Biology subjects

Elman, J. A.

Publications and source records attributed to Elman, J. A..

10 recordsLinked to original sources

bioRxiv2024

Testing the causal impact of amyloidosis on total Tau using a genetically informative sample of adult male twins.

INTRODUCTIONThe amyloid cascade hypothesis predicts that amyloid-beta (A{beta}) aggregation drives tau tangle accumulation. We tested competing causal and non-causal hypotheses regarding the direction of causation between A{beta}40 and A{beta}42 and total Tau (t-Tau) plasma biomarkers. METHODSPlasma A{beta}40, A{beta}42, t-Tau, and neurofilament light chain (NFL) were measured in 1,035 men (mean = 67.0 years) using Simoa immunoassays. Genetically informative twin modeling tested the direction of causation between A{beta}s and t-Tau. RESULTSNo clear evidence that A{beta}40 or A{beta}42 directly causes changes in t-Tau was observed; the alternative causal hypotheses also fit the data well. In contrast, exploratory analyses suggested a causal impact of the A{beta} biomarkers on NFL. Separately, reciprocal causation was observed between t-Tau and NFL. DISCUSSIONPlasma A{beta}40 or A{beta}42 do not appear to have a direct causal impact on t-Tau. In contrast, A{beta} aggregation may causally impact NFL in cognitively unimpaired men in their late 60s.

pathology↗

bioRxiv2022

The genetic and environmental etiology of blood-based biomarkers related to the risks of Alzheimer's Disease in a population-based sample of early old age men

The amyloid-tau-neurodegeneration (ATN) framework has led to an increased focus on Alzheimers disease (AD) biomarkers. The cost and invasiveness of obtaining biomarkers via cerebrospinal fluid has motivated efforts to develop sensitive blood-based biomarkers. Although AD is highly heritable, the biometric genetic and environmental etiology of blood-based biomarkers has never been explored. We therefore, analyzed plasma beta-amyloid (A{beta}40, A{beta}42, A{beta}42/40), total tautau (t-tautau), and neurofilament light (NFL) biomarkers in a sample of 1,050 men aged 60 to 73 years (m=68.2, SD=2.5) from the Vietnam Era Twin Study of Aging (VETSA). Unlike A{beta} and tautau, NFL does not define AD; however, as a biomarker of neurodegeneration it serves as the N component in the ATN framework. Univariate estimates suggest that familial aggregation in A{beta}42, A{beta}42/40, t-tau, and NFL is entirely explained by additive genetic influences accounting for 40%-58% of the total variance. All remaining variance is associated with unshared or unique environmental influences. For A{beta}40, a additive genetic (31%), shared environmental (44%), and unshared environmental (25%) influences contribute to the total variance. In the more powerful multivariate analysis of A{beta}42, A{beta}40, t-tau, and NFL, heritability estimates range from 32% to 58%. A{beta}40 and A{beta}42 are statistically genetically identical (rg = 1.00, 95%CI = 0.92,1.00) and are also moderately environmentally correlated (re = 0.66, 95%CI = 0.59, 0.73). All other genetic and environmental associations were non-significant or small. Our results suggest that plasma biomarkers are heritable and that A{beta}40 and A{beta}42 share the same genetic influences, whereas the genetic influences on plasma t-tau and NFL are mostly unique and uncorrelated with plasma A{beta} in early old-age men.

genetics↗

bioRxiv2021

The genetic etiology of longitudinal measures of predicted brain ageing in a population-based sample of mid to late-age males

Magnetic resonance imaging data are being used in statistical models to predicted brain ageing (PBA) and as biomarkers for neurodegenerative diseases such as Alzheimers Disease. Despite their increasing application, the genetic and environmental etiology of global PBA indices is unknown. Likewise, the degree to which genetic influences in PBA are longitudinally stable and how PBA changes over time are also unknown. We analyzed data from 734 men from the Vietnam Era Twin Study of Aging with repeated MRI assessments between the ages 52 to 72 years. Biometrical genetic analyses twin models revealed significant and highly correlated estimates of additive genetic heritability ranging from 59% to 75%. Multivariate longitudinal modelling revealed that covariation between PBA at different timepoints could be explained by a single latent factor with 73% heritability. Our results suggest that genetic influences on PBA are detectable in midlife or earlier, are longitudinally very stable, and are largely explained by common genetic influences. HighlightsWe explored the genetic and environmental etiology of MRI-based predicted brain age (PBA) in a longitudinal sample of males starting in midlife. Genetic influences on PBA are detectable in midlife or earlier, are longitudinally very stable, and largely explained by common genetic influences.

