPI’s is also higher among smokers and the obese, which are also risk factors for dementia.  Moreover, PPI users are ordinarily in poorer health and thus at greater risk for diabetes and stroke (Locke, 2016, February 17, para. 17-18).

The more education one has, the less likely he or she is to succumb to dementia because presumably this knowledge should translate into better lifestyle habits.  All the same, most older and middle-aged adults can point to numerous university-educated, individuals, who died from Alzheimer’s.  Moreover, only a randomized trial could conclusively prove that taking PPI’s for a year and a half or more drastically increases an older adult’s chances of developing dementia.

Molchan, Susan. (2016, February 16).  Our psychiatrist-reviewer analyzes news about proton pump inhibitors and dementia risk.  Heathewsreview.  Retrieved from http://www.healthnewsreview.org/2016/02/our-psychiatrist-reviewer-analyzes-news-about-proton-pump-inhibitors-dementia-risk/

Susan Molchan points out that an association between the regular use of PPI’s and a “significant” increase for the  risk of dementia doesn’t indicate cause and effect since only a randomized, controlled trial can prove more than a statistical correlation.  Moreover, she cautions that the abstract itself overstates the study’s findings (Molchan, 2016, February 16, para. 4-5).

Even so, the use of PPI’s by adults over age 75 might increase their risk of dementia for various reasons:

PPI’s cross the blood-brain barrier;

They lower vitamin B12 levels, which if too low can cause dementia;

They interact with amyloid and tau protein.

Nevertheless, the habitual use of PPI’s might in itself might not raise the risk of dementia since older adults often take lots of drugs for lots of different health conditions, such as cardiovascular disease, that also increase the risk of dementia (Molchan, 2016, February 16, para. 6). 

Molchan then goes on to note that the Food and Drug Administration has long warned that the use of PPI’s is associated with an increased risk of fractures, unhealthy magnesium and calcium levels, and severe diarrheal infections.  She also notes that physicians routinely over prescribe PPI’s  (Molchan, 2016, February 16, 7-8).

But, the statistical link is still troubling:

Proton pump inhibitors may be associated with increased dementia risk. (2016, February 15).  Neuroscience News.  Retrieved from http://neurosciencenews.com/proton-pump-inhibitor-dementia-3663/

Researchers affiliated with the German Center for Neurodegenerative Diseases in Bonn, using data culled from patient diagnoses and drug prescriptions found a statistical link between the regular use of proton pump inhibitors (at least one PPI prescription in each quarter of an 18-month interval) and an increased risk of dementia (Proton pump, 2016, February 15, para. 3).  The study examined the records of 218,493 Germans aged 75 and older, identifying 29,510 patients who eventually developed dementia (Proton pump, 2016, February 15, para. 4).  Regular users of PPI’s had a 44 percent increased risk of dementia, although the authors were only able to integrate some other risk factors in their analysis (Proton pump, 2016, February 15, para. 6-7).  A copy of the abstract follows Neuroscience News’ synopsis of the JAMA Neurology article.

Fortunately, some commentary delves a little deeper, noting that research associates regularly taking PPI’s with vitamin B ₁₂ deficiency, and they also warn that diet and weight control might contribute both the reasons for acid reflux and dementia.

Thomson, Dennis. (2016, February 15).  Popular heartburn drugs linked to risk of dementia.  Healthday.  CBSNews.  Retrieved from http://www.cbsnews.com/news/heartburn-drugs-ppi-prilosec-nexium-prevacid-risk-of-dementia/

German researchers have found that adults aged 75 and older who regularly take proton pump inhibitors, including Prilosec, Nexium, and Prevacid, had a 44 percent increased risk of dementia compared with those who didn’t use PPI’s, although correlation in this longitudinal study doesn’t necessarily mean causation (Thomson, 2016, February 15, para. 1-3).

These results are surprising enough that one leading expert on aging plans to share these results with older patients taking PPI’s since they may change the levels of amyloid beta and tau protein association with Alzheimer’s as well as lead to vitamin B12 deficiency, which previous researchers have long linked with cognitive decline (Thomson, 2016, February 15, para. 7 & 15). Some experts, however, caution that since researchers as yet do not know why the aging brain deteriorates, those taking PPI’s should not be too concerned since the researchers failed to control for diet and weight as risk factors (Thomson, 2016, February 15, para. 24-30).  

Nevertheless, those patients who want to “ease off” taking PPI’s can reduce excess acid and prevent acid reflux by eating smaller meals, cutting out caffeine and chocolate, and sitting upright for two or three hours after eating (Thomson, 2016, February 15, para. 22).

All the same, the PPI lansoprazole does enhance the production of beta amyloid plaque in lab rats:

Badiola N., Alcalde, V., and Pujol, A., et al. (2013). The proton-pump inhibitor Lansoprazole enhances amyloid beta production. PLoS ONE, 8(3), e58837. doi:10.1371/journal.pone.0058837.  [Open Access].  Retrieved from http://bio.davidson.edu/courses/genomics/2013/Systems.pdf

In cell models, the proton-pump inhibitor lansoprazole enhances Ab37, Ab40 and Ab42 production as well as lowering Ab38 levels in amyloid cell models. Additionally, acute lansoprazole treatment promotes higher Ab-40 levels I the brains of wild and transgenic mice.

Moreover, a previous, much smaller German study did control for such risk factors as ApoE status, taking additional medications, depression, diabetes, and cardiovascular disease.

Haenish, B., Von Holt, K., and Wiese, B. (2015, August).  Risk of dementia in elderly patients with the use of proton pump inhibitors.  European Archives of Psychiatry and Clinical Neuroscience, 265(5), pp. 419-28.  doi: 10.1007/s00406-014-0554-0.  [Abstract only].  Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/25341874

Assessing the association between the use of PPI’s and dementia in older adults, the German Study on Aging, Cognition and Dementia in Primary Care Patients analyzed 3,327 community dwelling adults 75 years of age and older, noting that participants receiving a PPI medication had a “significantly increased risk” of dementia compared with non-users after considering factors such as age, gender, ApoE status, additional medications, depression, diabetes, ischemic heart disease, and stroke (Haenish, 2015, August, Abstract, p. 419).

