Longitudinal Cognitive Performance Research Articles

Free-water: A promising structural biomarker for cognitive decline in aging and mild cognitive impairment.

Diffusion MRI derived free-water (FW) metrics show promise in predicting cognitive impairment and decline in aging and Alzheimer's disease (AD). FW is sensitive to subtle changes in brain microstructure, so it is possible these measures may be more sensitive than traditional structural neuroimaging biomarkers. In this study, we examined the associations among FW metrics (measured in the hippocampus and two AD signature meta-ROIs) with cognitive performance, and compared FW findings to those from more traditional neuroimaging biomarkers of AD. We leveraged data from a longitudinal cohort (nparticipants = 296, nobservations = 870, age at baseline: 73 ± 7 years, 40% mild cognitive impairment [MCI]) of older adults who underwent serial neuropsychological assessment (episodic memory, information processing speed, executive function, language, and visuospatial skills) and brain MRI over a maximum of four time points, including baseline (n = 284), 18-month (n = 246), 3-year (n = 215), and 5-year (n = 125) visits. The mean follow-up period was 2.8 ± 1.3 years. Structural MRI was used to quantify hippocampal volume, in addition to Schwarz and McEvoy AD Signatures. FW and FW-corrected fractional anisotropy (FAFWcorr) were quantified in the hippocampus (hippocampal FW) and the AD signature areas (SchwarzFW, McEvoyFW) from diffusion-weighted (dMRI) images using bi-tensor modeling (FW elimination and mapping method). Linear regression assessed the association of each biomarker with baseline cognitive performance. Additionally, linear mixed-effects regression assessed the association between baseline biomarker values and longitudinal cognitive performance. A subsequent competitive model analysis was conducted on both baseline and longitudinal data to determine how much additional variance in cognitive performance was explained by each biomarker compared to the covariate only model, which included age, sex, race/ethnicity, apolipoprotein-ε4 status, cognitive status, and modified Framingham Stroke Risk Profile scores. All analyses were corrected for multiple comparisons using an FDR procedure. Cross-sectional results indicate that hippocampal volume, hippocampal FW, Schwarz and McEvoy AD Signatures, and the SchwarzFW and McEvoyFW metrics are all significantly associated with memory performance. Baseline competitive model analyses showed that the McEvoy AD Signature and SchwarzFW explain the most unique variance beyond covariates for memory (ΔRadj 2 = 3.47 ± 1.65%) and executive function (ΔRadj 2 = 2.43 ± 1.63%), respectively. Longitudinal models revealed that hippocampal FW explained substantial unique variance for memory performance (ΔRadj 2 = 8.13 ± 1.25%), and outperformed all other biomarkers examined in predicting memory decline (pFDR = 1.95 x 10-11). This study shows that hippocampal FW is a sensitive biomarker for cognitive impairment and decline, and provides strong evidence for further exploration of this measure in aging and AD.

Impact of sleep disturbance on longitudinal cognitive performance in patients with transient ischemic attack or mild stroke

IntroductionSleep disturbances including obstructive sleep apnea (OSA) and poor sleep quality are common after stroke, while its association with cognitive changes following transient ischemic attack (TIA) or mild stroke remains unclear. We aim to determine whether sleep duration, OSA parameters, or nocturnal hypoxemia is associated with a greater cognitive decline after stroke. MethodsWe prospectively followed-up patients with acute TIA/mild stroke [National Institute Health Stroke Scale (NIHSS) < 7] who underwent baseline sleep questionnaire [Pittsburgh Sleep Quality Index (PSQI)], and serial cognitive assessments [Montreal Cognitive Assessment (MoCA) 5-min, Stroop Test] at baseline and one-year. We also evaluated apnea-hypopnea index (AHI) and nocturnal hypoxemia by Home Sleep Apnea Test (HSAT) at one-year. Primary outcome was one-year change in MoCA 5-min score. ResultsOne hundred and five patients with TIA/mild stroke (mean age 63 years, 65 % male) were included. Baseline short sleep (< 6 hour/night) and AHI ≥ 20/hour at one-year were independently associated with a decline in the MoCA 5-min total score after covariates adjustment [short sleep: β = −2.36 95 % confidence interval (CI) (−4.13, −0.59), p = 0.009; AHI ≥ 20/hour: β = −1.79 (−3.26, −0.32), p = 0.017; remained significant after multiple comparisons correction]. A lower mean MinSpO2 was associated with a decline in executive function [Stroop interference index: β = 0.29 (0.04, 0.53), p = 0.021], but not with MoCA 5-min score at one-year. Moderation analysis indicated AHI ≥ 20/hour was associated with a pronounced decline in executive function only in men. ConclusionsShort sleep after stroke onset, AHI ≥ 20/hour and nocturnal hypoxemia at one-year contributed to an impaired cognitive trajectory at one-year following stroke in patients with TIA/mild stroke.

