Perceived Stress, Blood Biomarkers, and Cognitive Functioning in Older Adults.

INTRODUCTION: There is a substantial gap in knowledge regarding how perceived stress may influence the relationship between serum-measured biomarkers for Alzheimer's disease and cognitive decline. METHODS: This study consists of 1,118 older adult participants from the Chicago Health and Aging Project (CHAP) (60% Black participants and 63% female participants). Linear mixed effects regression models were conducted to examine the role of perceived stress in the association between three blood biomarkers: total tau (t-tau), glial fibrillary acid protein (GFAP), and neurofilament light chain (NfL) on global cognitive decline. Stratified analysis by stress level was also conducted to evaluate the associations between each blood biomarker and baseline cognitive function and decline. All models adjusted for age, race, sex, education, time, and their interactions with time. RESULTS: The interaction of stress, NfL concentration, and time was statistically significant on global cognition (ß = -0.064 (SE = 0.028), p-value = 0.023) and on episodic memory (ß = -0.097 (SE = 0.036), p-value = 0.007). CONCLUSIONS: Greater stress level worsens the association between high NfL concentration and cognitive decline. Stress management interventions may be helpful to reduce rate of cognitive decline in individuals with high concentrations of NfL.

Unique transcriptional signatures correlate with behavioral and psychological symptom domains in Alzheimer's disease.

Despite the significant burden, cost, and worse prognosis of Alzheimer's disease (AD) with behavioral and psychological symptoms of dementia (BPSD), little is known about the molecular causes of these symptoms. Using antemortem assessments of BPSD in AD, we demonstrate that individual BPSD can be grouped into 4 domain factors in our cohort: affective, apathy, agitation, and psychosis. Then, we performed a transcriptome-wide analysis for each domain utilizing bulk RNA-seq of post-mortem anterior cingulate cortex (ACC) tissues. Though all 4 domains are associated with a predominantly downregulated pattern of hundreds of differentially expressed genes (DEGs), most DEGs are unique to each domain, with only 22 DEGs being common to all BPSD domains, including TIMP1. Weighted gene co-expression network analysis (WGCNA) yielded multiple transcriptional modules that were shared between BPSD domains or unique to each domain, and NetDecoder was used to analyze context-dependent information flow through the biological network. For the agitation domain, we found that all DEGs and a highly associated transcriptional module were functionally enriched for ECM-related genes including TIMP1, TAGLN, and FLNA. Another unique transcriptional module also associated with the agitation domain was enriched with genes involved in post-synaptic signaling, including DRD1, PDE1B, CAMK4, and GABRA4. By comparing context-dependent changes in DEGs between cases and control networks, ESR1 and PARK2 were implicated as two high-impact genes associated with agitation that mediated significant information flow through the biological network. Overall, our work establishes unique targets for future study of the biological mechanisms of BPSD and resultant drug development.

Statin Initiation and Risk of Incident Alzheimer Disease and Cognitive Decline in Genetically Susceptible Older Adults.

BACKGROUND AND OBJECTIVES: The association of statin initiation with incident Alzheimer disease (AD) dementia and cognitive decline by the APOE ε4 allele is unknown. Our objective was to examine whether the association of statin initiation with incident AD dementia and cognitive decline differs by the APOE ε4 allele. METHODS: This population-based longitudinal cohort study was conducted in 4 urban communities in Chicago, IL, United States, consisting of 4,807 participants. Statin initiation is based on the inspection of medications during home assessments. Clinical diagnosis for incident AD used the NINCDS-ADRDA criteria, and longitudinal measurements of global cognition consisted of episodic memory, perceptual speed, and the Mini-Mental State Examination tests. RESULTS: The study participants had a mean age of 72 years, consisting of 63% female individuals and 61% non-Hispanic Black individuals. During the study period, 1,470 (31%) participants reported statin initiation. In a covariate-adjusted competing risk model, statin initiation was associated with a reduced risk of incident clinical AD [hazard ratio (HR) 0.81 (95% CI 0.70-0.94)] compared with nonusers. This association was statistically significantly lower (p interaction = 0.015) among participants with the APOE ε4 allele [HR 0.60 (95% CI 0.49-0.74)] compared with those without the APOE ε4 allele [HR 0.96 (95% CI 0.82-1.12)]. The annual decline in global cognition (ß = 0.021, 95% CI 0.007-0.034) and episodic memory (ß = 0.020, 95% CI 0.007-0.033) was also substantially slower among participants with the APOE ε4 allele after statin initiation compared with nonusers. However, the association of statin initiation with cognitive decline was not significant among those without the APOE ε4 allele. DISCUSSION: Our findings suggest that statins might be associated with a lower risk of incident AD among individuals with the APOE ε4 allele. The benefits of statin therapy need further consideration in randomized clinical trials, especially among those with the APOE ε4 allele. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that among those aged 65 years or older, statin initiation was associated with a reduced risk of Alzheimer disease, especially in the presence of an APOE-e4 allele.