Furthermore, previous American studies emphasize that the use of PPI’s leads to the inability to effectively absorb vitamin B₁₂:

Jameson, R., Lam, M. P. H., and Schneider, J. L., et al. (2013, December 13).  Proton pump inhibitor and histamine ₂ receptor antagonist use and vitamin B₁₂ deficiency.  JAMA, 310(22), pp. 2435-2442).  [Full text]. doi: 10.1001/jama.2013.280490.  Retrieved from http://jama.jamanetwork.com/article.aspx?articleid=1788456

Proton pump inhibitors and histamine ₂ receptor antagonists not only suppress the production of gastric acid, but their regular use potentially leads to “malabsorption of vitamin B₁₂, according to an examination of electronic pharmacy, laboratory, and diagnostic records of 25,956 Northern California patients ensured through Kaiser Permanente.  Among patients diagnosed with incidental vitamin B₁₂ deficiency, 12 percent received two or more years of PPI prescriptions, and 4.2 percent received two or more years of H₂RA’s, and 83.8 percent didn’t take either PPI or H2RA prescriptions (Jameson, 2013, December 13, Abstract, para. 1-5, p. 2435).  “Left untreated, vitamin B₁₂ deficiency can lead to dementia, neurological damage, and other complications, which may be irreversible” (Jameson, 2013, December 13, Abstract, Conclusion, para. 7, p. 2435).

A New York Times article as well as an Alzheimer Research Foundation article also note the increased risk for vitamin B12 deficiency as pointed out by an earlier American study:

See also:

Saint Louis, Catherine. (2013, December 10).  Acid-suppressing drugs linked to vitamin B12 deficiency.  Well.  New York Times.  Retrieved from http://well.blogs.nytimes.com/2013/12/10/acid-suppressing-drugs-linked-to-vitamin-b12-deficiency/?_r=0

Individuals of all ages who use proton-pump inhibitors and histamine ₂ receptor antagonists two years or longer increase their risk for vitamin B₁₂ deficiency, which, in turn, can sometimes lead to anemia, neurological problems, or dementia (Saint Louis, 2013, December 10, para. 1-2). 

Thus, those taking these medications should be routinely screened for vitamin B₁₂ deficiency, according to Douglas A. Corley, who along with his colleagues at Kaiser Permanente examined the pharmaceutical and diagnostic records of 25,956 Californians  diagnosed with Vitamin B ₁₂ deficiency between 1997 and 2011 (Saint Louis, 2013, December 10, para. 3 & 5).  Researchers found that patients who took PPI’s for more than two years were 65 percent more likely to be deficient in vitamin B₁₂ as well as those who took higher dosages of PPI’s (Saint Louis, 2013, December 10, para. 6).

The benefits of PPI’s need to be weighed against their risks, including bone fractures, pneumonia, severe diarrhea, and vitamin B₁₂ deficiency.  Other factors, such as adhering to a vegetarian diet might also explain a vitamin B₁₂ deficiency (Saint Louis, 2013, December 10, para. 13-14). Additionally, when researchers analyzed 20 randomly-selected charts of PPI-using patients, they discovered that 25 percent had anemia and 15 percent suffered from memory loss.  Accordingly, physicians need to counsel patients on the overuse and abuse of PPI’s (Saint Louis, 2013, December 10, para. 15-16).

Netzer, W. J. (reviewer).  (2016). How heart burn drugs may lead to memory problems.  The Fisher Center for Alzheimer’s Research Foundation.  Retrieved from https://www.alzinfo.org/articles/how-heartburn-drugs-may-lead-to-memory-problems/

The use of both over the counter and prescription proton pump inhibitors used to treat gastro-esophageal reflux disease and stomach and intestinal ulcers and histamine ₂ receptor antagonists leads to an increased risk of low vitamin B₁₂ levels, which, in turn, correlates with an increased risk of dementia.  When low vitamin B₁₂ deficiency goes untreated, it can lead to irreversible dementia, neurological damage, and anemia (Netzer, 2016, para. 1-3). 

Four in ten Americans suffer from acid reflux, and thus taking these drugs might put them at additional risk for vitamin B₁₂ deficiency.  Adults over age 50 are particularly at risk for this deficiency because they have problems absorbing vitamin B₁₂ found in fish, meat, and dairy products, so taking vitamin B₁₂ supplements may be necessary (Netzer, 2016, para. 4 & 10).

These findings come from a survey of 25,956 Kaiser Permanente patients diagnosed with vitamin B12 deficiency, 12 percent of whom had been taking PPI’s for at least two years compared with 7.2 percent who weren’t taking any acid reflux medications. Although higher dosages of PPI’s put patients more at risk, this increased risk decreases after older adults stop taking PPI’s (Netzer, 2016, para. 5 & 6).  Thus, physicians should prescribe the lowest workable dosages for PPI’s as well as discussing the risk associated with them (Netzer, 2016, para. 7-8). 

Folic acid, Vitamin B6 and Vitamin B12 help keep “brain areas critical for memory and thinking in good health” particularly in those seniors already diagnosed with mild cognitive impairment (Netzer, 2016, para. 9).