Derivation of Indices of Cognitive Change Among Hispanic Adults and Elders.

Determining the influence of race and ethnicity on change in cognitive test performance has significant implications for clinical practice and research in populations at risk for Alzheimer disease. To evaluate the significance of race and ethnicity in predicting longitudinal cognitive test performance and to develop models to support evidence-based practice. This prognostic study included baseline and 24-month follow-up data that were obtained from the Health and Aging Brain Study-Health Disparities (HABS-HD) study, an ongoing longitudinal observational study of aging and dementia in a multiracial, multiethnic cohort. Participants included community-dwelling adults and elders living in the Dallas and Fort Worth metropolitan area who were Hispanic and non-Hispanic adults older than the age of 50 years and were cognitively unimpaired. The primary exposure of interest was time, measured in months. Demographic variables included age, sex, education, and race and ethnicity. Cognitive domains included attention and working memory, processing speed, language, memory, and executive functioning. Linear regression models predicted follow-up performance from baseline performance and demographic variables for 13 commonly used neuropsychological tests. Follow-up testing was the primary outcome for all domains. Raw scores from 13 standardized tests were used for analyses. This study included 799 adults who were cognitively unimpaired (352 Hispanic individuals [44.1%]; 447 non-Hispanic individuals [55.9%]; 524 female [65.6%]; mean [SD] age, 65.4 [8.1] years). In the regression models, all 13 follow-up scores were significantly predicted from their respective baseline scores and demographic variables. Baseline performance and education were the most consistent predictors of follow-up scores, contributing to all 13 models. Age was significantly associated with follow-up in 11 models, and sex was significant in 5 models. Race and ethnicity contributed to 10 of 13 models, with Hispanic participants predicted to have poorer follow-up scores than their non-Hispanic White counterparts on each test. In this longitudinal study of cognitive change in Hispanic and non-Hispanic older adults who were cognitively unimpaired, standardized regression-based models were influenced by multiple demographic variables, including race and ethnicity. These findings highlight the importance of including race and ethnicity in such cognitive change models. This ability to accurately predict cognitive change is expected to become increasingly important as clinical practice and clinical trials need to become more diverse and culturally appropriate in this burgeoning global medical and societal crisis.

CSF glial biomarkers are associated with cognition in individuals at risk of Alzheimer's disease.

We examined whether baseline glial markers soluble triggering receptor expressed on myeloid cell 2 (sTREM2), chitinase 3-like protein 1 (YKL-40), and glial fibrillary acidic protein (GFAP) in cerebrospinal fluid (CSF), and plasma GFAP are associated with cognitive change in cognitively unimpaired (CU) individuals at risk of Alzheimer's disease (AD). A total of 353 CU (mean age 60.9 years) participants were included (mean follow-up time 3.28 years). Linear regression models with cognition as outcome were used. We also tested whether amyloid beta (Aβ) status modified these associations. Higher baseline CSF sTREM2 was associated with a positive global cognition (Preclinical Alzheimer's Cognitive Composite) rate of change, and better memory and executive outcomes, independently of AD pathology. Higher baseline plasma GFAP was associated with a decline on attention rate of change. Stratified analyses by Aβ status showed that CSF sTREM2 and YKL-40 were positively associated with executive functioning in amyloid negative (Aβ-) individuals. Our results suggest that a TREM2-mediated microglial response may be associated with better longitudinal cognitive performance. Higher cerebrospinal fluid (CSF) soluble triggering receptor expressed on myeloid cell 2 (sTREM2) relates to better longitudinal cognitive performance. The association between CSF sTREM2 and cognition is independent of Alzheimer's disease (AD) pathology. Targeting microglial reactivity may be a therapeutic strategyfor AD prevention.

Neutrophil-to-lymphocyte ratio and longitudinal cognitive performance in Parkinson's disease.

