bluuebunny/crossref_metadata_2025_split huggingface dataset:
Risk and protective factors for cognitive decline in lower educated older adults with 15‐year follow‐up
Authors: Ribeiro Fabiana , Leist Anja K. 
Published: June 2023

AbstractBackgroundStudies have identified modifiable risk factors for both prevalence and incidence of cognitive impairment in lower educated older adults. However, patterns of cognitive change, and risk and protective factors for declining versus stable cognitive trajectories have rarely been described in this population. Our goal was to explore the long‐term trajectories of cognitive function and identify modifiable risk and protective factors for cognitive decline beyond education.MethodWe applied group‐based trajectory modelling and multinomial logistic regressions to explore possible trajectories and associated baseline factors on data from a population‐based Health, Welfare and Aging (SABE) survey collected in 2000, 2006, 2010, and 2015 in Sao Paulo, Brazil. Cognitive functioning was assessed using the abbreviated Mini‐Mental State Exam. A total of 354 respondents aged 60 + participating in all follow‐ups were included in the statistical analyses.ResultGroup‐based trajectory modelling identified three different cognitive trajectories, specifically groups with stable (37.4%), declining (53.8%), and strongly declining (8.8%) trajectories, with the last one reaching the threshold for cognitive impairment (Figure 1). Socioeconomic status, specifically living in rural areas during childhood and no schooling or primary education, as well as self‐identified race was systematically different between the groups (Table 1). Moreover, respondents in the stable trajectory were more likely to report living in urban areas, more than primary education, to be white, to earn more than four times the minimum wage/month, to practice manual work, craft or artistic activity at least once a week, and less likely to have had stroke or be widowed. On the other hand, those in the strongly declining trajectory were more likely to be black or mixed and smoke at baseline.ConclusionOur findings suggest substantial potential for modification of risk of cognitive decline even in lower educated older individuals at risk for cognitive impairment. Risk factors related to self‐identified race/ethnicity and socioeconomic status suggest systematic inequalities in brain health potential, with risk for later‐life cognitive impairment. Sample attrition suggests conservative estimates of the magnitude of the risk factors for cognitive decline. Health and social policies should address inequalities to improve later‐life cognitive function of at‐risk individuals.
Effects of ApoE in the Panama aging research initiative: A community‐dwelling older adults’ cohort in Panama
Authors: Villarreal Alcibiades E , Britton Gabrielle B , Oviedo Diana C , O'Bryant Sid E. , Edwards Melissa , Carreira Maria B , Rangel Giselle 
Published: June 2023

AbstractBackgroundThe Panama Aging Research Initiative (PARI) is a longitudinal study of more than 800 adults aged 60 years and older. The objective of this analysis consists of identifying the effects of Apolipoprotein E (ApoE) gene as a risk factor for sporadic Alzheimer’s disease (AD), with elevated risk for ε4‐carriers and reduced risk for ε2‐carriers.MethodOur ongoing community‐based cohort (n = 400) has undergone clinical interviews, neuropsychological testing, and assessments of frailty at two time points (14‐29 months apart). Fasting blood draws were obtained for measurements of genetic and blood‐based biological markers. DNA was extracted from whole blood and (ApoE) genotyping (n = 330) was conducted according to standardized PCR procedures. We will examine whether ε2 and ε4 are associated with differential rates of normal cognitive aging, and whether associations of ε4 with cognitive decline are modified by sex, education or other health conditions common among older adults in Panama, including chronic illnesses, polypharmacy and frailty.ResultOur study evaluate whether ApoE ε2, ε3 and ε4 allele frequency is a significant factor associated with cognition and daily function in elderly individuals. Specifically, we focus on evaluating the frequency of ApoE ε4 expression as a risk for cognitive impairment. Together these results contribute to our understanding of the risk factors of cognitive outcomes among Hispanic populations outside the US.ConclusionLittle is known about the factors associated to cognitive health at old age in Central American populations. Genetic biomarkers could be used as a tool for diagnostic testing. It is expected that ApoE‐ε4 polymorphism will correlate with cognitive deficit among the elderly population and those at risk for cognitive impairment.
Unbiased deep learning assessment of APOE4 risk for sporadic Alzheimer’s disease
Authors: Bae Jinhyeong , Nho Kwangsik , Saykin Andrew J. , Penchev Valentin , Apostolova Liana G. 
Published: June 2023

