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Marilyn S Albert

Publications and source records attributed to Marilyn S Albert.

At least 19 recordsLinked to original sources
PubMed2026

Genetic modifiers of APOE-ε4-associated cognitive decline.

The APOE-ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease. However, APOE-ε4 is not deterministic, highlighting the need to identify additional genetic and environmental factors. APOE-ε4 has been linked to accelerated cognitive decline, so we sought to investigate genetic factors that modify APOE-ε4-associated cognitive decline. We conduct cross-ancestry APOE-ε4-stratified and interaction GWAS using harmonized cognitive data from 32,778 participants, including 29,354 non-Hispanic White and 3,424 non-Hispanic Black individuals. Our primary outcome is late-life cognition, measured using harmonized composite scores for memory, executive function, and language, modeled as continuous traits reflecting both normative cognitive aging and disease-related decline. We identify two genome-wide significant loci in APOE-ε4 carriers, reaching genome-wide significance for executive function. These loci also demonstrate nominal associations across the other domains, suggesting broad effects on cognition. In non-carriers, we identify a genome-wide significant association at ITGB8 restricted to executive function, and another locus associated with language. We further link these loci to SEMA6D, GRIN3A, and ITGB8 through expression and methylation databases. Post-GWAS analyses implicate additional genes including SLCO1A2, and DNAH11. Genetic correlation analyses reveal differences by APOE-ε4 status for immune-related traits, suggesting immune-related predispositions may exacerbate cognitive risk in APOE-ε4 carriers.

Humans↗
PubMed2025

Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies known and novel cross-population and ancestry-specific associations as novel risk loci for Alzheimer's disease.

BACKGROUND: Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in ancestry groups of predominantly non-European ancestral background in genome-wide association studies (GWAS). We construct and analyze a multi-ancestry GWAS dataset in the Alzheimer's Disease Genetics Consortium (ADGC) to test for novel shared and population-specific late-onset Alzheimer's disease (LOAD) susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6728 African American, 8899 Hispanic (HIS), and 3232 East Asian individuals, performing within ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. RESULTS: We identify 13 loci with cross-population associations including known loci at/near CR1, BIN1, TREM2, CD2AP, PTK2B, CLU, SHARPIN, MS4A6A, PICALM, ABCA7, APOE, and two novel loci not previously reported at 11p12 (LRRC4C) and 12q24.13 (LHX5-AS1). We additionally identify three population-specific loci with genome-wide significance at/near PTPRK and GRB14 in HIS and KIAA0825 in NHW. Pathway analysis implicates multiple amyloid regulation pathways and the classical complement pathway. Genes at/near our novel loci have known roles in neuronal development (LRRC4C, LHX5-AS1, and PTPRK) and insulin receptor activity regulation (GRB14). CONCLUSIONS: Using cross-population GWAS meta-analyses, we identify novel LOAD susceptibility loci in/near LRRC4C and LHX5-AS1, both with known roles in neuronal development, as well as several novel population-unique loci. Reflecting the power of diverse ancestry in GWAS, we detect the SHARPIN locus with only 13.7% of the sample size of the NHW GWAS study (n = 409,589) in which this locus was first observed. Continued expansion into larger multi-ancestry studies will provide even more power for further elucidating the genomics of late-onset Alzheimer's disease.

Humans↗
PubMed2006

Alterations in memory networks in mild cognitive impairment and Alzheimer's disease: an independent component analysis.

Memory function is likely subserved by multiple distributed neural networks, which are disrupted by the pathophysiological process of Alzheimer's disease (AD). In this study, we used multivariate analytic techniques to investigate memory-related functional magnetic resonance imaging (fMRI) activity in 52 individuals across the continuum of normal aging, mild cognitive impairment (MCI), and mild AD. Independent component analyses revealed specific memory-related networks that activated or deactivated during an associative memory paradigm. Across all subjects, hippocampal activation and parietal deactivation demonstrated a strong reciprocal relationship. Furthermore, we found evidence of a nonlinear trajectory of fMRI activation across the continuum of impairment. Less impaired MCI subjects showed paradoxical hyperactivation in the hippocampus compared with controls, whereas more impaired MCI subjects demonstrated significant hypoactivation, similar to the levels observed in the mild AD subjects. We found a remarkably parallel curve in the pattern of memory-related deactivation in medial and lateral parietal regions with greater deactivation in less-impaired MCI and loss of deactivation in more impaired MCI and mild AD subjects. Interestingly, the failure of deactivation in these regions was also associated with increased positive activity in a neocortical attentional network in MCI and AD. Our findings suggest that loss of functional integrity of the hippocampal-based memory systems is directly related to alterations of neural activity in parietal regions seen over the course of MCI and AD. These data may also provide functional evidence of the interaction between neocortical and medial temporal lobe pathology in early AD.