Previous studies have suggested a link between peripheral inflammation and cognitive outcomes in the general population and individuals with Parkinson's disease (PD). We sought to test the association between peripheral inflammation, measured by the neutrophil-to-lymphocyte ratio (NLR), cognitive performance, and mild cognitive impairment (MCI) status in individuals with PD. A retrospective, longitudinal analysis was carried out using data from the Parkinson's Progression Markers Initiative (PPMI), including 422 participants with PD followed over 5 years. Cognitive performance was assessed using a neuropsychological battery including the Montreal Cognitive Assessment (MoCA) and tests of verbal learning, visuospatial function, processing speed, and executive function. Mixed-effect regression models were used to analyze the association between NLR, cognitive performance, and MCI status, controlling for age, sex, education, APOE genotype, and motor severity. There was a negative association between NLR and MoCA, even after adjusting for covariates (b = -0.12, p = 0.033). MoCA scores for individuals in the high NLR category exhibited a more rapid decline over time compared to the low NLR group (b = -0.16, p = 0.012). Increased NLR was associated with decreased performance across all cognitive domains. However, NLR was not associated with MCI status over 5 years of follow-up. This study demonstrates a link between elevated NLR and cognitive performance in PD, but not with MCI status over 5 years. This suggests that NLR is more strongly associated with day-to-day cognitive performance than with incident MCI, but this requires further study in more heterogeneous cohorts.

Multimorbidity, Social Engagement, and Age-Related Cognitive Decline in Older Adults from the Rancho Bernardo Study of Healthy Aging.

Multimorbidity is associated with increased rate of cognitive decline with age. It is unknown whether social engagement, which is associated with reduced risk of dementia, modifies associations between multimorbidity and cognitive decline. To examine the associations of multimorbidity with longitudinal cognitive test performance among community-dwelling older adults, and to determine whether associations differed by levels of social engagement. We used data from the Rancho Bernardo Study of Healthy Aging, a community-based prospective cohort study. Starting in 1992-1996, participants completed a battery of cognitive function tests at up to 6 study visits over 23.7 (mean = 7.2) years. Multimorbidity was defined as≥2 of 14 chronic diseases. Social engagement was assessed using items based on the Berkman-Syme Social Network Index. Multivariable linear mixed-effects models were used to test associations of multimorbidity and cognitive performance trajectories. Effect measure modification by social engagement was evaluated. Among 1,381 participants (mean age = 74.5 years; 60.8% women; 98.8% non-Hispanic White), 37.1% had multimorbidity and 35.1% had low social engagement. Multimorbidity was associated with faster declines in Mini-Mental State Examination (MMSE; β= -0.20; 95% CI -0.35, -0.04), Trail-Making Test Part B (β= 10.02; 95% CI 5.77, 14.27), and Category Fluency (β= -0.42; 95% CI -0.72, -0.13) after adjustment for socio-demographic and health-related characteristics. Multimorbidity was associated with faster declines in MMSE among those with low compared to medium and high social engagement (p-interaction < 0.01). Multimorbidity was associated with faster declines in cognition among community-dwelling older adults. Higher social engagement may mitigate multimorbidity-associated cognitive decline.

Associations between NIH‐Toolbox Flanker test and the Picture Sequence Memory Test and multimodal Alzheimer’s disease biomarkers in cognitively unimpaired individuals

AbstractBackgroundAlzheimer’s disease (AD) pathologic changes start years before cognitive symptoms appear; however, some early cognitive changes can be detected. We aimed to investigate the association between performance changes in two NIH‐Toolbox tests, Flanker test and Picture Sequence Memory Test (PSMT), and baseline AD biomarkers in cognitively unimpaired (CU) individuals.MethodWe studied 356 ALFA+ participants (mean [SD] age = 60.8 [4.72] years). The rate of cognitive change after 3 years was measured through delta scores (Follow‐up ‐ Baseline). Biomarker data included cerebrospinal fluid (CSF) β‐amyloid (Aβ) 42/40 ratio, phosphorylated‐tau‐181 (p‐tau), neurofilament light (NfL), and neuroimaging (MRI‐based cortical thickness AD signature, hippocampal volumes, and FDG‐PET‐SUVR (fluorodeoxyglucose ‐ positron emission tomography ‐ standardized uptake value ratio) metaROI) measures (Table 1). CSF Aβ40, Aβ42 and NfL were measured with the exploratory NTK robust immunoassays, while CSF p‐tau181 was measured using the electrochemiluminescence Elecsys® Phospho‐Tau (181P) CSF immunoassays (Roche Diagnostics International Ltd). AT groups were defined according to published cut‐offs (A+ Aβ 42/40 &lt;0.071; T+: p‐tau &gt; 24 pg/ml) (Milà‐Alomà et al., 2020). Baseline biomarker levels were used as predictors of cognitive change in linear models. Interactions and stratified analyses were also explored.ResultAT groups significantly differed in the change in the Flanker Test (p = 0.002), driven by poorer performance in A+T+ vs A‐T‐ groups (p = 0.001) (Figure1). Higher cortical thickness predicted better longitudinal cognitive performance in the Flanker Test in the whole group (p = 0.020; β = 0.983). We found a significant interaction between AT group and FDG‐PET‐SUVR (p = 0.042), and the right hippocampal volume (p = 0.001), but no significant associations were observed in analyses stratified by AT (Figure2A). A negative association between right hippocampal volume and Flanker test change was observed in A+T‐ (p = 0.026) and A+T+ (p = 0.029) (Figure2B). No associations were observed between the PSMT and AD biomarkers (Figure 1).ConclusionOur findings support the hypothesis that executive function show a steeper decline than episodic memory in CU individuals with evidence of pathologic AD biomarkers levels. We observed a negative association between executive change and neuroimaging neurodegeneration markers in A+T‐ and A+T+ groups. This is in accordance with previous studies that found non‐linear associations in incipient AD pathology.