AbstractBackgroundGenome wide association study (GWAS) presented that a cohort having one or two copies of APOE4 show about 2.84 or 8.07 times, respectively, higher risk of having Alzheimer’s disease (AD) than who do not. However, it is unclear how much impact does APOE4 have in progressing AD for an individual. We implemented a deep learning model to identify the APOE4’s risk impact at the individual level.MethodWe applied a novel deep learning model to the 266,161 SNP chromosome 19 data of 313 AD and 457 cognitively unimpaired (CU) ADNI patients. The whole dataset was divided into train, validation, and test set with a ratio of 60%, 20%, and 20% for model development. In the test set, 63.93% of AD participants were APOE4 carriers as opposed to 30.11% of CU participants. Therefore, APOE4 alone has a 67.5% diagnostic accuracy.ResultThe model achieved 68.18% in classifying CU vs. AD and recognized SNPs in APOC1 (rs12721051, rs56131196, rs12721046, and rs4420638) as strong AD risk factors. On the other hand, SNPs in APOE did not show a risk impact such that removal or replacement of the SNPs of the APOE haplotype (rs429358 and rs7412) did neither increase nor decrease the likelihood of AD for any of the 154 test set participants. Furthermore, rs429358 and rs7412 did not show any interaction effects with other SNPs in chromosome 19. Further closer examination of these results confirmed that the APOE haplotype (rs429358 and rs7412) and the APOC1 SNPs (rs12721051, rs56131196, rs12721046, and rs4420638) are in strong linkage disequilibrium (normalized correlation coefficients range 0.685‐0.844) which explains why only one of the two genes was selected by our model. These results were reproduced by 5‐fold cross validation as well as with the implementation of a different deep learning model architecture.ConclusionAPOC1 variants were ranked higher and selected by our deep learning algorithm over the APOE haplotype that has been established as the strongest sporadic AD risk factor to date. APOC1 might be a major AD risk gene that needs further exploration.
Severity and symptoms of depression in older adults presenting to mental health services during COVID‐19 lockdown – an experience from south London region
Authors: Velayudhan Latha , Cheung Wai Yan , Perera Gayan , Broadbent Matthew , Stewart Robert , Mueller Christoph 
Published: June 2023

AbstractBackgroundSocial restrictive measures during COVID‐19 pandemic has influenced people’s mental health conditions across different countries. Global studies indicated an increased prevalence of anxiety disorder and depression with varied impacts among different age groups. Most studies in the elderly have been done via surveys or internet medias missing out on people with no access to digital technology tools. We aimed to investigate the prevalence of depression among elderly people aged 65 years and above who attended mental health service for older adults (MHOA).MethodsRetrospective data was collected from the South London and Maudsley NHS Foundation Trust (SLaM) Biomedical Research Centre (BRC) Case Register for MHOA. Using this large mental health care database in South London, United Kingdom, we identified referrals to MHOA during the first UK lockdown (March ‐ July 2020) and compared those to a corresponding pre‐COVID period (February ‐ July 2019). Logistic regression analysis adjusted for age, gender, ethnicity, diagnosis and living conditions were done to examine association between COVID‐19 lockdown and severity and symptoms of depression.Results536 patients were referred and seen within the MHOA during the first UK COVID‐19 lockdown period compared to 1,455 patients during the pre‐COVID‐19 corresponding period. We found presence of COVID‐19 lockdown had no effect on overall severity of depression but significantly associated with depressive symptoms such as anhedonia (1.64, 95% CI 1.14‐2.37, p = 0.008), lack of energy (1.65. 95% CI 1.65 (1.25‐2.16), p<0.001), tearfulness (1.43, CI% 1.15‐1.78, p = 0.001), agitation (1.32, CI% 1.07‐1.63, p = 0.009), disturbed sleep (1.37, CI% 1.11‐1.70, p = 0.003) and guilt feelings (1.45, CI% 1.04‐2.03, p = 0.030)ConclusionsThere was an increased prevalence of certain depressive symptoms among older adults within MHOA during first COVID‐19 lockdown which implies impact of isolation and possibly physical ill‐health on mental well‐being. This needs to be explored further for potential prevention and managements.
Rapid suppression of macroscopic homomeric Kv1.2 and heteromeric Kv1.1/1.2 currents by amyloid beta (1‐42) peptide: Implications for Alzheimer’s disease
Authors: Jamshidi Dina , Watkins Joshua , DeBoeuf Kristi , Farley Joseph 
Published: June 2023

