Faster Rate Of Cognitive Decline Research Articles

Association of subjective memory complaints with serum biomarkers of neurodegeneration and cognition: A population-based study.

Subjective memory complaints (SMCs) refer to memory concerns reported by an individual, regardless of objective test impairment. We conducted a study to evaluate the association of SMCs with serum biomarkers of neurodegeneration, including neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and total tau (t-tau). In addition, we evaluated the association of SMCs with the rate of cognitive decline. This study included 1096 individuals participating in the Chicago Health and Aging Project, with data on SMCs, neurodegenerative biomarkers (NfL, GFAP, and t-tau), and global cognitive scores. The SMC score ranges from 0 to 8 and higher scores reflect more memory complaints. Linear regression models were developed to investigate the association of SMCs with serum biomarkers, adjusted by age, sex, race, education, and APOE e4. Linear mixed-effects models were used to examine the independent association of SMCs with cognitive decline in a multivariable model that was additionally adjusted by biomarkers of neurodegeneration. Of the 1096 individuals, 665 (60.7%) were female, 643 (58.7%) were African Americans, and the mean (SD) age at the baseline was 78.0 (5.8) years. Compared to individuals with fewer memory complaints (i.e., people in the first tertile of SMCs), those reporting more memory complaints (i.e., people in the third tertile of SMCs) had a 12.0% increase in serum concentrations of NfL and an 9.4% increase in GFAP. In addition, individuals reporting more memory complaints (i.e., those in the 3rd versus the 1st tertile of SMCs) had a faster rate of cognitive decline by 0.029 ( -0.029, 95% CI -0.046 to -0.013) standardized units per year. Individuals who reported more memory complaints had higher levels of biomarkers of neurodegeneration and a faster rate of cognitive decline, suggesting that SMCs may be valuable for identifying people at high risk of cognitive impairment.

Toxic air pollution and cognitive decline: Untangling particulate matter

There is increasing evidence indicating air pollution is an important factor influencing the aging brain. However, much of this work measures air pollution using particulate matter (PM). Yet we know that the chemical components of PM are not consistent across space or time. Rather, the possible chemical mixtures of PM vary and are therefore not reliably measuring the same thing across studies. In this study we attempt to disentangle the effects of the components of measured PM by using estimates of concurrent exposures of 415 industrial air toxics, as well as 44 neuro- and developmental toxics. Using bivariate latent curve models, we leverage individual level panel data from the bi-annual Health and Retirement Study to test how these exposures relate to cognitive score trajectories of respondents across the years 2002–2012. We find that more exposure to neurotoxics was associated with faster rate of cognitive decline by 1.09 points (p < 0.05).

Associations Between Self-Reported Visual Difficulty, Age of Onset, and Cognitive Function Trajectories Among Chinese Older Adults.

Objectives: This study examined the association between self-reported visual difficulty and age-related cognitive declines among older Chinese adults and how the timing of visual difficulty onset plays a role in cognitive trajectories. Methods: Data were drawn from the 2011-2018 wave of the China Health and Retirement Longitudinal Study, involving 9974 respondents aged 60years or older (mean age 65.44years, range 60-101years). Results: At baseline, 14.16% respondents had self-reported visual difficulty. Growth curve models showed that Chinese older adults with visual difficulty experienced a faster decline in cognitive function compared to those without visual difficulty (β = -0.02, p < .01). Older adults who began experiencing visual difficulty between 61 and 75years of age had steeper cognitive declines compared to those with earlier or later onset (β = -0.05, p < .01). Discussion: Older adults with self-reported visual difficulty experience faster rates of cognitive decline. Future research should explore potential factors that underlie the association between onset timing of visual difficulty and cognitive function.

Trends in Cognitive Function Before and After Diabetes Onset: The China Health and Retirement Longitudinal Study.

