Risk Of AD Research Articles

Association of AD risk factors with plasma GFAP levels in a memory clinic population

AbstractBackgroundPlasma glial fibrillary acidic protein (GFAP) is an emerging AD biomarker. We aimed to study how plasma GFAP correlated with age, clinical stage, sex, and the APOE4 status and whether amyloid pathology may mediate these associations.MethodsCohort of 330 individuals ranging from cognitively unimpaired to dementia due to AD from the Geneva Memory Center. Plasma GFAP was measured using Single molecule array (Simoa) technology. The effect of the variables of interest on plasma GFAP levels was assessed using linear regression models and partial eta squared (eta2 p). In a subset of 169 subject with amyloid PET, mediation analysis was performed to test the mediating effect of amyloid levels on the association between variable of interest and plasma GFAP.ResultsAge had the strongest effect on plasma GFAP levels (eta2 p = 0.39, p< 0.0001), followed by clinical stage (eta2 p = 0.10, p< 0.0001), sex (eta2 p = 0.06, p< 0.0001), and APOE4 (eta2 p = 0.02, p = 0.007). The effect of APOE4 status on plasma GFAP was fully mediated via the cortical amyloid uptake. The bootstrapped indirect effect was 0.09 (p< 0.0001) and the proportion of the effect of APOE4 status on GFAP that goes through the cortical amyloid uptake was 69%. No mediating effect by amyloid was found for age and sex.ConclusionThese results show that in a memory clinic population, i) AD risk factors and severity affected plasma GFAP levels and, ii) the effect of APOE4 on GFAP is amyloid‐dependent whereas that of age and sex is amyloid‐independent. GFAP cut‐offs for the early diagnosis of AD should take age and sex into account.

Effects of γ‐secretase modulator BPN‐15606 in amyloidogenic responses to air pollution in mouse cortex

AbstractBackgroundEpidemiological studies show chronic exposure to air pollution accelerates cognitive decline and increase AD risk. In mouse models, brain accumulation of amyloid beta (Aβ) is enhanced by air pollution. Pharmacological approaches show benefit of γ‐secretase modulation (GSM; BPN‐15606), decreasing Aβ42 and amyloid plaques in mouse brain. We hypothesize that GSM will limit Aβ42 production during air pollution exposure in the diesel exhaust particle (DEP) model.MethodC57BL/6 mice were exposed to DEP for 8 weeks. DEP from National Institute of Science and Technology (NIST 2975) was suspended in water and re‐aerosolized for 5 hr/day at concentration of 100 µg/m3. GSM was mixed into chow (10mg/day dose). Experimental groups were filtered air (FA), DEP, FA+GSM, and DEP+GSM; proteins from soluble fraction of cerebral cortex were analyzed by immunoblots.ResultGSM alone increased amyloid precursor protein (APP) and the Aβ38 peptide. Air pollution (DEP) increased APP, with no further change in DEP+GSM. PSEN1, key enzyme for γ‐secretase function, decreased with DEP+GSM, along with the Aβ42 peptide and the Aβ42/40 ratio.ConclusionDuring exposure to DEP, GSM decreased Aβ42 and the ratio of Aβ42/40. These results suggest that γ‐secretase modulation is beneficial during air pollution, preventing Aβ42 increases.

A CLU/APOJ GWAS AD risk variant suppresses the astrocytic response to plaques and reduces axonal and neuritic damage in 5xFAD mice

AbstractBackgroundGenome‐Wide Association Studies (GWAS) implicate clusterin (CLU, also known as apolipoprotein J) as a risk factor for late‐onset Alzheimer’s disease (LOAD), with elevated expression of CLU being associated with increased risk of LOAD. The region surrounding the SNP risk allele rs2279590 is poorly conserved within the mouse genome. Consequently, to model the effect of the rs2279590 risk allele on development of AD‐related pathology in mice we developed mice with a partially humanized allele of Clu.MethodCRISPR was used to substitute a 2kb region of human CLU (intron 7 to exon 9) containing the enhancer region and the rs2279590 SNP variant for the orthologous region of Clu within the C57BL/6J mouse genome. Clu‐rs2279590_h2kb mice were crossed with 5xFAD mice and aged to 4 and 12. Coronal brain sections were immunolabeled to visualize dense‐core plaques (ThioS), microglia (IBA1), astrocytes (S100β and GFAP), axonal (NfL) and neuritic (LAMP1) damage, confocal images of subiculum and cortical regions were taken and analyzed using Imaris software. In addition, brain Aβ and plasma NfL levels were quantified using meso scale discovery technology.Result5xFAD;Clu‐rs2279590_h2kb showed significantly reduced microglial density compared to 5xFAD mice in both brain areas at 4 months. By 12 months of age, microglial density was comparable between genotypes in cortex while in subiculum, elevated IBA1 cell density was observed in 5xFAD;Clu‐rs2279590_h2kb mice. Clu‐rs2279590_h2kb variant in 5xFAD background increased the density of S100β astrocytes in subiculum at 4 months and decreased the total S100β volume at 12 months. Reduced GFAP (reactive astrocytes) levels were found in cortex but not subiculum at 12 months. Despite comparable plaque load and insoluble Aβ42 levels, neuritic and axonal damage was decreased in the brain of 5xFAD;Clu‐rs2279590_h2kb compared to 5xFAD mice at 12 months. Plasma NfL was also significantly decreased.ConclusionDespite the minimal impact on Aβ plaque deposition, humanization of 2kb of Clu allele and introduction of rs2279590 risk SNP suppresses astrocytic response to plaques and is protective against axonal and neuritic damage which is mirrored by the reduced levels of plasma NfL.