Changes in Body Mass Index and Incident Mild Cognitive Impairment Among African American Older Adults.

BACKGROUND: Previous research suggests a decline in body mass index (BMI) among older adults is associated with negative health outcomes, including mild cognitive impairment (MCI) and incident dementia. However, no studies have examined the effects of education or developing MCI on BMI trajectories over time. The purpose of this investigation was to characterize trajectories of change in BMI among older adults who develop MCI. METHODS: Participants were from the Minority Aging Research Study (MARS), a longitudinal cohort study of cognitive decline and Alzheimer's disease in older African Americans living in the greater Chicago, Illinois, area. The study included annual clinical evaluations of cognitive status, as well as measurements of height and weight for BMI calculation. Older African American participants without cognitive impairment at baseline were included in the present analysis (N = 436, 78% women, mean baseline age = 72 [SD = 5.7], mean education = 15 [SD = 3.5]). RESULTS: In piecewise linear mixed-effects models that included a random intercept and 2 random slopes, BMI declined over time (B = -0.20, SE = 0.02, p < .001), with a faster decline after MCI diagnosis (additional decline, B = -0.15, SE = 0.06, p = .019). Older age was associated with lower baseline BMI (B = -0.19, SE = 0.05, p < .001), as was higher education (B = -0.34, SE = 0.09, p < .001). Further, higher education was associated with a slower decline in BMI before MCI (B = 0.02, SE = 0.006, p = .001), but a faster decline after MCI (B = -0.06, SE = 0.022, p = .003). CONCLUSIONS: These results suggest an accelerated decline in BMI following an MCI diagnosis, with higher education related to an even faster BMI decline.

Depressive Symptoms, Glial Fibrillary Acid Protein Concentrations, and Cognitive Decline in a Cohort Study.

BACKGROUND: Little is known about how depressive symptoms and glial fibrillary acid protein (GFAP) concentrations taken together may influence cognitive functioning. Understanding this relationship may inform strategies for screening and early intervention to decrease the rate of cognitive decline. METHODS: This study sample includes 1 169 participants from the Chicago Health and Aging Project (CHAP), consisting of 60% Black participants and 40% White participants, and 63% female participants and 37% male participants. CHAP is a population-based cohort study of older adults with a mean age of 77 years. Linear mixed-effects regression models tested the main effects of depressive symptoms and GFAP concentrations and their interactions on baseline cognitive function and cognitive decline over time. Models included adjustments for age, race, sex, education, chronic medical conditions, body mass index, smoking status, alcohol use, and their interactions with time. RESULTS: The interaction of depressive symptomology and GFAP (ß = -0.105 [standard error = 0.038], p = .006) on global cognitive function was statistically significant. Participants with depressive symptoms including and above the cutoff and high log of GFAP concentrations had more cognitive decline over time, followed by participants with depressive symptoms below the cutoff and high log of GFAP concentrations, depressive symptom scores including and above the cutoff and low log of GFAP concentrations, and depressive symptom scores below the cutoff and low log of GFAP concentrations. CONCLUSIONS: Depressive symptoms have an additive effect on the association between the log of GFAP and baseline global cognitive function.

Neuroticism, physical activity, and cognitive functioning in a population-based cohort of older adults.