Individuals with prevalent diabetes were known to have a higher risk of dementia and lower cognitive function. However, trends of cognitive function before diabetes and in the short term after new-onset diabetes remain unclear. This study included participants without baseline diabetes from the China Health and Retirement Longitudinal Study. Cognitive tests were conducted at baseline (wave 1) and at least one time from wave 2 (2013) to wave 4 (2018). Cognitive function was assessed using a global cognition score which was the summary measure of 4 cognitive tests. A linear mixed model was constructed to fit the trends in cognitive function before and after diabetes onset and the trends among nondiabetes. The threshold of statistical significance was p < 0.05. During the 7-year follow-up, 1,207 (9.7% of 12,422, 59.1 ± 8.6 years, 39.9% male participants) participants developed new-onset diabetes. The cognitive function of both the without diabetes group and the diabetes group declined annually during the follow-up. The annual decline rate of the diabetes group before diabetes onset was similar to that of the without diabetes group during the whole follow-up period. After diabetes onset, participants experienced statistically significant faster cognitive declines in global cognition (-0.023 SD/year; 95% CI -0.043 to -0.004; p = 0.019) and visuospatial abilities test (-0.036 SD/year; -0.061 to -0.011; p = 0.004), but not in tests of episodic memory (-0.018 SD/year; -0.041 to 0.004; p = 0.116), attention and calculation (-0.017 SD/year; -0.037 to 0.003; p = 0.090), or orientation (0.001 SD/year; -0.018 to 0.020; p = 0.894), compared with the cognitive slope before diabetes. In subgroup analysis, compared with those who developed diabetes between 45-54 years, those developing diabetes older (55-64 years, p for interaction = 0.701; 65-74 years, p for interaction = 0.996) did not demonstrate different rates of global cognitive decline after diabetes. Individuals experienced faster rate of cognitive decline in a few years after diabetes onset, but not during the prediabetes period. Age did not modify the effect of diabetes on postdiabetes cognitive decline. Efforts in eliminating the adverse impacts on cognition should be started on diagnosis of diabetes.

Impact of incidental synucleinopathy in mild cognitive impairment due to Alzheimer disease.

Recent evidence suggests that the presence of α-synuclein Lewy bodies (LBs) correlates with accelerated disease progression in patients with Alzheimer disease (AD) but it is unclear whether this effect is also exerted in the mild cognitive impairment (MCI) phase of AD. We sought to determine whether incidental LB pathology in patients with MCI due to AD is associated with a faster rate of cognitive decline compared to MCI controls without LB pathology. We identified patients within the National Alzheimer's Coordinating Center (NACC) database with MCI due to AD and stratified the cohort by the presence or absence of synucleinopathy. We utilized a repeated measures longitudinal analysis of Mini-Mental State Examination (MMSE) scores to determine whether the decline in performance occurred at a greater rate in the synucleinopathy patients. A total of 206 participants were studied; 80 had coincident synucleinopathy. The rate of decline in MMSE scores between the groups did not differ. This may suggest that a synergistic effect of LB and AD neuropathology is only appreciable in the later stages of disease progression. Further investigation into the effect of mixed LB and AD pathology in the early stages of cognitive impairment is warranted to highlight opportunities for targeted early intervention in patients.

Contributions of amyloid beta and cerebral small vessel disease in clinical decline.

We assessed whether co-morbid small vessel disease (SVD) has clinical predictive value in preclinical or prodromal Alzheimer's disease. In 1090 non-demented participants (65.4±10.7 years) SVD was assessed with magnetic resonance imaging and amyloid beta (Aβ) with lumbar puncture and/or positron emission tomography scan (mean follow-up for cognitive function 3.1±2.4 years). Thirty-nine percent had neither Aβ nor SVD (A-V-), 21% had SVD only (A-V+), 23% Aβ only (A+V-), and 17% had both (A+V+). Pooled cohort linear mixed model analyses demonstrated that compared to A-V- (reference), A+V- had a faster rate of cognitive decline. Co-morbid SVD (A+V+) did not further increase rate of decline. Cox regression showed that dementia risk was modestly increased in A-V+ (hazard ratio [95% confidence interval: 1.8 [1.0-3.2]) and most strongly in A+ groups. Also, mortality risk was increased in A+ groups. In non-demented persons Aβ was predictive of cognitive decline, dementia, and mortality. SVD modestly predicts dementia in A-, but did not increase deleterious effects in A+. Amyloid beta (Aβ; A) was predictive for cognitive decline, dementia, and mortality. Small vessel disease (SVD) had no additional deleterious effects in A+. SVD modestly predicted dementia in A-. Aβ should be assessed even when magnetic resonance imaging indicates vascular cognitive impairment.

