Early Markers of Alzheimer Disease

点击翻译按钮获取中文摘要

The Baltimore Longitudinal Study of Aging (BLSA) was established in 1958 and is one the oldest prospective studies of aging in the USA and the world. The mission of the BLSA is to learn what happens to people as they age and how to distinguish changes due to aging from those due to disease or other causes. Technological advances increasingly allow us to examine subclinical disease markers in the brain and body more generally, blurring distinctions between aging-related and disease-related changes. Thus, longitudinal studies have assumed increasing importance in elucidating the earliest changes that may be associated with later symptomatic cognitive impairment. The Early Markers of Alzheimer's Disease program continues to perform cognitive assessments and establish research diagnoses of Mild Cognitive Impairment and Alzheimer's Disease and related dementias for BLSA participants. This information is also used in multiple collaborative research projects conducted by intramural and extramural investigators, including our LBN studies of brain aging and neuroimaging biomarkers of cognitive decline and AD (reported separately). Over the last 2 years, we have spearheaded assays of plasma biomarkers of AD pathology and neurodegeneration, utilizing historical samples stored as part of BLSA studies of physical and cognitive aging. Several publications are highlighted in the following sections. In one key study, we investigated health conditions associated with Alzheimer Disease and Vascular Dementia in BLSA participants (Beason-Held et al., Annals of Neurology, 2023). Data were available for 347 Alzheimer's disease (AD), 76 vascular dementia (VaD), and 811 control participants without dementia. Logistic regressions were performed associating International Classification of Diseases, 9th Revision (ICD-9) health codes with dementia status across all time points, at 5 and 1 year(s) prior to dementia diagnosis, and at the year of diagnosis, controlling for age, sex, and follow-up length of the medical record. In AD, the earliest and most consistent associations across all time points included depression, erectile dysfunction, gait abnormalities, hearing loss, and nervous and musculoskeletal symptoms. Cardiomegaly, urinary incontinence, non-epithelial skin cancer, and pneumonia were not significant until 1 year before dementia diagnosis. In VaD, the earliest and most consistent associations across all time points included abnormal electrocardiogram (EKG), cardiac dysrhythmias, cerebrovascular disease, non-epithelial skin cancer, depression, and hearing loss. Atrial fibrillation, occlusion of cerebral arteries, essential tremor, and abnormal reflexes were not significant until 1 year before dementia diagnosis. Our findings suggest that selected health conditions are associated with future dementia beginning at least 5 years before dementia diagnosis and are consistently seen over time, while others only reach significance closer to the date of diagnosis. These results also show that there are both shared and distinctive health conditions associated with AD and VaD, and point to the possibility that medical intervention might mitigate the adverse impact of comorbidities in the aging population. In another key study, we continued our collaboration with Dr. Antonio Terracciano to better understand the neurobiology of associations between personality characteristics and dementia risk. In prior studies we investigated associations between personality characteristics and AD, using either neuropathologic measures of AD pathology or PET amyloid and tau imaging biomarkers. Using newly acquired plasma biomarkers in 786 BLSA participants, we investigated the relation between personality and plasma GFAP, a measure of astrogliosis, and neurofilament light (NfL), a marker of neuronal injury. Neuroticism (particularly vulnerability to stress, anxiety, and depression) was associated with higher GFAP and NfL. Conscientiousness was associated with lower GFAP. Extraversion (particularly positive emotions, assertiveness, and activity) was related to lower GFAP and NfL. The personality correlates of astrogliosis and neuronal injury tend to be similar, are found in individuals without cognitive impairment, and point to potential neurobiological underpinnings of the association between personality traits and neurodegenerative diseases. In collaboration with Drs. Tian and Ferrucci, we have continued analysis of associations of olfactory function with cognitive and brain aging. In one publication (Tian et al., Neurology 2023), we examined retrospective and prospective trajectories of cognitive (N=754)and brain volume (N=567) change in BLSA participants aged 50 and older. After adjustment for demographic variables and cardiovascular disease, higher odor identification scores were associated with prior and subsequent slower brain atrophy in the entorhinal cortex, hippocampus, and some frontal and temporal areas (all p < 0.05). Higher odor identification scores were also associated with prior slower decline in memory, attention, processing speed, and manual dexterity and subsequent slower decline in attention (all p < 0.05). Some associations were attenuated after exclusion of data points at and after symptom onset of cognitive impairment or dementia. While many of our studies focus on cortical and subcortical regions known to be involved in memory and other cognitive functions, in a recent paper we collaborated with LBN colleagues from the NAS to examine less studied cerebellum-memory associations (Cooper et al., Neuroimage2023). Linear mixed effects models and partial correlations, adjusted for age, sex, race and education, were used to examine the relationship between changes in cerebellum volumes and changes in verbal learning and memory in 549 BLSA participants. Cross-sectionally, the association of baseline cerebellum GM and WM with baseline verbal learning and memory was age-dependent, with the oldest individuals showing the strongest association between volume and performance. While baseline volumes were not significantly associated with changes in learning and memory, associations between changes in volumes and changes in verbal learning and memory showed that greater declines in verbal memory were associated with greater volume loss in cerebellum white matter, and preserved GM volume in cerebellum vermis lobules VI-VII. Our findings highlight that associations between cerebellum volume and verbal learning and memory may be age and region specific. We continue to collaborate extensively with both intramural and extramural investigators. In addition to the studies highlighted above, the data generated under this project continue to be used for studies of multi-sensory loss (Cai et al, 2023; Yesantharao et al, 2023), energetics, and circadian rhythms (Rabinowitz et al., 2022), dermatologic characteristics (Kim et al., 2023) and for neuropathological investigations in the autopsy subsample (e.g. Morris et al. 2023). We also continue active collaboration with a 5-study consortium of longitudinal studies focused on preclinical AD. Consortium participants are included if they are cognitively normal at baseline, have either PET-PiB or cerebral spinal fluid measures of amyloid status. In a recent consortium publication, we examined the impact of cognitive reserve on the relationship between AD polygenic risk scores and cognitive trajectories (Pettigrew et al., 2023).