Early Markers of Alzheimer Disease

National Institute On Aging

Investigators

Linked publications & trials

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 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. 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 have continued to investigate 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 behave been used in numerous studies of hearing loss, motor function, vestibular function, sleep, as well as genetic studies of a variety of neurodegenerative diseases. Several publications are highlighted in the following sections. In previous publications, we reported on cognitive change or inflection points for cognitive decline during the presymptomatic stage of Alzheimer's disease. Most recently, we showed the earliest change points in BLSA participants who went on to develop AD were in spatial rotational ability and memory, corresponding to early pathology in the precuneus and medial temporal lobe regions (Williams et al., Journal of Alzheimers Disease, 2020). In earlier work in collaboration with Dr. Ellen Grober, we reported that both immediate and delayed free recall also early presymptomatic changes in performance on the Free and Cued Selective Reminding Test (FCSRT). In a recent publication in collaboration with Dr. Grober, we extended this work to investigate the predictive validity of learning and retention measures and the picture version of the FCSRT in identifying incident mild cognitive impairment (MCI). Learning was defined by the sum of free recall (FR) and retention by delayed free recall (DFR) tested 15-20 min later. In 1422 BLSA participants who were cognitively normal at baseline, there were 187 incident cases of MCI over a median of 8.1 years of follow-up. Using Cox proportional hazards models, we found that both free recall and delayed free recall each predicted incident MCI adjusting for age, sex, and education. Each also remained a significant predictor when both were included in a single model, with similar effect sizes. These findings have a practical implication showing that when time is a major constraint, learning scores may be sufficient for prediction of incident MCI. We continue to collaborate extensively with both intramural and extramural investigators, including ongoing studies of motor function, sleep disturbance, hearing loss, and vision changes. In a study in collaboration with Drs. Teresa Tian and Luigi Ferrucci, we investigated cognitive and neuroimaging profiles of BLSA participants with dual decline in memory function and gait speed by comparing longitudinal rates of change in specific cognitive domains (n= 664) and brain volumes (n= 391; selected frontal, temporal, parietal, subcortical, and cerebellar areas). Compared to groups with typical age related changes or decline in only memory or only gait, dual decliners had steeper declines in verbal fluency, attention, and sensorimotor function by Pegboard nondominant hand performance. Dual decliners also had greater brain volume loss in superior frontal gyrus, superior parietal gyrus, precuneus, thalamus, and cerebellum. Participants with age-related dual decline experienced steeper declines in multiple cognitive domains and greater brain volume loss in cognitive, sensorimotor, and locomotion areas. Impaired sensorimotor integration and locomotion are underlying features of dual decline. Whether these features contribute to the increased risk of dementia should be investigated. 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. Several manuscripts based on this collaboration are in the final stages of preparation.