STATE-LEVEL EDUCATION CONTEXT AS A MODERATOR OF GENETIC RISK FOR POOR COGNITIVE FUNCTION ACROSS GENDER AND COHORT

Abstract APOE, specifically the e4 allele, is the strongest known genetic risk factor for late-onset dementia. Individuals with at least one copy of the e4 allele have a 3-15 times higher risk for dementia, and faster rates of cognitive decline, than those without it. Although education has been shown to moderate this relationship, the quality of U.S. education improved significantly over the first seven decades of the 20th century and saw greater access to educational opportunities among women. In this historical context, it is important to consider if genetic risk for poor cognitive function changes across successive cohorts and if it does so differentially by gender. Consequently, we use genetic and cognition data from the Health and Retirement Study (HRS) linked to state-level data on educational quality available from 1920-1974. Given well-known differences in the effect of APOE genotype on dementia risk based on global and local ancestry, we restrict our sample to non-Hispanic White men (n=5,256) and women (n=6,857) who provided at least one observation on cognitive function from 2006 – 2018. We examine the relationship across three measures of cognition – global functioning, episodic memory, and numeracy. We estimate gender and cohort stratified linear mixed models and determine if states with well-resourced education systems mitigate the genetic risk on cognitive health associated with the e4 allele and compare this relationship across cohorts for men and women. These results can help inform our understanding about how early life education can differentially shape genetic risk for cognitive decline in later life.

Region‐Specific Associations of Human Astrocytic Endfoot Genes with Alzheimer’s Disease Neuropathology and Cognitive Decline

AbstractBackgroundWe completed a well‐powered bulk transcriptomic analysis of the astrocytic water channel aquaporin‐4 (AQP4) and related glymphatic molecules and discovered significant associations with Alzheimer’s disease (AD) neuropathological and cognitive outcomes. Genes included AQP4 and dystrophin‐associated complex components, namely DMD, DTNA, DAG1, and SNTA1, which encode proteins responsible for anchoring the AQP4 channel to the astrocytic endfoot membrane.MethodLeveraging regional brain RNA sequencing from the ROS/MAP dataset (Table 1), we determined the effects of transcript‐level variation on neuropathological outcomes at autopsy and longitudinal cognition using multiple linear regression models and mixed effects models, respectively. Discrete brain regions included: the dorsolateral prefrontal cortex (DLPFC, N = 921), caudate nucleus (CN, N = 705), and posterior cingulate cortex (PCC, N = 516). Square‐root transformed neuropathological measures of amyloid and tau burden at autopsy were quantified using immunohistochemistry. Cognitive performance was assessed longitudinally with global cognition calculated as a composite score derived from 19 neuropsychological tests. All model covariates included age at death, sex, educational attainment, and post‐mortem interval. Longitudinal models also included latency to death and the fixed and random effect of interval between current and last visit.ResultHigher AQP4 expression in the DLPFC related to higher amyloid pathology (β = 0.21, P.fdr = 0.04). Similarly, higher DTNA expression was associated with higher tau burden (βDLPFC = 0.36, P.fdrDLPFC = 0.008) and a faster rate of cognitive decline (βDLPFC = ‐0.036, P.fdrDLPFC = 0.0004; βPCC = ‐0.037, P.fdrPCC = 0.02). Higher SNTA1 in the CN related to a faster rate of cognitive decline (β = ‐0.038, P.fdr = 0.03). A summary of significant associations is presented in Table 2 and select plots are provided in Figure 2. AQP4, DTNA, and SNTA1 showed comparable associations with clinical AD in independent datasets within the AMP‐AD project (https://agora.adknowledgeportal.org/).ConclusionOur results indicate that gene expression at the AQP4‐dystrophin axis relates to both AD neuropathology and cognition, particularly in the prefrontal cortex. Future analyses will incorporate single‐nucleus measures of gene expression and cell‐type deconvolution to clarify cell‐type specific contributions in this pathway. Together, these results highlight a set of genes relevant to glymphatic function that should be prioritized for future mechanistic studies.

The effect of basal forebrain atrophy on the rate of cognitive decline in older adults without dementia

