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Background and objectivesAmyloid pathology, vascular disease pathology, and pathologies affecting the medial temporal lobe are associated with cognitive trajectories in older adults. However, only limited evidence exists on how these pathologies influence cognition in the oldest old. We evaluated whether amyloid burden, white matter hyperintensity (WMH) volume, and hippocampal volume (HV) are associated with cognitive level and decline in the oldest old.MethodsThis was a longitudinal, observational community-based cohort study. We included participants with 18F-florbetapir PET and MRI data from the 90+ Study. Amyloid load was measured using the standardized uptake value ratio in the precuneus/posterior cingulate with eroded white matter mask as reference. WMH volume was log-transformed. All imaging measures were standardized using sample means and SDs. HV and log-WMH volume were normalized by total intracranial volume using the residual approach. Global cognitive performance was measured by the Mini-Mental State Examination (MMSE) and modified MMSE (3MS) tests, repeated every 6 months. We used linear mixed-effects models with random intercepts; random slopes; and interaction between time, time squared, and imaging variables to estimate the associations of imaging variables with cognitive level and cognitive decline. Models were adjusted for demographics, APOE genotype, and health behaviors.ResultsThe sample included 192 participants. The mean age was 92.9 years, 125 (65.1%) were female, 71 (37.0%) achieved a degree beyond college, and the median follow-up time was 3.0 years. A higher amyloid load was associated with a lower cognitive level (βMMSE = -0.82, 95% CI -1.17 to -0.46; β3MS = -2.77, 95% CI -3.69 to -1.84). A 1-SD decrease in HV was associated with a 0.70-point decrease in the MMSE score (95% CI -1.14 to -0.27) and a 2.27-point decrease in the 3MS score (95% CI -3.40 to -1.14). Clear nonlinear cognitive trajectories were detected. A higher amyloid burden and smaller HV were associated with faster cognitive decline. WMH volume was not significantly associated with cognitive level or decline.DiscussionAmyloid burden and hippocampal atrophy are associated with both cognitive level and cognitive decline in the oldest old. Our findings shed light on how different pathologies contributed to driving cognitive function in the oldest old.

Most neuroimaging studies linking regional brain volumes with cognition correct for total intracranial volume (ICV), but methods used for this correction differ across studies. It is unknown whether different ICV correction methods yield consistent results. Using a brain-wide association approach in the MRI substudy of UK Biobank (N = 41,964; mean age = 64.5 years), we used regression models to estimate the associations of 58 regional brain volumetric measures with eight cognitive outcomes, comparing no correction and four ICV correction approaches. Approaches evaluated included: no correction; dividing regional volumes by ICV (proportional approach); including ICV as a covariate in the regression (adjustment approach); and regressing the regional volumes against ICV in different normative samples and using calculated residuals to determine associations (residual approach). We used Spearman-rank correlations and two consistency measures to quantify the extent to which associations were inconsistent across ICV correction approaches for each possible brain region and cognitive outcome pair across 2320 regression models. When the association between brain volume and cognitive performance was close to null, all approaches produced similar estimates close to the null. When associations between a regional volume and cognitive test were not null, the adjustment and residual approaches typically produced similar estimates, but these estimates were inconsistent with results from the crude and proportional approaches. For example, when using the crude approach, an increase of 0.114 (95% confidence interval [CI]: 0.103-0.125) in fluid intelligence was associated with each unit increase in hippocampal volume. However, when using the adjustment approach, the increase was 0.055 (95% CI: 0.043-0.068), while the proportional approach showed a decrease of -0.025 (95% CI: -0.035 to -0.014). Different commonly used methods to correct for ICV yielded inconsistent results. The proportional method diverges notably from other methods and results were sometimes biologically implausible. A simple regression adjustment for ICV produced biologically plausible associations.

INTRODUCTION: We estimated the ages when associations between Alzheimers disease (AD) genes and brain volumes begin among middle-aged and older adults. METHODS: Among 45,616 dementia-free participants aged 45-80, linear regressions tested whether genetic risk score for AD (AD-GRS) had age-dependent associations with 38 regional brain magnetic resonance imaging volumes. Models were adjusted for sex, assessment center, genetic ancestry, and intracranial volume. RESULTS: AD-GRS modified the estimated effect of age (per decade) on the amygdala (-0.41 mm3 [-0.42, -0.40]); hippocampus (-0.45 mm3 [-0.45, -0.44]), nucleus accumbens (-0.55 mm3 [-0.56, -0.54]), thalamus (-0.38 mm3 [-0.39, -0.37]), and medial orbitofrontal cortex (-0.23 mm3 [-0.24, -0.22]). Trends began by age 45 for the nucleus accumbens and thalamus, 48 for the hippocampus, 51 for the amygdala, and 53 for the medial orbitofrontal cortex. An AD-GRS excluding apolipoprotein E (APOE) was additionally associated with entorhinal and middle temporal cortices. DISCUSSION: APOE and other genes that increase AD risk predict lower hippocampal and other brain volumes by middle age.