Proteomics identifies immunological drivers of post‐infection brain atrophy and cognitive decline

AbstractBackgroundPrior infections can modify the risk for dementia and neurodegenerative disease, yet the mechanisms by which infections contribute to neurodegeneration remain unclear.MethodWe examined how infection diagnoses documented in the Baltimore Longitudinal Study of Aging (BLSA) are associated with rates of change in brain volumes over time, and how these same infections relate to dementia risk using hospital records from UK Biobank and a Finnish multicohort sample (the Finnish Public Sector study, the Health and Social Support study, and the Still Working study). After determining how infections differentially relate to an immunological plasma proteome (942 proteins) in BLSA participants, we then identified a subset of infection‐related proteins that also predict changes in brain regions vulnerable to infection‐specific atrophy (candidate proteins). In addition to evaluating their associations with longitudinal cognitive performance as well as Alzheimer’s disease and related dementias (ADRD) plasma biomarkers (Aβ42/40, GFAP, NfL, pTau‐181), we also investigated the causal link between candidate proteins and longitudinal brain volume loss using Mendelian randomization. Study design is illustrated in Figure 1.ResultA total of 982 cognitively normal participants (age: 65.4 [SD 14.9]); 55.2% female; 66.9% white) were included in the primary MRI analysis. Of the 15 infections examined, we identified six diagnoses related to accelerated brain volume loss, including influenza, viral, respiratory, and skin/subcutaneous infections, with atrophy commonly observed in the temporal lobe. Each infection linked to brain volume loss in the BLSA was associated with increased risk of dementia in the UK Biobank (n = 495,896), with many also associated with increased risk in the Finnish multicohort sample (n = 273,132). From a set of 260 infection‐related proteins, we identified 35 candidate proteins that also predicted changes in brain regions vulnerable to infection‐specific atrophy (Figure 2A‐F). Many candidate proteins were related to cognitive decline, plasma ADRD biomarkers or mechanistically implicated in longitudinal brain volume loss in Mendelian randomization analyses (Figure 2G‐H; Figure 3A).ConclusionWe demonstrate that infections are linked to accelerated regional brain atrophy and dementia risk. Additionally, we identify molecular mediators by which infections may contribute to neurodegeneration (Figure 3B).

67 COVID-19 Mobile Brain Health

Objective:Over 80% of hospitalized COVID-19 patients have neurological symptoms, including memory loss, attention difficulties, and trouble thinking clearly that can last for months. The long-term neurological impact of the SARS-CoV-2 virus is unknown and it remains to be seen whether it would create a surge in cases of dementia and cognitive decline years later, which is already a global public health challenge. Examining the cognitive effects of the virus will help with understanding its impact on the brain and inform treatment options. The goal of the present study was to examine cognitive performance among those who have had COVID-19 via mobile-based assessments using smartphone-based cognitive tests. Participants with a previous COVID-19 diagnosis (COVID+) were expected to have worse cognitive performance at baseline than those without COVID-19 (COVID-).Participants and Methods:Participants (n=23) with self-reported positive or negative COVID-19 statuses based on polymerase chain reaction or antigen testing were recruited from the Boston area. Inclusion criteria included access to a smartphone with an Android or iOS operationsystem and to internet connectivity, along with proficiency in English. Cognitive performance was measured using Defense Automated Neurobehavioral Assessment (DANA) from AnthroTronix. Welch’s 2-sample t-test was used to compare cognitive performance among those with and without COVID-19.Results:The sample was comprised primarily of COVID+ (59%), female (59%), and Caucasian (50%) participants that were generally well educated (77% with a bachelor’s degree), and had &gt;1 COVID vaccination (95%). About 50% of the sample reported symptoms of depression and mild anxiety. Results were not indicative of significant differences between COVID+ and COVID- groups at baseline: Simple Reaction Time (Immediate; M = 5.62; p = 0.81), Code Substitution (M = 1.25; p = 0.77), Procedural Reaction Time (M = -7.26; p = 0.49), Spatial Processing (M = -3.14; p = 0.50), Go No Go (M = -1.37; p = 0.89), Match to Sample (M = 2.00; p = 0.57), Memory Search (M = -2.62; p = 0.75), and Simple Reaction Time (Delayed; M = 2.99; p = 0.81).Conclusions:Results indicate that cognitive performance at baseline does not differ based on COVID status, emphasizing the need for examination of longitudinal cognitive performance. Future directions include examining the impact of COVID disease severity and reinfection on cognition.