AbstractBackgroundIn early Alzheimer’s disease, degeneration of the cholinergic basal forebrain (BF) system correlates with amyloid‐β (Aβ) burden and contributes to cognitive decline, particularly in the domains of memory and attention processing. However, the nature of these interrelationships remains unclear. This study investigated the effects of Aβ and BF atrophy on cognitive decline of memory and attention in older individuals without dementia.MethodThe BF volumes were quantified from MRIs of 577 participants (73.3 ± 6.3 years old, 55.1% female) from the Australian Imaging, Biomarker and Lifestyle (AIBL) study, including 495 cognitive unimpaired (CU) individuals and 82 with mild cognitive impairment. Aβ‐PET assessment was completed at baseline, and Aβ+ was determined using Centiloid &gt; 20. The cognitive decline in memory and attention was assessed using the relevant AIBL composite scores, over 6.0 ± 3.1 years (up to 13 years). BF z‐scores were calculated using the mean and standard deviation of BF volumes in the CU Aβ‐ group, and z‐scores &lt; ‐1 was classified as BF atrophy (BF+). Participants were then grouped according to the Aβ status and presence of BF atrophy (Table 1). Linear mixed‐effects models assessed differences in rates of cognitive decline in memory and attention across different classification groups. Magnitudes of differences in slopes of decline were expressed using Cohen’s d. ResultIn Aβ‐ individuals, BF atrophy was associated with faster rates of cognitive decline in both memory and attention, with medium effect sizes (Table 2 and Figure 1). In re‐analyses restricted to Aβ+ subjects, BF atrophy remained related to memory decline (p = 0.035, d = 0.33) but not to decline in attention. Compared to Aβ‐ subjects without BF atrophy, both Aβ+ groups had faster decline in both domains, with large effect sizes (all d &gt; 0.8).ConclusionThese findings indicate that the effects of Aβ and BF atrophy are additive in terms of their influence on the rate of decline in memory. However, BF atrophy influences the rate of decline in attention only in the absence of abnormal Aβ burden.

Associations between depressive symptoms, glial fibrillary acid protein, and cognitive decline in a population‐based study

AbstractBackgroundDepressive symptoms are a known risk factor for dementia, and higher concentrations of glial fibrillary acid protein (GFAP) is associated with a faster rate of cognitive decline. However, it is unknown whether the two risk factors increase the risk of cognitive decline additively.MethodThis investigation is based on 1,169 participants from the Chicago Health and Aging Project (CHAP), a population‐based cohort study, who completed at least two cognitive performance assessments with baseline serum GFAP measurement. Depressive symptoms were determined utilizing a modified version of the Center for Epidemiologic Studies‐Depression Scale. A composite global cognitive function score was calculated using cognitive performance testing. Linear mixed effects regression models were conducted to examine the association of depressive symptoms and GFAP concentrations on baseline global cognitive function and the annual rate of cognitive decline. Regression models also adjusted for age, race, sex, education, chronic medical conditions, and their interactions with time.ResultOur study sample consisted of 60% African American participants and 63% female participants and had an average age of 77 (SD = 6.0) years. In our sample, 21% had few depressive symptoms (0‐2), and the remaining 79% had more depressive symptoms (3‐10). We found a statistically significant interaction between depressive symptoms and GFAP (β = ‐111 (SE = .039), p = .005) on global cognitive function. Stratified analysis showed that the associations between the log of GFAP and global cognitive function were statistically significant for participants with few (0‐2) depressive symptoms (β = ‐.223 (SE = .087), p = .010) and more (3‐10) depressive symptoms (β = ‐.781 (SE = .198), p = .000). Statistically significant associations were also observed between the log of GFAP and global cognitive decline for participants with few (β = ‐.069 (SE = .017), p = .000) and more (β = ‐.100 (SE = .040), p = .012) depressive symptoms.ConclusionOur findings show additive effects of depressive symptoms in the association between the log of GFAP with baseline global cognitive function and rate of cognitive decline. Prevention and treatment of depression in old age can significantly impact the risk of progressive cognitive decline, especially among individuals with higher concentrations of GFAP.

Disease trajectories in older adults with non-AD pathologic change and comparison with Alzheimer’s disease pathophysiology: A longitudinal study

Based on the 'AT(N)' system, individuals with normal amyloid biomarkers but abnormal tauopathy or neurodegeneration biomarkers are classified as non-Alzheimer's disease (AD) pathologic change. This study aimed to assess the long-term clinical and cognitive trajectories of individuals with non-AD pathologic change among older adults without dementia, comparing them to those with normal AD biomarkers and AD pathophysiology. Analyzing Alzheimer's Disease Neuroimaging Initiative data, we evaluated clinical outcomes and conversion risk longitudinally using mixed effects models and multivariate Cox proportional hazard models. We found that compared to individuals with A-T-N-, those with abnormal tauopathy or neurodegeneration biomarkers (A-T + N-, A-T-N + , and A-T + N + ) had a faster rate of cognitive decline and disease progression. Individuals with A-T + N + had a faster rate of decline than those with A-T + N-. Additionally, in individuals with the same baseline tauopathy and neurodegeneration biomarker status, the presence of baseline amyloid could accelerate cognitive decline and clinical progression. These findings provide a foundation for future studies on non-AD pathologic change and its comparison with AD pathophysiology.