IntroductionThe prevalence of poor sleep quality and sleep apnea differs by race and ethnicity and may contribute to racial disparities in cognitive aging. We investigated whether sleep quality and sleep apnea risk were associated with cognitive function and decline and whether the associations differed by race/ethnicity.MethodsParticipants from the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE; N = 1690; mean age: 75.7 years) study, a cohort of Asian, Black, Latino, and White participants, completed a modified Pittsburgh Sleep Quality Index assessing subjective sleep quality, latency, duration, disturbances, sleep medication use, and daytime dysfunction. Sleep apnea risk was measured by questions about snoring, tiredness, and whether apnea was observed. Executive function and verbal episodic memory were assessed at three time points over an average of 2.7 years with the Spanish and English Neuropsychological Assessment Scale. We fit linear mixed-effect models and stratified analyses by race/ethnicity.ResultsHigher sleep apnea risk was associated with faster declines in verbal episodic memory (β^ sleep apnea = -0.02, 95% confidence interval [CI], -0.04, -0.001) but not in executive function. Poorer sleep quality was associated with lower levels of and faster decline in executive function but not in verbal episodic memory. Race/ethnicity modified these associations: compared to estimated effects among White participants, poorer global sleep quality (β^ sleep*time = -0.02, 95% CI, -0.02, -0.01) was associated with larger effects on decline in executive function among Black participants. Estimated effects of some individual sleep quality components were also modified by race/ethnicity; for example, sleep medication use was associated with faster declines in executive function (β^ sleep*time = -0.05, 95% CI, -0.07, -0.03) and verbal episodic memory β^ sleep*time = -0.04, 95% CI, -0.07, -0.02) among Black participants compared to White participants.DiscussionObservational evidence indicates sleep quality is a promising target for addressing racial/ethnic disparities in cognitive aging, especially among Black older adults.HighlightsSleep apnea risk was associated with faster declines in verbal episodic memory but not executive function among all participants.Global sleep quality was associated with lower levels of and faster decline in executive function but not verbal episodic memory among all participants.Black older adults were particularly susceptible to the estimated adverse cognitive impacts of global sleep quality, particularly the use of sleep medication.

Epidemiological studies have identified an inverse association between cancer and dementia. Underlying methodological biases have been postulated, yet no studies have systematically investigated the potential for each source of bias within a single dataset. We used the UK Biobank to compare estimates for the cancer-dementia association using different analytical specifications designed to sequentially address multiple sources of bias, including competing risk of death, selective survival, confounding bias, and diagnostic bias. We included 140,959 UK Biobank participants aged ≥ 55 without dementia before enrollment and with linked primary care data. We used cancer registry data to identify cancer cases prevalent before UK Biobank enrollment and incident cancer diagnosed after enrollment. We used Cox models to evaluate associations of prevalent and incident cancer with all-cause dementia, Alzheimers disease (AD), and vascular dementia. We used time-varying models to evaluate diagnostic bias. Over a median follow-up of 12.3 years, 3,310 dementia cases were diagnosed. All-site incident cancer was positively associated with all-cause dementia incidence (hazard ratio [HR] = 1.14, 95% CI: 1.02-1.29), but prevalent cancer was not (HR = 1.04, 95% CI: 0.92-1.17). Results were similar for vascular dementia. AD was not associated with prevalent or incident cancer. Dementia diagnosis was substantially elevated in the first year after cancer diagnosis (HR = 1.83, 95% CI: 1.42-2.36), after which the association attenuated to null, suggesting diagnostic bias. Following a cancer diagnosis, health care utilization or cognitive consequences of diagnosis or treatment may increase chance of receiving a dementia diagnosis, creating potential diagnostic bias in electronic health records-based studies.