AbstractBackgroundThe roles of Aβ in the pathogenesis of Alzheimer ’s disease (AD) include disruption of 1) Ca2+ homeostasis, 2) synaptic communication and function, and 3) synaptic plasticity mechanisms thought to be critical for learning and memory. Exactly how these abnormalities arise is incompletely understood. Our lab has focused on the potential involvement of voltage‐gated potassium channels (VGKCs) in several of these processes. VGKCs are activated during an action potential and regulate Ca2+ influx, and inhibition of VGKCs can lead to synapto‐ and neuro‐toxicity. In the nervous system, members of the Kv1.x family can be expressed as homomers or select heteromers; e.g., Kv1.1 is often co‐expressed with Kv1.2. Studies in our lab have shown that Aβ peptides suppress VGKC activity, particularly Kv1.1. Here we asked if Aβ suppression is specific to Kv1.1 homomers, or if it affects other members of the Kv1.x family (e.g., Kv1.2) and/or heteromers also?MethodStage V/VI Xenopus laevis oocytes were acquired from Ecocyte Bioscience (Austin, TX) and injected with Kv1.2 cRNA for homomeric expression. Heteromeric expression was evaluated by coinjection of Kv1.1 and 1.2 cRNA. The effects of bath application (1 μM) of Aβ(1‐42) on macroscopic currents from homomeric Kv1.2 and 1.1/1.2 heteromeric channels were assessed using two‐electrode voltage clamp (TEVC). DMSO was used as a control.ResultAs seen for homomeric Kv1.1 channels, Aβ suppressed homomeric Kv1.2 channels by ∼50% in 30 min. About 50% of this suppression was dependent on intracellular Ca2+. Aβ(1‐42) suppressed macroscopic heteromeric Kv1.1/1.2 channels by ∼41% in 30 min. The suppression was independent of changes in activation‐deactivation kinetics or voltage dependency.ConclusionHeterologously expressed homomeric Kv1.2 and heteromeric Kv1.1/1.2 channels were both suppressed by Aβ(1‐42), similar to Kv1.1 homomers. Suppression of homomeric and heteromeric Kv1.x channels could potentially lead to larger and longer action potentials, resulting in a greater influx of Ca2+ into presynaptic terminals of excitatory neurons, and depolarization of dendritic spines. Both could contribute to synapto‐ and neuro‐toxicity via increased glutamate release and depolarization of NMDA receptors.
The reliability and validity of the snellen memory test for point‐of‐care detection of Alzheimer’s risk in cognitively unimpaired older adults
Authors: Gosselin Emma J , Thompson Louisa I , Sinoff Stuart , Strenger Jennifer , Snyder Peter J , Maruff Paul , Alber Jessica 
Published: June 2023

AbstractBackgroundEpisodic memory decline is one of the earliest cognitive indicators in Alzheimer’s disease (AD) with impairment in memory in older adults an important indicator of incipient AD. Optometry has potential for population based, point‐of‐care screening as retinal biomarkers can detect both symptomatic and preclinical AD. Here, we aimed to develop and optimize a test of episodic memory for use in clinical optometry/ophthalmology settings alongside retinal imaging methods to detect both preclinical and early symptomatic AD.Method30 cognitively normal (CN) older adults (55‐81 years; 68.5±7) from the Atlas of Retinal Imaging in Alzheimer’s Study (ARIAS) completed the Snellen Memory Test (SMT). Participants completed a a Snellen Eye Chart for three learning trials of 10 seconds exposures, followed by immediate free recall. After a 20‐minute delay, participants completed delayed free recall in which they were asked to recall as many of the letters as they had been shown. This was followed by a recognition test in which participants viewed a mock chart identifying the correct letters and if they were in the correct location as the original chart.ResultAn intraclass correlation coefficient was calculated to determine the inter‐rater reliability among three raters for 10 randomly selected administrations. Overall results indicated good reliability with a mean coefficient of 0.87 (95% CI: 0.71‐1.03). Convergent and divergent validity for the 30 participants was assessed by comparing SMT performance to RBANS indices and the Free and Cued Selective Reminding Test (FCSRT). The SMT significantly correlated with the RBANS Immediate Memory Index (r = 0.38‐0.52), Language Index (r = 0.39‐0.51), and Attention Index (r = 0.39‐0.46) as well as with selective reminding trial 1 and 2 (r = 0.45‐0.78), and free and cued recall for trial 3 (r = 0.45‐0.47).ConclusionThe SMT has potential as an episodic memory test that could be used for point of care detection of preclinical AD. Future work will continue to validate the SMT against reference standard neuropsychological assessments of episodic memory and against AD retinal imaging biomarkers.
Day‐to‐day sleep and circadian variability in association with Alzheimer’s Disease biomarkers
Authors: Baril Andree‐Ann , Picard Cynthia , Labonté Anne , Sanchez Erlan , Duclos Catherine , Ashton Nicholas J. , Zetterberg Henrik , Blennow Kaj , Breitner John C.S. , Villeneuve Sylvia , Poirier Judes ,   PREVENT‐AD Research Group
Published: June 2023