Aged↗
PubMed2006

An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest.

In this study, we have assessed the validity and reliability of an automated labeling system that we have developed for subdividing the human cerebral cortex on magnetic resonance images into gyral based regions of interest (ROIs). Using a dataset of 40 MRI scans we manually identified 34 cortical ROIs in each of the individual hemispheres. This information was then encoded in the form of an atlas that was utilized to automatically label ROIs. To examine the validity, as well as the intra- and inter-rater reliability of the automated system, we used both intraclass correlation coefficients (ICC), and a new method known as mean distance maps, to assess the degree of mismatch between the manual and the automated sets of ROIs. When compared with the manual ROIs, the automated ROIs were highly accurate, with an average ICC of 0.835 across all of the ROIs, and a mean distance error of less than 1 mm. Intra- and inter-rater comparisons yielded little to no difference between the sets of ROIs. These findings suggest that the automated method we have developed for subdividing the human cerebral cortex into standard gyral-based neuroanatomical regions is both anatomically valid and reliable. This method may be useful for both morphometric and functional studies of the cerebral cortex as well as for clinical investigations aimed at tracking the evolution of disease-induced changes over time, including clinical trials in which MRI-based measures are used to examine response to treatment.

Adult↗
PubMed2005

Differential amygdala habituation to neutral faces in young and elderly adults.

Habituation is a highly adaptive property of the nervous system, which allows for the allocation of attention and other cognitive resources to more imperative environmental events. The amygdala is an important site of habituation in humans, but no studies to date have examined the effects of aging on amygdala habituation. Given the amygdala's role in evaluating the salience of a stimulus and initiating behavioral responses, the potential importance of amygdala habituation in aging may be far-reaching. Therefore, we assessed for differences in habituation in the amygdalae of healthy young and elderly adults during repeated presentations of neutral human faces using functional magnetic resonance imaging (fMRI). In addition, we evaluated the relationship between amygdala volume and habituation, to examine the effects of atrophy. Eighteen healthy young controls and 18 healthy elderly subjects were scanned with fMRI during viewing of repeatedly presented neutral human face stimuli. Significant fMRI signal decrement was observed across all subjects for early versus late face presentations. Analysis of group, condition, and hemisphere revealed a significant three-way interaction, with right greater than left habituation in the young, but left greater than right amygdala habituation in the elderly. Volumetric and correlational analyses demonstrated that amygdala volume is associated with habituation in the right, but not left, hemisphere. We conclude that, in healthy elderly adults, the amygdala retains its adaptive habituation response, but speculate that intrinsic changes in amygdala anatomy during aging may modulate its laterality.

Adult↗
PubMed2005

Novel fearful faces activate the amygdala in healthy young and elderly adults.

Activation of the amygdala to emotionally valenced stimuli, and particularly to fearful faces, has been widely demonstrated in healthy young adults. However, recent studies assessing amygdala responses to fearful emotional faces in the normal elderly have not shown similar results. The reason for this is uncertain, but it may relate to life-span developmental changes in processing emotional stimuli or structural alterations in the amygdala with aging. In order to examine whether the amygdala could be activated in the elderly, we developed a paradigm designed to engage the amygdala on several levels. Based on recent imaging work indicating that novelty and stimulus change activates the amygdala, we assessed amygdala responses in young and elderly adults to novel fearful faces (versus familiar neutral ones). We demonstrate a robust activation in both groups, indicating that the amygdala remains responsive in aging. This activation did not differ between the two groups when we examined regions of interest in the amygdala based on functional or structural criteria. However, there were significantly greater activations in the inferior temporal cortex in the young versus elderly subjects.

