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BackgroundImportant insights into the early pathogenesis of Alzheimer's disease can be provided by studies of autosomal dominant Alzheimer's disease and Down syndrome. However, it is unclear whether the timing and spatial distribution of amyloid accumulation differs between people with autosomal dominant Alzheimer's disease and those with Down syndrome. We aimed to directly compare amyloid changes between these two groups of people.MethodsIn this cross-sectional study, we included participants (aged ≥25 years) with Down syndrome and sibling controls who had MRI and amyloid PET scans in the first data release (January, 2020) of the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study. We also included carriers of autosomal dominant Alzheimer's disease genetic mutations and non-carrier familial controls who were within a similar age range to ABC-DS participants (25-73 years) and had MRI and amyloid PET scans at the time of a data freeze (December, 2020) of the Dominantly Inherited Alzheimer Network (DIAN) study. Controls from the two studies were combined into a single group. All DIAN study participants had genetic testing to determine PSEN1, PSEN2, or APP mutation status. APOE genotype was determined from blood samples. CSF samples were collected in a subset of ABC-DS and DIAN participants and the ratio of amyloid β42 (Aβ42) to Aβ40 (Aβ42/40) was measured to evaluate its Spearman's correlation with amyloid PET. Global PET amyloid burden was compared with regards to cognitive status, APOE ɛ4 status, sex, age, and estimated years to symptom onset. We further analysed amyloid PET deposition by autosomal dominant mutation type. We also assessed regional patterns of amyloid accumulation by estimated number of years to symptom onset. Within a subset of participants the relationship between amyloid PET and CSF Aβ42/40 was evaluated.Findings192 individuals with Down syndrome and 33 sibling controls from the ABC-DS study and 265 carriers of autosomal dominant Alzheimer's disease mutations and 169 non-carrier familial controls from the DIAN study were included in our analyses. PET amyloid centiloid and CSF Aβ42/40 were negatively correlated in carriers of autosomal dominant Alzheimer's disease mutations (n=216; r=-0·565; p

Research suggests a link between Alzheimer's Disease in Down Syndrome (DS) and the overproduction of amyloid plaques. Using Positron Emission Tomography (PET) we can assess the in-vivo regional amyloid load using several available ligands. To measure amyloid distributions in specific brain regions, a brain atlas is used. A popular method of creating a brain atlas is to segment a participant's structural Magnetic Resonance Imaging (MRI) scan. Acquiring an MRI is often challenging in intellectually-imparied populations because of contraindications or data exclusion due to significant motion artifacts or incomplete sequences related to general discomfort. When an MRI cannot be acquired, it is typically replaced with a standardized brain atlas derived from neurotypical populations (i.e. healthy individuals without DS) which may be inappropriate for use in DS. In this project, we create a series of disease and diagnosis-specific (cognitively stable (CS-DS), mild cognitive impairment (MCI-DS), and dementia (DEM-DS)) probabilistic group atlases of participants with DS and evaluate their accuracy of quantifying regional amyloid load compared to the individually-based MRI segmentations. Further, we compare the diagnostic-specific atlases with a probabilistic atlas constructed from similar-aged cognitively-stable neurotypical participants. We hypothesized that regional PET signals will best match the individually-based MRI segmentations by using DS group atlases that aligns with a participant's disorder and disease status (e.g. DS and MCI-DS). Our results vary by brain region but generally show that using a disorder-specific atlas in DS better matches the individually-based MRI segmentations than using an atlas constructed from cognitively-stable neurotypical participants. We found no additional benefit of using diagnose-specific atlases matching disease status. All atlases are made publicly available for the research community.HighlightDown syndrome (DS) joint-label-fusion atlases provide accurate positron emission tomography (PET) amyloid measurements.A disorder-specific DS atlas is better than a neurotypical atlas for PET quantification.It is not necessary to use a disease-state-specific atlas for quantification in aged DS.Dorsal striatum results vary, possibly due to this region and dementia progression.

