Centenarians who were cognitively healthy maintained high levels of cognitive function over time despite being exposed to risk factors, including Alzheimer’s disease pathology, a prospective cohort study found.
“The centenarians in our cohort maintained their levels of performance in most cognitive domains for up to 4 years,” wrote Henne Holstege, PhD, of the Amsterdam University Medical College in the Netherlands, and co-authors, in JAMA Network Open. “We observed a slight decline in global cognition, which was driven by a decline in memory function.”
“Our findings suggest that after reaching age 100 years, cognitive performance remains relatively stable,” they added. “Therefore, these centenarians might be resilient or resistant against different risk factors of cognitive decline.”
Holstege and colleagues studied 340 patients with self-reported good cognitive health from the Dutch 100-Plus Study, a prospective cohort seen in home visits annually for assessment. Psychological evaluations (n=330) measured performance in specific domains (memory, executive function, fluency, visuospatial ability, and attention/processing) that were combined to form a global cognitive score.
The researchers found no decline across investigated cognitive domains, with the exception of memory function, which declined slightly (β −0.10 SD per year, 95% CI −0.14 to −0.05 SD, P< 0.001).
Overall, a higher Barthel index, which assesses independence in activities of daily living as a factor related to physical health, was associated with higher cognitive composite scores (β 0.37 SD per year, 95% CI 0.24-0.49, P < 0.001), but not with rate of cognitive decline.
Higher education levels, a factor related to cognitive reserve, also was associated with higher cognitive scores (β 0.41 SD per year, 95% CI 0.29-0.53, P< 0.001), but not with rate of cognitive decline.
Neuropathology reports for 44 participants showed no association with cognitive performance or rate of decline, despite varying Alzheimer’s disease pathology burden.
The findings imply that these centenarians have “resilience or resistance to Alzheimer’s disease and related dementias, despite the facts that they have the most potent risk factor in the general population, extreme old age, and that brain amyloid-β and tau deposition generally increase with age,” wrote Thomas T. Perls, MD, MPH, of Boston University, in an accompanying editorial. “Indeed, in 44 autopsies there were numerous instances of good cognitive function in the presence of substantial neuropathology, which is consistent with the presence of functional reserve or resilience.”
Evidence for decoupling of pathology burden and clinical dementia was emerging by the late 1980s, leading to a framework of resilience and resistance to interpret individual differences in pathologic burden and cognitive function. As distinct from resistance (not developing pathology), cognitive and brain resilience refers to preserved cognitive function and brain tissue structural integrity despite pathological burden. Cognitive reserve is the supposition that resilience involves greater ability to function for a given level of pathologic burden.
“By integrating neuropsychological assessments and neuropathological studies, subsets of centenarian cognitive superagers and offspring who are either resistant or resilient to Alzheimer’s disease neuropathologic changes can be identified,” Perls observed.
Data for the present study was captured from Jan. 2013 to April 2019. Mean follow-up was 1.6 years. The cohort was 72.4% women with median age of 100.5, and median MMSE score was 25.2.
The APOE4 allele was present in 16.8%of participants and APOE2 allele in 22.7%; neither was significantly associated with performance in any cognitive domain or with the rate of decline.
“This may suggest that the effects of APOE alleles are exerted before the age of 100 years,” Holstege and co-authors wrote. “This is in line with reports in prospective population studies that the fraction of APOE ε4 allele carriers progressively decreases in 80- and 90-year-olds. These ages represent the median age at death in most populations, such that the APOE alleles may exert its strong effects on selection during these ages.”
Additional physical health factors assessed in the study included hearing and vision (judged “good” in 56% and 66%, respectively), living situation (57% lived independently), and mobility (79% walked independently). Education level (median upper secondary level) and intelligence (mean intelligence quotient 98.2) were assessed as factors related to cognitive reserve.
Postmortem levels of Aβ plaques, neuritic plaques, and neurofibrillary tangles varied in the 44 autopsied brains. “It is intriguing that the highest stages of Aβ pathology were present in the brains of high performing centenarians, while the highest tau (i.e., neurofibrillary tangles) and neuritic plaque levels were not,” the researchers noted. “This indicates that maintained cognitive health may be explained by resilience to the effects of even the highest levels of Aβ pathology, and a combination of resilience and resistance against neurofibrillary tangles and neuritic plaques.”
Limitations include self-reported cognitive health as a prerequisite for entering the study. The findings do not represent all centenarians.
“Enrollees in centenarian studies are often substantially better off than centenarians in general because of a healthy volunteer bias, and this study is no exception,” Perls said. “As extreme outliers, these centenarians are likely an informative cohort for discovering behavioral, environmental, and/or biological mechanisms of resistance and resilience to Alzheimer’s disease and related dementias.”
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Centenarians who were cognitively healthy maintained high levels of cognitive function over time despite being exposed to risk factors including Alzheimer’s disease pathology, a prospective cohort study found.
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As extreme outliers, these centenarians may be an informative cohort for discovering behavioral, environmental, or biological mechanisms of resistance and resilience to Alzheimer’s disease and related dementias, the editorialist said.
Paul Smyth, MD, Contributing Writer, BreakingMED™
This work was supported by Stichting Alzheimer Nederland, Stichting Dioraphte, and Stichting Vumc Fonds. Research from the Alzheimer Center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience.
Holstege reported no disclosures.
Perls reported no disclsoures.
Cat ID: 404
Topic ID: 398,404,282,404,485,494,730,130,33,361,255,925