Adult↗
PubMed2005

Hippocampal and neocortical activation during repetitive encoding in older persons.

Episodic memory function is known to decline in the course of normal aging; however, compensatory techniques can improve performance significantly in older persons. We investigated the effects of the memory enhancing technique of repetition encoding on brain activation using event-related functional magnetic resonance imaging (fMRI). Twelve healthy older adults without cognitive impairment were studied with fMRI during repetitive encoding of face-name pairs. During the first encoding trials of face-name pairs that were subsequently remembered correctly, activation of the hippocampus and multiple neocortical regions, including prefrontal, parietal and fusiform cortices, was observed. The second and third encoding trials resulted in continued activation in neocortical regions, but no task-related response within the hippocampus. Functional imaging of successful memory processes thus permits us to detect regionally specific responses in the aging brain. Our findings suggest that hippocampal function is preserved in normal aging and that repetition-based memory enhancing techniques may engage primarily neocortical attentional networks.

Age Factors↗
PubMed2005

Association between mind-body and cardiovascular exercises and memory in older adults.

OBJECTIVES: To compare the memory function of older adults who regularly practiced mind-body (MB) or cardiovascular (CV) exercises with that of those who did not engage in regular exercise. Older adults who engaged in both types of exercise were also included to examine the combined effects. DESIGN: Cross-sectional study between 2002 and 2003. SETTING: Older adults from a local community in Hong Kong. PARTICIPANTS: One hundred forty adults aged 56 and older. MEASUREMENTS: The Hong Kong List Learning Test was used to assess the memory of all participants. It is a clinically validated Chinese verbal-memory test that measures various aspects of memory processing, including learning, retention, and retrieval abilities. MB and CV exercises were defined using three dimensions: motion speed, emphasis on relaxing the mind, and conscious control of movement. RESULTS: Older adults who practiced MB or CV exercises demonstrated a similar level of memory function, and their learning and memory was better than that of individuals who did not exercise regularly. Those who practiced both types of exercises outperformed all other groups, even after corrected for the total hours of exercise. Although memory change across age was found in older adults who did not exercise, this trend was not observed in individuals who practiced MB exercises. CONCLUSION: Practicing both MB and CV exercises appears to have a combined effect that might help to preserve memory in older adults. In addition, MB exercises may be considered as an alternative training for older adults who cannot practice strenuous physical exercise.

Aged↗
PubMed2004

Medial temporal lobe function and structure in mild cognitive impairment.

Functional magnetic resonance imaging (fMRI) was used to study memory-associated activation of medial temporal lobe (MTL) regions in 32 nondemented elderly individuals with mild cognitive impairment (MCI). Subjects performed a visual encoding task during fMRI scanning and were tested for recognition of stimuli afterward. MTL regions of interest were identified from each individual's structural MRI, and activation was quantified within each region. Greater extent of activation within the hippocampal formation and parahippocampal gyrus (PHG) was correlated with better memory performance. There was, however, a paradoxical relationship between extent of activation and clinical status at both baseline and follow-up evaluations. Subjects with greater clinical impairment, based on the Clinical Dementia Rating Sum of Boxes, recruited a larger extent of the right PHG during encoding, even after accounting for atrophy. Moreover, those who subsequently declined over the 2.5 years of clinical follow-up (44% of the subjects) activated a significantly greater extent of the right PHG during encoding, despite equivalent memory performance. We hypothesize that increased activation in MTL regions reflects a compensatory response to accumulating AD pathology and may serve as a marker for impending clinical decline.

Aged↗
PubMed2004

Structural modeling of dynamic changes in memory and brain structure using longitudinal data from the normative aging study.