Thus, physicians should monitor the levels of vitamin B12 in their patients who are taking either over-the-counter or prescription PPI’s.  Additionally, users of PPI’s age 50 and older should 1) try to improve the conditions that put them on PPI’s in the first place, better controlling their weight and diet, so they no longer need to take them, and 2) routinely take a vitamin supplement and recognize the signs of vitamin B₁₂ deficiency:

Nazario, Brunilda. (2015, July 23).  Vitamin B12 deficiency.  WebMD., pp. 1-2.  Retrieved from http://www.webmd.com/food-recipes/guide/vitamin-b12-deficiency-symptoms-causes

• Weakness, tiredness, or lightheadedness
• Heart palpitations and shortness of breath
• Pale skin
• A smooth tongue
• Constipation, diarrhea, a loss of appetite, or gas
• Nerve problems like numbness or tingling, muscle weakness, and problems walking
• Vision loss
• Mental problems like depression, memory loss, or behavioral changes

(Nazario, 2015, July 23, p. 2)

All of which means that older adults who use PPI's should take a multivitamin that contains vitamin B12 or a vitamin B12 supplement (Nazario, 2015, July 23, p. 2). 

Finally, the public should be weaned away from the idea that simply popping a pill is the cure for anything since maintaining a healthy mind and body often calls for lifestyle changes.

A Lifetime Diet Emphasizing Vegetables & Fish Slows Cognitive Decline

Eat Your Vegetables and Fish for a Healthy Mind into Old Age

Evelyn Smith, M. S. in Library Science, University of North Texas (2012)

While the news this week focused on how moderate (once a week) fish consumption might possibly slow the onset of Alzheimer's among individuals possessing the APOE gene variant, and last year's headlines emphasized the importance of including dark green leafy vegetables like spinach and kale in a diet as a way to delay cognitive decline, one truth lies behind these studies: A life-long diet that stresses the intake of  dark-green vegetables and fish while limiting the consumption of red meat, poultry, refined sugar, and processed foods can delay and perhaps even prevent cognitive decline. In other words, now more than ever, to use a cliche, "You are what you eat!"

___________

Weekly Fish Consumption May Delay Alzheimer's Disease for 30% of the Population with the APOE Gene

Clare, Martha Clare, Brockman, John, and Schneider, Julie A., et al. (2016, February 2). Association of seafood consumption, brain mercury level, and APOE ε4 status with brain neuropathy in older adults. JAMA, 315(5), pp. 489-497. doi:10.1001/jama.2015.19451. [Open Access]. Retrieved from http://jama.jamanetwork.com/article.aspx?articleid=2484683#References

Moderate seafood consumption correlates with a lower risk for Alzheimer's. Researchers arrived at this conclusion after an analysis of deceased participants in the Memory and Aging Project neuro-pathological cohort study that took place between 2004 and 2014. After performing autopsies on 286 brains of 554 deceased, predominantly women residents of Chicago, whose mean age at death was 89.9 years, and comparing their answers on a food frequency questionnaire filled out on average 4.5 years earlier, researchers discovered that those participants who ate seafood at least once per week were much less likely to develop Alzheimer's disease. The more seafood the participants consumed, the much less likely they were to develop Alzheimer's. Although the autopsies showed that higher levels of fish consumption correlated with higher levels of mercury in the brain, they didn't correlated with  the type of brain damage associated with Alzheimer's disease. Moreover, taking fish oil instead of actually eating the fish didn't confer the same benefits as actually eating the fish did (Clare, 2016, February 2, Abstract, p. 489).

See also:

Chew, Emily Y., Clemons, Traci E., Agrón, Elvira, et al. (2015, August 25). Effect of Omega-3 fatty acids, lutein/zeaxanthin, or other nutrient supplementation of cognitive function. JAMA, 314 (8), 791-801). doi: 10.1001/jama.2015.9677. [Full text]. Retrieved from http://jama.jamanetwork.com/article.aspx?articleid=2429713

In a double-masked, randomized trial, retina specialists in 82 United States academic and community medical centers over a five-year period not only observd 4,000 older patients at risk for macular degeneration, but they also administered cognitive tests via the telephone whereupon they discovered that oral Omega-3 fatty acid supplements had no effect on cognitive function (Chew, 2015, August 25, Abstract, p. 791). 

In other words,  eating fish regularly may delay or prevent cognitive decline, but taking fish oil supplements doesn't do so.

______

Kroger, Edeltraut, and Laforce, Robert. (2016, February 2). Fish consumption, brain mercury, and neuropathology in patients with Alzheimer disease and dementia. JAMA, 315(5), pp. 465-466. doi:10.1001/JAA.2016.0005. [Editorial extract only]. Retrieved from http://jama.jamanetwork.com/article.aspx?articleid=2484661

Alzheimer's is fast becoming an increasing concern as an aging population worldwide is living longer, which means there is a need for proactive preventive strategies to combat Alzheimer's; for example, adhering to a Mediterranean-style [or MIND or DASH] diet with regular fish intake and limiting red meat intake can benefit older adults seeking to maintain brain health.  Research studies have consistently associated a regular intake of n-3 fatty acid fish with a slowing of cognitive decline and a decreased risk for Alzheimer's (Kroger, 2016, February 2, Extract, p.489).

Go Fish: Popular Takes On the Importance of the MAP Study:

Gregory, Andrew. (2016, February 2). Seafood really is brain food say scientists who food it could reduce Alzheimer's risk . Mirror. Retrieved from http://www.mirror.co.uk/news/technology-science/science/seafood-really-brainfood-say-scientists-7295129

Although researchers are careful not to extend their findings on the benefits of regularly consuming seafood to a general population, a study published February 2, 2016, in the Journal for the American Medical Association reveals that for older adults with the APOE gene, eating at least one serving of seafood weekly greatly reduced their risk for developing Alzheimer's (Gregory, 2016, February 2, para. 1-6). However, investigators also stressed that the consumption of omega-3 fatty acid fish should be part of a balanced diet and that taking fish-oil supplements alone (rather than eating fish) does not confer the same brain-healthy benefits (Gregory, 2016, February 2, para. 7 & 9). They also admitted that the brains of those individuals who ate the most fish had the higher levels of mercury; but at the same time, they stressed that this didn't correlate with the changes that Alzheimer's makes in the brain (Gregory, 2016, February 2, para. 10). While a mix of factors, including age, lifestyle, and genetic risk, seems to determine Alzheimer's risk, evidence suggests that maintaining cardiovascular health by adhering to a balanced diet and regular exercise is also good for the brain (Gregory, 2016 February 2, para. 11-12).

