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  • 1
    In: Brain, Oxford University Press (OUP), Vol. 145, No. 7 ( 2022-07-29), p. 2541-2554
    Abstract: Approximately 30% of elderly adults are cognitively unimpaired at time of death despite the presence of Alzheimer’s disease neuropathology at autopsy. Studying individuals who are resilient to the cognitive consequences of Alzheimer’s disease neuropathology may uncover novel therapeutic targets to treat Alzheimer’s disease. It is well established that there are sex differences in response to Alzheimer’s disease pathology, and growing evidence suggests that genetic factors may contribute to these differences. Taken together, we sought to elucidate sex-specific genetic drivers of resilience. We extended our recent large scale genomic analysis of resilience in which we harmonized cognitive data across four cohorts of cognitive ageing, in vivo amyloid PET across two cohorts, and autopsy measures of amyloid neuritic plaque burden across two cohorts. These data were leveraged to build robust, continuous resilience phenotypes. With these phenotypes, we performed sex-stratified [n (males) = 2093, n (females) = 2931] and sex-interaction [n (both sexes) = 5024] genome-wide association studies (GWAS), gene and pathway-based tests, and genetic correlation analyses to clarify the variants, genes and molecular pathways that relate to resilience in a sex-specific manner. Estimated among cognitively normal individuals of both sexes, resilience was 20–25% heritable, and when estimated in either sex among cognitively normal individuals, resilience was 15–44% heritable. In our GWAS, we identified a female-specific locus on chromosome 10 [rs827389, β (females) = 0.08, P (females) = 5.76 × 10−09, β (males) = −0.01, P(males) = 0.70, β (interaction) = 0.09, P (interaction) = 1.01 × 10−04] in which the minor allele was associated with higher resilience scores among females. This locus is located within chromatin loops that interact with promoters of genes involved in RNA processing, including GATA3. Finally, our genetic correlation analyses revealed shared genetic architecture between resilience phenotypes and other complex traits, including a female-specific association with frontotemporal dementia and male-specific associations with heart rate variability traits. We also observed opposing associations between sexes for multiple sclerosis, such that more resilient females had a lower genetic susceptibility to multiple sclerosis, and more resilient males had a higher genetic susceptibility to multiple sclerosis. Overall, we identified sex differences in the genetic architecture of resilience, identified a female-specific resilience locus and highlighted numerous sex-specific molecular pathways that may underly resilience to Alzheimer’s disease pathology. This study illustrates the need to conduct sex-aware genomic analyses to identify novel targets that are unidentified in sex-agnostic models. Our findings support the theory that the most successful treatment for an individual with Alzheimer’s disease may be personalized based on their biological sex and genetic context.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    RVK:
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 1474117-9
    SSG: 12
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  • 2
    In: Alzheimer's & Dementia, Wiley, Vol. 14, No. 9 ( 2018-09), p. 1193-1203
    Abstract: Our objective was to investigate the effect of sex on cognitive decline within the context of amyloid β (Aβ) burden and apolipoprotein E genotype. Methods We analyzed sex‐specific effects on Aβ‐positron emission tomography, apolipoprotein, and rates of change on the Preclinical Alzheimer Cognitive Composite‐5 across three cohorts, such as the Alzheimer's Disease Neuroimaging Initiative, Australian Imaging, Biomarker and Lifestyle, and Harvard Aging Brain Study (n = 755; clinical dementia rating = 0; age (standard deviation) = 73.6 (6.5); female = 55%). Mixed‐effects models of cognitive change by sex, Aβ‐positron emission tomography, and apolipoprotein ε4 were examined with quadratic time effects over a median of 4 years of follow‐up. Results Apolipoprotein ε4 prevalence and Aβ burden did not differ by sex. Sex did not directly influence cognitive decline. Females with higher Aβ exhibited faster decline than males. Post hoc contrasts suggested that females who were Aβ and apolipoprotein ε4 positive declined faster than their male counterparts. Discussion Although Aβ did not differ by sex, cognitive decline was greater in females with higher Aβ. Our findings suggest that sex may play a modifying role on risk of Alzheimer's disease–related cognitive decline.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    Language: English
    Publisher: Wiley
    Publication Date: 2018
    detail.hit.zdb_id: 2201940-6
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  • 3
    In: Alzheimer's & Dementia, Wiley, Vol. 16, No. S2 ( 2020-12)
