Multiple factors predict resilience, resistance in aging

Long-term predictors of avoiding amyloid-beta (Aβ) deposition and maintaining unimpaired cognition in the oldest old included their baseline cognitive scores, genetics, pulse pressure, smoking status, paid work engagement, and life satisfaction, an observational cohort study showed.

Among 100 participants who were an average of 92 years old, the APOE2 allele predicted an absence of significant Aβ pathology (“resistance”), while performance on cognitive tests from 14 years prior was predictive of maintaining healthy cognition, reported Beth Snitz, PhD, of the University of Pittsburgh and co-authors.

Healthy cognition within Aβ-positivity (“resilience”) also was predicted by baseline cognitive test performance, as well as a history of never having smoked, they wrote in Neurology.

Baseline lower pulse pressure and APOE4 predicted overall Aβ deposition across time and current paid work engagement and life satisfaction were protective against memory decline, they added.

The cohort, former participants in the GEMS study, had regular Pittsburgh Compound B (PiB)-PET imaging and yearly clinical evaluations over 14 year mean cognitive follow-up. Average baseline age was 77.6, and at follow-up, 92.

“The APOE2 allele and lower pulse pressure predicts resistance to Aβ deposition in advanced aging,” Snitz and colleagues wrote. “Cognitive test scores 14 years prior, likely reflecting premorbid abilities, predict cognitive status and maintenance of unimpaired cognition in the presence of Aβ.”

“Recent studies, including this one, have shown that better cognitive performance is also associated with less risk of decline in individuals with Aβ positivity,” noted Claudia Kawas, MD, and Maria Corrada, ScM, ScD, both of the University of California Irvine, in an accompanying editorial.

“An important question to consider in studies of resilience is whether good performance in an individual with Aβ positivity reflects resilience to amyloid, or merely an earlier stage of Alzheimer disease process,” they added. “The 14-year window of this longitudinal study supports the notion that these individuals may indeed be resilient.”

The oldest old with preserved cognitive health present an opportunity to investigate factors that promote successful cognitive aging with or without Alzheimer’s disease pathology, which includes Aβ deposition. Some people with significant Aβ deposition seem to cope with it and maintain clinically normal cognition, while others with normal cognition may be resistant to Aβ accumulation.

The authors of a conceptual framework distinguishing resilience and resistance wrote: “We refer to resistance in the context of avoiding pathology, i.e., remaining cognitively normal with low Alzheimer disease pathologies. We refer to resilience in the context of coping with pathology, i.e., remaining cognitively normal despite substantial Alzheimer disease pathologies.”

Prior work has shown that better cognitive performance is associated with less risk of cognitive decline and incident dementia in the elderly.

The GEMS trial, a study of Ginkgo biloba and incident dementia, followed 3,069 participants between 2000 and 2008 with normal cognition or minimal cognitive impairment who were 75 or older, with follow-up every 6 months for incident dementia.

Snitz and colleagues conducted a longitudinal study with 100 former participants from GEMS. Mean follow-up time from baseline to last measured (PiB)-PET imaging Aβ status was 12.3 years and to last cognitive evaluation was 14.1 years.

Analysis by Aβ status found that the Aβ negative group had a higher proportion of APOE2 carriers than Aβ-positive (21.9% versus 4.8%, OR 5.5, 95% CI 1.3- 23.0, P=0.01), and only APOE2 predicted negative Aβ status (OR 5.99, 95% CI 1.34-27.03; P=0.02).

Analysis by cognitive status found that 30% of the cohort had normal cognition by the time of the most recent assessment, while measures of verbal memory and reasoning skills were significant as predictors.

Analysis of cognition in 66 participants who were all Aβ positive found that 14 (21%) were cognitively unimpaired (resilient); these 14 did not differ in demographic variables or APOE genotype compared with the remaining 52 impaired Aβ positive participants. Never smoking (OR 10.84, 95% CI 1.50-78.27; P=0.02) and a measure of reasoning skills were predictors of unimpaired cognition.

Longitudinal data showed that higher pulse pressure predicted greater increase in global PiB over time regardless of cognitive status, while paid work engagement (versus none) predicted less memory decline. Satisfaction with life predicted less executive function decline.

“A larger literature investigating sense of life purpose or meaning supports the notion that psychological well-being captured by broad constructs may offer protection against poorer cognitive as well as vascular and mortality outcomes,” Snitz and colleagues noted.

“Maintaining cognitive abilities throughout the lifespan would have staggering public health benefits and is ultimately the goal for all of us,” the editorialists observed. “With the help of oldest-old individuals, we can learn the biological underpinnings of successful aging and potential strategies for resistance and resilience.”

The study population — volunteers who were largely male, white, and well-educated — limited generalizability, the researchers noted. The analysis also was limited to AD-related pathology, though multiple neuropathological abnormalities are very common at very advanced ages.

“It is possible that the apparent resilience to AD pathology established by imaging merely reflects resistance to other non-AD pathologies, including hippocampal sclerosis, microvascular disease and Lewy bodies,” the editorialists pointed out. “To fully understand successful cognitive aging, it will be crucial to extend the study of resistance and resilience to all important dementia-related pathologies.”

  1. Performance on cognitive tests from 14 years prior was predictive of maintaining healthy cognition in the oldest old, who had an average age at most recent follow-up of 92.

  2. Genetics, pulse pressure, smoking status, paid work engagement, and life satisfaction also were tied to maintaining unimpaired cognition.

Paul Smyth, MD, Contributing Writer, BreakingMED™

Research was supported by the NIH grants from the National Center for Complementary and Alternative Medicine (NCCAM) and the Office of Dietary Supplements and National Institute on Aging; National Heart, Lung, and Blood Institute.

Snitz reported no disclosures.

The editorialists reported report no disclosures relevant to the manuscript.

Cat ID: 361

Topic ID: 82,361,282,404,494,730,361,192,255,925