This is an application of new longitudinal structural equation modeling techniques to time-dependent associations of memory and brain structure measurements. There were 225 participants aged 30-80 years at baseline who were measured again after a 7-year interval on both the lateral ventricular size and Wechsler memory score. Multiple regression analyses show nonlinear associations with age but no relationships among longitudinal changes. Mixed-effects latent growth curve analyses and analyses based on latent difference scores indicate that longitudinal changes in both variables are reasonably well described by an exponential or dual change model. Bivariate dynamic structural equation modeling analyses indicate age-lagged changes operate in a coupled-over-time fashion, with the brain measure (lateral ventricular size) as a leading indicator in time of memory (Wechsler memory score) declines.

Adult↗
PubMed2004

Dissociating confidence and accuracy: functional magnetic resonance imaging shows origins of the subjective memory experience.

Successful memory typically implies both objective accuracy and subjective confidence, but there are instances when confidence and accuracy diverge. This dissociation suggests that there may be distinct neural patterns of activation related to confidence and accuracy. We used event-related functional magnetic resonance imaging to study the encoding of novel face--name associations, assessed with a postscan memory test that included objective measures of accuracy and subjective measures of confidence. We showed specific neural activity in the left inferior prefrontal cortex associated with trials when subjects expressed high confidence that they had chosen the correct name for the face and made a correct identification. Moreover, we found that this region was also associated with imparting high confidence when subjects chose the incorrect name. However, medial temporal lobe regions showed activity only for high-confidence correct trials. Many functional magnetic resonance imaging studies have shown that the medial temporal lobe and left prefrontal regions are particularly important for the successful formation of memories by using a combination of subjective and objective measures. Our findings suggest that these regions may be differentially involved in the objective and subjective components of memory and that the origins of confidence-accuracy dissociations may be related to incomplete activation of the neural pattern seen in successful encoding. These findings may also aid understanding of eyewitness misidentifications and memory distortions.

Adult↗
PubMed2004

Quantitative SPECT leads to improved performance in discrimination tasks related to prodromal Alzheimer's disease.

UNLABELLED: We investigated the impact of the quantitation and reconstruction protocol on clinical tasks. The performance of standard clinical reconstruction procedures in discrimination tasks related to the diagnosis of prodromal Alzheimer's disease (AD) was compared with the performance of a quantitative approach incorporating improved corrections for scatter, attenuation, intrinsic spatial resolution, and distance-dependent spatial resolution. METHODS: Seventeen normal controls (normal group), 56 subjects who did not have dementia, who did have memory problems, but who did not develop AD within 5 y of follow-up (questionable group), and 27 subjects who did not have dementia, who did have memory problems, and who did develop AD over the follow-up period (converter group) were considered in this study. (99m)Tc-hexamethylpropyleneamine oxime SPECT and MRI studies were performed for each subject at baseline. The standard quantitation protocol (STD), routinely used in our clinic, consisted of Compton window scatter correction followed by filtered backprojection with attenuation correction using a uniform attenuation map. In the improved quantitative approach (QUAN), projections were corrected for scatter by use of a general spectral method and reconstructed by use of ordered-subset(s) expectation maximization, incorporating corrections for collimator response and attenuation using both a uniform attenuation map (QUANunif) and a nonuniform attenuation map (QUANnonunif). Mean SPECT activity concentration and MRI volume were estimated for 7 structures: rostral anterior cingulate gyrus, caudal anterior cingulate gyrus, posterior cingulate gyrus, hippocampus, basal forebrain, amygdala, and the banks of the superior temporal sulcus. Data were analyzed by pairwise discriminant analysis, and performance in binary group discrimination was measured by correlated receiver-operating-characteristic analysis. RESULTS: The use of QUANnonunif yielded a small but systematic improvement in discrimination accuracy for normal versus converter groups (accuracy or area under the receiver-operating-characteristic curve [Az], 0.965), normal versus questionable groups (Az, 0.973), and questionable versus converter groups (Az, 0.881) compared with the results obtained with QUANunif (Az, 0.955, 0.962, and 0.866, respectively). Discrimination performance was significantly lower (P < 0.05) with STD than with QUAN in all 3 tasks (Az with STD, 0.906, 0.878, and 0.768, respectively). MRI volume estimation led to a lower overall performance in all 3 tasks than did QUANnonunif (Az with MRI, 0.947, 0.917, and 0.872, respectively). CONCLUSION: Improved quantitative image reconstruction with accurate compensation for scatter, attenuation, and variable collimator response led to significantly better performance in discrimination tasks related to the diagnosis of prodromal AD than did standard clinical reconstruction procedures. The use of a nonuniform brain attenuation map yields a small improvement in discrimination accuracy.