    Abstract: Identifying genetic factors that provide resilience against the clinical consequences of Alzheimer’s disease (AD) pathology is likely to accelerate the development of novel therapeutics. Sex differences in AD prevalence, neuropathological presentation, and clinical progression suggest that exploring the sex‐specific genetic architecture of resilience to AD may be a critical first step towards the characterization and development of precision interventions. Method We completed sex‐stratified and sex‐interaction genome‐wide association studies (GWAS) of resilience across 5,109 non‐Hispanic white individuals from two autopsy cohorts (ACT and ROS/MAP) and two positron emission tomography (PET) cohorts (ADNI and A4). A continuous measure of resilience was quantified using latent variable modeling and represented better‐than‐expected cognition for the given level of amyloid in the brain. The final dataset included 2,130 males (77 ± 9 years) and 2,979 females (77 ± 10 years), the majority of whom were cognitively normal (73% of males; 76% of females). GWAS of resilience were performed in the combined autopsy dataset and combined PET dataset individually and then meta‐analyzed. Covariates included age and three principal components. Analyses were run in all individuals as well as in the subset of cognitively normal individuals. Result An intergenic variant on chromosome 10 (rs827389, MAF = 0.46) showed a female‐specific genome‐wide significant association with resilience in cognitively normal females (β = 0.08, p = 7.6 × 10 −9 ) but not in males (β = ‐5.3 × 10 ‐3 , p = 0.77; sex interaction p = 1.4 × 10 −4 ). This variant is a modest brain eQTL for the KIN gene that is implicated in DNA repair. We also observed a strong sex‐interaction effect among all individuals on chromosome 3 (rs113968105, MAF = 0.10, p = 7.5 × 10 −8 ), in which the minor allele was associated with higher resilience in males (β = 0.10, p = 4.2 × 10 −7 ) but lower resilience in females (β = ‐0.04, p = 0.03). This variant is an eQTL for three genes, including the acetylcholinesterase binding gene COLQ . Conclusion We identified two putative sex‐specific loci that provide protection against the downstream consequences of amyloid pathology. The associations implicate DNA damage repair genes among females, and acetylcholinesterase genes in males, suggesting the pathways providing neuroprotection may differ by sex.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2201940-6
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  • 4
    In: Alzheimer's & Dementia, Wiley, Vol. 17, No. S6 ( 2021-12)
    Abstract: Alongside the increased focus on detecting Alzheimer’s disease (AD) pathology in the preclinical stage, there is a need to more rapidly track AD‐related cognitive changes that may emerge during this stage. Computerized cognitive testing has the potential to achieve this by enabling more frequent, remote, unsupervised assessments. Here, we aimed to investigate whether monthly at‐home assessments of a modified version of the Behavioural Pattern Separation Task‐Object Version (BPSO) could detect cognitive change in cognitively unimpaired (CU) individuals with and without abnormal AD biomarkers. Method N=110 CU participants (age=77.1±4.9, 61% female, MMSE 29±1.3) from the Harvard Aging Brain Study completed the BPSO monthly at‐home on an iPad as part of the Cogstate C3 battery for up to one year (6.3±3.9 months follow‐up). All participants underwent PIB‐PET imaging (1.25±1.05 years before at‐home baseline) and a subset (n=82) underwent Flortaucipir PET (0.56±0.4 years before at‐home baseline). Primary outcome of the BPSO is a metric reflecting the ability to correctly discriminate between stimuli that are similar but not identical to previously learned targets (score range 0‐1, higher scores reflecting better performance). Linear mixed models were used to characterize BPSO performance over months (including both linear and quadratic time terms to investigate nonlinear change), and to examine associations with amyloid (dichotomous) and medial‐temporal tau deposition (continuous) while adjusting for age, sex, education and their interactions with time. Result Overall, individuals’ BPSO performance improved over months, as shown by a significant quadratic effect of time ( β =‐.002, p 〈 .001) with a plateauing learning curve (Figure 1). On average, amyloid‐positive individuals (n=29) showed slightly worse BPSO performance ( β =‐.06, p =.03) than amyloid‐negative individuals, but similar trajectories over time. However, the baseline amyloid effect was attenuated when limiting the sample to those with both amyloid and tau imaging. Less improvement over the year was associated with greater tau burden in the entorhinal cortex (Time*tau β =‐0.02, p= .019) (Figure 2). Conclusion We show that subtle alterations in pattern separation performance over repeated exposure in CU individuals are associated with tau deposition in the medial‐temporal lobe. This implies that unsupervised computerized testing using monthly learning paradigms may be an efficient way to early detect cognitive change associated with preclinical AD.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2201940-6
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  • 5
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S6 ( 2022-12)
