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Introduction: Identifying individuals who are most likely to accumulate tau and exhibit cognitive decline is critical for Alzheimer's disease (AD) clinical trials. Methods: Participants (N = 235) who were cognitively normal or with mild cognitive impairment from the Alzheimer's Disease Neuroimaging Initiative were stratified by a cutoff on the polygenic hazard score (PHS) at 65th percentile (above as high‐risk group and below as low‐risk group). We evaluated the associations between the PHS risk groups and tau positron emission tomography and cognitive decline, respectively. Power analyses estimated the sample size needed for clinical trials to detect differences in tau accumulation or cognitive change. Results: The high‐risk group showed faster tau accumulation and cognitive decline. Clinical trials using the high‐risk group would require a fraction of the sample size as trials without this inclusion criterion. Discussion: Incorporating a PHS inclusion criterion represents a low‐cost and accessible way to identify potential participants for AD clinical trials. [ABSTRACT FROM AUTHOR]

Introduction: The locus coeruleus (LC) undergoes extensive neurodegeneration in early Alzheimer's disease (AD). The LC is implicated in regulating the sleep–wake cycle, modulating cognitive function, and AD progression. Methods: Participants were 481 men (ages 62 to 71.7) from the Vietnam Era Twin Study of Aging. LC structural integrity was indexed by neuromelanin‐sensitive magnetic resonance imaging (MRI) contrast‐to‐noise ratio (LCCNR). We examined LCCNR, cognition, amnestic mild cognitive impairment (aMCI), and daytime dysfunction. Results: Heritability of LCCNR was.48. Participants with aMCI showed greater daytime dysfunction. Lower LCCNR was associated with poorer episodic memory, general verbal fluency, semantic fluency, and processing speed, as well as increased odds of aMCI and greater daytime dysfunction. Discussion: Reduced LC integrity is associated with widespread differences across cognitive domains, daytime sleep‐related dysfunction, and risk for aMCI. These findings in late‐middle‐aged adults highlight the potential of MRI‐based measures of LC integrity in early identification of AD risk. [ABSTRACT FROM AUTHOR]

Background: Composite scores of MRI‐based brain regions associated with Alzheimer's disease (AD) pathology, commonly termed 'AD signatures,' are tools developed to identify brain changes specific to mild AD. In recent work from our group, we found that a novel diffusion‐based cortical mean diffusivity (MD) signature among cognitively normal adults in their 50s aided prediction of 12‐year progression to MCI beyond age and polygenic risk for AD. Results held up after accounting for general brain age. In contrast, a cortical thickness/hippocampal volume‐based signature did not improve prediction. Given the importance of genetic influences on brain structure and AD, here we examined the phenotypic and genetic relationships among diffusion and structural AD signatures and brain age, and how those relationships change across midlife and early old age. Method: Our validated thickness/volume signature, novel MD signature, and a validated brain age measure were used in biometrical twin analyses to examine phenotypic, genetic, and environmental relationships both cross‐sectionally and longitudinally across 12 years. Participants were 736 men from three waves of the Vietnam Era Twin Study of Aging (VETSA; baseline age=56.1, SD=2.6, range=51.1‐60.2). Subsequent waves were at approximately 5.7‐year intervals. Result: Both AD signatures and brain age are heritable (56%‐72%), but each signature captured unique phenotypic and genetic variance that is also not explained by general brain aging. Genetic correlations across time within each signature were high (0.77‐0.98). Baseline MD signatures (age=56 years) predicted thickness/volume signatures over a decade later (r= ‐0.53, 95% CI: ‐0.62, ‐0.42), but baseline thickness/volume signatures showed a significantly weaker relationship with future MD signatures (r= ‐0.13, 95% CI: ‐0.24, ‐0.01). Interestingly, by wave 2 (average age=62 years), the thickness/volume signature appears to have caught up with the MD signature in terms of predictive ability. Conclusion: Findings lend further support to the idea that a signature based on brain microstructure captures very early AD‐related changes that are later reflected in the macrostructural signature. This MD signature explains substantial genetic variance that is consistent throughout midlife and into early old age, supporting the utility of the MD signature as a very early AD‐related neuroimaging biomarker and its potential role in clinical trials. [ABSTRACT FROM AUTHOR]