Aged↗
PubMed2003

Genetic association of Alzheimer's disease with multiple polymorphisms in alpha-2-macroglobulin.

Alpha-2-Macroglobulin (A2M) is a highly plausible candidate gene for Alzheimer's disease (AD) in a region of chromosome 12 that has numerous independent reports of genetic linkage. We previously reported that a 5 bp deletion in A2M was associated with AD in a subset of the National Institute of Health (NIMH) Genetics Initiative AD family sample. Efforts to replicate this association finding in case - control samples have been largely negative, while those in family samples have been more positive. We hypothesized that variable findings regarding this deletion, along with variable reports of association with V1000I, another polymorphism in the gene, result from linkage disequilibrium in the area as well as ascertainment differences between family-based and case-control studies. Thus, we resequenced the A2M locus to identify novel polymorphisms to test for genetic association with AD. We identified seven novel polymorphisms and tested them in the full NIMH sample of 1439 individuals in 437 families. We found significant genetic association of the 5 bp deletion and two novel polymorphisms with AD. Substantial linkage disequilibrium was detected across the gene as a whole, and haplotype analysis also showed significant association between AD and groups of A2M polymorphisms. Several of these polymorphisms and haplotypes remain significantly associated with AD even after correction for multiple testing. Taken together, these findings, and the positive reports in other family-based studies, continue to support a potential role for A2M or a nearby gene in AD. However, the negative case - control studies suggest that any underlying pathogenic polymorphisms have a modest effect, and may operate primarily among individuals with a family history of AD.

Aged↗
PubMed2003

Results of a high-resolution genome screen of 437 Alzheimer's disease families.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder of late life with complex inheritance. Mutations in three known genes lead to the rare early-onset autosomal dominant form of AD, while a common polymorphism (epsilon 4) in the gene encoding apolipoprotein E (APOE ) is a risk factor for more typical late-onset (>60 years) AD. A recent study concluded that there are up to four additional genes with an equal or greater contribution to the disease. We performed a 9 cM genome screen of 437 families with AD, the full National Institute of Mental Health (NIMH) sample, which has been carefully ascertained, evaluated and followed by our group over the last decade. Performing standard parametric and non-parametric linkage analyses, we observed a 'highly significant' linkage peak by Lander and Kruglyak criteria on chromosome 19q13, which probably represents APOE. Twelve additional locations-on 1q23, 3p26, 4q32, 5p14, 6p21, 6q27, 9q22, 10q24, 11q25, 14q22, 15q26 and 21q22-met criteria for 'suggestive' linkage [i.e. two-point lod score (TLS) >/=1.9 and/or multipoint lod score (MLS) >/=2.2] in at least one of our analyses. Although some of these will surely prove to be false positives, these linkage signals should provide a valuable framework for future studies aimed at identifying additional susceptibility genes for late-onset AD.

Aged↗
PubMed2003

MRI-guided SPECT perfusion measures and volumetric MRI in prodromal Alzheimer disease.