genetics↗

bioRxiv2020

Associations between Early Midlife Lifestyle Behaviors, Young Adult Cognitive Reserve and Advanced Predicted Brain Age in Late Midlife

ImportanceBoth cognitive reserve and modifiable lifestyle behaviors are associated with dementia risk. The effect of early lifestyle behaviors and cognitive reserve on late midlife brain aging could inform early identification and risk reduction of future dementia. ObjectiveDetermine associations of young adult cognitive reserve, early midlife lifestyle behaviors, and the reserve-by-lifestyle interaction on late midlife brain age. Examine the relationship between mild cognitive impairment (MCI) and brain age. DesignParticipants were from the nationally representative Vietnam Era Twin Study of Aging (VETSA). Cognitive reserve was assessed at median age 20 years (IQR=1.38) with the Armed Forces Qualification Test (AFQT). Lifestyle behaviors (smoking, alcohol consumption, and social engagement) were assessed at median age 41 (IQR=5.00). Structural brain imaging conducted at median age 69 (IQR=4.74) was used to construct predicted brain age difference scores (PBAD=chronological age minus predicted brain age) and MCI was ascertained. SettingIn-person cognitive testing (ages 20 and 69); mailed survey (age 41); structural MRI, MCI diagnosis at University of California, San Diego (age 69). Participants431 community-dwelling men. ExposuresAFQT; self-reported health and lifestyle behaviors. Main outcomes and measuresPBAD scores; MCI. ResultsIn fully adjusted mixed linear models, age 20 cognitive reserve and the age 41 lifestyle composite were associated with age 69 PBAD [t (104)=2.62, p=0.01, 95%CI 0.874, 6.285; t (104)=3.37, p=0.001, 95%CI 0.583, 2.249 respectively] as was the reserve-by-lifestyle interaction [t (104) = -2.29, p=0.02, 95%CI -2.330, -0.167]. Unfavorable lifestyle predicted more advanced brain age, but only for those with lower young adult cognitive reserve. The MCI group had more advanced brain age (F (2,130) = 3.13; p=0.05). Conclusions and relevanceFavorable lifestyle behaviors promoted resistance to accelerated brain aging 3 decades later for those with lower young adult cognitive reserve. High reserve appeared to be protective regardless of lifestyle. The association with MCI suggests that advanced PBAD scores reflect poorer brain integrity, although it is unclear if PBAD is related to Alzheimers dementia specifically. Lower cognitive reserve increases risk for dementia, but early lifestyle modification may promote healthier brain aging and dementia risk reduction, particularly in those with lower reserve. Study TypeCohort Study Key PointsO_ST_ABSQuestionC_ST_ABSDo modifiable lifestyle behaviors in early midlife predict later accelerated brain aging and is that association moderated by cognitive reserve? FindingsA lifestyle composite of smoking, alcohol consumption and social engagement at age 41 was associated with estimated brain age in late midlife. There was a significant moderation effect whereby more unfavorable lifestyle behaviors predicted more advanced brain aging, but only in those with low-to-moderate cognitive reserve. MeaningFavorable lifestyle behaviors appear to be protective for brain integrity especially among those with lower cognitive reserve. Early midlife efforts at prevention could be prioritized among those with lower cognitive reserve.

neuroscience↗

bioRxiv2019

Hippocampal subfield volumes are uniquely affected in PTSD and depression: International analysis of 31 cohorts from the PGC-ENIGMA PTSD Working Group

