Early Markers of Alzheimer Disease

National Institute On Aging

Investigators

Linked publications, trials & patents

Abstract

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). Due to the COVID-19 pandemic, the full BLSA participant schedule of visits was suspended in mid-March 2020. Participant studies subsequently resumed in summer 2020 but at less than 20% of the usual participant flow, which has increased over the last 6 months to about 75% of the prior level. Nevertheless, we have continued performing research diagnostic case conferences in collaboration with Dr. Moghekar of the Johns Hopkins ADRC to establish research diagnoses of cognitive impairment and have continued analyses to define age-associated cognitive changes. We also continued our studies of possible modifiers of cognitive aging, risk for dementia, and the presence of Alzheimer's pathology at autopsy. BLSA cognitive, imaging, and genetic (including whole genome sequencing) data continue to bbe used in numerous studies of hearing loss, visual impairment, vestibular function, motor function sleep, as well as genetic studies of a variety of neurodegenerative diseases. Several publications are highlighted in the following sections. Recent studies have used BLSA data to investigate the prevalence of multisensory impairment (Armstrong et al., 2021) and shown that multisensory impairments are common in older adults. The most common co-occurring impairments were in hearing and vision (17.4%). Further, in a collaborative study with investigators at Columbia University (Irace et al., 2022), we found that even subclinical hearing loss was associated with cognitive decline on a measure of letter fluency. In collaboration with investigators at Johns Hopkins School of Public Health, we also investigated whether performance on cognitive tests was biased by hearing and visual impairments (Nichols et al., 2022). We hypothesized that scores on tests dependent on hearing or vision would differ across specific tests among participants with hearing or visual impairments, controlling for underlying cognition. Surprisingly, we found differences between sensory impaired and unimpaired individuals that did not depend on test administration characteristics, which could indicate that elevated cognitive load among persons with sensory impairment plays is more important than the specific modality of test presentation. Over the last year, we have begun analysis and publication of measures of olfactory function that were implemented in BLSA prior to the COVID19 pandemic. In an initial publication (Tian et al., 2022) we investigated the relation between olfactory function and cognitive impairment and AD biomarkers measured with PET scanning of amyloid and tau burden. We first investigated the relation between baseline olfaction data and incident MCI in 364 initially cognitively normal participants during an average 2.4-year. 17 (5%) participants developed MCI. Each unit lower odor identification score was associated with 22% higher risk of developing MCI (p=0.04). A subset of 129 participants had PET-PiB (ABeta) (n=72 repeated) and 105 had 18F-flortaucipir (FTP)-PET (tau) (n=44 repeated) scans. Lower olfaction scores were associated with higher amyloid burden in orbitofrontal cortex (OFC), precuneus, and middle temporal gyrus (p0.04), and this association was limited to the group of individuals with amyloid positive scans. In addition with found that greater longitudinal decline in the odor identification score was associated with greater increase in anterior OFC amyloid burden and entorhinal tau. These findings showed that poorer olfaction predicts incident MCI and is associated with greater overall and regional amyloid, and that greater declines in olfaction are associated with greater increases in AD neuropathology measured by PET scanning. Ongoing studies are investigations whether olfaction predicts MRI volume losses in AD-affected brain regions. We continue to collaborate extensively with both intramural and extramural investigators, including ongoing studies of motor function and energy utilization. Publications over the last year include studies of combined slow gait and low activity fragmentation with later cognitive impairment (Tian et al., 2022), daily physical activity and cognitive impairment (Wanigatunga et al., 2022), and associations between walking energetics and brain atrophy (Dougherty et al., 2021) and amyloid burden (Dougherty et al. 2021). We also continue a very active collaboration with a 5-study consortium of longitudinal studies focused on preclinical AD. Participants at the study sites are included in the consortium if they are cognitively normal at baseline, have either PET-PiB or cerebral spinal fluid measures of amyloid-beta and serial cognitive assessments. The collaboration and larger sample sizes provided by the 5 studies and the University of Pennsylvania image analysis core will allow tests of more complex interactions influencing risk and protective factors for Alzheimer's disease during the preclinical asymptomatic stage. Data from the preclinical AD consortium have been included in a number of publications from the iSTAGING consortium (described in separate reports).