Park, Alice. (2016 February 2). Fish, mercury and Alzheimer's risk. Time. Retrieved from http://time.com/4201808/fish-mercury-and-alzheimers-risk/

While regular consumption of seafood protects the heart and brain, an analysis of the autopsies on the brains of the participants in a Rush University study also shows that eating fish at least once weekly accumulates mercury in the brain. However, for the 30 percent of the population who have at least one copy of the APOE gene variant, eating seafood regularly just might outweigh the risk of brain toxicity since doing so lowers the amount of Alzheimer's-related proteins in the brain (Park, 2016, February 2, para. 1-5). Moreover, even individuals without this gene might also benefit from eating seafood regularly (Park, 2016, February 2, para. 6). Thus, the study eases fears that mercury in seafood causes dementia (Park, 2016, February 2, para. 8).

Pollario, Karen. (2016, February 2). Seafood may help those at risk of Alzheimer's: Study also finds mercury in fish isn't linked to dementia symptoms. WebMD. Retrieved from http://www.webmd.com/alzheimers/news/20160202/seafood-might-protect-brain-in-people-at-genetic-risk-for-alzheimers

Data released from the Memory and Aging Project published in the JAMA February 2, 2016, issue posits that mercury in fish does not lead to cognitive decline while a healthy diet featuring regular seafood consumption might stave off Alzheimer's disease in adults who have the APOE gene (Pollario, 2016, February 2, para. 1, 11, & 14).

Even though the autopsied brains of older study participants who regularly consumed more seafood had greater levels of mercury in their brains, researchers did not find a link between these higher levels of that heavy metal and the brain damage that is typical in Alzheimer's patients (Pollario, 2016, February 2, para. 2). Thus, older adults with the APOE gene who regularly eat fish while also adhering to a healthy diet do not need to be overly concerned about mercury contamination while they are reaping the protective effects of a diet with moderate levels of seafood.   For these individuals, regularly eating fish correlates with a decreased risk for Alzheimer's and a slower rate of Alzheimer's disease progression (Pollario, 2016, February 2, para. 5-6 & 9).

In the case of the MAP participants, the questionnaire they filled out to measure seafood consumption provided them with four choices: 1) Tuna sandwich, 2) fish sticks, cake, or sandwich, 3) fish served as a main dish, 4) or shrimp, lobster, or crab. Researchers also not only analyzed tissue samples from their autopsied brains for metal concentrations, but  they also looked for evidence of strokes and micro-strokes, and the plaque and tangles associated with Alzheimer's as well as the Lewy bodies found in the brains of individuals diagnosed with Parkinson's (Pollario, 2016, February 2, para. 12-13).

By comparing the regular diets of older adults with their subsequent brain autopsies, researchers determined that eating one or more servings of seafood a week meant that older adults with the APOE gene were less likely to develop Alzheimer's. They didn't associate the same protective link that lowers the odds of developing Alzheimer's for individuals without the APOE alle. However, they did find that those brains with higher levels of the fatty-acids found in plants had fewer strokes (Pollario, 2016, February 2, para. 15-16). Thus, since few middle-aged and older adults have been tested for the APOE gene, adopting a diet that features fresh vegetables and fruit as well as one or two serving of fish weekly is a prudent step to take if one wants to prevent or delay dementia.

Eating Fish Is Only Part of Adhering to a Mostly Vegetarian MIND or Mediterranean-style Diet

Feart, C. Samieri, C., and Alles, B., et al. (2013, February). Potential benefits of adherence to the Mediterranean diet on cognitive health. The Proceedings of the Nutrition Society, 72 (1), pp. 140-52. [Abstract Only]. doi: 10.1017/S0029665112002959. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/23228285

A Mediterranean diet characterized primarily by the consumption of plant foods, olive oil, and a low to moderate intake of fish, and low-levels of consumption for both meat and poultry as well as a low to moderate consumption of wine during meals correlates with a decline in the risk for dementia (Feart, 2013, February, Abstract, p. 140).

The MIND Diet recommends, '"Eat this, not that!"

Hosking, D. E. Nettlebeck, T., and Wilson, C., et al. (2014, July 28). Retrospective lifetime dietary patterns predict cognitive performance in community-dwelling older Australians.  British Journal of Nutrition, pp. 112(2), 228-37. doi: 10.1017/0007114514000646.  [Abstract only].  Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/24709049

In a cognitively-healthy sample of 352 Australians aged 65 and older, after controlling for such factors as current diet, age, gender, years of education, smoking, income level, physical activity, and the inheritance of the APOE gene, the survey documented that those Australians who spent a life time taking their coffee with sugar and eating a high-fat diet exhibited slower reaction times, poorer working and short-term memories, retrieval fluency, and reasoning skills than those who ate more vegetables and non-processed foods. These dietary choices had a positive effect on their perceptual speed and retrieval frequency (Hosking, 2014, July 28, Abstract, p. 228).

Morris, M. C., Tangney, C. C., and Wang, Y., et al. (2015, September). Alzheimer's & Dementia: The Journal of the Alzheimer's Association, 11 (9), pp. 1015-22.  doi: 10.1016/j.jalz.2015.04.011. [Abstract only]. Retrieved from 
http://www.ncbi.nlm.nih.gov/pubmed/26086182

The older adults participating in the Memory and Aging Project study who followed the MIND diet—a combination of the Mediterranean Diet and DASH, a dietary plan used to control hypertension, on average slowed their cognitive decline by 4.7 years (Morris, 2015, September, Abstract, p. 1015).