BackgroundPTSD and depression commonly co-occur and have been associated with smaller hippocampal volumes compared to healthy and trauma-exposed controls. However, the hippocampus is heterogeneous, with subregions that may be uniquely affected in individuals with PTSD and depression.\n\nMethodsWe used random effects regressions and a harmonized neuroimaging protocol based on FreeSurfer (v6.0) to identify sub-structural hippocampal markers of current PTSD (C-PTSD), depression, and the interaction of these conditions across 31 cohorts worldwide (N=3,115; Mage=38.9{+/-}13.9 years). Secondary analyses tested these associations by sex and after modeling the simultaneous effects of remitted PTSD, childhood trauma, mild traumatic brain injury, and alcohol use disorder.\n\nResultsA significant negative main effect of depression (n=800, vs. no depression, n=1456) was observed in the hippocampal tail ({beta}=-0.13) and CA1 ({beta}=-0.09) after adjusting for covariates and multiple testing (adjusted ps (q)=0.028). A main effect of C-PTSD (n=1042 vs. control, n=1359) was not significant, but an interaction between C-PTSD and depression was significant in the CA1 ({beta}=-0.24, q=0.044). Pairwise comparisons revealed significantly smaller CA1 volumes in individuals with C-PTSD+Depression than controls ({beta}=-0.12, q=0.012), C-PTSD-only ({beta}=-0.17, q=0.001), and Depression-only ({beta}=-0.18, q=0.023). Follow-up analyses revealed sex effects in the hippocampal tail of depressed females, and an interaction effect of C-PTSD and depression in the fimbria of males.\n\nConclusionsCollectively our results suggest that depression is a stronger predictor of hippocampal volumetry than PTSD, particularly in the CA1, and provide compelling evidence of more pronounced hippocampal phenotypes in comorbid PTSD and depression compared to either condition alone.

neuroscience↗

bioRxiv2019

Semantic Fluency Predicts Six-Year Progression to Mild Cognitive Impairment in Middle-Aged Men

ObjectiveTest the hypothesis that individual differences in episodic memory and verbal fluency in cognitively normal middle-aged adults will predict progression to amnestic MCI after 6 years.\n\nMethodThe analysis sample included 842 male twins who were cognitively normal at baseline (M=56 years), completed measures of episodic memory and verbal fluency at baseline and again 6 years later (M=62 years).\n\nResultsPoor episodic memory predicted progression to both amnestic MCI (OR=4.42, 95% CI [2.44, 10.60]) and non-amnestic MCI (OR=1.92, 95% CI [1.32, 3.44]). Poor semantic verbal fluency also independently predicted progression to amnestic MCI (OR=1.86, 95% CI [1.12, 3.52]). In the full sample, a semantic-specific fluency latent variable at wave 1 (which controls for letter fluency) predicted change in episodic memory at wave 2 ({beta}=.13), but not vice-versa ({beta}=.04). Associations between episodic memory and verbal fluency factors were primarily explained by genetic, rather than environmental, correlations.\n\nConclusionsAmong individuals who were cognitively normal at wave 1, episodic memory moderately-to-strongly predicted progression to MCI at average age 62, emphasizing the fact that there is still meaningful variability even among cognitively normal individuals. Episodic memory, which is typically a primary focus for AD risk, declined earlier and more quickly than fluency. However, semantic fluency at average age 56 predicted 6-year change in memory as well as progression to amnestic MCI even after accounting for baseline memory performance. These findings emphasize the utility of memory and fluency measures in early identification of AD risk.

genetics↗

bioRxiv2019

Pupillary dilation responses as a midlife indicator of risk for Alzheimer’s Disease: Association with Alzheimer’s disease polygenic risk

Pathological changes in Alzheimers disease (AD) begin decades before dementia onset. Because locus coeruleus tau pathology is the earliest occurring AD pathology, targeting indicators of locus coeruleus (dys)function may improve midlife screening for earlier identification of AD risk. Pupillary responses during cognitive tasks are driven by the locus coeruleus and index cognitive effort. Several findings suggest task-associated pupillary response as an early marker of AD risk. Requiring greater effort suggests being closer to ones compensatory capacity, and adults with mild cognitive impairment (MCI) have greater pupil dilation during digit span tasks than cognitively normal individuals, despite equivalent task performance. Higher AD polygenic risk scores (AD-PRSs) are associated with increased odds of MCI and tau positivity. We hypothesized that AD-PRSs would be associated with pupillary responses in cognitively normal middle-aged adults. We demonstrated that pupillary responses during digit span tasks were heritable (h2=.30-.36) in 1119 men ages 56-66. We then examined associations between AD-PRSs and pupillary responses in a cognitively normal subset who all had comparable span capacities (n=539). Higher AD-PRSs were associated with greater pupil dilation/effort in a high (9-digit recall) cognitive load condition; Cohens d=.36 for the upper versus lower quartile of the AD-PRS distribution. Results held up after controlling for APOE genotype. The results support pupillary response--and by inference, locus coeruleus dysfunction--as a genetically-mediated biomarker of early MCI/AD risk. In some studies, cognition predicted disease progression earlier than biomarkers. Pupillary responses might improve screening and early identification of genetically at-risk individuals even before cognitive performance declines.

