Concerted research has focused on characterizing sensitive biological and neuropsychological markers of Alzheimer?s Disease (AD) at the preclinical stage in order to identify high-risk individuals for secondary prevention trials. At the same time, there has been limited progress in defining late-life emotional and behavioral changes in relation to AD biomarkers and preclinical staging criteria, even though these symptoms are established predictors of progression from normal cognition to MCI, and may occur even earlier than subtle cognitive changes. Loneliness is a perceived but measurable state of social and emotional isolation that has been associated with cognitive and functional decline and increased risk of AD dementia. As such, loneliness may be a sensitive yet unrecognized marker of pathological brain changes in clinically normal (CN) older people. The goal of this study is to examine loneliness as a prototypical and leading neuropsychiatric manifestation of preclinical AD. CN elderly are a heterogeneous group of people without overt cognitive impairment, including those with AD-related brain changes or subtle memory declines, despite normal performance on cognitive tests. Our central hypothesis is that loneliness occurs as a symptom of pathological amyloid and tau accumulation, hallmark AD proteinopathies, which are detectable in vivo in CN older people using PiB-PET and T807 PET. This hypothesis has been formulated on the basis of our preliminary data in 79 CN older adults, demonstrating that higher cortical amyloid was significantly associated with greater loneliness, controlling for age, social network, socioeconomic status, depression and anxiety. The rationale for this research is that recognizing phenotypic emotional and behavioral symptoms in preclinical AD and understanding their relationship to AD pathophysiology will provide key missing insights for earlier and more sensitive risk assessment. Leveraging the extensive neuroimaging and clinical data of the Harvard Aging Brain Study, a cohort study of cognitive aging and preclinical AD that is beginning a second 5-year cycle, we will add specialized instruments for loneliness, anxiety and social network in 200 CN older adults to pursue the following specific aims: 1) To examine the cross-sectional relation of brain amyloid, determined by PiB-PET, to loneliness, controlling for age, sex, Apolipoprotein E ?4 carrier status, socioeconomic status, social network, depression and anxiety, 2) To examine the cross-sectional associations of regional tau, using T807 PET, to loneliness using the same biological, neuropsychiatric and social covariates, and 3) To examine the cross- sectional relation of loneliness to performance on sensitive memory tests, adjusting for age and cognitive reserve. This study will define the relations of loneliness to AD biomarkers and memory function in CN older adults capitalizing on a unique neuroimaging dataset. Access to in vivo tau and amyloid imaging data within this specialized cohort provides an unprecedented opportunity to localize non-cognitive symptoms, such as loneliness, in the temporal and anatomic progression of preclinical AD.
This work will advance the understanding of both loneliness and AD, two major determinants of suffering, disability and mortality in aging, which are rarely studied together. Our findings will inform new research into the neural underpinnings, disease mechanisms and treatments relevant to late-life loneliness and it will advance early detection and intervention initiatives in AD. This proposal responds to the National Plan to Address Alzheimer?s Disease Strategy 1C, ?Accelerate Efforts to Identify Early and Pre-symptomatic Stages of Alzheimer?s Disease? and the NIA strategic goal D,? Improve our understanding of the aging brain, Alzheimer?s disease and other neurodegenerative diseases.?
| d'Oleire Uquillas, Federico; Jacobs, Heidi I L; Biddle, Kelsey D et al. (2018) Regional tau pathology and loneliness in cognitively normal older adults. Transl Psychiatry 8:282 |