BACKGROUND: Little is known about how physical activity influences the relationship between neuroticism and cognitive function and cognitive decline. METHODS: Data from the Chicago Health and Aging Project (CHAP) was utilized to conduct this study. CHAP is a population-based cohort study of chronic conditions in older adults. Participants completed in-home interviews cycles of three years from 1993-2012. Mixed effects regression models were conducted to test the associations between physical activity, neuroticism, and the interaction between neuroticism and physical activity on outcomes: global cognitive function, global cognitive decline, episodic memory, decline in episodic memory, perceptual speed, and decline in perceptual speed. Stratified mixed effects regression models by physical activity level were conducted to test the associations between neuroticism and global cognitive function and global cognitive decline. RESULTS: A total of 7,685 participants were eligible for this study. Participants were 62% female and 64% African American. We found statistically significant associations for the interaction of high physical activity and neuroticism on baseline global cognitive function (ß = 0.017 (SE = 0.007), p = .010) and on the interaction of neuroticism and high physical activity on baseline episodic memory (ß = 0.020 (SE = .009), p = .021) and on decline in episodic memory over time (ß = -0.003 (SE = .001), p = .039). CONCLUSION: Higher physical activity lessened the association between higher neuroticism and poor cognitive outcomes.

Selective serotonin reuptake inhibitor use, age-related neuropathology and cognition in late-life.

The objective of this study was to evaluate an association of selective serotonin reuptake inhibitor (SSRI) use with late life cognitive decline and further investigate the association with brain pathology. Using the data are from two harmonized clinical-pathologic cohort studies with annual cognitive testing we found that SSRI use was associated with significantly faster global cognitive decline and this association was present in those with and without pre-existing cognitive impairment at the time of SSRI initiation. In separate analyses of persons who died during the study and underwent neuropathologic examination, SSRI use was related to higher level of paired helical filament tau tangles and faster rate of global cognitive decline. However, when SSRI use and tangles were included in the same model, the association of SSRI use with rate of global cognitive decline was reduced by more than 50% and no longer statistically significant. SSRI use was associated with higher postmortem level of tau tangles, possibly because SSRI are being used to treat neurobehavioral symptoms associated with dementia, and this relationship appears to partly account for the association of SSRI use with more rapid cognitive decline.

Primacy and recency effects in verbal memory are differentially associated with post-mortem frontal cortex p-tau 217 and 202 levels in a mixed sample of community-dwelling older adults.

INTRODUCTION: Serial position effects in verbal memory are associated with in vivo fluid biomarkers and neuropathological outcomes in Alzheimer's disease (AD). To extend the biomarker literature, associations between serial position scores and postmortem levels of brain phosphorylated tau (p-tau) were examined, in the context of Braak stage of neurofibrillary tangle progression. METHOD: Participants were 1091 community-dwelling adults (Mage = 80.2, 68.9% female) from the Rush University Religious Orders Study and Memory and Aging Project who were non-demented at enrollment and followed for a mean of 9.2 years until death. The CERAD Word List Memory test administered at baseline and within 1 year of death was used to calculate serial position (primacy, recency) and total recall scores. Proteomic analyses quantified p-tau 217 and 202 from dorsolateral prefrontal cortex samples. Linear regressions assessed associations between cognitive scores and p-tau with Braak stage as a moderator. RESULTS: Cognitive status proximal to death indicated 34.7% were unimpaired, 26.2% met criteria for MCI, and 39.0% for dementia. Better baseline primacy recall, but not recency recall, was associated with lower p-tau 217 levels across Braak stages. Delayed recall showed a similar pattern as primacy. There was no main effect of immediate recall, but an interaction with Braak stages indicated a negative association with p-tau 217 level only in Braak V-VI. Within 1 year of death, there were no main effects for cognitive scores; however, recency, immediate and delayed recall scores interacted with Braak stage showing better recall was associated with lower p-tau 217 only in Braak V-VI. No associations were observed with p-tau 202. CONCLUSIONS: Primacy recall measured in non-demented adults may be sensitive to emergent tau phosphorylation that occurs in the earliest stages of AD. Serial position scores may complement the routinely used delayed recall score and p-tau biomarkers to detect preclinical AD.

Prevalence of Alzheimer's disease dementia in the 50 US states and 3142 counties: A population estimate using the 2020 bridged-race postcensal from the National Center for Health Statistics.