Plasma Aβ42/40 and cognitive variability are associated with cognitive function in Black Americans: Findings from the AA-FAIM cohort.

It is critical to develop more inclusive Alzheimer's disease (AD) research protocols to ensure that historically excluded groups are included in preclinical research and have access to timely diagnosis and treatment. If validated in racialized groups, plasma AD biomarkers and measures of subtle cognitive dysfunction could provide avenues to expand diversity in preclinical AD research. We sought to evaluate the utility of two easily obtained, low-burden disease markers, plasma amyloid beta (Aβ)42/40, and intra-individual cognitive variability (IICV), to predict concurrent and longitudinal cognitive performance in a sample of Black adults. Two hundred fifty-seven Black participants enrolled in the African Americans Fighting Alzheimer's in Midlife (AA-FAIM) study underwent at least one cognitive assessment visit; a subset of n = 235 had plasma samples. Baseline IICV was calculated as the standard deviation across participants' z scores on five cognitive measures: Rey Auditory Verbal Learning Test Delayed Recall, Trail Making Test Parts A and B (Trails A and B), and Boston Naming Test. Using mixed effects regression models, we compared concurrent and longitudinal models to baseline plasma Aβ42/40 or IICV by age interactions. PrecivityAD assays quantified baseline plasma Aβ42/40. IICV was associated with concurrent/baseline performance on several outcomes but did not modify associations between age and cognitive decline. In contrast, plasma Aβ42/40 was unrelated to baseline cognitive performance, but a pattern emerged in interactions with age in longitudinal models of Trails A and B and Rey Auditory Verbal Learning Test total learning trials. Although not significant after correcting for multiple comparisons, low Aβ42/40 was associated with faster cognitive declines over time. Our results are promising as they extend existing findings to an Black American sample using low-cost, low-burden methods that can be implemented outside of a research center, thus supporting efforts for inclusive AD biomarker research.

Relationship of APOE genotypes and level of cognitive reserve to cognitive trajectories among cognitively normal individuals

AbstractBackgroundPrior findings indicate that both genetic factors and indices of cognitive reserve (CR) influence risk of cognitive decline, with APOE4 genetic status increasing risk, and APOE2 genetic status and higher CR indices decreasing risk. However, it remains unclear whether these genetic and lifestyle variables interact to influence long‐term cognitive trajectories. This study examined whether these variables modify baseline cognitive scores and longitudinal cognitive trajectories in N = 1819 participants who were cognitively normal at baseline and included in the Preclinical AD Consortium (PAC).MethodPAC datasets include harmonized data from five longitudinal cohort studies: ACS, AIBL, BIOCARD, BLSA, and WRAP. Longitudinal cognitive performance was measured by harmonized factor scores for global cognition, memory, and executive function (M follow‐up = 9.8y; Table 1). APOE genotypes were coded with separate indicator variables for APOE2 (n = 233) and APOE4 (n = 581), with APOE3/3 (n = 1005) as the reference group. A CR index was calculated by combining years of education and literacy scores.ResultIn longitudinal mixed effect models, using time since baseline as the timescale (Table 2), higher CR index scores were associated with better baseline cognitive performance for all cognitive factor scores, but not with rate of change in cognition over time. In contrast, APOE4 genotype was associated with more negative rates of cognitive change. For the global and memory scores, there were also 3‐way CR index x APOE4 x time interactions, indicating the negative effect of APOE4 genotype on global and memory score change was attenuated among individuals with higher CR index scores (Figure 1). When the models were re‐run with the term for APOE4 genetic status reflecting the number of APOE4 alleles (i.e., 0, 1, 2; Table 3), the patterns of results were similar, except the 3‐way CR index x APOE4 x time interaction for global cognition was only marginal (p = 0.06).ConclusionHigher CR proxy scores are associated with higher levels of cognitive performance, whereas APOE4 genetic status is associated with greater rates of cognitive decline. Higher levels of CR may attenuate APOE4‐related declines in global cognition and memory, but level of CR and APOE4 have largely independent effects on executive function.

Genetic Variants Associated with Longitudinal Cognitive Performance in Older Breast Cancer Patients and Controls.