    Abstract: The ATN framework is defined by cross‐sectional biomarkers of β‐amyloid (Aβ), tau and neurodegeneration. Given that prevention trials, e.g., AHEAD 3‐45, are focused on individuals who have lower Aβ than established thresholds, we investigated whether defining the ATN framework using longitudinal biomarker trajectories might better identify an at‐risk sample within this boundary. Here, we applied a data‐driven method to re‐define the ATN with longitudinal biomarker data from the Harvard Aging Brain Study (HABS) and we then replicated this longitudinal framework in ADNI. Method 157 HABS participants were clinically‐normal at baseline and underwent at least two Pittsburgh Compound‐B [PiB]‐PET, Flortaucipir‐PET, and T1‐weighted MRI scans. To define longitudinal ATN, we applied latent class mixture models (LCMM) to each biomarker (global Aβ DVR, entorhinal tau SUVr, ICV‐adjusted hippocampal volume) separately, adjusting for age, and including random intercept and slopes. Akaike information criteria (AIC) determined the best‐fitting models out of two‐group or three‐group solutions with linear or spline‐link functions. We compared longitudinal ATN profiles on demographics and an optimized estimate of cognitive change (derived from longitudinal Preclinical Alzheimer Cognitive Composite (PACC) data). Result Aβ trajectories (Fig.1a) were best categorized by one stable (A→) and two accumulating subgroups, a predominantly amyloid‐negative at baseline subgroup (A‐↑) and an entirely amyloid positive at baseline subgroup (A+↑). Tau (Fig.1b) and neurodegeneration (Fig.1c) were optimally defined by stable (T→/N→) vs accumulating/atrophying (T↑/N↑) groups, respectively. These groups were replicated in ADNI (Fig.2). The entire A‐↑ subgroup were stable on T and N (A‐↑/T→/N→) and were predominantly A‐/T‐/N‐ at baseline (86%; Table 1). By contrast, 38% of A+↑ individuals changed on T, or T & N. A‐↑/T→/N→ demographically most closely resembled the longitudinally‐stable ATN group (A→/T→/N→), but were older, more likely to carry e4+ and exhibited higher baseline Aβ (Table 2). Although demonstrating Aβ accumulation, A‐↑/T→/N→ did not exhibit greater cognitive decline versus the stable group (A→/T→/N→; Fig. 3). Conclusion Our findings suggest that a longitudinal biomarker run‐in of Aβ‐PET may be useful for the identification of early‐risk groups for prevention trials. Future work will establish whether other features (e.g. genetics, neuroinflammatory markers, functional imaging) can help to distinguish this cohort.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2201940-6
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  • 6
    In: Frontiers in Aging Neuroscience, Frontiers Media SA, Vol. 13 ( 2022-1-13)
    Abstract: Introduction: We investigated whether monthly assessments of a computerized cognitive composite (C3) could aid in the detection of differences in practice effects (PE) in clinically unimpaired (CU) older adults, and whether diminished PE were associated with Alzheimer's disease (AD) biomarkers and annual cognitive decline. Materials and Methods: N = 114 CU participants (age 77.6 ± 5.0, 61% female, MMSE 29 ± 1.2) from the Harvard Aging Brain Study completed the self-administered C3 monthly, at-home, on an iPad for one year. At baseline, participants underwent in-clinic Preclinical Alzheimer's Cognitive Composite-5 (PACC5) testing, and a subsample ( n = 72, age = 77.8 ± 4.9, 59% female, MMSE 29 ± 1.3) had 1-year follow-up in-clinic PACC5 testing available. Participants had undergone PIB-PET imaging (0.99 ± 1.6 years before at-home baseline) and Flortaucipir PET imaging ( n = 105, 0.62 ± 1.1 years before at-home baseline). Linear mixed models were used to investigate change over months on the C3 adjusting for age, sex, and years of education, and to extract individual covariate-adjusted slopes over the first 3 months. We investigated the association of 3-month C3 slopes with global amyloid burden and tau deposition in eight predefined regions of interest, and conducted Receiver Operating Characteristic analyses to examine how accurately 3-month C3 slopes could identify individuals that showed & gt;0.10 SD annual decline on the PACC-5. Results: Overall, individuals improved on all C3 measures over 12 months (β = 0.23, 95% CI [0.21–0.25], p & lt; 0.001), but improvement over the first 3 months was greatest (β = 0.68, 95% CI [0.59–0.77], p & lt; 0.001), suggesting stronger PE over initial repeated exposures. However, lower PE over 3 months were associated with more global amyloid burden ( r = −0.20, 95% CI [−0.38 – −0.01], p = 0.049) and tau deposition in the entorhinal cortex ( r = −0.38, 95% CI [−0.54 – −0.19], p & lt; 0.001) and inferior-temporal lobe ( r = −0.23, 95% CI [−0.41 – −0.02], p = 0.03). 3-month C3 slopes exhibited good discriminative ability to identify PACC-5 decliners (AUC 0.91, 95% CI [0.84–0.98]), which was better than baseline C3 ( p & lt; 0.001) and baseline PACC-5 scores ( p = 0.02). Conclusion: While PE are commonly observed among CU adults, diminished PE over monthly cognitive testing are associated with greater AD biomarker burden and cognitive decline. Our findings imply that unsupervised computerized testing using monthly retest paradigms can provide rapid detection of diminished PE indicative of future cognitive decline in preclinical AD.