Unfortunately, this measured approach to diet as a means to slow cognitive decline turned into hyperbole in the following news article. Even so, Hyslop's claims underline the idea that a diet that consists primarily of plant-based foods does slow cognitive decline:  

Hyslop, Leah. (2015, March 31).  Eating spinach every day could*make your brain 11 years younger.  Telegraph.  Retrieved from 

http://www.telegraph.co.uk/foodanddrink/foodanddrinknews/11505924/Eating-spinach-every-day-could-make-your-brain-11-years-younger.html

When researchers at Chicago's Rush University evaluated the diet and health of 950 older adults every day for from two to ten years, they found that eating spinach and or kale once or twice a day experiences “significantly less” cognitive decline even when researchers made allowances for their educational levels, frequency of exercise, and family history of dementia. On average, a diet that emphasized eating dark green leafy vegetables delayed mental decline by 11 years (Hyslop, 2015, March 31, para. 2-5). Lead researcher, Martha Clara Morris, attributed this benefit to the high levels of vitamin K, lutein, folate and beta carotene found in dark green leafy vegetables (Hyslop, 2015, March 31, para. 7).

*Emphasis added.

Cures for Depression & Aggression in Mild Cognitive Impairment & Dementia Patients

Depression & Aggression: Alleviating Dementia & MCI Symptoms

Evelyn Smith

M.S. In Library Science, University of North Texas (2012)

The mind is indeed a terrible thing to waste.

Recognize the Neuropsychiatric Symptoms that Correlate with Dementia

Research has substantiated that dementia correlates with late-life depression. However, the jury is still out on whether depression causes dementia, or dementia causes depression. Certainly, the loss of memory and function doesn't help the mood of older-adults who are suffering from memory loss and the ability to think and reason as well as to perform successfully the activities of daily living.

However, other neuropsychiatric symptoms of depression in order of their prevalence include aggression, anxiety, sleep disorders, irritability, appetite disorders, aberrant motor behavior, delusions, uninhibited behavior, hallucinations, and in rare instances, euphoria (Zhao, 2016, January 15, abstract). Obviously, older adults who are use to taking care of themselves are more apt to display depression, aggression, and anxiety,and lying aware worried about memory loss certain takes away a good night's sleep, but eating too little or too much (as in the case of Frontotemporal dementia), aberrant motor behavior, delusions, and uninhibited behavior might come as a surprise to family members. Even so, this post surveys recent studies that equate depression, apathy, and aggression that often accompany Mild Cognitive Impairment, Alzheimer's and other dementias as well as cost effective, primarily homeopathic ways to ameliorate them. All the same, this guide shouldn't replace a visit to a neurologist who treats Alzheimer's and other diseases that cause cognitive decline.

Cherbuin, N., Kim, S., and Anstey, K. J. (2015, December 21). Dementia risk estimates associated with measures of depression: a systematic review and meta-analysis. BMJ Open, 5(12):e008853. doi: 10.1136/bmjopen-2015-008853. [Full text]. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/26692556

Searching PubMed, PsycInfo, and Cochrane databases through February 28, 2014, researchers discovered that the increased risk of dementia didn't differ significantly with the type of dementia, but late-life depression consistently correlated with a “twofold increased risk of dementia”.

Cines, S., Ferrell, M., and Steffener J., et al. (2015, December). Examining the pathways between self-awareness and well-being in Mild to Moderate Alzheimer Disease. American Journal of Geriatric Psychiatry, 23(12): 1297-306. doi: 10.1016/j.jagp.2015.05.005. [Abstract only]. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/26560509.

Columbia University Medical Center and the University of Pennsylvania researchers rated how aware 104 study participants were of their memory loss in order to establish a relationship between awareness, depression, and Quality of Life. This study thus discovered a direct association between how aware dementia patients were of their memory loss and whether or not they were depressed, but it only found an indirect association between this awareness and the patients' QOL.

Herbert, J. and Lucassen, P. J. (2015, December 30). Depression as a risk factor for Alzheimer's disease: Genes, steroids, cytokines and neurogenesis--What do we need to know? Frontiers in Neuroendocrinology, 15, pii: S0091-3022. doi: 10.1016/j.yfrne.2015.12.001. [Abstract only]. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/26746105

While depression predicts the onset of Alzheimer's and is a component of Alzheimer's, it may also be a trigger for Alzheimer's. Thus, intervention that successfully treat depression in older adults may prevent the onset of Alzheimer's.

Mourao, R., Mansur, G., and Malloy-Diniz, L. E., et al. (2015, December 15). Depressive symptoms increase the risk of progression to dementia in subjects with mild cognitive impairment: systematic review and meta-analysis. International Journal of Geriatric Psychiatry. doi: 10.1002/gps.4406. [Epub ahead of print], [Abstract only]. Retrieved from  http://www.ncbi.nlm.nih.gov/pubmed/26680599

A meta-analysis that evaluated and compared the risk of dementia in 10,861 patients with Mild Cognitive Impairment and depressive symptoms with MCI patients with and without depressive symptoms, showed that depression increased their risk of progressing to dementia if patients showed signs of depression.

Additionally, the Staunton-Carson study identified apathy as an often undiagnosed symptom of memory loss that medications can successfully treat.

Stanton, B. R., and Carson, A. (2016, February). Apathy: A practical guide for neurologists. Practical Neurology, 16(1), 42-7. doi: 10.1136/practneurol-2015-001232. [Abstract only]. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/26502729

Apathy is an under diagnosed symptom of memory loss that can be treated with cholinesterase inhibitors, dopamine agonists, and stimulants. Furthermore, treatment for apathy improves the functioning and quality of life in older adults diagnosed with mild cognitive impairment as well as lowering the stress of their caregivers.

Finally, recently published research has underlined the importance of recognizing the neuropsychiatric symptoms of Alzheimer's disease, so that family members of individuals with symptoms of cognitive impairment and dementia seek treatment for their loved ones earlier.