AbstractBackgroundIncreasing evidence shows that Alzheimer’s Disease (AD) pathology, i.e., the Aß peptide, tau tangles and the APOEε4 allele, have all been associated with disrupted sleep and change in circadian rhythms. However, objective sleep measurements are often assessed over a single night. Measures of day‐to‐day variability might reveal unstable sleep and circadian rhythms that may reflect neurodegenerative processes. We sought to evaluate the association between AD biomarkers and sleep and circadian variability measured over a week of actigraphy.Method203 dementia‐free participants (age: 68.5±5.4 years, 151 women) from the PREVENT‐AD cohort with known APOEε4 carrier status were tested with a week of actigraphy. Overlapping subsamples were tested for determination of cerebrospinal fluid (CSF) Aß1‐42, total t‐tau and p(181)‐tau (n = 100); CSF apoE protein (n = 69); and plasma Aß1‐42 (n = 144). Day‐to‐day variability in actigraphy circadian and sleep measures were assessed using the standard deviation of individual results. Day‐to‐day variability was compared between APOEε4 carriers were compared to non‐carriers using t‐tests. Linear regressions were performed between day‐to‐day variability with CSF and plasma, adjusted for age, sex, and time interval between measurements. An interaction term for APOEε4 carrier status was additionally tested in regression models.ResultAPOEε4 carriers did not differ meaningfully from non‐carriers regarding sleep and circadian variability. Lower CSF Aß1‐42 was associated with higher day‐to‐day variability of time of morning awakening and nighttime sleep duration (ß = ‐0.263, p = 0.009; b = ‐0.206, p = 0.041). Higher plasma Aß1‐42 was also associated with higher day‐to‐day variability for time in bed, activity counts, sleep onset latency, sleep efficiency, and nighttime sleep duration (ß = 0.160 to 0.242; p = 0.010 to 0.002). Lower CSF apoE protein was associated with increased day‐to‐day variability for time of morning awakening, time in bed, activity counts, and nighttime sleep duration (ß = ‐0.243 to ‐0.420; p = 0.042 to <0.001). Higher CSF t‐tau, and a trend for p(181)‐tau were associated with time of morning awakening day‐to‐day variability inε4 carriers only (interaction p<0.001;ß = 0.330, p = 0.047; b = 0.281, p = 0.094).ConclusionSleep and circadian variability are associated with biomarkers of AD pathology and apoE metabolism. These results may suggest that unstable sleep promotes neurodegeneration or, conversely, that AD neuropathology disrupts sleep and circadian function.
Transcriptomic profiling of brain amyloidosis and Alzheimer’s disease phenotypes identifies novel gene targets from peripheral blood gene expression data
Authors: Sanjay Apoorva Bharthur , Svaldi Diana , Logan Paige E. , Stage Eddie , Apostolova Liana G. 
Published: June 2023