    Type of Medium: Online Resource
    ISSN: 1663-4365
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2558898-9
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  • 7
    In: Alzheimer's & Dementia, Wiley, Vol. 16, No. S6 ( 2020-12)
    Abstract: Depressive symptoms are thought to be among the earliest behavioral changes in preclinical Alzheimer's disease (AD). However, the association between AD pathology and depressive symptoms in preclinical AD remains poorly understood. In the current study we examined the impact of pathology burden (amyloid‐β and tau) on longitudinal change in depressive symptoms in cognitively unimpaired adults. Method 252 adults (age: 70.8 ±8.2; 61% females) from the Harvard Aging Brain Study completed annual assessment with the 30‐item Geriatric Depression Scale (GDS) (average follow‐up=5.87 annual visits). All were cognitively normal, without clinically significant depression at study entry (mean GDS=3.19±3.12; range: (0‐16)). All underwent tau ( 18 F‐Flortaucipir) and amyloid‐β ( 11 C‐Pittburgh Compound B) PET at study year 3 or 4 to derive measures of inferior temporal (IT) and entorhinal cortex (EC) tau and cortical amyloid. A mixed model was employed with dependent variable GDS (for each annual study visit), a random intercept and slope for each participant, and fixed predictors: tau (IT or EC, at study year 3/4), cortical amyloid (at year closest to tau), time (time of tau PET), covariates: age, sex, education; and the interaction of predictors with time. Result Baseline tau burden was associated with increasing GDS over time. In the model with predictor EC tau, EC tau X time was a significant predictor of GDS (β=0.48; t=3.80; 95% CI (0.23, 0.73); p=0.0002). Findings were similar for IT tau:(β = 0.71; t=3.67; 95% CI (0.33, 1.1); p=0.0002). By contrast, amyloid was not a significant predictor of longitudinal GDS in tau models: (β=‐0.14; t=‐1.58; 95% CI(‐0.23, ‐0.08); p=0.11). Conclusion Baseline tau, but not amyloid, is independently associated with increasing depressive symptoms over time. Future research incorporating longitudinal tau PET and individuals with more severe depressive symptoms is needed to delineate the temporal sequence of rising depressive symptoms and increasing tauopathy in preclinical AD.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2201940-6
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  • 8
    In: Journal of Alzheimer's Disease, IOS Press, Vol. 94, No. 1 ( 2023-06-27), p. 217-226
    Abstract: Background: Detecting clinically meaningful changes in instrumental activities of daily living (IADL) at the earliest stages of Alzheimer’s disease (AD) is critical. Objective: The objective of this exploratory study was to examine the cross-sectional relationship between a performance-based IADL test, the Harvard Automated Phone Task (APT), and cerebral tau and amyloid burden in cognitively normal (CN) older adults. Methods: Seventy-seven CN participants underwent flortaucipir tau and Pittsburgh Compound B amyloid PET. IADL were assessed using the three Harvard APT tasks: prescription refill (APT-Script), health insurance company call (APT-PCP), and bank transaction (APT-Bank). Linear regression models were used to determine associations between each APT task and entorhinal cortex, inferior temporal, or precuneus tau with or without an interaction with amyloid. Results: Significant associations were found between APT-Bank task rate and interaction between amyloid and entorhinal cortex tau, and APT-PCP task and interactions between amyloid and inferior temporal and precuneus tau. No significant associations were found between the APT tasks and tau or amyloid alone. Conclusion: Our preliminary findings suggest an association between a simulated real-life IADL test and interactions of amyloid and several regions of early tau accumulation in CN older adults. However, some analyses were underpowered due to the small number of participants with elevated amyloid, and findings should be interpreted with caution. Future studies will further explore these associations cross-sectionally and longitudinally in order to determine whether the Harvard APT can serve as a reliable IADL outcome measure for preclinical AD prevention trials and ultimately in the clinic setting.