INTRODUCTION: This study estimates the prevalence and number of people living with Alzheimer's disease (AD) dementia in 50 US states and 3142 counties. METHODS: We used cognitive data from the Chicago Health and Aging Project, a population-based study, and combined it with the National Center for Health Statistics 2020 bridged-race population estimates to determine the prevalence of AD in adults ≥65 years. RESULTS: A higher prevalence of AD was estimated in the east and southeastern regions of the United States, with the highest in Maryland (12.9%), New York (12.7%), and Mississippi (12.5%). US states with the highest number of people with AD were California, Florida, and Texas. Among larger counties, those with the highest prevalence of AD were Miami-Dade County in Florida, Baltimore city in Maryland, and Bronx County in New York. DISCUSSION: The state- and county-specific estimates could help public health officials develop region-specific strategies for caring for people with AD.

Cognitive Activity Is Associated with Cognitive Function over Time in a Diverse Group of Older Adults, Independent of Baseline Biomarkers.

BACKGROUND: More frequent engagement in cognitive activity is associated with better cognitive function in older adults, but the mechanism of action is not fully understood. Debate remains whether increased cognitive activity provides a meaningful benefit for cognitive health or if decreased cognitive activity represents a prodrome of cognitive impairment. Neurological biomarkers provide a novel way to examine this relationship in the context of cognitive aging. METHODS: We examined the association of self-reported cognitive activity, cognitive function, and concentrations of three biomarkers in community-dwelling participants of a longitudinal, population-based study. Cognitive activity was measured at baseline by asking participants to rate the frequency of 7 activities: (1) viewing television, (2) listening to the radio, (3) visiting a museum, (4) playing games, such as cards, checkers, crosswords, or other puzzles or games, (5) reading books, (6) reading magazines, and (7) reading newspapers. Cognitive function was measured with a battery of four tests (Mini-Mental State Examination, Digit Symbol Test, and the immediate and delayed recall of the East Boston Test) averaged into a composite score. At baseline, we evaluated the concentration of total tau (tau), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP). RESULTS: The study sample comprised 1,168 older participants, primarily non-Hispanic Blacks (60%) and women (63%). At baseline, they were an average of 77 years old with 12.6 years of education. Mixed-effects models showed that cognitive activity was associated with better cognitive functioning at baseline and over time. These relationships remained after each biomarker was added to the model. Over an average of 6.4 years of follow-up, cognitive activity was associated with cognitive decline in the model with tau (estimate = 0.0123; p value = 0.03) and was mildly attenuated in the models with NfL (estimate = 0.0110; p value = 0.06) and GFAP (estimate = 0.0111; p value = 0.06). Biomarkers did not modify the association between cognitive activity and cognitive function over time. CONCLUSION: The benefits of cognitive activity on cognition appear to be independent of biomarkers: tau, NfL, and GFAP, measured at baseline. More frequent cognitive activity may benefit the cognitive health of older adults with a wide range of potential disease risk and presentations.

Stability and change in acculturation-related characteristics in older Latinos: Implications for culturally compatible ADRD research.

Introduction: Acculturation-related characteristics, that is, factors directly connected to culture and familial relationships, are associated with engaged research participation within Latino communities. Despite this, little empirical data exists on whether acculturation changes over time in older Latinos, which has potential implications for Alzheimer's disease and related dementias (ADRD) research study design including longer duration clinical trial implementation. Methods: Self-identified Latinos (n = 222; mean age = 71, 76% female) participating in one of three ongoing longitudinal community-based cohort studies of aging who reported their nativity outside of the United States/District of Columbia (US/DC) contributed, on average, 4.0 ± 1.2 years of annually collected data. This included acculturation-related characteristics of total, language-, and social-based scores from the Short Acculturation Scale for Hispanics (SASH) and total and domain-specific scores from an abbreviated Sabogal Familism questionnaire. We used ordinal mixed effects models and linear mixed effects models (as appropriate) to assess change in acculturation metrics after adjusting for age, sex, education, income, and duration of time in the US/DC. Results: Although none of the SASH metrics changed over time (P-values ≥ 0.25), all Familism metrics declined over time (P-values ≤ 0.044). Additionally, select participant-based characteristics including years of education were significantly (and differentially) associated with level of, but not change in, acculturation-related outcomes. Discussion: Results suggest that specific acculturation-related factors (i.e., familism) change over time in older Latinos, and participant-based characteristics associated with baseline levels of (but not change in) acculturation more generally. Thus, acculturation-related characteristics are not all static, trait-like qualities but rather a multi-faceted, and at times evolving, construct. Considering this dynamic phenotyping is important when contextualizing older Latinos' lived experience, and when designing, adapting, and conducting ADRD clinical trials and other health-related interventions.