Zhao, Q. F., Tan, L., and Wang, H. F., et al. (2016, January 15). The prevalence of neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta-analysis. Journal of Affective Disorders, 190:264-71. doi: 10.1016/j.jad.2015.09.069. [Abstract only]. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/26540080

After surveying studies published from 1964 to September 30, 2014 from the PubMed and Embase databases as well as reference lists and conference abstracts, researchers identified 12 neuropsychiatric symptoms common to Alzheimer's, which they listed in the order of their frequency: 1) apathy (49 percent), 2) depression (42 percent), 3) aggression (40 percent), 4) anxiety (39 percent), 5) sleep disorder (39 percent), 6) irritability (36 percent), 7) appetite disorder (34 percent), 8) aberrant motor behavior (32 percent), 9) delusion (31 percent), 10) uninhibited behavior (17 percent), 11) hallucination (16 percent). and 12) euphoria (7 percent).

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Ways to Delay, Relieve, & Possibly Prevent Depression & Anxiety in MCI & Alzheimer's

.

So if a family member with a failing memory and a declining ability to fend for him or herself is apathetic, depressed, and agitated, what are some of the ways that caregivers can lift their mood and ameliorate some of these symptoms, thus delaying his or her slide into loss of self?

 Meditation Reduces Stress & 

Improves Memory

Khalsa, D. S. (2015). Stress, meditation, and Alzheimer's disease prevention: Where the evidence stands. Journal of Alzheimer's Disease: JAD, 48(1), 1-12. doi: 10.3233/JAD-142766. [Abstract only]. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/26445019

Khalsa highlights Kirtan Kriya as a easy time-and cost-effective meditative technique for improving memory in those diagnosed with Mild Cognitive Impairment. Khalsa claims this meditation technique that takes only twelve minutes per day not only improves sleep and decreases depression and anxiety, but it also regulates inflammatory genes, adjusts immune genes, improves insulin and glucose regulatory genes and increases telomerase by 43 percent—not to mention improving psycho-spiritual well being.

See also:

Practice the 12-minute yoga meditation exercise. (2015). Alzheimer's Research and Prevention Foundation. Retrieved from http://www.alzheimersprevention.org/research/12-minute-memory-exercise

Kirtan Kriya, a 12-minute, non-religious meditative exercise, reduces stress and increasing memory. In Sanskrit, kirtan translates as “song”,and kriya refers to a specific set of movements; in this case, the movement of the fingers (Practice, 2015, para. 1-2). Thus, those practicing this form of yoga should repeat the mantra “Saa, taa, naa, maa” while seated in an upright position with the spine straight and the hands closed, singing in a natural voice for two minutes, then whispering the syllables for two minutes, and finally saying them silently for four minutes before reversing the process. While singing saa, touch the index finger in both hands to the thumb; on taa, touch the middle finger in both hands to the thumb; on saying naa, touch the middle finger in both hands to the thumb, and on maa, place the little finger on both hands on the thumb (Practice, 2015, para. 7-8).

Lavretsky, Helen. (2013, November 15). Kirtan Kriya meditation: 12-minute brain boost for stressed-out people. Bottom Line Health. Retrieved from http://bottomlinehealth.com/kirtan-kriya-meditation-12-minute-brain-boost-for-stressed-out-people/

After two eight week repetitions of either listening to soothing instrumental music with the eyes closed or practicing Kirtan Kriya meditation, 65 percent of the caregivers of patients with mild to moderate Alzheimer's alleviated their own symptoms of depression compared with only 31 percent of those listening to calming instrumental music while 52 percent of the caregivers improved their mental health, but only 19 percent of those listening to music did so. Moreover, while meditation increased telomerse activity in 43 percent of those practicing Kirtan Kriva, listening to music only lengthened telomeres in four percent of those listening to music (Lavretsky, 2013, November 15, para 8-15).

Numerous YouTube videos also illustrate the practice of Kirtan Kriva.

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Art, Dance, & Music Ease Depression

Sing-a-longs ease depression and improve quality of life.

Music and dancing also decrease depression as well as increase cognitive function in older adults diagnosed with depression, Alzheimer's, and Mild Cognitive Impairment.

Kim, S. H., Kim, M., and Ahn, Y. B., et al. (2011, December 1). Effect of dance exercise on cognitive function with metabolic syndrome: A pilot study. Journal of Sports Science, and Medicine, 10(4), 671-8. [Free article]. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/24149557

Since metabolic syndrome is associated with an increase risk of cognitive decline, this Korean study examined the effects of dance exercise in older patients with metabolic syndrome in 38 elderly metabolic syndrome patients, 26 of whom performed dance exercise twice a week; and then, researchers compared their results with the 12 members of the control group. Compared with the control group, the dance exercise group “significantly improved” their verbal fluency, word list delayed recall, word recognition, and over all cognitive function score. However, no significant differences occurred in their body mass index, blood pressure, waist circumference, fasting plasma glucose, and triglyceride and HDL cholesterol levels over the six-month period. Thus, researchers concluded that dance exercise may reduce the risk for cognitive disorders in older adults with diagnosed with metabolic syndrome.

Ray, K., and Mittelan, M. S. (2015, October). Music therapy: A non-pharmacological approach to the care of agitation and depressive symptoms for nursing home residents with dementia. Dementia (London). Pii: 1471301215613779. [Abstract only]. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/26519453

After researchers evaluated 132 nursing home patients with moderate to severe depression for depressive symptoms, agitation, and monitoring, two assessments further evaluated their behavior both two weeks before and two weeks after an intervention—two weeks of music therapy. After two weeks of music therapy, symptoms of depression and agitated “significantly reduced” although no change in wandering behavior occurred. The results thus suggested that music therapy in long-term setting might reduce symptoms of depression and agitation.

Ridder, H. M., Stige, B., and Qvale, L. G., et al. (2013). Individual music therapy for agitation in dementia: an exploratory randomized controlled trial. Aging and Mental Health, 17(6), 667-78. doi: 10.1080/13607863.2013.790926. [Free text]. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/23621805

A crossover trail of 42 nursing home patients assessed the benefits of music therapy in a randomized trial that analyzed the effects of six-weeks of individual music therapy versus six weeks of standardized care, evaluating agitation levels, quality of life, and the need for psychotropic medication. Agitation and disruptive behavior significantly decreased during music therapy as did the need for psychotropic meds while demand for mood-altering drugs increased when patients. These positive results led researchers to call for a larger sampling size to further tests the positive effects of music therapy.