Introduction Alzheimer's Disease Neuroimaging Initiative (ADNI) is now in its 10th year. The primary objective of the magnetic resonance imaging (MRI) core of ADNI has been to improve methods for clinical trials in Alzheimer's disease (AD) and related disorders. Methods We review the contributions of the MRI core from present and past cycles of ADNI (ADNI-1, -Grand Opportunity and -2). We also review plans for the future-ADNI-3. Results Contributions of the MRI core include creating standardized acquisition protocols and quality control methods; examining the effect of technical features of image acquisition and analysis on outcome metrics; deriving sample size estimates for future trials based on those outcomes; and piloting the potential utility of MR perfusion, diffusion, and functional connectivity measures in multicenter clinical trials. Discussion Over the past decade the MRI core of ADNI has fulfilled its mandate of improving methods for clinical trials in AD and will continue to do so in the future. [ABSTRACT FROM AUTHOR]

Background: Unusually successful cognitive aging (e.g. SuperAging) may reflect underlying resistance to age‐associated cognitive decline and the neuropathologic markers of Alzheimer's disease (AD). However, it is unknown whether these individuals vary in their genetic protection from AD relative to other clinically normal elderly individuals. Method: The Northwestern SuperAgers cohort (n=41) was limited to clinically normal individuals who were at least 80 years old but performed at or above normative values for average 50 to 65‐year‐olds on delayed recall of the Rey Auditory Verbal Learning Test and within one standard deviation of the average normative range for their age, or better, on non‐episodic memory tests including the 30‐item Boston Naming Test, Trail Making Test Part‐B and Category Fluency Test (Animals). The UC San Diego (UCSD) Shiley Marcos Alzheimer's Disease Research Center and Alzheimer's Disease Neuroimaging Initiative (ADNI) comparison cohorts (n=17 and 46, respectively) included all clinically normal individuals with available genetic data who were at least 80 years old but did not meet the criteria for SuperAgers outlined above. Polygenic hazard scores (PHS) were downloaded from ADNI and calculated for each participant as described (Desikan et al., 2017) for the Northwestern and UCSD cohorts. Briefly, the PHS combines an individual's genotype for 31 AD‐associated SNPs in addition to APOE. Result: All three cohorts were similar in age (range: 80‐101) and years of education (range: 12‐20). However, there were significantly more women in the Northwestern SuperAgers cohort (p < 0.001). The mean PHS in each cohort was negative, indicating that these individuals had less than average population risk for AD. However, there were no significant differences in PHS between cohorts. Conclusion: As a group, SuperAgers did not have lower polygenic risk for AD than clinically normal elderly individuals, suggesting determinants of superior memory performance in older age cannot be solely explained by having unusually low risk for AD as assessed by common genetic variants. Given the sex differences in these cohorts, future work should consider whether sex‐specific polygenic risk for AD contributes to the superior memory performance of SuperAgers. [ABSTRACT FROM AUTHOR]

Background: Longitudinal studies of aging are central to identifying early predictors of and mechanisms underlying late‐life cognitive decline and dementia. However, these studies typically lack cognitive data from earlier ages. It is therefore unclear how peak young adult general cognitive ability (GCA) and maintenance of GCA from young adulthood impact subsequent cognitive trajectories. To further understand GCA change from young adulthood, we evaluated whether poor GCA maintenance coincided with accelerated brain aging and was associated with key contributors to cognitive decline in later life, namely, aggregate vascular risk and Alzheimer's disease polygenic risk (AD‐PRS). Method: In the Vietnam Era Twin Study of Aging (VETSA), 1173 individuals were administered the same measure of GCA at average age 20 and at three VETSA waves beginning at average age 56. GCA maintenance scores were created by residualizing VETSA baseline GCA on age 20 GCA. Thus, good GCA maintenance was based on observed relative to expected scores. VETSA baseline GCA and GCA maintenance scores were entered into mixed effects models to predict specific cognitive abilities across three VETSA waves (∼6 years apart). Associations between GCA maintenance scores and indices of accelerated brain aging, aggregate vascular risk, and AD‐PRS were evaluated. Result: Better GCA maintenance was associated with better VETSA baseline memory, semantic fluency, general fluency, processing speed, executive function, and working memory. However, given equivalent age 56 GCA, those who declined in GCA from age 20 outperformed those with stable GCA in memory, verbal fluency, executive function, and working memory at age 56. Thus, despite poor cognitive maintenance, some element of high peak cognitive reserve in early adulthood still confers benefit. All specific cognitive abilities declined over time, but neither VETSA baseline GCA nor GCA maintenance predicted extent of decline. Poor GCA maintenance from young adulthood was associated with accelerated brain aging and aggregate vascular risk, but not AD‐PRS. Conclusion: Both peak young adult GCA and GCA maintenance are important contributors to late midlife cognitive ability. Poor maintenance of GCA from young adulthood being associated with worse vascular health and coinciding with accelerated brain aging argues against a simple regression to the mean explanation. [ABSTRACT FROM AUTHOR]