Joint associations of physical activity and sleep duration with cognitive ageing: longitudinal analysis of an English cohort study

Physical activity and sleep duration are key factors associated with cognitive function and dementia risk. How physical activity and sleep interact to influence cognitive ageing is not well explored. We aimed to examine the associations of combinations of physical activity and sleep duration with 10-year cognitive trajectories. In this longitudinal study, we analysed data from the English Longitudinal Study of Ageing collected between Jan 1, 2008, and July 31, 2019, with follow-up interviews every 2 years. Participants were cognitively healthy adults aged at least 50 years at baseline. Participants were asked about physical activity and nightly sleep duration at baseline. At each interview, episodic memory was assessed using immediate and delayed recall tasks and verbal fluency using an animal naming task; scores were standardised and averaged to produce a composite cognitive score. We used linear mixed models to examine independent and joint associations of physical activity (lower physical activity or higher physical activity, based on a score taking into account frequency and intensity of physical activity) and sleep duration (short [<6 h], optimal [6-8 h], or long [>8 h]) with cognitive performance at baseline, after 10 years of follow-up, and the rate of cognitive decline. We included 8958 respondents aged 50-95 years at baseline (median follow-up 10 years [IQR 2-10]). Lower physical activity and suboptimal sleep were independently associated with worse cognitive performance; short sleep was also associated with faster cognitive decline. At baseline, participants with higher physical activity and optimal sleep had higher cognitive scores than all combinations of lower physical activity and sleep categories (eg, difference between those with higher physical activity and optimal sleep vs those with lower physical activity and short sleep at baseline age 50 years was 0·14 SDs [95% CI 0·05-0·24]). We found no difference in baseline cognitive performance between sleep categories within the higher physical activity category. Those with higher physical activity and short sleep had faster rates of cognitive decline than those with higher physical activity and optimal sleep, such that their scores at 10 years were commensurate with those who reported low physical activity, regardless of sleep duration (eg, difference in cognitive performance after 10 years of follow-up between those with higher physical and optimal sleep and those with lower physical activity and short sleep was 0·20 SDs [0·08-0·33]; difference between those with higher physical activity and optimal sleep and those with lower physical activity and short sleep was 0·22 SDs [0·11-0·34]). The baseline cognitive benefit associated with more frequent, higher intensity physical activity was insufficient to ameliorate the more rapid cognitive decline associated with short sleep. Physical activity interventions should also consider sleep habits to maximise benefis of physical activity for long-term cognitive health. UK Economic and Social Research Council.

Metabolic Asymmetry Relates to Clinical Characteristics and Brain Network Abnormalities in Alzheimer's Disease.

Metabolic asymmetry has been observed in Alzheimer's disease (AD), but different studies have inconsistent viewpoints. To analyze the asymmetry of cerebral glucose metabolism in AD and investigate its clinical significance and potential metabolic network abnormalities. Standardized uptake value ratios (SUVRs) were obtained from 18F-FDG positron emission tomography (PET) images of all participants, and the asymmetry indices (AIs) were calculated according to the SUVRs. AD group was divided into left/right-dominant or bilateral symmetric hypometabolism (AD-L/AD-R or AD-BI) when more than half of the AIs of the 20 regions of interest (ROIs) were < -2SD, >2SD, or between±1SD. Differences in clinical features among the three AD groups were compared, and the abnormal network characteristics underlying metabolic asymmetry were explored. In AD group, the proportions of AD-L, AD-R, and AD-BI were 28.4%, 17.9%, and 18.5%, respectively. AD-L/AD-R groups had younger age of onset and faster rate of cognitive decline than AD-BI group (p < 0.05). The absolute values of AIs in half of the 20 ROIs became higher at follow-up than at baseline (p < 0.05). Compared with those in AD-BI group, metabolic connection strength of network, global efficiency, cluster coefficient, degree centrality and local efficiency were lower, but shortest path length was longer in AD-L and AD-R groups (p < 0.05). Asymmetric and symmetric hypometabolism may represent different clinical subtypes of AD, which may provide a clue for future studies on the heterogeneity of AD and help to optimize the design of clinical trials.