Dementia Risk Factors Predict Individual Differences in Cognitive Function

AbstractBackgroundTwelve modifiable risk factors have been estimated to account for 40% of dementia incidence worldwide (Livingston et al., 2020). Growing understanding of these risk factors presents the possibility that dementia risk can be partially mitigated via non‐pharmacological means, such as changes in lifestyle (e.g., alcohol consumption, social activity). We sought to provide the first systematic investigation of whether this set of risk factors also contributes to individual differences in cognitive function in a cognitively‐normal sample, and which risk factors provide the strongest contribution.MethodWe investigated cross‐sectionally the association between eight of these risk factors and cognition in 246 cognitively‐normal adults, aged 50‐90 from the Dallas Lifespan Brain Study. Risk factors included alcohol use (drinks per week), body mass index (BMI), cigarettes smoked per day, depressive symptoms (CESD scale), years of education, exercise frequency (20+ min sessions), pulse pressure, and frequency of social activity. A general measure of cognition, fluid ability, was used as the outcome variable and it was an average of six commonly used assessments of processing speed, working memory, and reasoning.ResultIn a multiple regression controlled for age and sex, 15.6% of fluid ability variance was accounted for by years of education (R 2 = .040, p = .002), frequency of social activity (R 2 = .034, p = .004), BMI (R 2 = .030, p = .008), cigarettes smoked per day (R 2 = .020, p = .032), and depressive symptoms (R 2 = .017, p = .047), as well as non‐significant contributions from alcohol use, exercise frequency, and pulse pressure. Further analysis examining cortical amyloid‐beta burden as a predictor and moderating effects of age will be discussed.ConclusionThe findings illustrate that levels of these modifiable risk factors affect cognition, even in a large sample of adults unselected for AD risk. We report differences in magnitude of effects for adults who showed cognitive decline over 10 years compared to those who were stable.

Bayesian network analysis of BIN1 risk allele and other risk factors and biomarkers of Alzheimer’s disease

AbstractBackgroundThe Bridging Integrator I (BIN1) is a significant genetic risk gene, second only to the established risk gene apolipoprotein E (APOE4), for late‐onset Alzheimer’s disease (LOAD, AD) (Carrasquillo, 2011). BIN1 rs744733 risk allele was shown to affect tau pathology and cognitive decline (Franzmeier, 2021).In this study, we compared BIN1 risk allele rs6733839 with APOE4 on interdependency among AD risk factors and biomarkers by applying Bayesian Network (BN) modeling (Scutari, 2017) to data from Lilly AD clinical trials.MethodData from A05C (n = 142, NCT01565382), A05E (n = 217, NCT02016560), and untreated arms of AZES (n = 206, NCT02245737), LLCF (n = 229, NCT02791191), and LZAX (n = 194, NCT01900665) trial participants were used for the analysis (table 1). We constructed graphs representing the dependencies among the variables, including demographics, genetic risk genes, brain amyloid and tau measured by 18F‐Florbetapir or 18F‐Flortaucipir positron emission tomography (PET) imaging quantified globally and regionally as a standardized uptake value ratio. Longitudinal tau changes from baseline were computed for a sub cohort (n = 234). Conditional Gaussian Bayesian Network (CGBN) was used to model discrete (gender, genotype) and continuous (age, PET quantifications) variables. Directed Acyclic Graphs (DAG) structure was learned using constraint‐based Incremental Association (iamb) algorithm and score‐based Hill‐Climbing (hc) algorithm with one‐sided type I error rate at 10%. The connection strength was estimated by bootstrap resampling and computing the probability of any variable influencing another variable. Model parameters were estimated using the maximum likelihood estimation method.ResultThe result shows that age influences baseline amyloid (Strength s = 1.0) and parietal tau (s = 0.83). APOE4 influences baseline amyloid (s = 0.75) and tau at four lopes with strength ranging from 0.84 to 0.31 in the order of frontal, parietal, occipital, and temporal lobes. BIN1 influences baseline tau at the parietal lobe (s = 0.42) and other lobes with strength below 0.3. We have not observed consistent dependency between variables and change in tau, likely due to the small sample size (n = 234).ConclusionOur study result is consistent with current knowledge of APOE4 influencing amyloid and tau. The finding that BIN1 influences tau supports the observation of BIN1 rs744373, in linkage disequilibrium with rs6733839, in ADNI and BioFINDER studies (Franzmeier, 2021).