See also:

Art and music therapy for Alzheimer's disease. (2016). Alzheimer's Disease Health Center. Web MD. http://www.webmd.com/alzheimers/guide/alzheimers-therapies-music-art-more

Music therapy soothes agitation, triggers long-term memory, engages the mind, and sometimes improves appetite (Art & music, 2016, para. 3).

Try golden oldies, karaoke, and sing-a-longs to bring back old memories; use toe-tapping, up-tempo dance music to stimulate mental and physical activity, and use easy listening music and lullabies to relieve anxiety (Art & music, 2016, para. 4).

Rely on facial cues to determine whether or not the Alzheimer's patient likes a particular type of music or individual song (Art & music, 2016, para. 5).

Art therapy helps Alzheimer's patients to communicate when they are at a loss for words. Try asking the patient to paint or draw their memories, encourage free-form abstract paintings, and refrain from criticism (Art & music, 2016, para. 6).

Additional therapies commonly used with Alzheimer's patients include massage, pet therapy [if the patient like dogs], or helping mild to moderate Alzheimer's patients to participate in previous hobbies like gardening or cooking (Art & music, 2016, para. 7).

Clair, Alicia Ann, and Tomaino, Concetta M. (2015). Education and Care. Music. Alzheimer's Foundation of America. Retrieved from http://www.alzfdn.org/EducationandCare/musictherapy.html

Since rhythmic and well-rehearsed responses don't require much thought, but instead rely primarily on auditory cues, even late-stage dementia patients respond favorably to music (Clair, 2015, para. 3).

Previous experiences with a song or melody is most likely to elicit a response. Therefore, music that was popular during the dementia patient's young adult years from 18 to 25 is most likely to bring about a positive response during the early to mid-stages of dementia. However, as Alzheimer's progresses into its later stages, music from childhood also stimulates favorable responses (Clair, 2015, para. 5, 8, & 10).

Quick tempos stimulate while ballads and lullabies sedate (Clair, 2015, para. 11-12).

Musical activities, such as singing, playing rhythm band instruments, like tambourines, rain forest drums, and castanets, dancing, and exercising to music, diffuse aggression even in late-stage dementia. For best results, schedule music therapy just before the time disruptive behavior is most likely to occur (Clair, 2015, para. 14 & 16).

Listening to music can also elicit emotional responses and mutual affection between dementia patients and their caregivers (Clair, 2015, para. 15-17).

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 A How to Guide for Re-introducing Music & Dance to

Mild Cognitive Impairment  & Dementia Patients

Nursing home residents benefit from exercising to music.

Mild Cognitive Impairment and Early Stage Dementia:

Go out dancing or dance around the house with the MCI or dementia patient;

Play music from the MCI or dementia patient's past;

Experiment to decide what type of music works best;

Encourage former musicians to continue to play a musical instrument as long as possible;

Compile the patient's music history [assembling CD's that bring back memories].

(Clair, 2015, para. 18)

Early to Middle Alzheimer's:

Play music that allows Alzheimer's patients to improve their walking gait;

Play background music to enhance the mood of Alzheimer's patients;

Play relaxing instrumental music to reduce sun downing (night-time wandering) and other night problems.

(Clair, 2015, para. 19)

Late-stage Alzheimer's:

Continue to play the music that worked well in the earlier stages of Alzheimer's;

Lead sing-a-longs with Alzheimer's patients;

Play soothing music especially before bedtime;

Assist patients  as they exercise to music;

Help patients participate in drumming and rhythmic-based activities.

(Clair, 2015, para 21)

__________

Sarkamo, T., Laitinen, S., and Kuri, M., et al. (2015, October 19). Clinical and demographic factors associated with the cognitive and emotional efficacy of regular musical activities in dementia. Journal of Alzheimer's Disease: JAD, 49(3) 76781. doi: 10.3233/JAD-150453. [Abstract only]. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/26519435

In a randomized-controlled trial, 89 dementia patients and caregiver partners received 10-week intervention training in either singing or listening to music or standardized care after the dementia patients received extensive neuropsychological testing and were assessed to determine their mood and quality of life. Although variables like dementia etiology and severity, age, care situation, and musical background effected the effectiveness of music therapy, singing improved especially beneficial in improving the working memory of patients with mild dementia as well as in maintaining executive function and orientation in younger dementia patients while listening to music supported cognition, working memory and quality of life especially in those dementia patients diagnosed with moderate dementia not caused by Alzheimer's disease. Both singing and listening to music alleviated depression especially in those individuals diagnosed with mild dementia.

Nesher. (2010, March 3). Dance therapy for Alzheimer's patients. Alzheimer's diseases, causes, symptoms, treatment. Blogger. Retrieved from http://alzheimers-review.blogspot.com/2010/03/dance-therapy-for-alzheimers-patients.html

Dance therapy improves physical and psychological well-being either through participating in structured dances, such as ballroom or folk dancing with a partner, or improvisation that links thoughts to movement. Sessions should last about an hour to reduce the symptoms of Alzheimer's from hindering the dancer's progress (Nesher, 2010, March 3, para. 3).

Social dancing with a partner develops procedural and long-term memory as well as concentration while free-style dancing that encourages participants to focus on creative expression enhances mood and relationships (Nesher, 2010, March 3, para. 4-5).

The accompanying music improves autobiographic memory and reduces agitation, anxiety, and delusions as well as other behavioral symptoms of dementia. Meanwhile, exercise slows the progress of Alzheimer's cognitive symptoms while increasing the concentration of insulin-like growth factors and reducing serum homocystene levels (Nesher, 2010, March 3, para. 7-8).

