Cognitive Resilience to Alzheimer's Disease Pathology in the Human Brain

Abstract

Background: Past research has focused on risk factors for developing dementia, with increasing recognition of "resilient" people who live to old age with intact cognitive function despite pathological features of Alzheimer's disease (AD).

Objective: To evaluate demographic factors, mid-life characteristics, and non-AD neuropathology findings that may be associated with cognitive resilience to AD pathology.

Methods: We analyzed data from 276 autopsy cases with intermediate or high levels of AD pathology from the Adult Changes in Thought study. We defined cognitive resilience as having Cognitive Abilities Screening Instrument scores ≥86 within two years of death and no clinical dementia diagnosis; non-resilient people had dementia diagnoses from AD or other causes before death. We compared mid-life characteristics, demographics, and additional neuropathology findings between resilient and non-resilient people. We used multivariable logistic regression to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for being resilient compared to not being resilient adjusting for demographic and neuropathology factors.

Results: We classified 68 (25%) people as resilient and 208 (75%) as not resilient. A greater proportion of resilient people had a college degree (50%) compared with non-resilient (32%, p = 0.01). The odds of being resilient were significantly increased among people with a college education (OR = 2.01, 95% CI = 1.01-3.99) and significantly reduced among people with additional non-AD neuropathology findings such as hippocampal sclerosis (OR = 0.28, 95% CI = 0.09-0.89) and microinfarcts (OR = 0.34, 95% CI = 0.15-0.78).

Conclusion: Increased education and absence of non-AD pathology may be independently associated with cognitive resilience, highlighting the importance of evaluating co-morbid factors in future research on mechanisms of cognitive resilience.

Keywords: Aging; Alzheimer’s disease; cognition; dementia; education; neuropathology.

Figure 1.

Flow chart of study population. This figure shows the number of people included in the study population, and the number excluded for each reason.

Figure 2a and 2b.

Distribution of multiple neuropathology characteristics across ACT study participants, stratified by cognitively resilient and non-resilient groups. This figure shows the distribution of five neuropathology findings (Lewy Body Disease, hippocampal sclerosis, 2+ microvascular infarcts, Braak stage V/VI, and frequent CERAD score) by number of non-resilient (2a) and cognitively resilient (2b) study participants. The figure shows the combinations of various neuropathology findings and the proportions of non-resilient (2a) and cognitively resilient (2b) groups that have <1, <2, <3 or <4 findings. People with no findings have Braak stage III/IV and intermediate CERAD score.