“Our findings contradict many but not all previous studies and is currently controversial” Nawab Qizilbash, MBChB, MRCP (UK), head of OXON Epidemiology Ltd, and honorary senior lecturer in epidemiology, London School of Hygiene and Tropical Medicine, United Kingdom, told Medscape Medical News.

The study was published online April 9 in The Lancet Diabetes & Endocrinology.

Using the UK Clinical Practice Research Datalink (CPRD), the researchers analyzed the medical records of nearly 2 million (1,958,191) people with an average age of 55 years at the outset and an average BMI of 26.5 kg/m². During an average follow-up of 9 years (range, 6.3 to 12.6 years), nearly 45,507 were diagnosed with dementia, at a rate of 2.4 cases per 1000 person-years.

Compared with middle-aged adults with a normal weight (BMI, 20 to 24.9 kg/m²), those who were underweight were roughly a third more likely to develop dementia during follow-up. And the incidence of dementia fell with increasing BMI.

Table. Risk for Dementia by BMI Category

The pattern persisted throughout follow-up, after adjustment for potential confounders and allowance for the J-shape association of BMI with mortality, the researchers say.

“The jury is out” on why higher BMI in mid-life might help protect against dementia, Dr Qizilbash told Medscape Medical News. Factors postulated to explain the previously observed protective effect of increased BMI on late-life dementia include low late-life blood pressure; high late-life cholesterol levels; higher leptin levels; age-related regulatory changes in carbohydrate, lipid, or protein metabolism; and increased intake of vitamin E antioxidant and vitamin D. “Clearly more investigation is required,” Dr Qizilbash said.

In a statement, study investigator Stuart Pocock, PhD, from the London School of Hygiene & Tropical Medicine, said the findings “open up an intriguing new avenue in the search for protective factors for dementia — if we can understand why people with a high BMI have a reduced risk of dementia, it’s possible that further down the line, researchers might be able to use these insights to develop new treatments for dementia.”

Not the Final Word

In a linked Comment, Deborah Gustafson, PhD, from SUNY Downstate Medical Center in New York, urges caution in interpreting the findings. “There are some key issues with the study design that influence the validity of the results presented. I hope the Commentary sheds light on this,” she told Medscape Medical News.

She notes that the published literature on BMI and dementia is “equivocal. Some studies report a positive association between high mid-life BMI and dementia, whereas others do not.”

“Many considerations are needed in the assessment of the epidemiology of the association between BMI and late-onset dementia, as is the case for many recorded associations involving late-life disorders,” Dr Gustafson writes. For example, BMI trajectory throughout life, baseline BMI, competing causes of death, and adiposity measurement (total vs central) are “important considerations.”

“To understand the association between BMI and late-onset dementia should sober us as to the complexity of identifying risk and protective factors for dementia. The report by Qizilbash and colleagues is not the final word on this controversial topic,” Dr Gustafson concludes.

“Our results highlight the importance of maintaining high levels of cognitive and social stimulation throughout work and retiree life and emphasize the need for interventions and policies to help older individuals achieve such cognitive and social engagement,” stated Dr. Dufouil, Director of Research in Neuroepidemiology at INSERM in Paris.

Even after adjustment for white matter changes seen on MRI and history of stroke, those who met criteria for physical activity had significantly lower risks of developing any cognitive impairment, any dementia, and vascular dementia over a 3-year period, according to Ana Verdelho, MD, of the University of Lisbon in Portugal, and colleagues.

The relationship between physical activity and vascular dementia remained significant after further adjustment for baseline cognitive function (HR 0.49, 95% CI 0.26 to 0.94), the researchers reported online in Stroke: Journal of the American Heart Association.

“Our data support the conviction that older subjects with vascular risk factors and evidence for vascular cerebral damage benefit from regular physical activity,” Verdelho and colleagues wrote. “We think that [the] relation between physical activity and cognitive impairment should be further studied by interventional studies.”

Previous analyses have identified associations between physical activity and lower risks of cognitive decline and progression to dementia, with possible explanations including mental and social stimulation from exercise, improved cerebral blood flow, reduced vascular risk factors, decreased stress hormone levels, stimulation of brain plasticity, enhanced endothelial function, and decreased progression of intima-media thickness.

Verdelho and colleagues turned to the European LADIS (Leukoaraiosis and Disability) study to explore the issue in nondisabled individuals ages 65 to 84 who were living on their own, presented with minor neurological, cognitive, mood, or motor complaints that did not affect daily activities, and who had white matter changes seen on MRI.

The participants were evaluated at baseline and annually for 3 years. At each assessment, they underwent a battery of neuropsychological tests. MRI was performed at baseline and at the end of the study to assess the severity of the white matter changes.