Impact of Incidental Synucleinopathy in Mild Cognitive Impairment due to Alzheimer’s Disease (P7-6.003)

<h3>Objective:</h3> We sought to determine whether incidental LB pathology in patients with MCI due to AD is associated with faster rate of cognitive decline in the pre-clinical phase compared to MCI controls without mixed pathology. <h3>Background:</h3> The hallmark neuropathologies of Alzheimer’s disease include amyloid plaques and tau neurofibrillary tangles. Recent evidence suggests that incidental co-occurrence of Lewy Bodies (LB), correlates with accelerated disease progression in AD patients. It is unclear whether this effect is also exerted in the pre-dementia phase of AD, in patients with mild cognitive impairment (MCI). <h3>Design/Methods:</h3> 6654 subjects were identified from the National Alzheimer’s Coordinating Center (NACC) database with autopsy-confirmed AD pathology who remained in the MCI, (Albert 2011 criteria), throughout their ADRC annual assessments. 89 subjects had co-incident Lewy Bodies while the remaining 6565 controls lacked any mixed pathology. We utilized a repeated measures longitudinal analysis of multiple cognitive performance markers to determine whether decline in scores occurred at a greater rate in the synucleinopathy subjects. <h3>Results:</h3> For MCI-LB, mean age and education was (72.2± 8.9 and 15.7± 5.8). For MCI+LB subjects mean age and education was (77..9± 7.8 and 16.6± 6.8). 44 MCI +LB subjects and 2555 MCI -LB had complete data for MMSE scores and were included in the corresponding analysis and a subset had complete data for the Weschler Adult Intelligence Scale (WAIS) Digit Symbols test. The rate of decline in overall MMSE scores and WAIS-R Digit Symbols test did not differ between the two groups. <h3>Conclusions:</h3> While mixed LB pathology correlates with a greater rate of cognitive decline in patients with AD, our results do not suggest that co-incident LB accelerates decline in subjects remaining in MCI. To further characterize the effect of mixed pathology on AD disease course, next steps may include investigating whether co-occurrent LB pathology hastens progression to meeting criteria for AD diagnosis. <b>Disclosure:</b> Ms. Shriram has nothing to disclose. Michael Malek-Ahmadi has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Signant Health. Dr. Sabbagh has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Eisai. Dr. Sabbagh has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genetech=Roche. Dr. Sabbagh has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novo Nordisk. Dr. Sabbagh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Lilly. Dr. Sabbagh has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Synaptogenix. Dr. Sabbagh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Signant Health. Dr. Sabbagh has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for T3D. Dr. Sabbagh has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for EIP Pharma. Dr. Sabbagh has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Quince-Cortexyme. Dr. Sabbagh has stock in Neurotau. Dr. Sabbagh has stock in Seq Biomarque. Dr. Sabbagh has stock in uMethod Health. Dr. Sabbagh has stock in Athira. Dr. Sabbagh has stock in Lighthouse Pharmaceuticals. Dr. Sabbagh has stock in Alzheom. The institution of Dr. Sabbagh has received research support from NIH. The institution of Dr. Sabbagh has received research support from ADDF. Dr. Sabbagh has received publishing royalties from a publication relating to health care.

Methylation status and sulfur amino-acids as risk factors for cognitive decline over 12 years: A longitudinal population based study (P4-6.002)

<h3>Objective:</h3> To investigate the association of vitamin B12, folate, and sulfur amino-acids with cognitive decline in a large sample of community dwelling older adults. <h3>Background:</h3> Impairment of methylation status and raised values of homocysteine and cysteine are common conditions in older adults and may be modifiable risk factors for cognitive decline. <h3>Design/Methods:</h3> From the Swedish National Study of Aging and Care in Kungsholmen (SNAC-K), 2900 dementia-free individuals at baseline aged 60–102 years with comprehensive assessments and Mini-mental state examination (MMSE) were recruited. A total of 2202 participants underwent repeated MMSE assessments up to 5 occasions over 12 years. The association of baseline vitamin B12, holotranscobalamin, folate, homocysteine, methionine, cystathionine, cysteine, glutathione, and methylation status (defined as serum methionine/homocysteine ratio) with rate of cognitive decline was examined using linear mixed models, adjusted for several potential confounders, including common vascular risk factors. <h3>Results:</h3> After adjusting for age, sex, education, creatinine, albumin, smoking status, systolic blood pressure, and <i>APOE</i>ɛ4 status, raised baseline serum total homocysteine and cysteine values were associated with a faster rate of cognitive decline: for the highest quartile compared with the lowest, β coefficient and standard error (SE) were −0.0058 (0.002) for homocysteine (p=0.004) and −0.0051 (0.002) for cysteine (p=0.014). In contrast, a better methylation status was associated with less MMSE decline over 15 years: β (SE) was 0.0058 (0.002) for the highest quartile compared with the lowest (p=0.004). Furthermore, elevated methionine values tended to slow rate of cognitive decline (p=0.079). No relationships were found for other sulfur amino acids, vitamin B12 or folate. <h3>Conclusions:</h3> Markers of methylation status and raised cysteine values were related to more rapid cognitive decline over 12 years, suggesting that optimizing homocysteine, cysteine, and methionine values may be important in reducing the risk of cognitive decline in older adults. <b>Disclosure:</b> Babak Hooshmand has nothing to disclose.