Background: There have been no published genome-wide studies of the genetics of cancer- and treatment-related cognitive decline (CRCD); the purpose of this study is to identify genetic variants associated with CRCD in older female breast cancer survivors. Methods: Analyses included white non-Hispanic women with non-metastatic breast cancer aged 60+ (N = 325) and age-, racial/ethnic group-, and education-matched controls (N = 340) with pre-systemic treatment and one-year follow-up cognitive assessment. CRCD was evaluated using longitudinal domain scores on cognitive tests of attention, processing speed, and executive function (APE), and learning and memory (LM). Linear regression models of one-year cognition included an interaction term for SNP or gene SNP enrichment*cancer case/control status, controlling for demographic variables and baseline cognition. Results: Cancer patients carrying minor alleles for two SNPs, rs76859653 (chromosome 1) in the hemicentin 1 (HMCN1) gene (p = 1.624 × 10-8), and rs78786199 (chromosome 2, p = 1.925 × 10-8) in an intergenic region had lower one-year APE scores than non-carriers and controls. Gene-level analyses showed the POC5 centriolar protein gene was enriched for SNPs associated with differences in longitudinal LM performance between patients and controls. Conclusions: The SNPs associated with cognition in survivors, but not controls, were members of the cyclic nucleotide phosphodiesterase family, that play important roles in cell signaling, cancer risk, and neurodegeneration. These findings provide preliminary evidence that novel genetic loci may contribute to susceptibility to CRCD.

Longitudinal Cognitive Screening Findings in Pediatric MS vs. Pediatric Controls and Adult MS in a Multi-center Cohort (S31.008)

Longitudinal Cognitive Screening Findings in Pediatric MS vs. Pediatric Controls and Adult MS in a Multi-center Cohort (S31.008)

Alzheimer’s disease genetic risk and cognitive reserve in relationship to long-term cognitive trajectories among cognitively normal individuals

BackgroundBoth Alzheimer’s disease (AD) genetic risk factors and indices of cognitive reserve (CR) influence risk of cognitive decline, but it remains unclear whether they interact. This study examined whether a CR index score modifies the relationship between AD genetic risk factors and long-term cognitive trajectories in a large sample of individuals with normal cognition.MethodsAnalyses used data from the Preclinical AD Consortium, including harmonized data from 5 longitudinal cohort studies. Participants were cognitively normal at baseline (M baseline age = 64 years, 59% female) and underwent 10 years of follow-up, on average. AD genetic risk was measured by (i) apolipoprotein-E (APOE) genetic status (APOE-ε2 and APOE-ε4 vs. APOE-ε3; N = 1819) and (ii) AD polygenic risk scores (AD-PRS; N = 1175). A CR index was calculated by combining years of education and literacy scores. Longitudinal cognitive performance was measured by harmonized factor scores for global cognition, episodic memory, and executive function.ResultsIn mixed-effects models, higher CR index scores were associated with better baseline cognitive performance for all cognitive outcomes. APOE-ε4 genotype and AD-PRS that included the APOE region (AD-PRSAPOE) were associated with declines in all cognitive domains, whereas AD-PRS that excluded the APOE region (AD-PRSw/oAPOE) was associated with declines in executive function and global cognition, but not memory. There were significant 3-way CR index score × APOE-ε4 × time interactions for the global (p = 0.04, effect size = 0.16) and memory scores (p = 0.01, effect size = 0.22), indicating the negative effect of APOE-ε4 genotype on global and episodic memory score change was attenuated among individuals with higher CR index scores. In contrast, levels of CR did not attenuate APOE-ε4-related declines in executive function or declines associated with higher AD-PRS. APOE-ε2 genotype was unrelated to cognition.ConclusionsThese results suggest that APOE-ε4 and non-APOE-ε4 AD polygenic risk are independently associated with global cognitive and executive function declines among individuals with normal cognition at baseline, but only APOE-ε4 is associated with declines in episodic memory. Importantly, higher levels of CR may mitigate APOE-ε4-related declines in some cognitive domains. Future research is needed to address study limitations, including generalizability due to cohort demographic characteristics.

TREM2 gene expression associations with Alzheimer’s disease neuropathology are region-specific: implications for cortical versus subcortical microglia

Previous post-mortem assessments of TREM2 expression and its association with brain pathologies have been limited by sample size. This study sought to correlate region-specific TREM2 mRNA expression with diverse neuropathological measures at autopsy using a large sample size (N = 945) of bulk RNA sequencing data from the Religious Orders Study and Rush Memory and Aging Project (ROS/MAP). TREM2 gene expression of the dorsolateral prefrontal cortex, posterior cingulate cortex, and caudate nucleus was assessed with respect to core pathology of Alzheimer’s disease (amyloid-β, and tau), cerebrovascular pathology (cerebral infarcts, arteriolosclerosis, atherosclerosis, and cerebral amyloid angiopathy), microglial activation (proportion of activated microglia), and cognitive performance. We found that cortical TREM2 levels were positively related to AD diagnosis, cognitive decline, and amyloid-β neuropathology but were not related to the proportion of activated microglia. In contrast, caudate TREM2 levels were not related to AD pathology, cognition, or diagnosis, but were positively related to the proportion of activated microglia in the same region. Diagnosis-stratified results revealed caudate TREM2 levels were inversely related to AD neuropathology and positively related to microglial activation and longitudinal cognitive performance in AD cases. These results highlight the notable changes in TREM2 transcript abundance in AD and suggest that its pathological associations are brain-region-dependent.