THE IMPORTANCE OF MODIFIED BRONCHOPHONOGRAPHY IN THE DIAGNOSIS OF RECURRENT BRONCHOOBSTRUCTIVE SYNDROME IN CHILDREN

Abstract. Purpose of the study: to establish the diagnostic and prognostic significance of modified bronchophonography in bronchobstructive syndrome in children. Material and methods of research. The paper presents the results of examinations of children with bronchoobstructive syndrome. The patients were divided into 3 groups of 60 patients: Group I - patients with acute obstructive bronchitis (AOB), acute bronchiolitis (ABL), Group II - children with recurrent obstructive bronchitis (ROB) and bronchial asthma (BA), Group III - patients with acute bronchitis without bronchial obstruction (BA). Results of the study and discussion. Analysis of modified bronchophonography indices in groups I-II showed that on admission, E:I index>1.6 indicating bronchial obstruction of the II degree (P<0.001). On the 2nd day of observation, E:I index significantly decreased in patients with ROB, BA and was significantly lower in comparison with indices of patients with OOB, OBL (P<0,05). On the 3rd day of observation and at discharge, the indices were relatively equal, no significant difference was observed (P>0.2; P>0.1). When constructing the ROC-curve and analysing the curve coordinates, it was found that in determining the risk of ROB and AD in children, the diagnostic significance of the E:I index≥1.78, with a sensitivity of 71.7% and specificity of 61.1%. Conclusions. The values of E:I index≥1.78 are predictors of the risk of ROS and BA development, the diagnostic significance of which is confirmed by high sensitivity and specificity, which can be recommended for detecting the risk of recurrent course of BOS in children.

Energy-adjusted dietary inflammatory index and cognitive function in Chinese older adults: a population-based cross-sectional study

ABSTRACT Diet can regulate systemic inflammation, which may play an important role in the development and progression of cognitive impairment and dementia. To explore the relationship between the dietary inflammatory potential and cognitive ability. A total of 2307 adults aged 60 years or older were recruited from the Fujian Provincial Hospital (Fujian, China). Dietary inflammatory properties were analyzed using the energy-adjusted dietary inflammatory index (E-DII). The Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were used to assess cognitive function. Logistic regression and restricted cubic spline (RCS) were fit to assess the associations between variables. The MCI subjects with the highest E-DII scores had a higher risk of AD compared to subjects with the lowest E-DII scores (OR = 1.98, 95%CI = 1.49–2.64, P for trend < 0.001). Subjects with the highest E-DII levels were at increased risk of cognitive impairment compared to those with the lowest E-DII levels (OR = 1.56, 95%CI = 1.25–1.93, P for trend < 0.001). The link between E-DII and cognitive impairment was significant in a nonlinear dose response analysis (P for nonlinear = 0.001). Higher E-DII scores were associated with an increased risk of developing AD or cognitive impairment. These findings may contribute to the effective prevention of cognitive impairment by constructing a multidisciplinary synergistic prevention strategy and controlling dietary inflammation levels.

Dietary inflammatory index, genetic susceptibility and risk of incident dementia: a prospective cohort study from UK biobank.

Genetic factors, diet and inflammation are associated with the development of dementia. In this study, we aimed at evaluating the impact of the dietary inflammatory index (DII) scores and genetic susceptibility on the development of dementia. This prospective study involved 207,301 participants aged between 39 and 72years from UK biobank. A web-based 24-h dietary questionnaire was collected at least once from participants between 2006 and 2012. The DII was calculated based on inflammatory effect score of nutrients. Individual AD-GRS (Alzheimer's disease genetic risk score) was calculated. Incident dementia was ascertained through hospital or death records. Of all 207,301 participants, 468 incident cases of all-cause dementia (165 AD, 91 VD and 26 FTD) were reported during a follow-up period of 11.4years. The participants in the highest quintile (Q) of DII scores reported a higher risk for all-cause dementia (Q5 vs. Q3, hazard ratio (HR) = 1.702; 95% CI: 1.285-2.255) and VD (Q5 vs. Q3, HR = 2.266, 95% CI: 1.133-4.531) compared to participants in the Q3. Besides, when compared with the Q1, there was a higher risk for AD in the subjects of Q5 (Q5 vs. Q1, HR = 1.590; 95% CI: 1.004-2.519). There was a non-linear relationship between DII score and all-cause incidence (P for non-linear = 0.038) by restricted cubic splines. Subgroup analysis found that the increased risk for all-cause dementia and AD was more pronounced in the elderly, women, and higher educated population. Cox regression models indicated that compared with the participants who had a low AD-GRS risk and in the lowest tertile of DII, participants had a high AD-GRS and the highest tertile of DII were associated with a higher risk of AD (HR = 1.757, 95% CI: 1.082-2.855, P = 0.023). The DII scores were independently associated with an augmented risk for all-cause dementia, AD and VD. Additionally, high AD-GRS with higher DII scores was significantly associated with ahigher risk of AD.