High-Sensitivity C-Reactive Protein, Its Change, and Cognitive Function: A National Population-Based Cohort Study.

This study aimed to evaluate the associations of baseline high-sensitivity C-reactive protein (Hs-CRP) and its change with subsequent cognitive decline and cognitive impairment. Data for this study were obtained from the China Health and Retirement Longitudinal Study, a national community-based prospective cohort study. Hs-CRP level and cognitive function were measured repeatedly over a 7-year follow-up. Linear mixed models and cox proportional hazard models were used to evaluate the associations. The study comprised 7385 participants (50.67% women, mean age 59.08 ± 8.86 years) with baseline Hs-CRP ranging from 0.03 to 178.10 mg/L (median: 1.01 mg/L, IQR: 0.55-2.11 mg/L). During a median of 5.79 years follow-up, the highest quartile of the Hs-CRP group showed a faster rate of cognitive decline (-0.0053 SD/year, p = 0.006) and a higher risk of cognitive impairment (HR 1.0814, p = 0.044) than those in the lowest quartile. Individuals in the elevated group of Hs-CRP change had a significantly faster cognitive decline (-0.0070 SD/year, p = 0.016) compared with those in the stable group. In this study, significant longitudinal associations between baseline Hs-CRP, elevated Hs-CRP, and long-term cognitive deterioration were observed. Hs-CRP level could perhaps serve as a predictor for cognitive deterioration in middle-aged and older adults.

Neuropathology-Independent Association Between APOE Genotype and Cognitive Decline Rate in the Normal Aging-Early Alzheimer Continuum.

We previously found that the APOE genotype affects the rate of cognitive decline in mild-to-moderate Alzheimer disease (AD) dementia independently of its effects on AD neuropathologic changes (ADNC) and copathologies. In this study, we tested the hypothesis that the APOE alleles differentially affect the rate of cognitive decline at the normal aging-early AD continuum and that this association is independent of their effects on classical ADNC and copathologies. We analyzed APOE associations with the cognitive trajectories (Clinical Dementia Rating scale Sum of Boxes [CDR-SOB] and Mini-Mental State Examination [MMSE]) of more than 1,000 individuals from a national clinicopathologic sample who had either no, mild (sparse neuritic plaques and the Braak neurofibrillary tangle [NFT] stage I/II), or intermediate (moderate neuritic plaques and the Braak NFT stage III/IV) ADNC levels at autopsy via 2 latent classes reverse-time longitudinal modeling. Carrying the APOEε4 allele was associated with a faster rate of cognitive decline by both CDR-SOB and MMSE relative to APOEε3 homozygotes. This association remained statistically significant after adjusting for ADNC severity, comorbid pathologies, and the effects of ADNC on the slope of cognitive decline. Our modeling strategy identified 2 latent classes in which APOEε4 carriers declined faster than APOEε3 homozygotes, with latent class 1 members representing slow decliners (CDR-SOB: 76.7% of individuals, 0.195 vs 0.146 points/y in APOEε4 vs APOEε3/ε3; MMSE: 88.6% of individuals, -0.303 vs -0.153 points/y in APOEε4 vs APOEε3/ε3), whereas latent class 2 members were fast decliners (CDR-SOB: 23.3% of participants, 1.536 vs 1.487 points/y in APOEε4 vs APOEε3/ε3; MMSE: 11.4% of participants, -2.538 vs -2.387 points/y in APOEε4 vs APOEε3/ε3). Compared with slow decliners, fast decliners were more likely to carry the APOEε4 allele, younger at initial visit and death, more impaired at initial and last visits, and more likely to have intermediate (vs none or mild) ADNC levels, as well as concurrent Lewy bodies and hippocampal sclerosis at autopsy. In a large national sample selected to represent the normal aging-early AD continuum, the APOEε4 allele is associated with a modest but statistically significant acceleration of the cognitive decline rate even after controlling for its effects on ADNC and comorbid pathologies.