Well-Being and Aging-Related Decline in Financial and Health Literacy in Advanced Age.

OBJECTIVES: Emerging evidence suggests that financial and health literacy deteriorates in advanced age. By contrast, well-being promotes health in aging. This study tested the hypothesis that well-being is associated with slower aging-related literacy decline. METHODS: Participants were 1,099 community-based older adults without dementia at baseline. Financial and health literacy was assessed at baseline and annually thereafter via a 32-item measure. Well-being was assessed at baseline via the 18-item version of Ryff's Scales of Psychological Well-Being. RESULTS: During up to 12 years of annual follow-up, literacy declined about 1 percentage point per year on average (ß = -0.91, standard error [SE] = 0.08, p < .001); however, there was considerable variation in change in literacy between participants (random slopes variance = 1.24, SE = 0.15, p < .001). In a linear mixed-effects model adjusted for age, sex, and education, higher well-being was associated with higher starting level of literacy (ß = 2.31, SE = 0.67, p = .001) and, critically, slower literacy decline (ß = 0.29, SE = 0.11, p = .01). The association of higher well-being with slower literacy decline persisted in models that additionally adjusted for income, medical conditions, depressive symptoms, and a robust measure of global cognition. DISCUSSION: This study suggests that well-being helps stave off aging-related literacy decline.

Polygenic risk score penetrance & recurrence risk in familial Alzheimer disease.

OBJECTIVE: To compute penetrance and recurrence risk using a genome-wide PRS (including and excluding the APOE region) in families with Alzheimer's disease. METHODS: Genotypes from the National Institute on Aging Late-Onset Alzheimer's Disease Family-Based Study and a study of familial Alzheimer's disease in Caribbean Hispanics were used to compute PRS with and without variants in the 2 MB region flanking APOE. PRS was calculated in using clumping/thresholding and Bayesian methods and was assessed for association with Alzheimer's disease and age at onset. Penetrance and recurrence risk for carriers in highest and lowest PRS quintiles were compared separately within APOE-ε4 carriers and non-carriers. RESULTS: PRS excluding the APOE region was strongly associated with clinical and neuropathological diagnosis of AD. PRS association with AD was similar in participants who did not carry an APOE-ε4 allele (OR = 1.74 [1.53-1.91]) compared with APOE-ε4 carriers (1.53 [1.4-1.68]). Compared to the lowest quintile, the highest PRS quintile had a 10% higher penetrance at age 70 (p = 0.0006) and a 20% higher penetrance at age 80 (p < 10e-05). Stratifying by APOE-ε4 allele, PRS in the highest quintile was significantly more penetrant than the lowest quintile, both, within APOE-ε4 carriers (14.5% higher at age 80, p = 0.002) and non-carriers (26% higher at 80, p < 10e-05). Recurrence risk for siblings conferred by a co-sibling in the highest PRS quintile increased from 4% between the ages of 65-74 years to 39% at age 85 and older. INTERPRETATION: PRS can be used to estimate penetrance and recurrence risk in familial Alzheimer's disease among carriers and non-carries of APOE-ε4.

Change in Decision-Making Analysis and Preferences in Old Age.

OBJECTIVES: To test the hypotheses that decision making ability declines in old age and that a higher level of cognitive reserve is associated with a reduced rate of decline. METHODS: As part of an ongoing cohort study, 982 older adults without dementia at study enrollment completed measures of purpose in life and cognitive activity which were used as markers of cognitive reserve. At annual intervals thereafter, they completed 6 tests of decision making. RESULTS: In a factor analysis of baseline decision making scores, 3 measures (financial/health literacy, financial/health decision making, scam susceptibility) loaded on an "analytic" factor and 3 (temporal discounting small stakes, temporal discounting large stakes, risk aversion) loaded on a "preferences" (for temporal discounting and avoiding risk) factor. During a mean of 4.7 years of follow-up (standard deviation = 2.9), analytic factor scores decreased (mean = 0.042-unit per year, standard error [SE] = 0.006, p < .001) and preferences factor scores increased (mean = 0.021-unit per year, SE = 0.006, p < .001), with a correlation of 0.13 (p < .001) between rates of change. Evidence of an association between cognitive reserve and decision making was mixed with purpose in life related to change in analytic decision making, whereas past (but not current) cognitive activity was related to change in decision making preferences. DISCUSSION: Decision making analysis and preferences change over time in late life. Change over time in decision making components is relatively independent and differentially related to age and cognitive reserve.