Age at Diagnosis of Atrial Fibrillation and Incident Dementia.

Epidemiological evidence regarding the association between atrial fibrillation (AF) onset age and risk of incident dementia remains unexplored. To examine whether age at AF diagnosis is associated with risk of incident dementia and its subtypes. This prospective, population-based cohort study used data from UK Biobank, a public, open-access database in the UK with baseline information collected from 2006 to 2010. A total of 433 746 participants were included in the main analysis after excluding participants with a diagnosis of dementia or AF at baseline, missing data on covariates, or having dementia before AF onset during a median follow-up of 12.6 years. Data were analyzed from October to December 2022. AF diagnosis and age at AF diagnosis according to age groups (<65 years, 65-74 years, or ≥75 years). Incident dementia, ascertained through linkage from multiple databases until December 31, 2021. Cox proportional hazards models and the propensity score matching method were adopted to estimate the association between AF onset age and incident dementia. Of 433 746 included participants, 236 253 (54.5%) were female, the mean (SD) age was 56.9 (8.1) years, and 409 990 (94.5%) were White. Compared with individuals without AF, 30 601 individuals with AF had a higher risk of developing all-cause dementia (adjusted hazard ratio [HR], 1.42; 95% CI, 1.32-1.52) and vascular dementia (VD; adjusted HR, 2.06; 95% CI, 1.80-2.36), but not Alzheimer disease (AD; adjusted HR, 1.08; 95% CI, 0.96-1.21). Among participants with AF, younger age at AF onset was associated with higher risks of developing all-cause dementia (adjusted HR per 10-year decrease, 1.23; 95% CI, 1.16-1.32), AD (adjusted HR per 10-year decrease, 1.27; 95% CI, 1.13-1.42), and VD (adjusted HR per 10-year decrease, 1.35; 95% CI, 1.20-1.51). After propensity score matching, individuals with AF diagnosed before age 65 years had the highest HR of developing all-cause dementia (adjusted HR, 1.82; 95% CI, 1.54-2.15), followed by AF diagnosed at age 65 to 74 years (adjusted HR, 1.47; 95% CI, 1.31-1.65) and diagnosed at age 75 years or older (adjusted HR, 1.11; 95% CI, 0.96-1.28). Similar results can be seen in AD and VD. In this prospective cohort study, earlier onset of AF was associated with an elevated risk of subsequent all-cause dementia, AD, and VD, highlighting the importance of monitoring cognitive function among patients with AF, especially those younger than 65 years at diagnosis.

Abstract 12289: A Postpartum Diastolic Murmur

A 44-year-old G3P1011 underwent uncomplicated Caesarian section for obstetric indications with delivery of a healthy girl. Several hours postpartum, she developed hypoxemia requiring transient supplemental oxygen. Cardiology was consulted for further evaluation. Upon initial assessment, she appeared comfortable with an oxygen saturation of 93% on room air. She reports an otherwise uneventful pregnancy. Her past medical history is significant for chronic hypertension on propranolol. She was afebrile with a HR of 91, BP 147/66 (left arm) and 155/68 (right arm). Her JVP was 10-11 cm H20. There was a III/IV low-pitched decrescendo early-mid diastolic murmur, loudest at the left lower sternal border, radiating to the apex, and a systolic ejection murmur. EKG (panel A) showed normal sinus rhythm, with no ischemic abnormalities. Due to the discovery of a new murmur, there was concern for valvular pathology as a cause for her suspected heart failure, particularly aortic regurgitation (AR). An urgent TTE (panel C-E) was requested and showed a dissection flap in the ascending aorta, effacement of the sinotubular junction, and severe AR. CT angiogram confirmed the diagnosis of type A aortic dissection (AD; panel B). Twelve hours after the delivery of her baby, she underwent emergent aortic valve repair and aortic arch replacement. She recovered well and was discharged home post-op day 6. Though no human data exists, animal data suggests increased AD risk in breastfeeding animals with Marfan Syndrome. Due to her near catastrophic presentation, she elected to not breastfeed. Her genetic testing results are pending. AD in pregnancy is rare. There is an increased risk of AD in pregnant compared to non-pregnant women. AD often occurs in the third trimester or postpartum, and most women are unaware of a preexisting arteriopathy. In this case, the detection of a diastolic murmur resulted in rapid diagnosis and treatment, essential in the management of this life-threatening condition.

