Evidence before this study Using PubMed and Google Scholar the authors reviewed prior work on longitudinal neuroimaging markers of Alzheimer pathology with a focus on autosomal dominant Alzheimer disease (ADAD). We searched for all articles prior to October 31 st , 2017 with no language restrictions for the keywords Alzheimer's, Alzheimer, longitudinal, positron emission tomography, PET, MRI, atrophy, FDG, hypometabolism, familial, and autosomal. Theories proposed initially in 2010 by Jack and colleagues and revised in 2013 posited temporal trajectories of Alzheimer biomarkers relative to each other and clinical decline. Work by Bateman and colleagues in 2012, Benzinger and colleagues in 2013, and Fleisher and colleagues in 2015 depict such temporal ordering of biomarkers in ADAD populations derived from cross-sectional analyses. There was also a small subset of longitudinal ADAD studies, but these had one or more limitation such as small populations (n<50), examination of only one biomarker, not accounting for regional differences or correlations in the brain, or had a short duration of longitudinal followup. Added value of this studyOur study presents the first known work examining both the longitudinal temporal trajectories and spatial patterns of Alzheimer pathology in ADAD cohorts using neuroimaging. This work also presents the largest known cohort to date of ADAD individuals studied longitudinally with multiple neuroimaging biomarkers. Longitudinal analyses can provide a more accurate and powerful way to model the temporal emergence of pathology in ADAD. We find that mutation carriers first display Aβ accumulation, followed by hypometabolism, and finally structural atrophy; this is consistent with theoretical models and cross-sectional estimates from ADAD. Most importantly we consider such temporal relationships not in one singular summary measure, but characterize these trajectories throughout the brain. We found that the accrual of pathology varied throughout the brain and by modality in terms of the time of initial emergence and the rates of longitudinal change. These findings suggest region specific vulnerabilities to β-amyloidosis, metabolic decline, and atrophy that change over the course of the disease. Implications of all the available evidenceOur results build upon existing evidence characterizing biomarkers in clinical and preclinical Alzheimer disease. Our findings suggest that imaging biomarkers follow a sequential pattern, with β-amyloidosis, hypometabolism, and structural atrophy emerging more than twenty, fifteen, and ten years respectively before the expected onset of dementia. Although there is a general hierarchical pattern, there was considerable regional heterogeneity. Most commonly, regions demonstrated an increase in β-amyloidosis and structural atrophy, but there was not evidence of metabolic declines. Further, rather than being homogenous, the same biomarker often demonstrates different longitudinal trajectories across brain regions. Characterizing the temporal and regional dynamics...

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Introduction Structural magnetic resonance imaging is a marker of gray matter health and decline that is sensitive to impaired cognition and Alzheimer's disease pathology. Prior work has shown that both amyloid β (Aβ) and tau biomarkers are related to cortical thinning, but it is unclear what unique influences they have on the brain. Methods Aβ pathology was measured with [ 18 F] AV-45 (florbetapir) positron emission tomography (PET) and tau was assessed with [ 18 F] AV-1451 (flortaucipir) PET in a population of 178 older adults, of which 123 had longitudinal magnetic resonance imaging assessments (average of 5.7 years) that preceded the PET acquisitions. Results In cross-sectional analyses, greater tau PET pathology was associated with thinner cortices. When examined independently in longitudinal models, both Aβ and tau were associated with greater antecedent loss of gray matter. However, when examined in a combined model, levels of tau, but not Aβ, were still highly related to change in cortical thickness. Discussion Measures of tau PET are strongly related to gray matter atrophy and likely mediate relationships between Aβ and gray matter.

