Willa D. Brenowitz

Objective: To test whether decline in specific cognitive domains associated with Alzheimer disease neuropathologic change (ADNC) is modified by co-occurrence of other neuropathologies such as Lewy body disease (LBD) or vascular brain injury (VBI). Methods: Data came from 1,603 autopsied participants evaluated at US Alzheimer9s Disease Centers. Standardized z scores in memory, attention, language, and executive function were derived from neuropsychological test scores assessed at each annual visit. Multivariable linear mixed-effects models assessed associations between neuropathologies and longitudinal trajectories of domain scores. Results: Compared to other participants, those with ADNC + LBD generally had worse cognitive trajectories, particularly lower initial executive function and faster attention decline. Participants with ADNC + VBI typically had less impairment and slower decline. Interactions were significant between LBD and ADNC for memory (p = 0.046) and between VBI and ADNC for language (p = 0.03); decline was slower than expected if these neuropathologies acted additively on the rate of decline. In secondary models, these interactions were limited to those with high ADNC (but not intermediate ADNC). In a subset of 260 participants with data on microinfarct location, cortical and subcortical microinfarcts were associated with decline in memory, language, and executive function in those without ADNC, but this effect was reduced among those with ADNC. Conclusions: ADNC + LBD (but not ADNC + VBI) was associated with poorer executive function and attention compared to other pathology groupings. However, the effect of co-occurring pathologies on cognitive trajectories may depend on the severity of ADNC. Future studies using antemortem biomarkers should seek to replicate these neuropathologic observations.

Introduction: Whether co‐occurring neuropathologies interact or independently affect clinical disease progression is uncertain. We estimated rates of clinical progression and tested whether associations between clinical progression and Alzheimer's disease neuropathology (ADNP) were modified by co‐occurring Lewy body disease (LBD) or vascular brain injury (VBI).Methods: Linear mixed effects models evaluated longitudinal trends in the Clinical Dementia Rating Scale Sum of Boxes on 2046 autopsied participants seen at a U.S. Alzheimer's Disease Center.Results: Annual clinical progression was slightly faster for ADNP + LBD compared with ADNP only (P = .06) and slightly slower for ADNP + VBI (P = .003). Differences in progression were less than expected if each neuropathology independently contributed to progression; ADNP interacted with LBD (P = .002) and VBI (P = .003). In secondary models, the effect of additional pathologies on clinical progression was greater in those with intermediate compared with high levels of ADNP.Discussion: The impact of co‐occurring pathologies on progression may depend on severity of ADNP.

Although self-rated health (SRH) and performance-based physical function (PPF) are both strong predictors of mortality, little research has investigated the relationships between them. The objective of this study was to evaluate longitudinal, bi-directional associations between SRH and PPF. We evaluated longitudinal associations between SRH and PPF in 3,610 adults aged 65–89 followed for an average of 4.8 (standard deviation [SD]: 4.4) years between 1994 and July 2011 in the Adult Changes in Thought study, a population-based cohort in the Seattle area. SRH was assessed with a single-item question in the ACT study. Participants were asked at each evaluation to rate their health as “excellent”, “very good”, “good”, “fair”, or “poor” in response to the question “In general, how would you rate your health at this time”. PPF scores (ranging from 0–16, with higher indicating better performance) included walking speed, chair rises, grip strength, and balance. At the baseline visit, participants averaged 74.5 (SD: 5.8) years of age and 2,115 (58.6%) were female. In multivariable linear mixed models, PPF declined with age, with more rapid decreases associated with very good, good, and fair (vs. excellent) baseline SRH. Adjusted annual change in PPF was −0.17 points (95% confidence interval [CI]: −0.19, −0.15) for individuals with excellent baseline SRH and −0.21 points (95% CI: −0.22, −0.19) for participants with fair SRH. In multivariable generalized linear mixed models, lower baseline PPF quartiles were associated with lower odds of excellent/very good/good SRH at age 75, however, differences between baseline PPF quartiles diminished with age. These results suggest that less than excellent SRH predicts decline in physical functioning, however, poor physical functioning may not predict change in SRH in a reciprocal fashion. SRH provides a simple assessment tool for identifying individuals at increased risk for decline in physical function.

Social relationships are hypothesized to prevent or slow cognitive decline. We sought to evaluate associations between social relationships and mild cognitive impairment (MCI). Participants from the National Alzheimer’s Coordinating Center database who were cognitively normal, aged 55 and older at baseline, and had at least 2 in-person visits (n=5335) were included. Multivariable Cox proportional hazard models evaluated the association between 4 social relationships at baseline (marital status, living situation, having children, and having siblings) and risk of developing MCI (on the basis of clinician diagnosis following established criteria). Primary models were adjusted for baseline demographics. Participants were followed, on average, for 3.2 years; 15.2% were diagnosed with MCI. Compared with married participants, risk of MCI was significantly lower for widowed participants (hazard ratio: 0.87; 95% confidence interval: 0.76, 0.99) but not for divorced/separated or never-married participants. Compared with living with a spouse/partner, risk of MCI was significantly higher for living with others (hazard ratio: 1.35; 95% confidence interval: 1.03, 1.77) but not for living alone. Risk of MCI was not associated with having children or having siblings. These results did not consistently identify social relationships as a strong risk factor for, or independent clinical predictor of, MCI.