12 Traumatic Brain Injury as a Moderator on Apolipoprotein-E Risk Associated with Earlier Onset of Alzheimer's Disease

Objective:Prior studies have determined the Apolipoprotein-E (ApoE) ε4 allele presents a greater risk for developing Alzheimer's disease and for earlier onset of cognitive decline compared to individuals without the gene. Research has also recognized that traumatic brain injuries (TBIs) with loss of consciousness increase the risk for earlier development of the disease. This study sought to determine the moderating factor of TBI history on ApoE-ε4 risk associated with earlier Alzheimer's disease onset.Participants and Methods:Participants included 9,585 individuals with autopsy confirmed Alzheimer's disease pathology, that had available ApoE genotype data, TBI data, and clinician determined age of cognitive decline, representing disease onset. A 2x3 factorial ANOVA was conducted to compare the main effects of ApoE-ε4 status and TBI history and the interaction effect between the two on disease onset. The analyses used three ApoE-ε4 groups and two TBI groups. The groups included: (1) no ApoE-ε4 allele; (2) one ApoE-ε4 allele; (3) two ApoE-ε4 alleles; (4) no TBI history, (5) positive TBI history.Results:Results indicated a significant interaction effect between ApoE-ε4 status and TBI history. Secondary analyses determined the driving force behind the interaction was the effect of ApoE-ε4, which had a significant impact on the age of onset in both TBI groups, while TBI history only significantly impacted onset in individuals without an ApoE-ε4 allele.Conclusions:Contrary to prior research, these findings did not indicate TBI was significant in determining earlier onset. However, it is important to consider the large variability within the TBI group from the lack of differentiation between mild, moderate, and severe TBIs. Overall, these findings underline the greater risk and stronger impact that ApoE-ε4 poses for Alzheimer's disease onset compared to TBI. The results of this study emphasize the importance of evaluating ApoE-ε4 status for determining risk of earlier onset AD. Clinicians can better determine risk by considering patients' ApoE-ε4 status alongside TBI history.

Pesticide Exposure and Alzheimer's Disease: A Case-control Study.

63 AD patients and 50 healthy individuals participated, and the levels of some OCPs derivatives (including; α-HCH, β-HCH, γ-HCH, 2,4-DDT, 4,4-DDT, 2,4-DDE, and 4,4-DDE), total antioxidant capacity (TAC), protein carbonyl (PC), malondialdehyde (MDA), Nitric oxide (NO) along with the activity of superoxide dismutase (SOD), glutathione peroxidase (GPx), paraoxonase 1(PON1), and acetylcholinesterase (AChE) were measured. The mean OCP level of OCPs in AD patients was significantly higher than in the control group. However, the patients' mean levels of TAC, PC, MDA and activity of SOD, GPx, PON1 and AChE were significantly lower than controls. A significant positive correlation was also observed between 2,4-DDE and MDA and between γ-HCH and PC in AD patients. These findings showed that pesticide exposure is associated with an increased risk of AD. Furthermore, the mean levels of oxidative stress markers, which may result from pesticide exposure, were significantly lower in AD patients compared to healthy individuals. Therefore, it may conclude that pesticides, at least in part, contribute to AD development through several mechanisms, including the induction of oxidative stress.

2 Reading Aloud Elicits Connected Speech and Autocorrection: a Novel Marker of Alzheimer’s Disease and Risk

Objective:Spontaneous speech involves tight coordination of a constellation of cognitive mechanisms (including planning, lexical selection, grammatical encoding, internal &amp; external monitoring). Recent years brought a flurry of interest in detailed analysis of spontaneous speech in search of markers of prodromal Alzheimer’s disease. This work dates back to the nun studies by Snowdon et al (1996) and reveals promise for early detection through identification of subtle but significant changes in the nature of speech output years prior to diagnosis of dementia. A major challenge for neuropsychology is to develop methods to harness the potential sensitivity of language to subtle cognitive changes when testing individuals in clinical settings. In this talk I will present two lines of research that illustrate how reading aloud can be used to engage the cognitive mechanisms of spontaneous speech production in a manner that provides an easily accessible measure of Alzheimer’s disease/risk.Participants and Methods:In the first study, Spanish-English bilinguals with mild-to-moderate Alzheimer’s disease (n=20) and proficiency matched controls (n=29) read aloud mixed-language paragraphs with a small number of language-switched words, and we recorded the number of times they automatically translated switch words by accident (e.g., saying pero instead of but; effectively autocorrecting language switches to avoid producing switches overtly). In the second study, cognitively normal monolinguals at risk for AD based on CSF biomarkers (n=14) and controls (n=50) read aloud short paragraphs in which ten critical target words were replaced with autocorrect targets (e.g., The player who scored that final [paint] for the local team reported [him] experience). Participants were instructed to avoid autocorrecting (e.g., avoid saying point instead of paint or his instead of him), and we recorded the number of times they autocorrected by accident.Results:Bilinguals with AD translated switch words more often than controls, and ROC curves revealed good-to-excellent discrimination between patients and controls based solely on the number of errors produced during reading aloud (AUC or Area Under the Curve values ranged from .71-.92). In the second study, cognitively normal monolinguals with high CSF Tau/Aß42 (i.e., an AD-like biomarker profile) produced more autocorrect errors (e.g., saying point instead of paint)than those below the biomarker threshold, and autocorrection errors showed potential for discriminating individuals with higher AD risk from controls (AUC=.76; 95%CI .62-.90).Conclusions:Difficulty stopping automatic translation of language switch words and autocorrection during reading aloud reveals promise as a diagnostic tool. Reading aloud elicits rapid production of hundreds of words while maintaining tight experimental control over the content of speech and harnessing the power and complexity of language to enable detection of very subtle cognitive changes through simple analysis of critical targets. I will discuss the theoretical implications of this work for understanding how bilinguals choose a single language for production, the nature of cognitive impairments in early AD and areas of need for further research to maximize the potential utility of reading aloud for detection of cognitive impairment.