OBJECTIVE: To identify group differences in the prodromal phase of Alzheimer disease (AD) using quantitative single-photon emission computed tomography (SPECT) perfusion and magnetic resonance imaging (MRI) volume measures within specific volumes of interest. SETTING: Gerontology research unit. PARTICIPANTS: There were 17 healthy controls, 56 nondemented patients with memory problems who did not develop AD during 3 to 5 years of follow-up (questionables), and 27 nondemented patients with memory problems who developed AD during follow-up (converters). METHODS: A Tc 99m hexamethylpropyleneamine oxime SPECT study and an MRI were performed in each participant at baseline. Mean SPECT activity concentration and MRI volume were estimated within 9 structures: rostral anterior cingulate, caudal anterior cingulate, posterior cingulate, hippocampus, entorhinal cortex, basal forebrain, temporal horn, amygdala, and the banks of the superior temporal sulcus. Data were analyzed using overall and pairwise discriminant analysis, and performance in pairwise group discrimination was measured using correlated receiver operating characteristic curve analysis. RESULTS: The overall (3-group) discriminant function was significant for SPECT (F test, P<.001) and MRI (F test, P<.0001). For the SPECT analysis, the ranking of structures for discriminating among the 3 groups was, in order of decreasing discriminating power, caudal anterior cingulate, temporal horn, superior temporal sulcus, entorhinal cortex, hippocampus, rostral anterior cingulate, amygdala, basal forebrain, and posterior cingulate. For the MRI analysis, this ranking was entorhinal cortex, superior temporal sulcus, temporal horn, hippocampus, amygdala, caudal anterior cingulate, rostral anterior cingulate, basal forebrain, and posterior cingulate. Combining the 2 modalities yielded significantly better discrimination performance than did either alone. Furthermore, the correlation between SPECT and MRI measures was low. CONCLUSION: Measures of structure activity concentration and volume carry independent information; both reveal group differences in prodromal AD.

Aged↗
PubMed2002

Predicting cognitive impairment in high-functioning community-dwelling older persons: MacArthur Studies of Successful Aging.

OBJECTIVES: To examine whether simple cognitive tests, when applied to cognitively intact older persons, are useful predictors of cognitive impairment 7 years later. DESIGN: Cohort study. SETTING: Durham, North Carolina; East Boston, Massachusetts; and New Haven, Connecticut, areas that are part of the National Institute on Aging Established Populations for Epidemiological Studies of the Elderly. PARTICIPANTS: Participants, aged 70 to 79, from three community-based studies, who were in the top third of this age group, based on physical and cognitive functional status. MEASUREMENTS: New onset of cognitive impairment as defined by a score of less than 7 on the Short Portable Mental Status Questionnaire (SPMSQ) in 1995. RESULTS: At 7 years, 21.8% (149 of 684 subjects) scored lower than 7 on the SPMSQ. Using multivariate logistic regression, three baseline (1988) cognitive tests predicted impairment in 1995. These included two simple tests of delayed recall-the ability to remember up to six items from a short story and up to 18 words from recall of Boston Naming Test items. For each story item missed, the adjusted odds ratio (AOR) for cognitive impairment was 1.44 (95% confidence interval (CI) = 1.16-1.78, P <.001). For each missed item from the word list, the AOR was 1.20 (95% CI = 1.09-1.31, P <.001). The Delayed Recognition Span, which assesses nonverbal memory, also predicted cognitive impairment, albeit less strongly (odds ratio = 1.06 per each missed answer, 95% CI = 1.003-1.13, P =.04). CONCLUSIONS: This study identifies measures of delayed recall and recognition as significant early predictors of subsequent cognitive decline in high-functioning older persons. Future efforts to identify those at greatest risk of cognitive impairment may benefit by including these measures.

Aged↗
PubMed2002

Achieving and maintaining cognitive vitality with aging.

Cognitive vitality is essential to quality of life and survival in old age. With normal aging, cognitive changes such as slowed speed of processing are common, but there is substantial interindividual variability, and cognitive decline is clearly not inevitable. In this review, we focus on recent research investigating the association of various lifestyle factors and medical comorbidities with cognitive aging. Most of these factors are potentially modifiable or manageable, and some are protective. For example, animal and human studies suggest that lifelong learning, mental and physical exercise, continuing social engagement, stress reduction, and proper nutrition may be important factors in promoting cognitive vitality in aging. Manageable medical comorbidities, such as diabetes, hypertension, and hyperlipidemia, also contribute to cognitive decline in older persons. Other comorbidities such as smoking and excess alcohol intake may contribute to cognitive decline, and avoiding these activities may promote cognitive vitality in aging. Various therapeutics, including cognitive enhancers and protective agents such as antioxidants and anti-inflammatories, may eventually prove useful as adjuncts for the prevention and treatment of cognitive decline with aging. The data presented in this review should interest physicians who provide preventive care management to middle-aged and older individuals who seek to maintain cognitive vitality with aging.

Aging↗