Longitudinal assessment of cognitive decline and resilience in high-level Alzheimer disease neuropathologic change

BACKGROUND: Alzheimer disease neuropathologic change (ADNC) is the most common pathology underlying cognitive impairment and dementia in the aging population, but there is significant variation in outcome between affected individuals. Moreover, other common neurodegenerative processes are often concurrent and may significantly worsen cognition, but the degree to which these processes interact and affect the rate of cognitive decline remains unclear. Herein, we aim to investigate features influencing cognitive trajectories over the final 15 years of life in individuals with high-level ADNC. METHODS: We performed a cross-sectional cohort study of 586 participants from the National Alzheimer’s Coordinating Center (NACC) database, who were ≥ 65 years of age and displayed high-level ADNC at autopsy, and who had available longitudinal cognitive data and Clinical Dementia Rating (CDR) performed within the final 24 months of life. This cohort was subdivided into “resilient” individuals/those with minimal progression of cognitive decline (MinP; n = 75), intermediate/moderate progression of cognitive decline (ModP; n = 255), and rapid/maximal progression of cognitive decline (MaxP; n = 256) as determined by global cognitive performance and the rate of cognitive decline. Demographic, neuropathologic, genetic, and clinical features were evaluated using multivariable logistic regression analysis. RESULTS: Individuals with rapid progression were more likely to have at least one APOE ε4 allele (OR: 2.08 [95% CI: 1.16–3.74], p < 0.01), higher Braak stage (2.19 [1.20–3.98], p < 0.01), higher Thal phase (2.45 [1.24–4.83], p < 0.01), more severe white matter rarefaction (1.68 [1.21–2.35], p < 0.01), and in the final 24 months of life, more frequent untreated/undertreated hyperlipidemia (1.74 [1.35–5.56], p < 0.01) and less frequent untreated/undertreated depression (0.40 [0.17–0.91], p < 0.05). Conversely, resilient individuals harbored less frequent APOE ε4 alleles (0.17 [0.06–0.55], p < 0.01), lower Thal phase (0.33 [0.12–0.95], p < 0.05), lower CERAD neuritic plaque score (0.32 [0.11–0.97], p < 0.05), less frequent untreated/undertreated psychosis (0.06 [0.01–0.39], p < 0.01), and more frequent untreated/undertreated depression (8.73 [2.12–35.85], p < 0.01). CONCLUSIONS: These data suggest that resilience and progression in ADNC are impacted by AD-relevant genetics and the severity of late-stage ADNC (even within the narrow range of values compatible with high-level ADNC), additional pathologic features, and potentially the clinical management of underlying systemic disorders.