However, dance therapy is effective only after a period of regular sessions. Moreover, while dementia patients might have a higher risk of falling during dancing, such exercise might also reduce their risk of falling by improving stability as well as existing chronic health problems that might result in falls (Nesher, 2010, March 3, para. 20).

Dancing might also act as a preventive factor, warding off Alzheimer's and other dementia by accelerating cognitive reserve, reducing brain atrophy, invigorating the brain's ability to grow and change, and increasing brain perfusion (Nesher, 2010, March 3, para. 21).

Serlin, Ilene, (2013,November 2). Dancing away dementia. Psychology Today. Retrieved from https://www.psychologytoday.com/blog/make-your-life-blessing/201311/dancing-away-dementia

Frequent free-style dancing reduces the risk of dementia by 76 percent—twice as much as reading does.

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Effective Sensory, Psychological, & Behavioral Interventions: Leisure Activities & Hobbies

Playing games can help alleviate depression and delay or prevent dementia.

Livingston, G., Kelly, L., and Lewis-Holmes, E., et al. (2014, June). A systematic review of the clinical effectiveness and cost-effectiveness of sensory, psychological and behavioural interventions for managing agitation in older adults with dementia. Health Technology Assessment (Winchester, England), 18(39), 1-226, vi-vi. doi: 10.3310/hta18390. [Free text]. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/24947468

A British meta analysis turned up 160 relevant studies out of 1,916 papers screened in a search for cost-effective, long-term ways to relieve dementia patients' agitation and depression. Of these ways to ameliorate depression and aggression, better person-centered care, improved communication skills, and modified Dementia Care Mapping [where caregivers make effective changes in an individual's environment after observing how he or she spends his or her day] were the most effective means in reducing agitation immediately as well as for six-months afterward. Leisure activities and music therapy as well as sensory intervention also reduced mean levels of agitation. However, therapeutic touch, individualized activities, aroma therapy, and light therapy didn't effectively relieve depression or lessen aggression. Moreover, the few studies documenting activities of daily living and quality of life also produced no improvement.

Verghese, J., Liton, R. B., and Kratz, M. J. (2003, June). Leisure activities and the risk of dementia in the elderly. New England Journal of Medicine, 348 (25), 2508-16). [Abstract only]. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/12815136

In a cohort of 469 community-welling, cognitively healthy older adults, aged 75 and older, researchers survey their frequency of participation in leisure activities and their risk of developing dementia over 5.1 years and found that regularly taking part in leisure activities and hobbies, including reading, board games, playing a musical instrument, and dancing, all reduced the risk of dementia.

Lee, J., Lee B., and Park, Y., et al. (2015, October 27).  Effects of combined fine motor skill and cognitive therapy to cognition, degree of dementia, depression, and activities of daily living in the elderly with Alzheimer's disease. Journal of Physical Therapy Science, 10: 3151-4. doi: 10.1589/jpts.27.3151. [Free text]. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/26644663

After 26 patients were divided into an experimental group that received therapy in fine motor skills and cognitive therapy and a control group who only received general medical care, the experimental group improved their cognitive skills, showed decreased signs of dementia and depression, and enhanced their activities necessary for daily living when compared with the control group patients who only received medical care.

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A Mediterranean Diet Featuring Omega-3 Fatty Acid Fish Improves Mood & Memory

More than ever, the elderly are what they eat!

Scarmeas, N., Stern, Y. , and Mayeux, R. (2006, December ). Mediterranean diet, Alzheimer disease, and vascular mediation. JAMA Neurology, 63 (12). [Full text]. Retrieved from http://archneur.jamanetwork.com/article.aspx?articleid=792992

Adherence to a Mediterranean diet was the primary predictor of whether or not older adults were diagnosed with Alzheimer's in a New York community-based study that compared 194 patients diagnosed with Alzheimer's versus 1,790 non-demented patients after adjusting for age, gender, ethnicity, years of formal education, apolipopprotein E genotype, caloric intake, smoking, medical comorbidity, and Body Mass Index factors.

Song, C., Shieh, C. H., and Wu, Y. S., et al. (2016, January 4). The role of omega-3 polyunsaturated fatty acids eicosapentaenoic and docosahexaenoic acids in the treatment of major depression and Alzheimer's disease: Acting separately or synergistically? Progress in Lipid Research. 15, pii: S0163-7827doi: 10.1016/j.plipres.2015.12.003. [Abstract only]. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/26763196

Omega-3 polyunsaturated fatty acids (n-3-PUFAs) improve or prevent some neurodegenertive diseases in both experimental and clinical studies by modulating neuroimmune and apoplectic pathways, changing membrane function and/or competing with n-6 PUFAs, even though their exact role remains unclear.

See also:

Boutziouka, V., Polychronopoulos, E., and Zelmbekis, A. (2009 September). Long-term fish intake is associated with less severe depressive symptoms among elderly men and women: The Medis (MEDiterranean Islands Elderly) epidemiological study. Journal of Aging and Health, 21(6), 864-8. doi: 10.1177/0898264309340693. [Abstract only]. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/19587361

From 2005 to 2007, Greek researchers studied 1,190 Greek and Cyprus men and women over age 65 and found that those who increased their weekly fish intake by one portion were 0.58 percent less likely to suffer from depression. [Given their locale, most probably they already ate several servings of fish per week].

Psaltopoulou T., Sergentanis T. N, Panagiotakos, D. B. (2013 October).  Mediterranean diet, stroke, cognitive impairment, and depression: A meta-analysis.  Annals of Neurology, 74(4), 580-91. doi: 10.1002/ana.23944. [Abstract only]. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/23720230

After analyzing 22 studies estimating the relative risk for the association between adhering to a Mediterranean diet and stroke, depression, cognitive impairment, and depression, researchers concluded that strict adherence to a Mediterranean Diet consistently equated with a reduced risk of stroke, depression, and cognitive impairment while a moderate adherence to such a diet reduced the incidence of depression and dementia.