Background: Cytoarchitectural brain changes during normal aging remain poorly characterized, with further uncertainty whether patterns of brain aging underlying cognitive dysfunction differ by sex. Prior studies have demonstrated that the diffusion MRI technique restriction spectrum imaging (RSI) predicts cognitive decline and pathology in Alzheimer's disease (Reas et al., 2017,2018,2019), but sensitivity of RSI to typical brain aging has not been assessed. Method: This study used RSI to examine sex differences in associations of brain microstructure with age and cognition in community‐dwelling participants of the Rancho Bernardo Study. Ninety women and 57 men aged 56‐99 completed RSI and cognitive assessment (global cognitive function, executive function, verbal memory, visual memory, logical memory). RSI metrics of restricted, hindered, and free water diffusion were computed in cortical gray matter, hippocampus, and white matter fibers. Sex‐specific correlations assessed associations of RSI with age and with cognitive function. Mediation analyses examined whether RSI measures mediated effects of age on cognitive performance. Result: Age‐related increases in free water, and decreases in measures thought to reflect intraneurite (restricted) and extraneurite (hindered) diffusion, and neurite complexity, were observed throughout gray matter and fibers. Associations remained after adjusting for cortical thinning, and regional associations emerged after adjustment for global microstructure. Associations of microstructure with age and with cognitive function were stronger and more widespread for women than men. Adjustment for age attenuated RSI‐cognition correlations for both sexes, as well as sex differences in these associations. Microstructure partially mediated effects of age on cognitive performance for men and women. Whereas age more strongly correlated with RSI and cognitive measures for women, RSI measures more strongly mediated age effects on cognitive function for men. Conclusion: Microstructural brain changes, which may reflect cell shrinkage, demyelination, axonal and dendritic loss, or reduced neurite complexity, occur with typical aging and correlate with performance in multiple cognitive domains. Age‐related microstructural injury is more pronounced for women, and patterns by which microstructure mediates cognitive aging differ by sex. Normal aging may be accompanied by cytoarchitectural damage that underlies cognitive decline, and the mechanisms by which age‐related neural injury impairs cognitive function may differ between men and women. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) brain signatures based on cortical thickness, with or without hippocampal volume, predict progression from mild cognitive impairment (MCI) to AD. It would be advantageous if AD signatures could predict earlier progression to MCI. Toward that end, a signature sensitive to microstructural changes that may predate macrostructural atrophy should be useful. We hypothesized that: 1) AD signatures in cognitively normal middle‐aged adults can predict progression to MCI; and 2) Gray matter mean diffusivity (MD) may capture earlier microstructural changes associated with AD. Method: We investigated the ability of a published cortical thickness/volume signature and a novel MD signature to predict incident MCI in 261 cognitively normal middle‐aged men from the Vietnam Era Twin Study of Aging (VETSA) (baseline age=56.28±2.56; follow‐up age=67.50±2.61). The thickness/volume signature was a weighted average of 8 bilateral regions found to maximally discriminate AD from healthy controls. The same weights were applied to MD in these regions to create an MD signature in 206 subjects with diffusion‐weighted MRI data at baseline. Logistic regression and ROC curves were used to compare models with baseline thickness/volume signature, MD signature, age, and an AD polygenic risk score (ADPRS) predicting MCI at follow‐up. Result: Thickness/volume signature, MD signature, age, and ADPRS together predicted progression to MCI an average of 12 years later with 77.85% specificity, 80% sensitivity, and area‐under‐the‐curve (AUC) of 0.822 (95% CI=0.729‐0.914) (Figure 1). Age and ADPRS alone yielded a significantly lower AUC of 0.633 (95% CI=0.561‐0.705; n=601). Adding the MD signature significantly improved prediction over age and ADPRS (AUC=0.811 vs. 0.633; p=.002) but adding the thickness/volume signature did not (AUC=0.746; p=.069). Conclusion: AD brain signatures can predict 12‐year progression to MCI among cognitively normal adults who are only in their 50s, but our novel MD signature may be more sensitive to AD‐related changes than traditional thickness/volume signatures. Notably, the MD signature was limited by being yoked to the thickness/volume signature weightings. An independently derived MD signature may provide even stronger prediction. The results are thus promising with respect to early identification of AD and the potential value of MD‐ and/or multimodal AD brain signatures. [ABSTRACT FROM AUTHOR]