The study included 638 people. The average age was 74.1 and 55% were female.

At baseline, 64% of the participants were considered physically active, defined as performing at least 30 minutes of activity at least 3 days a week.

The initial MRI revealed a severity of white matter changes that was mild in 44%, moderate in 31%, and severe in 25%.

At the end of follow-up, 90 patients had dementia, including 54 with vascular dementia, 34 with Alzheimer’s disease with a vascular component, and two with frontotemporal dementia. Another 147 had cognitive impairment that was not dementia.

After adjustment for age, education, the severity of white matter changes, medial temporal atrophy, previous and incident stroke, and diabetes, being physically active was associated with significantly lower risks of the following outcomes:

• Any cognitive impairment, including dementia (HR 0.64, 95% CI 0.48 to 0.85)
• Any dementia (HR 0.61, 95% CI 0.38 to 0.98)
• Vascular dementia (HR 0.42, 95% CI 0.22 to 0.80)

Physical activity was not, however, related to Alzheimer’s disease risk.

After further adjustment for baseline cognitive function, the results remained significant for any cognitive impairment and vascular dementia, but not for any dementia.

The authors said that the main limitation of the study was related to the selection of the participants. The study included those who had minor complaints and, thus, probably catches nondisabled patients with white matter changes when they are first seeking medical attention.

Primary source: Stroke: Journal of the American Heart Association
Source reference:
Verdelho A, et al “Physical activity prevents progression for cognitive impairment and vascular dementia: results from the LADIS (Leukoaraiosis and Disability) study” Stroke 2012; DOI: 10.1161/STROKEAHA.112.661793.

By Todd Neale, Senior Staff Writer, MedPage Today
Published: November 01, 2012
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and Dorothy Caputo, MA, BSN, RN, Nurse Planner

VANCOUVER—The quality and quantity of sleep may be associated with the risk for cognitive decline, according to four studies presented at the 2012 Alzheimer’s Association International Conference. Treatments for insomnia or circadian rhythm delay might reduce or prevent cognitive decline, investigators reported.

Sleep Duration and Cognition
Compared with a sleep duration of seven hours per day, sleep durations of five or fewer hours per day and of nine or more hours per day were associated with worse average memory at older ages, according to Elizabeth Devore, ScD, Associate Epidemiologist at Brigham and Women’s Hospital in Boston. Short and long sleep durations at midlife and in later life were both associated with worse memory in later life.

Dr. Devore and her colleagues examined 15,263 women age 70 or older who had participated in the Nurses’ Health Study. The researchers performed one initial cognitive assessment and three biennial follow-up assessments of each participant. At baseline, the subjects reported sleep duration in midlife and in later life. The investigators used multivariable-adjusted mixed linear regression models to estimate mean differences in slopes of cognitive decline in several categories of sleep duration. Multivariable-adjusted linear regression was used to estimate mean differences in overall cognitive status at older age.

Women with sleep durations that changed two hours per day or more between midlife and later life had worse average memory at older ages, compared with those whose sleep duration did not change. “Regardless of where women started out in midlife, in terms of their sleep duration, the big changes seemed to be a problem for memory,” said Dr. Devore. “These findings indicate that extreme sleep durations or greater changes in sleep duration over time may contribute to cognitive decrements in older adults.”

The study showed that patients with MCI who have a plasma caffeine level of 1200 ng/mL avoided progression to dementia over the following 2 to 4 years.

These patients exhibited a plasma cytokine profile that was exactly the same as that of Alzheimer’s disease (AD) transgenic mice that were given caffeinated coffee and didn’t progress to dementia. It’s therefore very likely that it’s caffeine from coffee, and not from other sources, that affords the cognitive protection, said study senior author Gary W. Arendash, PhD, research scientist, Bay Pines Veterans Affairs Hospital, St. Petersburg, Florida.

The research also suggests that certain cytokine patterns could signal for impending conversion to dementia among those with MCI, said Dr. Arendash.

Lower Caffeine Levels

The new case-control study included 2 cohorts of 124 participants in a Florida Alzheimer’s Disease Research Center study of persons aged 65 years and older. All participants had undergone a battery of baseline neurologic assessments and cognitive tests and were categorized as normal, MCI, or dementia. As well, researchers had access to fasting blood samples taken at baseline.

Over the next 2 to 4 years, researchers annually reassessed the cognition of the participants. They separated the participants into 5 groups: (1) initially normal and remained normal, (2) initially normal but converted to MCI, (3) initially MCI and remained so, (4) initially MCI but converted to dementia, and (5) initially dementia and remained so.

Analysis of plasma caffeine levels from the initial visit showed significantly lower caffeine levels in participants with MCI relative to the normal group (P < .03). Caffeine levels were also lower in participants with dementia than in those with normal cognition, but this association did not reach statistical significance (P < .07).

