The association between caffeine and cognitive decline: examining alternative causal hypotheses.

BACKGROUND: Numerous studies suggest that higher coffee consumption may reduce the rate of aging-related cognitive decline in women. It is thus potentially a cheap and widely available candidate for prevention programs provided its mechanism may be adequately understood. The assumed effect is that of reduced amyloid deposition, however, alternative pathways notably by reducing depression and diabetes type 2 risk have not been considered. METHODS: A population study of 1,193 elderly persons examining depressive symptomatology, caffeine consumption, fasting glucose levels, type 2 diabetes onset, serum amyloid, and factors known to affect cognitive performance was used to explore alternative causal models. RESULTS: Higher caffeine consumption was found to be associated with decreased risk of incident diabetes in men (HR = 0.64; 95% CI 0.42-0.97) and increased risk in women (HR = 1.51; 95% CI 1.08-2.11). No association was found with incident depression. While in the total sample lower ratio Aß42/Aß40 levels (OR = 1.36, 95% CI 1.05-1.77, p = 0.02) were found in high caffeine consumers, this failed to reach significance when the analyses were stratified by gender. CONCLUSIONS: We found no evidence that reduced risk of cognitive decline in women with high caffeine consumption is moderated or confounded by diabetes or depression. The evidence of an association with plasma beta amyloid could not be clearly demonstrated. Insufficient proof of causal mechanisms currently precludes the recommendation of coffee consumption as a public health measure. Further research should focus on the high estrogen content of coffee as a plausible alternative explanation.

MAPT STUDY: A MULTIDOMAIN APPROACH FOR PREVENTING ALZHEIMER'S DISEASE: DESIGN AND BASELINE DATA.

OBJECTIVE: The Multidomain Alzheimer Preventive Trial (MAPT study) was designed to assess the efficacy of isolated supplementation with omega-3 fatty acid, an isolated multidomain intervention (consisting of nutritional counseling, physical exercise, cognitive stimulation) or a combination of the two interventions on the change of cognitive functions in frail subjects aged 70 years and older for a period of 3 years. Ancillary neuroimaging studies were additionally implemented to evaluate the impact of interventions on cerebral metabolism (FDG PET scans) and atrophy rate (MRIs), as well as brain amyloïd deposit (AV45 PET scans). DESIGN PATIENTS: 1680 subjects (mean age: 75.3 years; female: 64.8 %), enrolled by 13 memory clinics, were randomized into one of the following four groups: omega-3 supplementation alone, multidomain intervention alone, omega-3 plus multidomain intervention, or placebo. Participants underwent cognitive, functional and biological assessments at M6, M12, M24 and M36 visits. The primary endpoint is a change of memory function at 3 years, as assessed by the Free and Cued Selective Reminding test. All participants will be followed for 2 additional years after the 3-years intervention (MAPT PLUS extension study). INTERVENTIONS: 1/Omega-3 supplementation: two soft capsules daily as a single dose, containing a total of 400 mg docosahexaenoic acid (DHA), i.e., 800 mg docosahexaenoic acid per day, for 3 years. 2/ Multidomain intervention: collective training sessions conducted in small groups (6-8 participants) in twelve 120-minute sessions over the first 2 months (two sessions a week for the first month, and one session a week the second month) then a 60-minute session per month in the following three areas: nutrition, physical activity, and cognition until the end of the 3 years. In addition to the collective sessions, individualized preventive outpatient visits exploring possible risk factors for cognitive decline are performed at baseline, M12 and M24. BASELINE POPULATION: For cognition, the mean MMSE at baseline was 28.1 (± 1.6). About 58% and 42% of participants had a CDR score equal to 0 and 0.5, respectively. Regarding mobility status, 200 (11.9%) had a 4-m gait speed lower or equal to 0.8 m/s. According to the Fried criteria, 673 (42.1%) participants were considered pre frail, and 51 (3.2%) frail. The red blood cell DHA content was 26.1 ± 8.1 µg/g. Five hundred and three participants underwent baseline MRI. AV45 PET scans were performed in 271 individuals and preliminary results showed that 38.0% had a cortical SUVR > 1.17, which gave an indication of significant brain amyloïd deposit. DISCUSSION: The MAPT trial is presently the first largest and longest multidomain preventive trial relevant to cognitive decline in older adults with subjective memory complaints. The multidomain intervention designed for the MAPT trial is likely to be easily implemented within the general population.

Recruitment strategies for preventive trials. The MAPT study (MultiDomain Alzheimer Preventive Trial).

1680 participants were randomized over the recruitment period in MAPT study. A total of 1290 participants were recruited in the 7 University Hospital centers, and 390 participants in the 6 memory clinics around Toulouse Gerontopole / Alzheimer Disease research clinical center. The first randomization was on May 30, 2008, and the targeted number of randomized participants was reached on February 24, 2011; 2595 subjects were finally screened, of which 1680 fulfilled the eligibility criteria which represents 64.8%. Approximately, one quarter of screened people refused to participate after the detailed presentation of the study and 4.3% were still interested in participating but missed for unknown reasons the baseline visit even after repeated contacts. Of the 1810 subjects who signed the consent for participating to the study at the baseline visit, 130 (7.1%) were excluded because one of the eligibility criteria was not satisfied. Interestingly, the higher percentage of randomizations compared to screened participants is the personal contact source; almost 85 % of screened participants entered in the study. In an equivalent way, Medias and conferences are efficient recruiting sources to enrol volunteers in the study. Unexpectedly, only about 60% of screened participants from the hospital and GP sources were randomized and 33.2% from health care services. Almost a quarter of the randomized participants come from the hospital outpatients clinics and approximately 20% from public conferences. A total of 1128 contacts yielded to 556 screened volunteers and 345 randomized participants in the coordinating center of Toulouse. Thus, 30 % of contacts were recruited.

The neuroprotective effects of caffeine: a prospective population study (the Three City Study).

OBJECTIVE: To examine the association between caffeine intake, cognitive decline, and incident dementia in a community-based sample of subjects aged 65 years and over. METHODS: Participants were 4,197 women and 2,820 men from a population-based cohort recruited from three French cities. Cognitive performance, clinical diagnosis of dementia, and caffeine consumption were evaluated at baseline and at 2 and 4 year follow-up. RESULTS: Caffeine consumption is associated with a wide range of sociodemographic, lifestyle, and clinical variables which may also affect cognitive decline. Multivariate mixed models and multivariate adjusted logistic regression indicated that women with high rates of caffeine consumption (over three cups per day) showed less decline in verbal retrieval (OR = 0.67, CI = 0.53, 0.85), and to a lesser extent in visuospatial memory (OR = 0.82, CI = 0.65, 1.03) over 4 years than women consuming one cup or less. The protective effect of caffeine was observed to increase with age (OR = 0.73, CI = 0.53, 1.02 in the age range 65 to 74; OR = 0.3, CI = 0.14, 0.63 in the range 80+). No relation was found between caffeine intake and cognitive decline in men. Caffeine consumption did not reduce dementia risk over 4 years. CONCLUSIONS: The psychostimulant properties of caffeine appear to reduce cognitive decline in women without dementia, especially at higher ages. Although no impact is observed on dementia incidence, further studies are required to ascertain whether caffeine may nonetheless be of potential use in prolonging the period of mild cognitive impairment in women prior to a diagnosis of dementia.