Background: The locus coeruleus (LC) serves as the primary source of norepinephrine for the brain. Findings that the LC is one of the earliest sites of tau pathology make it a key structure in the early stages of Alzheimer’s disease (AD) progression. An important question is whether measures of LC integrity are associated with indexes of brain structure that may suggest broader patterns of neurodegeneration, particularly if such patterns are detectable prior to substantial macrostructural change. We therefore examined whether LC structural integrity was associated with differences in cortical gray matter microstructure among adults in early old age. Method: Participants were 435 men (mean age=67.5; range=62‐71.7) from the Vietnam Era Twin Study of Aging (VETSA). Rostral LC structural integrity was indexed by contrast‐to‐noise ratio (LCCNR) from a neuromelanin‐sensitive MRI scan. Restriction spectrum imaging (RSI), an advanced multi‐shell diffusion technique, was used to characterize cortical microstructure, modeling diffusion in restricted, hindered, and free water compartments. Associations between LCCNR and isotropic diffusion within each compartment were examined for bilateral averages of 34 cortical ROIs defined by the Desikan‐Killiany parcellation. As a sensitivity analysis, we also examined whether LCCNR was associated with mean diffusivity (MD), a conventional diffusion tensor imaging (DTI) metric, or cortical thickness in the same regions. Result: After correction for multiple comparisons, higher LCCNR (greater structural integrity) was significantly associated with higher hindered isotropic diffusion and lower free water diffusion across multiple brain regions. In contrast, LCCNR was only associated with lower MD in one brain region and there were no associations with cortical thickness after correction. Conclusion: These results provide evidence that lower MRI‐assessed LC integrity is associated with patterns of cortical microstructure that may reflect a reduction in cellular membranes due to broader neurodegenerative processes. Individual differences in LC integrity were only detected with more advanced measures of microstructure that may be more sensitive to early changes than conventional diffusion imaging or macrostructural measures. These results highlight the potential utility for MRI of the LC and cortical microstructure in early identification of AD risk. [ABSTRACT FROM AUTHOR]

Background: Composite scores of MRI‐based brain morphometry, commonly termed ‘Alzheimer’s disease (AD) signatures,’ have demonstrated associations with AD symptom severity and progression to AD. Our group recently showed that two AD signatures, a cortical thickness/volume and mean diffusivity (MD) signature, aid prediction of progression to mild cognitive impairment among cognitively normal adults in their 50s. Genetic and environmental influences on these signatures, and whether the signatures capture unique AD‐related variance, remains unclear. Method: Participants were from the Vietnam Era Twin Study of Aging (age=56.18, SD=2.61). Our previously published thickness/volume signature, a novel MD signature using the same regions and weights as the thickness/volume signature, and an MRI‐based measure of predicted brain age (ns=310‐502) were used in trivariate twin models to determine the relative influence of genetic and environmental factors on each phenotype. Correlations were examined to determine if the latent genetic and environmental influences overlap among the three phenotypes. Result: Heritability estimates were similar for the signatures and predicted brain age (0.68‐0.71). Phenotypic correlations ranged from ‐0.47 to 0.27. Genetic correlations were: 0.33 [95% CI: 0.19,0.47] (thickness/volume signature and predicted brain age); ‐0.55 [95% CI: ‐0.66,‐0.42] (MD signature and predicted brain age); and ‐0.36 [95% CI: ‐0.51,‐0.20] (thickness/volume and MD signatures). Conclusion: Both AD brain signatures are highly heritable. However, despite very similar heritability estimates among the three phenotypes, genetic correlations demonstrated that the two AD signatures are not redundant with each other or with a measure of predicted brain age. The results suggest that each AD signature captures some unique genetic variance, including genetic influences that are distinct from genetic influences on general brain aging. [ABSTRACT FROM AUTHOR]