Contribution of health history and neuropathologic changes to the likelihood of dementia in those with intermediate/high Alzheimer's pathology: findings from The 90 + Study

Although intermediate/high Alzheimer's Disease Neuropathologic Change (ADNC) is associated with dementia in many older adults, some remain cognitively normal and are often referred to as resilient to ADNC. We aim to examine health, lifestyle, and neuropathologic factors that distinguish older adults with dementia vs. normal cognition in the presence of intermediate/high ADNC. Participants were from The 90 + Study, a longitudinal study of aging in southern California. This cross-sectional analysis included participants with an intermediate/high ADNC on neuropathologic exam and normal cognition or dementia diagnosis on case conference. We analyzed 11 neuropathologic changes, both vascular and neurodegenerative, dichotomized as present/absent, and the total number of neuropathologies. To examine the association of health and lifestyle factors and neuropathologic changes (predictors) with cognitive diagnosis at consensus case conference, dementia vs. normal cognition, (outcome), we used logistic regression adjusted for demographics. Among 235 participants (mean age at death = 98 years, 70% women), 33% maintained normal cognition. Participants with heart disease (OR = 0.45; 95% CI = 0.25, 0.81) and hypertension (OR = 0.53; 95% CI = 0.29, 0.95) had lower likelihood of dementia. In contrast, participants with a history of transient ischemic attacks (OR = 3.00; 95% CI = 1.46, 6.18), Lewy Body Disease (OR = 2.73; 95% CI = 1.14, 6.58), hippocampal sclerosis (OR = 2.70; 95% CI = 1.06, 6.86), Limbic-predominant Age-related TDP-43 Encephalopathy neuropathologic change (OR = 2.80; 95% CI = 1.53, 5.12), and a high number of non-ADNCs (OR = 4.46; 95% CI = 2.01, 9.92) had higher likelihood of dementia. Arteriolosclerosis, atherosclerosis, cerebral amyloid angiopathy, and microvascular lesions were not associated with dementia. In this study, the presence of neurodegenerative neuropathologic changes other than ADNC and the absence of hypertension distinguish oldest old individuals with dementia from those with normal cognition. Understanding mechanisms underlying normal cognition in those with ADNC may provide important clues to prevention and resilience to the effects of AD neuropathology.