genetics↗

bioRxiv2019

Multiple memory tests in midlife improve prediction of mild cognitive impairment

INTRODUCTIONPredicting risk for Alzheimers disease when most people are likely still biomarker negative would aid earlier identification. We hypothesized that combining multiple memory tests and scores in middle-aged adults would provide useful, and non-invasive, prediction of 6-year progression to MCI.\n\nMETHODSWe examined 849 men who were cognitively normal at baseline (mean age=55.69{+/-}2.45).\n\nRESULTSCalifornia Verbal Learning Test learning trials was the best individual predictor of amnestic MCI (OR=4.75). A latent factor incorporating 7 measures across 3 memory tests provided much stronger prediction (OR=9.88). This compared favorably with biomarker-based prediction in a study of much older adults.\n\nDISCUSSIONNeuropsychological tests are sensitive and early indicators of Alzheimers disease risk at an age when few individuals are likely to have yet become biomarker positive. Single best measures may appear time- and cost-effective, but 30 additional minutes of testing, and use of multiple scores within tests, provides substantially improved prediction

pathology↗

bioRxiv2019

Aβ-Positivity Predicts Cognitive Decline but Cognition Also Predicts Progression to Aβ-Positivity

IntroductionBiomarker positivity predicts cognitive decline and Alzheimers dementia. But what predicts biomarker positivity? We hypothesized that cognitive function and p-tau would predict progression from normal to abnormal levels of {beta}-amyloid (A{beta}). MethodsBaseline cognition in 292 non-demented, A{beta}-negative Alzheimers Disease Neuroimaging Initiative (ADNI) participants was measured with two cognitive composites and compared between those that progressed to A{beta}-positivity versus A{beta}-stable. Follow-up analyses included continuous CSF A{beta} and p-tau levels to examine subthreshold effects. ResultsContinuously measured baseline subthreshold A{beta} and p-tau predicted progression to A{beta}-positivity, but both baseline cognitive measures predicted progression to A{beta}-positivity even after controlling for baseline biomarker levels. DiscussionCurrent A{beta} thresholds may be ignoring relevant subthreshold pathology. Importantly, cognitive function can be an important early predictor of future risk, even earlier than the key biomarkers as currently measured. Moreover, A-/T+ individuals may still be on the AD pathway because p-tau also predicted progression to positivity.

neuroscience↗

bioRxiv2018

Genetic risk for coronary heart disease alters the influence of Alzheimer’s genetic risk on mild cognitive impairment

BACKGROUNDAlzheimers disease (AD) is under considerable genetic influence. However, known susceptibility loci only explain a modest proportion of variance in disease outcomes. This small proportion could occur if the etiology of AD is heterogeneous. We previously found that an AD polygenic risk score (PRS) was significantly associated with mild cognitive impairment (MCI), an early stage of AD. Poor cardiovascular health is also associated with increased risk for AD and has been found to interact with AD pathology. Conditions such as coronary artery disease (CAD) are also heritable, and may contribute to heterogeneity if there are interactions of genetic risk for these conditions as there is phenotypically. However, case-control designs based on prevalent cases of a disease with relatively high case-fatality rate such as CAD may be biased toward individuals who have long post-event survival times and may therefore also identify loci with protective effects.\n\nMETHODSWe compared interactions between an AD-PRS and two CAD-PRSs, one based on a GWAS of incident cases and one on prevalent cases, on MCI status in 1,209 individuals.\n\nRESULTSAs expected, the incidence-based CAD-PRS interacts with the AD-PRS to further increase MCI risk. Conversely, higher prevalence-based CAD-PRSs reduced the effect of AD genetic risk on MCI status.\n\nCONCLUSIONSThese results demonstrate: i) the utility of including multiple PRSs and their interaction effects; ii) how genetic risk for one disease may modify the impact of genetic risk for another; and iii) the importance of considering ascertainment procedures of GWAS being used for genetic risk prediction.

genomics↗