    Type of Medium: Online Resource
    ISSN: 1387-2877 , 1875-8908
    Language: Unknown
    Publisher: IOS Press
    Publication Date: 2023
    detail.hit.zdb_id: 2070772-1
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  • 9
    In: Alzheimer's & Dementia, Wiley, Vol. 16, No. S5 ( 2020-12)
    Abstract: Depressive symptoms are thought to be among the earliest behavioral changes in preclinical Alzheimer's disease (AD). However, the association between AD pathology and depressive symptoms in preclinical AD remains poorly understood. In the current study we examined the impact of pathology burden (amyloid and tau) on longitudinal change in depressive symptoms in cognitively unimpaired adults. Method 252 adults (age: 70.8 ±8.2; 61% females) from the Harvard Aging Brain Study completed annual assessment with the 30‐item Geriatric Depression Scale (GDS) (average follow‐up=5.87 annual visits). All were cognitively normal, without clinically significant depression at study entry (mean GDS=3.19±3.12; range: (0‐16)). All underwent tau ( 18 F‐Flortaucipir) and amyloid‐β( 11 C‐Pittburgh Compound B) PET at study year 3 or 4 to derive measures of inferior temporal (IT) and entorhinal cortex (EC) tau and cortical amyloid. A mixed model was employed with dependent variable GDS (for each annual study visit), a random intercept and slope for each participant, and fixed predictors: tau (IT or EC, at study year 3/4), cortical amyloid (at year closest to tau), time (time of tau PET), covariates: age, sex, education; and the interaction of predictors with time. Result Baseline tau burden was associated with increasing GDS over time. In the model with predictor EC tau, EC tau X time was a significant predictor of GDS (β=0.48; t=3.80; 95% CI (0.23, 0.73); p=0.0002). Findings were similar for IT tau:(β = 0.71; t=3.67; 95% CI (0.33, 1.1); p=0.0002). By contrast, amyloid was not a significant predictor of longitudinal GDS in tau models: (β=‐0.14; t=‐1.58; 95% CI(‐0.23, ‐0.08); p=0.11). Conclusion Baseline tau, but not amyloid, is independently associated with increasing depressive symptoms over time. Future research incorporating longitudinal tau PET and individuals with more severe depressive symptoms is needed to delineate the temporal sequence of rising depressive symptoms and increasing tauopathy in preclinical AD.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2201940-6
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  • 10
    In: Neurology, Ovid Technologies (Wolters Kluwer Health), Vol. 96, No. 4 ( 2021-01-26), p. e619-e631
    Abstract: As clinical trials move toward earlier intervention, we sought to redefine the β-amyloid (Aβ)-PET threshold based on the lowest point in a baseline distribution that robustly predicts future Aβ accumulation and cognitive decline in 3 independent samples of clinically normal individuals. Methods Sequential Aβ cutoffs were tested to identify the lowest cutoff associated with future change in cognition (Preclinical Alzheimer Cognitive Composite [PACC]) and Aβ-PET in clinically normal participants from the Harvard Aging Brain Study (n = 342), Australian Imaging, Biomarker and Lifestyle study of aging (n = 157), and Alzheimer's Disease Neuroimaging Initiative (n = 356). Results Within samples, cutoffs derived from future Aβ-PET accumulation and PACC decline converged on the same inflection point, beyond which trajectories diverged from normal. Across samples, optimal cutoffs fell within a short range (Centiloid 15–18.5). Discussion These optimized thresholds can help to inform future research and clinical trials targeting early Aβ. Threshold convergence raises the possibility of contemporaneous early changes in Aβ and cognition. Classification of Evidence This study provides Class II evidence that among clinically normal individuals a specific Aβ-PET threshold is predictive of cognitive decline.
    Type of Medium: Online Resource
    ISSN: 0028-3878 , 1526-632X
    RVK:
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
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