Psychological Well-being Relates to Healthcare and Financial Decision Making in a Study of Predominantly White Older Adults.

The purpose of this study was to test the hypotheses that psychological well-being is associated with healthcare and financial decision making in older adults and that this association varies by the level of cognitive function. Participants were 1082 older adults (97% non-Latino White; 76% women; mean age = 81.04 years; SD = 7.53) without dementia (median MMSE score = 29.00, IQR = 27.86-30.00). In a regression model adjusted for age, gender, and years of education, higher levels of psychological well-being were associated with better decision making (estimate = 0.39, standard error [SE] = 0.11, p < .001), as was better cognitive function (estimate = 2.37, SE = 0.14, p < .0001). In an additional model, an interaction of psychological well-being and cognitive function was significant (estimate = -0.68, SE = 0.20, p < .001), such that higher levels of psychological well-being were most beneficial for decision making among participants with lower levels of cognitive function. Higher levels of psychological well-being may help sustain decision making among older persons, particularly those with lower levels of cognitive function.

Predicting age at Alzheimer's dementia onset with the cognitive clock.

INTRODUCTION: Intervention of Alzheimer's dementia hinges on early diagnosis and advanced planning. This work utilizes the cognitive clock, a novel indicator of brain health, to develop a dementia prediction model that can be easily applied in broad settings. METHODS: Data came from over 3000 community-dwelling older adults. Cognitive age was estimated by aligning Mini-Mental State Examination (MMSE) scores to a clock that represents the typical cognitive aging profile. We identified a mean cognitive age at Alzheimer's dementia onset and predicted the corresponding chronological age at person-specific level. RESULTS: The mean chronological age at baseline was 78 years. A total of 881 (28%) participants developed Alzheimer's dementia. The mean cognitive age at onset was 91 years. The predicted chronological age at onset had a mean (standard deviation) of 87.6 (6.7) years. The model's prediction accuracy was supported by multiple testing statistics. DISCUSSION: Our model offers an easy-to-use tool for predicting person-specific age at Alzheimer's dementia onset.

Race and Apolipoprotein E-e4 Allele Status Differences in the Association Between Loneliness and Cognitive Decline.

OBJECTIVE: This study aimed to examine race and apolipoprotein E-e4 allele (APOE-e4) status differences in the longitudinal associations between loneliness and cognitive decline. METHODS: The study sample is composed of participants ( N = 7696, 64% Black participants and 36% White participants) from the Chicago Health and Aging Project, a population-based cohort study. Mixed-effects regression models were conducted to examine the longitudinal associations between loneliness on global cognitive function and individual tests of cognitive function. Models were also stratified by race and APOE-e4. RESULTS: A greater percentage of Black participants (17%) reported loneliness at baseline visit compared with White participants (12%). Black and White participants who were lonely individuals had a similar rate of decline in global cognitive function at 0.075 (95% confidence interval [CI] = -0.082 to -0.068) standard deviation unit (SDU) per year for Black participants and at 0.075 (95% CI = -0.086 to -0.063) SDU per year for White participants. Lonely participants with APOE-e4 had a higher rate of global cognitive decline at -0.102 (95% CI = -0.115 to -0.088) SDU per year than for lonely participants without APOE-e4 at -0.052 (95% CI = -0.059 to -0.045) SDU per year. CONCLUSIONS: The burden of loneliness and its relation to cognitive decline is higher among participants with APOE-e4 compared with those without APOE-e4. Loneliness is associated with cognitive decline in both Black and White participants.

Unique Transcriptional Signatures Correlate with Behavioral and Psychological Symptom Domains in Alzheimer's Disease.