There was a 26% lower plasma level of caffeine in normal persons who converted to MCI over the course of the study compared with those who remained normal, but this was not significant because of considerable variability in caffeine levels among individuals in both of these subgroups.

However, 11 patients with MCI who progressed to dementia had plasma caffeine levels that were 51% below levels at study initiation vs those with MCI who remained MCI (P < .02).

None of the MCI participants who converted to dementia had initial caffeine levels above 1200 ng/mL while half of those with stable MCI had higher levels. Baseline plasma caffeine levels greater than 1200 ng/mL in MCI patients were associated with a 100% chance of avoiding progression to dementia during the 2- to 4-year follow-up.

Patients with MCI in both the Miami (n = 81) and the Tampa (n = 43) study cohorts independently showed the same relationship between blood caffeine levels and later risk for dementia progression.

Critical Level

That 1200-ng/mL level appears to be an important threshold, said Dr. Arendash. The amount of coffee needed to reach this critical level appears to be 3 to 5 cups of daily, with a target of 5 cups or 500 mg of caffeine. Those previous AD mouse studies showed that 1 to 2 cups, or between 100 and 200 mg of caffeine (which is what typical Americans drink daily), was not enough to ward off dementia, he said. It’s not known whether it’s necessary to spread those 5 cups throughout the day, he added.

It’s important to remember, though, that half of the patients with stable MCI in the study who had caffeine levels below 1200 ng/mL also didn’t progress to dementia. Clearly, other factors play a role. Such factors probably include the level of cognitive and physical activity, the presence of hypertension, and antioxidant intake, especially from fruits and vegetables, said Dr. Arendash.

The study also found that 3 cytokines — granulocyte colony-stimulating factors (G-CSF), interleukin-10, and interleukin-6 — were lower in the plasma of patients with MCI who were destined for AD conversion than in both the nonconverting MCI participants and the participants with dementia. None of the 8 other plasma cytokines that were measured showed any such profile when the same 2 MCI subgroups were compared.

“When that initial blood sample was taken, MCI patients that went on to convert to AD had low levels of all those cytokines,” said Dr. Arendash. “That could be diagnostic; it could be a very important plasma indicator of impending AD.”

The studies of AD transgenic mice, which produce the same abnormal human protein as the human brain, amyloid-beta, demonstrated that long-term oral administration of caffeinated coffee prevents cognitive impairment.

The cytokine profile of the participants in this current study was the same as that in these AD mice. “Their profiles matched identically to the mice given coffee but not other sources of caffeine;” said Dr. Arendash. “That’s why we strongly believe that most, if not all, of those MCI patients who did not convert were on habitual coffee intake.”

The mouse research allowed investigators to identify disease-modifying mechanisms for caffeine. The studies showed that caffeine alone suppresses brain levels of enzymes required for amyloid-beta production via targeting of specific signal transduction mechanisms. This research also suggested that something in coffee increases plasma levels of those 3 key cytokines: G-CSF, interleukin-10, and interleukin-6. G-CSF, in particular, has beneficial cognitive actions in AD mice that involve synaptogenesis and neurogenesis.

Aside from caffeine, coffee is rich in antioxidants and anti-inflammatory compounds that may also contribute to reduced risk for AD.

This study was a retrospective analysis, so a definitive relationship will have to be derived through a clinical trial in which participants consume caffeinated coffee, other caffeinated products, or decaffeinated coffee, over a period several years, said Dr. Arendash. He suggested that residents of China, where coffee consumption is very rare, would make an ideal control population for such research.

Accumulating Evidence

Reached for a comment, Karen Ritchie, PhD, Faculty of Medicine, Imperial College, London, United Kingdom and Directeur de Recherche, Institut National de la Santé et de la Recherche Médicale, Montpellier, France, said the study, which involved a direct measure of caffeine in plasma rather than just reports of caffeine consumption, adds to accumulating evidence of a beneficial effect of caffeine.

However, she told Medscape Medical News, the study’s “weak point” is that, unlike the epidemiologic studies, such as the ones she and her colleagues have carried out, alternative explanations of this observation were not taken into account.

“For example, persons drinking less coffee may also have more hypertension, more depression, more heart disease, less social activity than those with higher levels, and these factors are in themselves related to onset of dementia.”

Still, one of Dr. Ritchie’s own previous studies, published in Neurology , concluded that the psychostimulant properties of caffeine appear to reduce cognitive decline in women without dementia, especially at higher ages.

The question of whether some people are protected against dementia because they drink coffee or because they do or have something else that non–coffee drinkers don’t, remains unanswered, she said.