IntroductionThe challenge of accounting for practice effects (PEs) when modeling cognitive change was amplified by the COVID-19 pandemic, which introduced period and mode effects that may bias the estimation of cognitive trajectory.MethodsIn three Kaiser Permanente Northern California prospective cohorts, we compared predicted cognitive trajectories and the association of grip strength with cognitive decline using three approaches: (1) no acknowledgment of PE, (2) inclusion of a wave indicator, and (3) constraining PE based on a preliminary model (APM) fit using a subset of the data.ResultsAPM-based correction for PEs based on balanced, pre-pandemic data, and with current age as the timescale produced the smallest discrepancy between within-person and between-person estimated age effects. Estimated associations between grip strength and cognitive decline were not sensitive to the approach used.DiscussionConstraining PEs based on a preliminary model is a flexible, pragmatic approach allowing for meaningful interpretation of cognitive change.HighlightsThe magnitude of practice effects (PEs) varied widely by study. When PEs were present, the three PE approaches resulted in divergent estimated age-related cognitive trajectories. Estimated age-related cognitive trajectories were sometimes implausible in models that did not account for PEs. The associations between grip strength and cognitive decline did not differ by the PE approach used. Constraining PEs based on estimates from a preliminary model allows for a meaningful interpretation of cognitive change.

BACKGROUND: The objective of this study was to evaluate associations of diabetes overall, type 1 diabetes (T1D), and type 2 diabetes (T2D) with breast cancer (BCa) risk. METHODS: We included 250,312 women aged 40-69 years between 2006 and 2010 from the UK Biobank cohort. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) were calculated for associations of diabetes and its two major types with the time from enrollment to incident BCa. RESULTS: We identified 8182 BCa cases during a median follow-up of 11.1 years. We found no overall association between diabetes and BCa risk (aHR = 1.02, 95% CI = 0.92-1.14). When accounting for diabetes subtype, women with T1D had a higher risk of BCa than women without diabetes (aHR = 1.52, 95% CI = 1.03-2.23). T2D was not associated with BCa risk overall (aHR = 1.00, 95% CI = 0.90-1.12). However, there was a significantly increased risk of BCa in the short time window after T2D diagnosis. CONCLUSIONS: Though we did not find an association between diabetes and BCa risk overall, an increased risk of BCa was observed shortly after T2D diagnosis. In addition, our data suggest that women with T1D may have an increased risk of BCa.

ImportanceAdults with Alzheimer disease and related dementias (ADRD) are particularly vulnerable to the direct and indirect effects of the COVID-19 pandemic. Deaths associated with ADRD increased substantially in pandemic year 1. It is unclear whether mortality associated with ADRD declined when better prevention strategies, testing, and vaccines became widely available in year 2.ObjectiveTo compare pandemic-era excess deaths associated with ADRD between year 1 and year 2 overall and by age, sex, race and ethnicity, and place of death.Design, setting, and participantsThis time series analysis used all death certificates of US decedents 65 years and older with ADRD as an underlying or contributing cause of death from January 2014 through February 2022.ExposureCOVID-19 pandemic era.Main outcomes and measuresPandemic-era excess deaths associated with ADRD were defined as the difference between deaths with ADRD as an underlying or contributing cause observed from March 2020 to February 2021 (year 1) and March 2021 to February 2022 (year 2) compared with expected deaths during this period. Expected deaths were estimated using data from January 2014 to February 2020 fitted with autoregressive integrated moving average models.ResultsOverall, 2 334 101 death certificates were analyzed. A total of 94 688 (95% prediction interval [PI], 84 192-104 890) pandemic-era excess deaths with ADRD were estimated in year 1 and 21 586 (95% PI, 10 631-32 450) in year 2. Declines in ADRD-related deaths in year 2 were substantial for every age, sex, and racial and ethnic group evaluated. Pandemic-era ADRD-related excess deaths declined among nursing home/long-term care residents (from 34 259 [95% PI, 25 819-42 677] in year 1 to -22 050 [95% PI, -30 765 to -13 273] in year 2), but excess deaths at home remained high (from 34 487 [95% PI, 32 815-36 142] in year 1 to 28 804 [95% PI, 27 067-30 571] in year 2).Conclusions and relevanceThis study found that large increases in mortality with ADRD as an underlying or contributing cause of death occurred in COVID-19 pandemic year 1 but were largely mitigated in pandemic year 2. The most pronounced declines were observed for deaths in nursing home/long-term care settings. Conversely, excess deaths at home and in medical facilities remained high in year 2.