AbstractBackgroundIn an effort towards pre‐symptomatic risk assessment, precision medicine and biomarker development in AD, we evaluated the efficacy of characterizing and clustering peripheral blood transcriptomic data with respect to brain amyloidosis.Method356 ADNI participants with blood gene expression, Florbetapir SUVR, neurodegeneration measures and CSF measures (CN = 120, EMCI = 130, LMCI = 72 and AD = 34) were identified (Table‐1). Differential expressed genes from ∼50,000 transcripts (p<0.001) were identified. Pairwise euclidean distance between genes was used to construct a gene‐gene distance matrix followed by K‐means clustering (Figure‐1). Gene enrichment analysis was performed on each cluster to identify biological processes associated with the cluster. “Eigengene”; a data vector representing the whole cluster was obtained for each cluster using Principal Component Analyses. The top driver genes were identified from each cluster. We used the tool MAGMA (Multi‐marker Analysis of GenoMic Annotation) to analyze variants in the driver genes. Voxel‐wise multiple regression in SPM12 with age and sex as covariates was used to visualize the pattern of association of driver gene expression with brain amyloidosis. The association of the transcripts identified through our analyses to amyloid SUVR, and disease diagnosis were validated in the external ImaGene(n = 160) dataset.ResultWe identified five clusters with distinct biological processes highly relevant in AD. All five clusters were significantly associated with Florbetapir SUVR and CSF Abeta measures (p<0.05) (Figure‐2). 28 driver genes were identified. Six driver genes (BAIAP3, E2F2, PSMF1, SMOX, UBE20 and RNF11) had negative association with amyloidosis in the lateral temporal, lateral parietal and temporo‐ and parieto‐occipital areas, in addition to regions of the frontal lobe (Figure‐3). One of the driver genes, KANK2, and overall, 29 of the differentially expressed genes had SNPs significantly associated with AD and MCI phenotype (Table‐2). The top driver genes showed similar correlation to amyloid SUVR in the ImaGene dataset (Figure‐4B). A logistic regression model with 28 driver genes, and age and sex as covariates predicted amnestic MCI diagnosis in the external dataset with an AUC of 0.82(Figure‐4A).ConclusionUsing a data driven approach we identified novel gene targets from peripheral blood which directly correlate to amyloid‐related pathogenesis and AD phenotype
Phenoconversion and disease progression observed in mutation carriers of familial Frontotemporal Lobar Degeneration in the ALLFTD Consortium
Authors: Heuer Hilary W. , Clark Annie L , Brushaber Danielle , Forsberg Leah K. , Miyagawa Toji , Staffaroni Adam M. , Huey Edward D. , Boeve Brad F. , Rosen Howard J. , Boxer Adam L. , Investigators ALLFTD 
Published: June 2023

AbstractBackgroundThe ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study is designed to characterize both sporadic and familial FTLD (f‐FTLD) through annual detailed clinical, neuropsychological, biomarker, and neuroimaging assessments to capture disease onset and trajectory in preparation for therapeutic trails in FTLD. Transitions from asymptomatic to mild disease, or from mild to overt, may reveal critical windows for intervention.Method169 f‐FTLD participants carrying mutations in the main FTLD‐associated genes (79 C9orf72; 37 GRN; 53 MAPT) with at least two clinical assessments were included for analysis of phenoconversion from asymptomatic or mild disease. [CDRÒ + NACC FTLD global scores (Miyagawa et al, 2020) were used to define baseline status at first visit: “asymptomatic” = 0 and “mild” = 0.5. Conversion was defined as “partial” (asymptomatic to mild), “definite” (asymptomatic to overt [CDRÒ + NACC FTLD > = 1) and “mild to overt” (0.5 to > = 1).ResultDefinite conversion occurred most often in MAPT mutation carriers, with 5/43 asymptomatic carriers transitioning through mild to overt across multiple visits. Definite conversion was also seen in 2/65 C9orf72 expansion carriers and 1/30 GRN mutation carriers. All definite converters were assessed as mild (CDRÒ + NACC FTLD = 0.5) for at least one intermediate visit; definite conversion was observed from 2‐4 years from initial assessment. Partial conversions also occurred in all three genetic groups (MAPT: 6; C9orf72: 5; GRN: 5). Further conversion is expected to be observed in these participants in additional follow‐up visits. C9orf72 expansion carriers were less likely to progress from a baseline of mild to overt (3/14) than GRN carriers (4/6) or MAPT (7/10).ConclusionLongitudinal assessment through natural history studies can capture early phenoconversion in carriers of FTLD‐associated genetic mutations; corresponding imaging, cognitive, and biomarker profiles captured may provide insights into disease mechanisms and trajectories.