5 Intraindividual Variability in Processing Speed on Digital Cognitive Assessments Differs by Amyloidosis Status in Cognitively Normal Older Adults

Objective:Intraindividual variability (IIV) is defined as fluctuations in an individual’s cognitive performance over time1. IIV has been identified as a marker of neurobiological disturbance making it a useful method for detecting changes in cognition among cognitively healthy individuals as well as those with prodromal syndromes2. IIV on laboratory-based computerized tasks has been linked with cognitive decline and conversion to mild cognitive impairment (MCI) and/or dementia (Haynes et al., 2017). Associations between IIV and AD risk factors including apolipoprotein (APOE) ε4 carrier status, neurodegeneration seen on brain imaging, and amyloid (Aß) Positron emission tomography (PET) scan status have also been observed1. Recent studies have demonstrated that evaluating IIV on smartphone-based digital cognitive assessments is feasible, has the capacity to differentiate between cognitively normal (CN) and MCI individuals, and may reduce barriers to cognitive assessment3. This study sought to evaluate whether such differences could be detected in CN participants with and without elevated AD risk.Participants and Methods:Participants (n=57) were cognitively normal older adults who previously received an Aß PET scan through the Butler Hospital Memory and Aging Program. The sample consisted of primarily non-Hispanic (n=49, 86.0%), White (n=52, 91.2%), college-educated (M=16.65 years), females (n=39, 68.4%). The average age of the sample was 68 years old. Approximately 42% of the sample (n=24) received a positive PET scan result. Participants completed brief cognitive assessments (i.e., 3-4 minutes) three times per day for eight days (i.e., 24 sessions) using the Mobile Monitoring of Cognitive Change (M2C2) application, a mobile app-based cognitive testing platform developed as part of the National Institute of Aging’s Mobile Toolbox initiative (Sliwinski et al., 2018). Participants completed visual working memory, processing speed, and episodic memory tasks on the M2C2 platform. Intraindividual standard deviations (ISDs) across trials were computed for each person at each time point (Hultsch et al., 2000). Higher ISD values indicate more variability in performance. Linear mixed effects models were utilized to examine whether differences in IIV existed based on PET scan status while controlling for age, sex at birth, and years of education.Results:n interaction between PET status and time was observed on the processing speed task such that Aß- individuals were less variable over the eight assessment days compared to Aß + individuals (B= -5.79, SE=2.67, p=.04). No main or interaction effects were observed on the visual working memory task or episodic memory task.Conclusions:Our finding that Aß- individuals demonstrate less variability over time on a measure of processing speed is consistent with prior work. No associations were found between IIV in other cognitive domains and PET status. As noted by Allaire and Marsiske (2005), IIV is not a consistent phenomenon across different cognitive domains. Therefore, identifying which tests are the most sensitive to early change is crucial. Additional studies in larger, more diverse samples are needed prior to widespread clinical use for early detection of AD.

Circulating metabolites and risk of incident dementia: Aprospective cohort study.