Body Mass Index and Cognition: Associations Across Mid- to Late Life and Gender Differences.

Higher mid-life body mass index (BMI) is associated with lower late-life cognition. Associations between later-life BMI and cognition are less consistent; evidence suggests reverse causation may play a role. We aimed to characterize associations between BMI and cognition across a wide age range during mid- to late life (55-85years) and examine whether associations vary by gender. We used data from the Health and Retirement Study (HRS) (N=39,153) to examine the association between BMI and 3 cognitive outcomes: cognitive level, cognitive decline, and cognitive impairment. We used a series of linear regression, mixed effects regression, and logistic regression models, adjusting for potential confounders. Higher BMI before age 65 (midlife) was associated with lower cognitive performance, faster rates of cognitive decline, and higher odds of cognitive impairment in late life. Averaging across analyses assessing associations between BMI measured before age 60 and late-life cognition, a 5-unit higher level of BMI was associated with a 0.26 point lower cognitive score. Beyond age 65, associations flipped, and higher BMI was associated with better late-life cognitive outcomes. Associations in both directions were stronger in women. Excluding those with BMI loss attenuated findings among women in older ages, supporting the reverse causation hypothesis. In this sample, age 65 represented a critical turning point between mid- and late life for the association between BMI and cognition, which has important implications for recruitment strategies for studies focused on risk factors for late-life cognitive outcomes. Evidence of gender differences raises the need to further investigate plausible mechanisms.

White matter hyperintensity, neurofilament light chain, and cognitive decline.

We aimed to determine whether combining white matter hyperintensity (WMH) with neurofilament light chain (NfL) could provide additional information for cognition in older adults. Utilizing data from the population-based Chicago Health and Aging Project, we studied 701 individuals with both biomarkers and cognitive data during the follow-up period. NfL was measured using an ultrasensitive immunoassay, single-molecule array technology. MRI scans of the brain were acquired using 1.5-T systems. Global cognitive function was created as a composite measure of four neuropsychological tests, standardized and averaged to z-scores. Multivariable linear mixed-effects models were used to evaluate the association of WMH and NfL with the rate of cognitive decline. Higher WMH and NfL were associated with a faster rate of cognitive decline during the follow-up; -coefficients (95%CIs) were -0.011 (-0.02, -0.001) and -0.010 (-0.017, -0.003), respectively. In individuals with lower concentration of NfL (i.e., bottom tertile), a higher WMH volume was associated with a faster cognitive decline ( : -0.030; 95%CI -0.046, -0.014). Similarly, in individuals with lower volumes of WMH (i.e., bottom tertile), a higher concentrations of NfL was associated with a faster cognitive decline ( : -0.023; 95%CI -0.042, -0.005). When we combined WMH with NfL, we noted a graded association with increasing volumes of WMH, particularly in people with lower NfL values. While both biomarkers, WMH and NfL, were similarly associated with the annual rate of cognitive decline, our study suggests that they provide different underlying mechanisms affecting cognition.

RELATIONSHIP QUALITY AND OLDER PARENTS' COGNITIVE TRAJECTORIES: A NATIONAL LONGITUDINAL STUDY IN THE UNITED STATES

Abstract This study aims to assess the impact of the relationship quality between parents and children on parents’ cognitive function in later life, with an additional focus on variation by parents’ gender. We analyze data from a nationally representative longitudinal panel survey of participants age 50 and older. We employ latent growth curve models (LGCM) to estimate how changes in parent-child relationship quality are related to cognitive trajectories over time. Maintaining frequent contact with children and receiving more support from children are associated with a slower rate of cognitive decline for older parents whereas experiencing relationship strain with children is associated with a faster rate of cognitive decline for older parents. These associations are stronger for mothers than fathers. This study highlights the importance of the “linked lives” of aging parents and their children. The findings have implications for the development of interventions and strategies to protect cognitive function in later life.