Introduction: In 2015, the US Alzheimer’s Disease Centers (ADC) implemented Version 3 of the Uniform Data Set (UDS). This paper describes the history of Version 3 development and the UDS data that are freely available to researchers. Methods: UDS Version 3 was developed after years of coordination between the National Institute on Aging-appointed Clinical Task Force (CTF), clinicians from ∼30 ADCs, and the National Alzheimer’s Coordinating Center (NACC). The CTF recognized the need for updates to align with the state of the science in dementia research, while being flexible to the diverse needs and diseases studied at the ADCs. Version 3 also developed a nonproprietary neuropsychological battery. Results: This paper focuses on the substantial Version 3 changes to the UDS forms related to clinical diagnosis and characterization of clinical symptoms to match updated consensus-based diagnostic criteria. Between March 2015 and March 2018, 4820 participants were enrolled using UDS Version 3. Longitudinal data were available for 25,337 of the 37,568 total participants using all UDS versions. Discussion: The results from utilization of the UDS highlight the possibility for numerous research institutions to successfully collaborate, produce, and use standardized data collection instruments for over a decade.

Neuropathologic evaluation remains the gold standard for determining the presence and severity of aging-related neurodegenerative diseases. Researchers at U.S. Alzheimer’s Disease Centers (ADCs) have worked for >30 years studying human brains, with the goals of achieving new research breakthroughs. Harmonization and sharing among the 39 current and past ADCs is promoted by the National Alzheimer’s Coordinating Center (NACC), which collects, audits, and disburses ADC-derived data to investigators on request. The past decades have witnessed revised disease definitions paired with dramatic expansion in the granularity and multimodality of the collected data. The NACC database now includes cognitive test scores, comorbidities, drug history, neuroimaging, and links to genomics. Relatively, recent advances in the neuropathologic diagnoses of Alzheimer’s disease, frontotemporal lobar degeneration (FTLD), and vascular contributions to cognitive impairment and dementia catalyzed a 2014 update to the NACC Neuropathology Form completed by all ADCs. New focal points include cerebrovascular disease (including arteriolosclerosis, microbleeds, and microinfarcts), hippocampal sclerosis, TDP-43, and FTLD. Here, we provide summary data and analyses to illustrate the potential for both hypothesis-testing and also generating new hypotheses using the NACC Neuropathology data set, which represents one of the largest multi-center databases of carefully curated neuropathologic information that is freely available to researchers worldwide.

Recently, a consensus working group provided new terminology for a common disease entity, limbic predominant age-related TDP-43 encephalopathy (LATE), and its neuropathological substrate (LATE-NC). LATE-NC not only often co-occurs with Alzheimer disease neuropathological change (ADNC), but also may present in isolation. The present study aimed to investigate potential risk factors and neuropathological characteristics associated with LATE-NC. A sample of 616 autopsied participants (>75 years at death), with TDP-43 immunohistochemical studies performed, was obtained from the National Alzheimer’s Coordinating Center. Logistic regression analyses examined associations between demographic, clinical and neuropathological characteristics and LATE-NC (TDP-43 in amygdala, hippocampus, or entorhinal/inferior temporal cortex) (alpha = 0.05). Adjusted models indicated that ADNC, hippocampal sclerosis (HS), arteriolosclerosis, and limbic or amygdala-predominant Lewy body disease (LBD), but not other LBD subtypes, were associated with higher odds of LATE-NC, whereas congestive heart failure (CHF) and motor problems as first predominant symptom were associated with lower odds of LATE-NC. Our findings corroborate previous studies indicating associations between LATE-NC and ADNC, HS, and arteriolosclerosis. Novel findings suggest the association with LATE-NC is restricted to amygdala/limbic-predominant subtype of LBD, and a possible protective (or competing risk) association with CHF. This study may inform future hypothesis-driven research on LATE-NC, a common brain disease of aging.

