β-Amyloid plaques and tau-containing neurofibrillary tangles are the two neuropathological hallmarks of Alzheimer’s disease (AD) and are thought to play crucial roles in a neurodegenerative cascade leading to dementia. Both lesions can now be visualized in vivo using positron emission tomography (PET) radiotracers, opening new opportunities to study disease mechanisms and improve patients’ diagnostic and prognostic evaluation. In a group of 32 patients at early symptomatic AD stages, we tested whether β-amyloid and tau-PET could predict subsequent brain atrophy measured using longitudinal magnetic resonance imaging acquired at the time of PET and 15 months later. Quantitative analyses showed that the global intensity of tau-PET, but not β-amyloid–PET, signal predicted the rate of subsequent atrophy, independent of baseline cortical thickness. Additional investigations demonstrated that the specific distribution of tau-PET signal was a strong indicator of the topography of future atrophy at the single patient level and that the relationship between baseline tau-PET and subsequent atrophy was particularly strong in younger patients. These data support disease models in which tau pathology is a major driver of local neurodegeneration and highlight the relevance of tau-PET as a precision medicine tool to help predict individual patient’s progression and design future clinical trials.

Objective: To determine the rate of tau accumulation in healthy older adults (OA) and patients with Alzheimer disease (AD), as well as the relationship of tau accumulation to cortical atrophy. Methods: Two longitudinal flortaucipir (FTP) positron emission tomography (PET) and magnetic resonance imaging (MRI) scans were acquired from 42 OA (21 Pittsburg compound B [PiB] + , age = 77.6 AE 4.6 years, 25 female [F]/17 male [M]) and 19 PiB + patients with AD (age = 63.1 AE 10.3 years, 12 F/7 M) over 1 to 3 years of follow-up. FTP change, structural MRI measures of atrophy, and cross-modal correlations were examined on a voxelwise level. Regional annual percentage change in FTP was also calculated. Results: Voxelwise FTP change in AD showed the greatest increases in lateral and medial frontal lobes. Atrophy over the same interval was more widespread and included posteromedial cortical areas, where tau accumulation rates were lower. In OA, FTP binding increased in bilateral temporal lobe and retrosplenial cortex, accompanied by atrophy in the same regions. There were no associations between voxelwise change in FTP and sex, PiB, or APOE. Regional FTP significantly increased at follow-up in OA and patients with AD. Mixed effects models showed greater FTP increases in AD compared to OA, and no differences within OA based on PiB status. Interpretation: Our findings indicate that tau accumulates even in amyloid-negative healthy OA and this process can be measured with in vivo tau-PET. In OA, tau accumulation and atrophy share a similar topography. In AD, tau increases more rapidly and accumulation occurs in frontal regions that are not yet undergoing significant atrophy.

Background Many of the symptoms, consequences, and risk factors for frailty are shared with late-life depression. However, thus far, few studies have addressed the conceptual and empirical interrelationships between these conditions. This review synthesizes existing studies that examined depression and frailty among older adults and provides suggestions for future research. Methods A search was conducted using PubMed for publications through 2010. Reviewers assessed the eligibility of each report and abstracted information on study design, sample characteristics, and key findings, including how depression and frailty were conceptualized and treated in the analysis. Results Of 133 abstracted articles, 39 full-text publications met inclusion criteria. Overall, both cross-sectional (n = 16) and cohort studies (n = 23) indicate that frailty, its components, and functional impairment are risk factors for depression. Although cross-sectional studies indicate a positive association between depression and frailty, findings from cohort studies are less consistent. The majority of studies included only women and non-Hispanic Whites. None used diagnostic measures of depression or considered antidepressant use in the design or analysis of the studies. Conclusions A number of empirical studies support for a bidirectional association between depression and frailty in later life. Extant studies have not adequately examined this relationship among men or racial/ethnic minorities, nor has the potential role of antidepressant medications been explored. An interdisciplinary approach to the study of geriatric syndromes such as late-life depression and frailty may promote cross-fertilization of ideas leading to novel conceptualization of intervention strategies to promote health and functioning in later life.

Introduction We investigated plasma proteomic markers of astrocytopathy, brain degeneration, plasticity, and inflammation in sporadic early‐onset versus late‐onset Alzheimer's disease (EOAD and LOAD). Methods Plasma was analyzed using ultra‐sensitive immuno‐based assays from 33 EOAD, 30 LOAD, and 36 functionally normal older adults. Results Principle component analyses identified 3 factors: trophic (BDNF, VEGF, TGFβ), degenerative (GFAP, NfL), and inflammatory (TNFα, IL‐6, IP‐10, IL‐10). Trophic factor was elevated in both AD groups and associated with cognition and gray matter volumes. Degenerative factor was elevated in EOAD, with higher levels associated with worse functioning in this group. Biomarkers of inflammation were not significantly different between groups and were only associated with age. Disucssion Plasma proteomic biomarkers provide novel means of investigating molecular processes in vivo and their contributions to clinical outcomes. We present initial investigations of several of these fluid biomarkers, capturing aspects of astrocytopathy, neuronal injury, cellular plasticity, and inflammation in EOAD versus LOAD.