Identifying circulating metabolites associated with dementia, cognition, and brain volume may improve the understanding of dementia pathogenesis and provide novel insights for preventive and therapeutic interventions. This cohort study included a total of 87 885 participants (median follow-up of 9.1 years, 54% female) without dementia at baseline from the UK Biobank. A total of 249 plasma metabolites were measured using nuclear magnetic resonance spectroscopy at baseline. Cox proportional regression was used to examine the associations of each metabolite with incident dementia (cases = 1134), Alzheimer's disease (AD; cases = 488), and vascular dementia (VD; cases = 257) during follow-up. Dementia-associated metabolites were further analyzed for association with cognitive deficits (N = 87 885) and brain volume (N = 7756) using logistic regression and linear regression. We identified 26 metabolites associated with incident dementia, of which 6 were associated with incident AD and 5 were associated with incident VD. These 26 dementia-related metabolites were subfractions of intermediate-density lipoprotein, large low-density lipoprotein (L-LDL), small high-density lipoprotein (S-HDL), very-low-density lipoprotein, fatty acids, ketone bodies, citrate, glucose, and valine. Among them, the cholesterol percentage in L-LDL (L-LDL-C%) was associated with lower risk of AD (HR [95% CI] = 0.92 [0.87-0.97], p = 0.002), higher brain cortical (β = 0.047, p = 3.91 × 10-6 ), and hippocampal (β = 0.043, p = 1.93 × 10-4 ) volume. Cholesteryl ester-to-total lipid ratio in L-LDL (L-LDL-CE%) was associated with lower risk of AD (HR [95% CI] = 0.93 [0.90-0.96], p = 1.48 × 10-4 ), cognitive deficits (odds ratio = 0.98, p = 0.009), and higher hippocampal volume (β = 0.027, p = 0.009). Cholesteryl esters in S-HDL (S-HDL-CE) were associated with lower risk of VD (HR [95% CI] = 0.81 [0.71-0.93], p = 0.002), but not AD. Taken together, circulating levels of L-LDL-CE% and L-LDL-C% were robustly associated with risk of AD and AD phenotypes, but not with VD. S-HDL-CE was associated with lower risk of VD, but not with AD or AD phenotypes. These metabolites may play a role in the advancement of future intervention trials. Additional research is necessary to gain a complete comprehension of the molecular mechanisms behind these associations.

A two-sample Mendelian randomization study of atherosclerosis and dementia

The causality between atherosclerosis and dementia remains unclear. This study aimed to explore the causal effect of atherosclerosis related indicators on dementia risk based on two-sample Mendelian randomization (MR) using summary statistics of genome-wide association studies (GWASs). The inverse variance weighted (IVW) method was performed as the main analysis, supplemented by different sensitivity analyses. Suggestive evidence indicated that peripheral arterial disease (PAD) (odds ratio (OR): 0.864, 95% confidence interval (CI): 0.797-0.937), coronary atherosclerosis (CoAS) (OR: 0.927, 95% CI: 0.860-0.998) and atherosclerosis, excluding cerebral, coronary, and PAD (ATHSCLE) (OR: 0.812, 95% CI: 0.725-0.909) were inversely associated with the risk of AD. The sensitivity analysis confirmed a suggestive reverse effect of ATHSCLE on the risk of frontotemporal dementia (FTD) (OR, 0.812, 95% CI, 0.725-0.909). Findings provide suggestive evidence that PAD, CoAS, and ATHSCLE might be associated with the risk of AD or FTD, which requires further exploration in larger samples.

Causal relationships between blood lipids and major psychiatric disorders: Univariable and multivariable mendelian randomization analysis

BackgroundWhether the positive associations of blood lipids with psychiatric disorders are causal is uncertain. We conducted this two-sample Mendelian randomization (MR) analysis to comprehensively investigate associations of blood lipids with psychiatric disorders.MethodsUnivariable and multivariable models were established for MR analyses. Inverse variance-weighted (IVW) MR was employed as the main approach; weighted median and MR-Egger were used as sensitivity analysis methods. The possibility of violating MR assumptions was evaluated utilizing several sensitivity analyses, including heterogeneity statistics, horizontal pleiotropy statistics, single SNP analysis, leave-one-out analysis and MR-PRESSO analysis. As instrumental variables, we screened 362 independent single-nucleotide polymorphisms (SNP) related to blood lipids from a recent genome-wide association study involving 76,627 individuals of European ancestry, with a genome-wide significance level of p < 5 × 10− 8. Summary-level information for the six psychiatric disorders was extracted from Psychiatric Genomics Consortium and Alzheimer Disease Genetics Consortium.ResultsWe observed eight significant associations in univariable MR analysis, four of which were corroborated by multivariable MR (MVMR) analysis modified for the other three lipid traits: high-density lipoprotein cholesterol (HDL-C) level with the risk of PTSD (OR = 0.91, 95% CI = 0.85–0.97, p = 0.002) and AD (OR = 0.79, 95% CI = 0.71–0.88, p < 0.001) and triglycerides (TG) level with the risk of MDD (OR = 1.02, 95% CI = 1.003–1.03, p = 0.01) and panic disorder (OR = 0.83, 95% CI = 0.74–0.92, p < 0.001). In addition, four associations were not significant in MVMR analysis after adjustment for three lipid traits: total cholesterol (TC) level with the risk of PTSD, low-density lipoprotein cholesterol (LDL-C) level with the risk of MDD and AD and TG level with the risk of AD.ConclusionsOur results show that blood lipids and psychiatric disorders may be related in a causal manner. This shows that abnormal blood lipid levels may act as reliable biomarker of psychiatric disorders and as suitable targets for their prevention and treatment.