Despite the significant burden, cost, and worse prognosis of Alzheimer's disease (AD) with behavioral and psychological symptoms of dementia (BPSD), little is known about the molecular causes of these symptoms. Using antemortem assessments of BPSD in AD, we demonstrate that individual BPSD can be grouped into 4 domain factors in our sample: affective, apathy, agitation, and psychosis. Then, we performed a transcriptome-wide analysis for each domain utilizing bulk RNA-seq of post-mortem anterior cingulate cortex (ACC) tissue. Though all 4 domains are associated with a predominantly downregulated pattern of hundreds of differentially expressed genes (DEGs), most DEGs are unique to each domain, with only 22 DEGs being common to all BPSD domains, including TIMP1. Weighted gene co-expression network analysis (WGCNA) yielded multiple transcriptional modules that were shared between BPSD domains or unique to each domain, and NetDecoder was used to analyze context-dependent information flow through the biological network. For the agitation domain, we found that all DEGs and a highly correlated transcriptional module were functionally enriched for ECM-related genes including TIMP1, TAGLN, and FLNA. Another unique transcriptional module also associated with the agitation domain was enriched with genes involved in post-synaptic signaling, including DRD1, PDE1B, CAMK4, and GABRA4. By comparing context-dependent changes in DEGs between cases and control networks, ESR1 and PARK2 were implicated as two high impact genes associated with agitation that mediated significant information flow through the biological network. Overall, our work establishes unique targets for future study of the biological mechanisms of BPSD and resultant drug development.

Brain ß-Amyloid Links the Association of Change in Body Mass Index With Cognitive Decline in Community-Dwelling Older Adults.

BACKGROUND: We tested the hypothesis that indices of Alzheimer's disease and related dementia (ADRD) pathologies may explain associations between change in body mass index (BMI) and cognitive decline in old age. METHOD: We used data from 436 older decedents participating in a prospective longitudinal cohort study who had undergone annual cognitive and BMI assessments and postmortem collection of indices of 12 brain pathologies. We identified ADRD brain pathologies associated with BMI range, a previously published metric of change in BMI. We employed sigmoidal mixed-effect models of cognitive decline to examine the associations of change in BMI and cognitive decline with and without terms for ADRD brain pathologies. RESULTS: Average age at baseline was 78.6 years, SD = 6.5 years with 64% female. On average, 9 cognitive assessments were obtained with average age at death 88.4 years (SD = 6.2 years). Change in BMI as measured by BMI range was associated with cognitive decline (θ 2 = 0.260). ß-Amyloid, hippocampal sclerosis, and substantia nigra neuronal loss were associated with BMI range. ß-Amyloid strongly attenuated the association of BMI range with cognitive decline. Hippocampal sclerosis showed only partial attenuation of the association of BMI range and cognitive decline and nigral neuronal loss did not attenuate this association. CONCLUSION: Changes in BMI and cognitive decline in older adults may be affected by similar mechanisms underlying the accumulation of brain pathologies like ß-amyloid in aging brains. Elucidating the molecular mechanisms underlying these associations may provide novel targets for developing interventions that maintain brain health and metabolic homeostasis in old age.

Childhood socioeconomic status interacts with cognitive function to impact scam susceptibility among community-dwelling older adults.

OBJECTIVES: We examined whether childhood socioeconomic status (SES) is related to scam susceptibility in old age and tested the hypothesis that childhood SES interacts with cognitive function to impact scam susceptibility. METHODS: This study employed a cross-sectional design. All data were collected in participants' community-based residences. Participants were 1071 older adults (mean age = 81.05 years, SD = 7.53) without dementia (median MMSE score = 28.29, IQR = 27.86-30.00). Participants completed assessments of childhood SES, cognitive function, and scam susceptibility. We used linear regression models to examine the associations of childhood SES and cognitive function with scam susceptibility. RESULTS: In a regression model adjusted for age, gender, and education, poorer cognitive function was associated with higher scam susceptibility, but childhood SES was not. However, in an additional model that included the interaction of childhood SES and cognitive function, the interaction was significant, such that lower childhood SES was associated with higher scam susceptibility among participants with lower cognitive function. CONCLUSION: Lower childhood SES is associated with higher scam susceptibility among older adults with lower levels of cognitive function. Thus, older adults who experienced limited resources in childhood and have lower cognitive function may represent a specific group for interventions to increase scam awareness and prevent financial exploitation.