Background The aim of this study is to identify differentially methylated regions (DMRs) in the genomes of a sample of cognitively healthy individuals and a sample of individuals with LOAD, all of them nonagenarians from Costa Rica. Methods In this study, we compared whole blood DNA methylation profiles of 32 individuals: 21 cognitively healthy and 11 with LOAD, using the Infinium MethylationEPIC BeadChip. First, we calculated the epigenetic age of the participants based on Horvath’s epigenetic clock. DMRcate and Bumphunter were used to identify DMRs. After in silico and knowledge-based filtering of the DMRs, we performed a methylation quantitative loci (mQTL) analysis (rs708727 and rs960603). Results On average, the epigenetic age was 73 years in both groups, which represents a difference of over 20 years between epigenetic and chronological age in both affected and unaffected individuals. Methylation analysis revealed 11 DMRs between groups, which contain six genes and two pseudogenes. These genes are involved in cell cycle regulation, embryogenesis, synthesis of ceramides, and migration of interneurons to the cerebral cortex. One of the six genes is PM20D1, for which altered expression has been reported in LOAD. After genotyping previously reported mQTL SNPs for the gene, we found that average methylation in the PM20D1 DMR differs between genotypes for rs708727, but not for rs960603. Conclusions This work supports the possible role of PM20D1 in protection against AD, by showing differential methylation in blood of affected and unaffected nonagenarians. Our results also support the influence of genetic factors on PM20D1 methylation levels.

Objective To study the association of dementia with APOE-e4 and its interaction with age in a nonagenarian Costa Ricans (N-sample) and a general elderly contrast group (GE-sample). Methods In both case-control studies, participants were cognitively intact or demented. The N-sample (N=112) was at least age 90; the GE-sample (N=98) was at least age 65. Results Dementia and APOE-e4 were not significantly associated in the N-sample, but were in the GE-sample. There was a significant interaction of age with APOE-e4 in the N-sample, but not in the GE-sample. Descriptively dividing the N-sample at the median (age 93) showed a group interaction: APOE-e4 was more associated with dementia in the younger N-sample than in the older N-sample, where six of seven APOE-e4 carriers were cognitively intact. Conclusions The results support the reduction in association of APOE-e4 with dementia in extreme old age, consistent with a survivor effect model for successful cognitive aging.

We sought to identify cognitive phenotypes for family/genetic studies of successful cognitive aging (SCA; maintaining intact cognitive functioning while living to late old age).We administered a battery of neuropsychological tests to nondemented nonagenarians (n = 65; mean age = 93.4±3.0) and their offspring (n = 188; mean age = 66.4±5.0) from the Central Valley of Costa Rica. After covarying for age, gender, and years of education, as necessary, heritability was calculated for cognitive functions at three pre-defined levels of complexity: specific neuropsychological functions (e.g., delayed recall, sequencing), three higher level cognitive domains (memory, executive functions, attention), and an overall neuropsychological summary. The highest heritability was for delayed recall (h2 = 0.74, se = 0.14, p < 0.0001) but significant heritabilities involving memory were also observed for immediate recall (h2 = 0.50), memory as a cognitive domain (h2 = 0.53), and the overall neuropsychological summary (h2 = 0.42). Heritabilities for sequencing (h2 = 0.42), fluency (h2 = 0.39), abstraction (h2 = 0.36), and the executive functions cognitive domain (h2 = 0.35) were also significant. In contrast, the attention domain and memory recognition were not significantly heritable in these families. Among the heritable specific cognitive functions, a strong pleiotropic effect (i.e., evidence that these may be influenced by the same gene or set of genes) for delayed and immediate recall was identified (bivariate statistic = 0.934, p < 0.0001) and more modest but significant effects were found for four additional bivariate relationships. The results support the heritability of good cognitive function in old age and the utilization of several levels of phenotypes, and they suggest that several measures involving memory may be especially useful for family/genetic studies of SCA.

To find associations of age, sex, and education with neuropsychological test performance in cognitively normal Spanish-speaking Costa Rican nonagenarians with little education; to provide norms; and to compare their performance with similar Puerto Ricans. For 95 Costa Ricans (90–102 years old, 0–6 years of education), multiple regression assessed associations with demographics of performance on six neuropsychological tests. Analyses of covariance compared them with 23 Puerto Ricans (90–99 years old). Younger age and being female—but not education—were associated with better performance on some neuropsychological tests, in particular episodic memory. The Puerto Ricans performed better on learning and memory tasks. In cognitively intact Spanish-speaking nonagenarians with little or no education, education did not affect test performance. Additional studies of the effect of education on cognitive performance are warranted in other samples with extremely low education or old age. National differences in performance highlight the importance of group-specific norms.

Harriet Hardy, protégé of Alice Hamilton, spent 1948 in the Health Division of Los Alamos Scientific Laboratory. The contemporary campaign for federal legislation to compensate nuclear workers brought to the fore living retirees in whose cases of occupational illness Hardy had a role in diagnosis or case management. A third case is documented in archival records. Methods of participatory action research were used to better document the cases and strategize in light of the evidence, thereby assisting the workers with compensation claims. Medical and neuropsychological exams of the mercury case were conducted. Hardy's diary entries and memoirs were interpreted in light of medicolegal documentation and workers' recollections. Through these participatory research activities, Harriet Hardy's role and influence both inside and outside the atomic weapons complex have been elucidated. An important lesson learned is the ongoing need for a system of protective medical evaluations for nuclear workers with complex chemical exposures.