TOMM40 '523 Genotype Distinguishes Patterns of Cognitive Improvement for Executive Function in APOEɛ3 Homozygotes.

TOMM40 '523 has been associated with cognitive performance and risk for developing Alzheimer's disease independent of the effect of APOE genotype. Few studies have considered the longitudinal effect of this genotype on change in cognition over time. Our objective was to evaluate the relationship between TOMM40 genotype status and change in cognitive performance in the TOMMORROW study, which was designed to prospectively evaluate an algorithm that includes TOMM40 '523 for genetic risk for conversion to mild cognitive impairment. We used latent growth curve models to estimate the effect of TOMM40 allele carrier (short, very long) status on the intercept and slope of change in cognitive performance in four broad cognitive domains (attention, memory, executive function, and language) and a combined overall cognitive score over 30 months. TOMM40 very long allele carriers had significantly lower baseline performance for the combined overall cognitive function score (B = -0.088, p = 0.034) and for the executive function domain score (B = -0.143, p = 0.013). Slopes for TOMM40 very long carriers had significantly greater increases over time for the executive function domain score only. In sensitivity analyses, the results for executive function were observed in participants who remained clinically stable, but not in those who progressed clinically over the study duration. Our results add to the growing body of evidence that TOMM40, in the absence of APOEɛ4, may contribute to cognitive changes with aging and dementia and support the view that mitochondrial function is an important contributor to Alzheimer's disease risk.

Stress, depression, and risk of dementia – a cohort study in the total population between 18 and 65 years old in Region Stockholm

BackgroundChronic stress and depression are potential risk factors for mild cognitive impairment and dementia, including Alzheimer disease. The aim was to investigate whether any such risk is additive.MethodsCohort study including 1 362 548 people (665 997 women, 696 551 men) with records in the Region Stockholm administrative healthcare database (VAL).Exposure was a recorded ICD-10 diagnosis of chronic stress, depression, or both, recorded in 2012 or 2013. Outcome was a diagnosis of Alzheimer disease, other dementia, or mild cognitive impairment recorded from 2014 through 2022. Odds ratios with 99% confidence intervals (CI) adjusted for age, sex, neighborhood socioeconomic status, diabetes, and cardiovascular disorders were calculated.ResultsDuring the exposure period, 4 346 patients were diagnosed with chronic stress, 40 101 with depression, and 1 898 with both. The average age at baseline was around 40 years in all groups. In the fully adjusted model, the odds ratio of Alzheimer disease was 2.45 (99% CI 1.22–4.91) in patients with chronic stress, 2.32 (99% CI 1.85–2.90) in patients with depression, and 4.00 (99% CI 1.67–9.58) in patients with chronic stress and depression. The odds ratio of mild cognitive impairment was 1.87 (99% CI 1.20–2.91) in patients with chronic stress, 2.85 (99% CI 2.53–3.22) in patients with depression, and 3.87 (99% CI 2.39–6.27) in patients with both. When other dementia was analyzed, the odds ratio was significant only in patients with depression, 2.39 (99% CI 1.92–2.96).ConclusionsDocumented chronic stress increased the risk of mild cognitive impairment and Alzheimer disease. The same was seen with depression. The novel finding is the potential additive effect of chronic stress to depression, on risk of MCI and AD.

Test-retest reliability of short- and long-term heart rate variability in individuals with spinal cord injury

Study designCross-sectional.ObjectivesTo investigate test-retest reliability of heart rate variability (HRV) metrics in SCI without restriction of activity over long (24-h) and shorter durations (5-min, 10-min, 1-h, 3-h and 6-h).SettingsUniversity hospital in Khon Kaen, Thailand.MethodsForty-five participants (11 with tetraplegia and 34 with paraplegia) underwent two 24-h recordings of RR-intervals to derive time and frequency HRV metrics. Relative reliability was assessed by intraclass correlation coefficient (ICC) and absolute reliability by coefficient of variation (CV) and Bland–Altman limits of agreement (LoA).ResultsFor 5- and 10-min durations, eight of eleven HRV metrics had moderate to excellent reliability (ICC 0.40–0.76); the remaining three were poor (ICC < 0.4). HRV values from 1-h and 3-h durations showed moderate to excellent reliability (ICC of 0.46–0.81), except for 1-h reliability of ULF and TP (ICC of 0.06 and 0.30, respectively). Relative reliability was excellent (ICC of 0.77–0.92) for 6-h and 24-h durations in all HRV metrics. Absolute reliability improved as recording duration increased (lower CVs and narrower LoAs). Participants with high AD risk (SCI level at or above T6) showed lower test-retest reliability of HF and LF values than participants with low AD risk.ConclusionRelative reliability of HRV was excellent for 6-h and 24-h. The best absolute reliability values were for 24-h duration. Time-domain outcomes were more reliable than frequency domain outcomes. Participants with high risk of AD, particularly those with tetraplegia, showed lower reliability, especially for HF and LF.