Re-remembering the influence of randomized β-carotene on cognitive decline.

The wave of individuals impacted by dementia continues to rise rapidly as worldwide lifespan increases. Dietary strategies to slow cognitive decline and prolong time to clinical dementia remain understudied, but with potentially powerful public health consequences. Indeed, previously conducted large, randomized, placebo-controlled trials of micronutrients remain an under-leveraged resource to study changes in cognitive performance. As a motivating example, we highlight an ancillary report from the Physicians' Health Study, where subjects randomized to β-carotene (a provitamin A carotenoid) had a more attenuated change in longitudinal global cognitive performance and verbal memory, as compared to subjects randomized to placebo. Despite mechanistic evidence from cell and animal studies supporting a vitamin A-mediated role in the biology associated with cognition, limited follow-up work has been conducted. We argue that dietary factors (including provitamin A) deserve a second look, leveraging multi-omic approaches, to elucidate how they may mitigate cognitive decline and dementia risk.

Effect of Metabolic Syndrome Risk Factors on Processing Speed and Executive Function in Three Racialized Groups.

Metabolic syndrome (MetS) has been associated with increased risk for Alzheimer's disease and related dementias (ADRD). Understanding the association of MetS risk factors to processing speed and executive function in the pre-clinical stages of ADRD in under-represented groups would offer insight on potential mechanisms through which MetS associates with ADRD risk. Examine association of MetS features and processing speed and executive function across three racial groups. Cognitively unimpaired adults from the Wisconsin Alzheimer's Disease Research Center and the Wisconsin Registry for Alzheimer's Disease Prevention completed blood-draws and neuropsychological testing. Six cognitive outcomes were assessed in association to MetS risk factors: Trailmaking Tests A and B, Animal Fluency, Digit Symbol, and composite scores for Processing Speed and Executive Function. Linear mixed effect models were used to assess the relationship between MetS risk factor count and longitudinal cognitive performance across three racialized groups. Participant sample sizes varied by outcome analyzed (N = 714-1,088). African American and Native American groups exhibited higher rates of MetS than non-Hispanic Whites. MetS was associated with processing speed and executive function across all racialized groups. Three-way interaction by racialized group was limited to one cognitive outcome: Trailmaking Test A. Metabolic dysfunction incrementally affects cognitive trajectory, with generally similar associations across racial groups. Since racialized groups exhibit higher levels of both MetS and ADRD, MetS may represent a driving factor for increased ADRD risk experience by racialized group and an important and modifiable target through which to reduce risk of ADRD.

Sex hormones, SHBG and cognitive performance among older Australian women: an observational study

Objective This study aims to explore the associations between sex hormones and cognitive performance in older women. Methods Associations between sex hormones, sex hormone binding globulin (SHBG) and cognitive performance were examined in women aged at least 70 years, without dementia and not using medications that influence sex hormones. Linear and generalized linear regression models included age, body mass index, education, smoking, alcohol, living circumstances, diabetes, hypertension, depression and impaired renal function. Results The included 5511 women had a median (interquartile range) age of 73.9 (71.6–77.6) years. No associations were found for estrone, estradiol, testosterone or dehydroepiandrosterone and cognitive performance. SHBG concentrations above quartile 1 (Q1) were significantly inversely associated with processing speed (Q2, β = –0.94, 95% confidence interval [CI] − 1.64 to −0.24, p = 0.009; Q3, β = –0.82, 95% CI −1.53 to −0.10, p = 0.025; and Q4, β = –0.95, 95% CI −1.70 to −0.20, p = 0.013). Conclusions Sex hormones were not associated with cognitive performance. The finding that low SHBG is associated with better processing speed warrants further investigation. The null findings for the sex hormones establish a firm baseline to confidently explore the association between sex hormones and longitudinal cognitive performance in this population. Trial Registration International Standard Randomized Controlled Trial Number Register (ISRCTN83772183) and ClinicalTrials.gov (NCT01038583).

