The 100-plus Study of cognitively healthy centenarians: rationale, design and cohort description

Abstract

Although the incidence of dementia increases exponentially with age, some individuals reach more than 100 years with fully retained cognitive abilities. To identify the characteristics associated with the escape or delay of cognitive decline, we initiated the 100-plus Study ( www.100plus.nl ). The 100-plus Study is an on-going prospective cohort study of Dutch centenarians who self-reported to be cognitively healthy, their first-degree family members and their respective partners. We collect demographics, life history, medical history, genealogy, neuropsychological data and blood samples. Centenarians are followed annually until death. PET-MRI scans and feces donation are optional. Almost 30% of the centenarians agreed to post-mortem brain donation. To date (September 2018), 332 centenarians were included in the study. We analyzed demographic statistics of the first 300 centenarians (25% males) included in the cohort. Centenarians came from higher socio-economic classes and had higher levels of education compared to their birth cohort; alcohol consumption of centenarians was similar, and most males smoked during their lifetime. At baseline, the centenarians had a median MMSE score of 25 points (IQR 22.0-27.5); most centenarians lived independently, retained hearing and vision abilities and were independently mobile. Mortality was associated with cognitive functioning: centenarians with a baseline MMSE score ≥ 26 points had a mortality percentage of 17% per annual year in the second year after baseline, while centenarians with a baseline MMSE score < 26 points had a mortality of 42% per annual year (p = 0.003). The cohort was 2.1-fold enriched with the neuroprotective APOE-ε2 allele relative to 60-80 year-old population controls (p = 4.8 × 10^-7), APOE-ε3 was unchanged and the APOE-ε4 allele was 2.3-fold depleted (p = 6.3 × 10^-7). Comprehensive characterization of the 100-plus cohort of cognitively healthy centenarians might reveal protective factors that explain the physiology of long-term preserved cognitive health.

Keywords: 100-plus Study; Centenarians; Cognitive health longevity; Prospective cohort study.

Fig. 1

Overview of the 100-plus Study, Phase 2: During home visits we inquire about life-history of the centenarians, their family history, medical history, and current health. We assess their performance on neuropsychological tests, measure blood pressure and grip strength and we collect a blood sample, for blood testing and genetic analyses. Optional parts of the study are: a visit to the outpatient clinic for PET–MRI and/or PET–CT imaging, feces donation to investigate the gut microbiome, and the generation of iPS cells from peripheral blood. Furthermore, all participants are informed about the option of post-mortem brain donation in collaboration with the Netherlands Brain Bank [37]. This is optional and not required for study participation. We evaluate changes in general well-being and in neuropsychological test performance during (half-)yearly follow-up visits. Next to the centenarians, we also include their first-degree family members and their partners. *Collected in Phase-2 of the 100-plus Study, started in September 2017

Fig. 2

Diagram of visit procedures of 100-plus Study: ¹Half yearly follow-up by telephone is performed for centenarians who agreed to brain donation. ²Collected in phase-2 of the 100-plus Study, started in September 2017. ³Data from centenarian-children and children in-laws will be obtained during the visit with the centenarian

Fig. 3

Data collection from centenarians and their family-members: In Phase-2 of the 100-plus Study (since September 2017), we obtain blood-samples from centenarians (black), and when willing, their siblings, their children (dark grey) and their respective partners (light grey). We will inquire about longevity and incidence of dementia in relatives from the same generation as the centenarian (white). Square: male, circle: female, diamond: both genders are possible

Fig. 4

Flowchart of study inclusion: *Not available: centenarians were on vacation, not interested or too frail for a follow-up visit. When possible, follow-up was performed by telephone and/or informant questionnaires. In several cases, centenarians were available for follow-up one year later, such that this ‘unavailable’ group was formally kept in the study until death. ^#Not eligible: centenarians were not yet included in the study long enough to be eligible for the next follow-up visit

Fig. 5

Overall cognitive functioning (Mini–Mental State Examination): a Mini–Mental State Examination (MMSE) scores. b Researcher impression of cognitive health at first visit, compared to MMSE score. c Mortality rate of centenarians with high and low performance on the MMSE

Box-Figure: Instant mortality and dementia rates in centenarian birth cohort. Blue line: Male mortality. Shades of blue represent confidence intervals (CI) on the mortality rate by 10-percentile increments [84]; for ages 0–59 years we used only the mortality statistics of individuals born in 1912 (as to avoid blurring specific mortality peaks), and for ages 60–100 years we combined statistics of the 1910–1915 birth cohorts, which reduced CIs. Mortality after age 100 years was extrapolated in accordance with the Gompertz’ law of mortality [85]. Purple line: Female mortality with CIs [84]. Red line: Median incidence of overall dementia with CIs for age groups 55–59, 60–64, 65–65, 70–74, 75–79, 80–84, 85–89 years [1]. To define mean age per age-group, we assumed that the ages of the individuals that constituted each age-group were distributed according to associated mortality statistics. Red dots: Dementia incidence for age groups: 90–94 years (mean age 92.7), 95–99 years (mean age 96.4) and 100 + (mean age 101.3) [2]. Green line: Alzheimer’s Disease (AD) incidence with CIs [1]. Dashed red line: extrapolation of dementia incidence according to its exponential increase. To extrapolate dementia incidence, we fitted a Gompertz curve on available dementia incidence data [1, 2]. For the reported age ranges we compared the estimated dementia incidence with the reported incidence through a binomial distribution. This resulted in a log-likelihood, which was optimized (see ESM.pdf for mortality calculations)