Objectives African Americans are at greater risk for developing Alzheimer's disease (AD) dementia than non‐Hispanic whites. In addition to biological considerations (eg, genetic influences and comorbid disorders), social and environmental factors may increase the risk of AD dementia. This paper (1) assesses neuroimaging biomarkers of amyloid (A), tau (T), and neurodegeneration (N) for potential racial differences and (2) considers mediating effects of socioeconomic status (SES) and measures of small vessel and cardiovascular disease on observed race differences. Methods Imaging measures of AT(N) (amyloid and tau positron emission tomography [PET]) structural magnetic resonance imaging (MRI), and resting state functional connectivity (rs‐fc) were collected from African American (n = 131) and white (n = 685) cognitively normal participants age 45 years and older. Measures of small vessel and cardiovascular disease (white matter hyperintensities [WMHs] on MRI, blood pressure, and body mass index [BMI]) and area‐based SES were included in mediation analyses. Results Compared to white participants, African American participants had greater neurodegeneration, as measured by decreased cortical volumes (Cohen's f2 = 0.05, p < 0.001). SES mediated the relationship between race and cortical volumes. There were no significant race effects for amyloid, tau, or rs‐fc signature. Interpretation Modifiable factors, such as differences in social contexts and resources, particularly area‐level SES, may contribute to observed racial differences in AD. Future studies should emphasize collection of relevant psychosocial factors in addition to the development of intentional diversity and inclusion efforts to improve the racial/ethnic and socioeconomic representativeness of AD studies. ANN NEUROL 2021;89:254–265

Neurofilament light chain (NfL) is a protein that is selectively expressed in neurons. Increased levels of NfL measured in either cerebrospinal fluid or blood is thought to be a biomarker of neuronal damage in neurodegenerative diseases. However, there have been limited investigations relating NfL to the concurrent measures of white matter (WM) decline that it should reflect. White matter damage is a common feature of Alzheimer's disease. We hypothesized that serum levels of NfL would associate with WM lesion volume and diffusion tensor imaging (DTI) metrics cross-sectionally in 117 autosomal dominant mutation carriers (MC) compared to 84 non-carrier (NC) familial controls as well as in a subset ( N = 41) of MC with longitudinal NfL and MRI data. In MC, elevated cross-sectional NfL was positively associated with WM hyperintensity lesion volume, mean diffusivity, radial diffusivity, and axial diffusivity and negatively with fractional anisotropy. Greater change in NfL levels in MC was associated with larger changes in fractional anisotropy, mean diffusivity, and radial diffusivity, all indicative of reduced WM integrity. There were no relationships with NfL in NC. Our results demonstrate that blood-based NfL levels reflect WM integrity and supports the view that blood levels of NfL are predictive of WM damage in the brain. This is a critical result in improving the interpretability of NfL as a marker of brain integrity, and for validating this emerging biomarker for future use in clinical and research settings across multiple neurodegenerative diseases.

Highlights Cortical signatures selective to AD could provide an early MRI biomarker. Autosomal dominant Alzheimer disease (ADAD) may model an ideal AD signature. ADAD and late-onset maps overlap in parietal cortex but contain unique features. Signatures predicted increasing amyloid within their own, but not across cohorts. These results indicate atrophy in AD can take multiple spatial patterns.

Importance: Female sex is a major risk factor for late-onset Alzheimer disease (AD), and sex hormones have been implicated as a possible protective factor. Neuroimaging studies that evaluated the effects of sex hormones on brain integrity have primarily emphasized neurodegenerative measures rather than amyloid and tau burden. Objective: We compared cortical amyloid and regional tau positron emission tomography (PET) deposition between cognitively normal males and females. We also compared preclinical AD pathology between females who have and have not used hormone therapy (HT). Finally, we compared the effects of amyloid and tau pathology on cognition, testing for both sex and HT effects. Design, Setting, and Participants: We analyzed amyloid, tau, and cognition in a cognitively normal cross-sectional cohort of older individuals (n=148) followed at the Knight Alzheimer Disease Research Center. Amyloid and tau PET, medication history, and neuropsychological testing were obtained for each participant. Results: Within cognitively normal individuals, there was no difference in amyloid burden by sex. Whether or not we controlled for amyloid burden, female participants had significantly higher tau PET levels than males in multiple regions, including the rostral middle frontal and superior and middle temporal regions. HT accounted for a small reduction in tau PET; however, males still had substantially lower tau PET compared with females. Amyloid PET and tau PET burden were negatively associated with cognitive performance, although increasing amyloid PET did not have a deleterious effect on cognitive performance for women with a history of HT. Conclusions and Relevance: Regional sex-related differences in tau PET burden may contribute to the disparities in AD prevalence between males and females. The observed decreases tau PET burden in HT users has important implications for clinical practice and trials and deserves future consideration in longitudinal studies.