Objectives Summarise studies of outdoor green space exposure and brain health measures related to Alzheimer’s disease and related disorders (ADRD), and determine scientific gaps for future research. Design Rapid review of primary research studies. Methods and outcomes PubMed, Embase and Web of Science Core Collection were searched for articles meeting the criteria published on/before 13 February 2020. The review excluded papers not in English, focused on transient states (eg, mental fatigue) or not using individual-level measures of brain health (eg, average school test scores). Brain health measures of interest included cognitive function, clinical diagnosis of cognitive impairment/dementia/ADRD and brain biomarkers such as those from MRI, measures typically associated with ADRD risk and disease progression. Results Twenty-two papers were published from 2012 to 2020, 36% on <18 years old, 32% on 18–64 years old and 59% on ≥65 years old. Sixty-four per cent defined green space based on the Normalised Difference Vegetation Index (‘greenness’/healthy vegetation) and 68% focused on cognitive measures of brain health (eg, memory). Seventeen studies (77%) found green space-brain health associations (14 positive, 4 inverse). Greater greenness/green space was positively associated various cognitive domains in 10 studies and with MRI outcomes (regional brain volumes, cortical thickness, amygdala integrity) in three studies. Greater neighbourhood greenness was associated with lower odds/risk of cognitive impairment/ADRD in some studies but increased odds/risk in others (n=4 studies). Conclusions Published studies suggest positive green space-brain health associations across the life course, but the methods and cohorts were limited and heterogeneous. Future research using racially/ethnically and geographically diverse cohorts, life course methods and more specific green space and brain health measures (eg, time spent in green spaces, ADRD biomarkers) will strengthen evidence for causal associations.

Preliminary evidence suggests that neighborhood environments, such as socioeconomic disadvantage, pedestrian and physical activity infrastructure, and availability of neighborhood destinations (e.g., parks), may be associated with late-life cognitive functioning and risk of Alzheimer’s disease and related disorders (ADRD). The supposition is that these neighborhood characteristics are associated with factors such as mental health, environmental exposures, health behaviors, and social determinants of health that in turn promote or diminish cognitive reserve and resilience in later life. However, observed associations may be biased by self-selection or reverse causation, such as when individuals with better cognition move to denser neighborhoods because they prefer many destinations within walking distance of home, or when individuals with deteriorating health choose residences offering health services in neighborhoods in rural or suburban areas (e.g., assisted living). Research on neighborhood environments and ADRD has typically focused on late-life brain health outcomes, which makes it difficult to disentangle true associations from associations that result from reverse causality. In this paper, we review study designs and methods to help reduce bias due to reverse causality and self-selection, while drawing attention to the unique aspects of these approaches when conducting research on neighborhoods and brain aging.

This study examined differences in neuropsychological test scores between individuals with primary age-related tauopathy (PART) and Alzheimer disease (AD) using cross-sectional data from the National Alzheimer’s Coordinating Center. Linear regression tested for differences in 4 cognitive domains stratified by cognitive status (global Clinical Dementia Rating [CDR]). The sample included 240 participants with no neuritic plaques (NP) (definite PART), 186 with sparse NP (possible PART), and 510 with moderate/frequent NP (AD). Four cognitive domain z-score outcome variables (memory, attention, executive function, and semantic memory/language) were calculated using 12 neuropsychological tests. Definite PART participants had a sparing of semantic memory/language compared to those with AD, with a mean adjusted z-score difference of 0.37 (95% confidence interval [CI]: 0.16–0.58) for those with CDR = 0.5 or 1 and of 0.92 (CI: 0.22–1.63) for those with CDR = 2 or 3. Compared to participants with AD, definite PART participants with CDR = 0.5 or 1 had sparing of memory (adjusted z-score difference: 0.61; CI: 0.39–0.84) and definite PART participants with CDR = 2 or 3 had sparing of attention (adjusted z-score difference: 0.76: CI: 0.09–1.43). Patterns of cognitive impairment differed between definite PART and AD, suggesting significant differences in clinical presentation between individuals from these 2 groups.