Abstract B116: Cognitive performance and cognitive decline following cancer among middle-aged and older adults in the study of Latinos-investigation of neurocognitive aging and HCHS/SOL

Abstract BACKGROUND: Cognitive impairment is a frequently reported side-effect of cancer therapies affecting attention, concentration, memory, and executive function. However, the long-term impacts of cancer and its treatments on cognitive function and cognitive decline in Hispanics/Latinos is unknown. Herein, we examined the associations between a self-reported history of cancer and cognitive test performance cross-sectionally and longitudinally among middle-aged and older Hispanic/Latino adults. METHODS: Participants included 9,639 Hispanic/Latino adults [mean age=56.4 (SE=0.14); 54.7% female] of diverse backgrounds [30.8% Mexican, 27.2% Cuban, and 18.1% Puerto Rican; 10.0% Central American; 9.0% Dominican; and 7% South American] from the population-based, prospective, multi-site Hispanic Community Health Study/Study of Latinos. At enrollment in 2008-2011 (Visit 1), participants self-reported their history of cancer (yes/no) and cancer site(s). Cognitive function was assessed at Visit 1 and again at a 7-year follow-up assessment (Visit 2) using the Brief-Spanish English Verbal Learning Test (BSEVLT-Sum, episodic learning; and BSEVLT-Recall, memory), the Word Fluency Test (WF, verbal fluency), and the Digit Symbol Substitution Test (DSS, processing speed and executive functioning) via the Study of Latinos-Investigation of Neurocognitive Aging (SOL-INCA). Changes in cognitive test performance were calculated using survey linear regression models predicting cognitive performance at Visit 2 as a function of Visit 1 cognitive performance with adjustment for time between assessments. Test scores/changes in tests scores were standardized and averaged as composites of global cognition/cognitive change. We used survey linear regression models to estimate the adjusted associations between history of cancer and baseline and longitudinal cognitive test performance. We examined these associations overall and by sex and for the most prevalent sex-specific cancers [i.e., cervical (n=121), breast (n=115), uterine (n=67), and prostate (n=48) cancers]. RESULTS: Cross-sectionally, a history of cancer (n=546) versus no history of cancer (n=9,093) was associated with higher WF scores (β=0.13, SE=0.06; P=0.03) and global cognition (β=0.08, SE=0.04; P=0.06) among all participants overall. Among men, but not among women, a history of cancer was associated with longitudinal increases in SEVLT-Sum (β=0.29, SE=0.14; P=0.04; PInteraction=0.04), and SEVLT-Recall (β=0.36, SE=0.15; P=0.02; PInteraction=0.01) scores. Among women, a history of cervical cancer was associated with longitudinal decreases in SEVLT-Recall scores (β=-0.30, SE=0.13; P=0.03) and among men, a history of prostate cancer was associated with higher baseline WF scores (β=0.29, SE=0.12; P=0.02). CONCLUSION: Cancer or its treatments may influence long-term cognition among Hispanics/Latino cancer survivors. The potential impacts of cancer or cancer treatment on cognition may vary by sex or cancer type. Citation Format: Humberto Parada Jr., Margaret Pichardo, Linda C. Gallo, Frank J. Penedo, David J. Lee, Gregory A. Talavera, Hector M. Gonzalez. Cognitive performance and cognitive decline following cancer among middle-aged and older adults in the study of Latinos-investigation of neurocognitive aging and HCHS/SOL [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr B116.

Tracking cognition with the T-MoCA in a racially/ethnically diverse older adult cohort.

We investigated the utility of the Telephone-Montreal Cognitive Assessment (T-MoCA) to track cognition in a diverse sample from the Einstein Aging Study. Telephone and in-person MoCA data, collected annually, were used to evaluate longitudinal cognitive performance. Joint models of T-MoCA and in-person MoCA compared changes, variance, and test-retest reliability measured by intraclass correlation coefficient by racial/ethnic group. There were no significant differences in baseline performance or longitudinal changes across three study waves for both MoCA formats. T-MoCA performance improved over waves 1-3 but declined afterward. Test-retest reliability was lower for the T-MoCA than for the in-person MoCA. In comparison with non-Hispanic Whites, non-Hispanic Blacks and Hispanics performed worse at baseline on both MoCA formats and showed lower correlations between T-MoCA and in-person versions. The T-MoCA provides valuable information on cognitive change, despite racial/ethnic disparities and practice effects. We discuss implications for health disparity populations. We assessed the comparability of Telephone-Montreal Cognitive Assessment (T-MoCA) and in-person MoCA for tracking cognition.Changes within 3 years in T-MoCA were similar to that for the in-person MoCA.T-MoCA is subject to practice effects and shows difference in performance by race/ethnicity.Test-retest reliability of T-MoCA is lower than that for in-person MoCA.