Background: Women carrying the APOE4 allele are at greater risk of developing Alzheimer's disease (AD) from ages 65-75 years compared to men. To better understand the elevated risk conferred by APOE4 carrier status among midlife women, we investigated the separate and interactive associations of endogenous estrogens, plasma AD biomarkers, and APOE4 carrier status on regional brain volumes in a sample of late midlife postmenopausal women. Methods: Participants were enrolled in MsBrain, a cohort study of postmenopausal women (n = 171, mean age = 59.4 years, mean MoCA score = 26.9; race = 83.2% white, APOE4 carriers = 40). Serum estrone (E1) and estradiol (E2) levels were assessed using liquid chromatography-tandem mass spectrometry. APOE genotype was determined using TaqMan SNP genotyping assays. Plasma AD biomarkers were measured using single molecule array technology. Cortical volume was measured and segmented by FreeSurfer software using individual T1w MPRAGE images. Multiple linear regression models were conducted to determine whether separate and interactive associations between endogenous estrogen levels, plasma AD biomarkers (Aβ42/Aβ40, Aβ42/p-tau181), and APOE4 carrier status predict regional brain volume (21 regions per hemisphere, selected a priori); and, whether significant interactive associations between estrogens and AD biomarkers on brain volume differed by APOE4 carrier status. Results: There was no main effect of APOE4 carrier status on regional brain volumes, endogenous estrogen levels, or plasma AD biomarkers. Estrogens did not associate with regional brain volumes, except for positive associations with left caudal middle frontal gyrus and fusiform volumes. The interactive association of estrogens and APOE4 carrier status on brain volume was not significant for any region. The interactive association of estrogens and plasma AD biomarkers predicted brain volume of several regions. Higher E1 and E2 were more strongly associated with greater regional brain volumes among women with a poorer AD biomarker profile (lower Aβ42/40, lower Aβ42/p-tau181 ratios). In APOE4- stratified analyses, these interactions were driven by non-APOE4 carriers. Conclusion: We demonstrate that the brain volumes of postmenopausal women with poorer AD biomarker profiles benefit most from higher endogenous estrogen levels. These findings are driven by non-APOE4 carriers, suggesting that APOE4 carriers may be insensitive to the favorable effects of estrogens on brain volume in the postmenopause. [ABSTRACT FROM AUTHOR]

ObjectiveMild parkinsonian signs (MPS) are an underappreciated neurologic condition in older adults; we assessed associations of MPS with measures of dopaminergic (catechol-O-methyltransferase [COMT] genotype, an indicator of synaptic dopamine levels) and vascular (white matter hyperintensities [WMH], an indicator of cerebral small vessel disease) factors.MethodsIn a cohort of older adults (mean age 82.6 years [SD 2.6]; 58.0% female; 38.8% black), we assessed cross-sectional associations of WMH volume and COMT Val158Met (rs4680) genotype (n = 35 Met/Met, n = 180 Val carriers) with MPS by regression models adjusted for demographic and health characteristics. Interactions between WMH and COMT were assessed and analyses were repeated stratified by COMT genotype (Met/Met related to higher synaptic dopamine vs Val carriers related to lower synaptic dopamine).ResultsMPS was present in 42.3% of our sample. WMH (odds ratio [OR] 1.16, confidence interval [CI] 1.05-1.27) but not COMT (Met/Met compared to Val carrier: OR 0.62, CI 0.27-1.42) was related to MPS. There was a significant interaction between WMH and COMT (p = 0.03). Stratified analyses reveled a strong association between WMH and MPS among COMT Val carriers (OR 1.23, CI 1.09-1.38), but not for Met/Met (OR 0.68, CI 0.45-1.02), independent of covariates.ConclusionsWMH had a direct relation with MPS. In contrast, COMT was not associated with MPS, but it did modify the effect of WMH on MPS. The dopaminergic system may provide compensation for the effects of WMH on MPS. These findings suggest that MPS has a vascular rather than dopaminergic origin in older adults, but both factors are important in MPS manifestation.

Previous studies have shown that more active older adults have better cognition and brain health based on a variety of structural neuroimaging measures. Nevertheless, the effects of maintaining physical activity (PA) over an extended period of time on future changes in older adults' cognition and brain structure are unknown. Participants were 141 initially well-functioning community-dwelling older adults (aged 70-79 years at baseline; 60% female; 42% black) studied over a 13-year period. PA (self-reported time spent walking) was assessed annually from years 1 to 10. Magnetic resonance imaging with diffusion tensor was performed at years 10 and 13. Time spent walking decreased on average by 8.4% annually from year 1 to year 10. Independent of initial time spent walking, demographics, and APOE e4 status, better maintenance of time spent walking over the decade predicted less reduction in hippocampal volume (p = 0.03), smaller increases in global gray matter mean diffusivity and white matter axial diffusivity (p < 0.01), and maintenance of general cognitive performance (p < 0.01). Maintenance of cognitive performance was associated with smaller increases in white matter axial diffusivity (p < 0.01). PA at baseline and at year 10, as well as changes in PA over a 5-year period, was less predictive of future changes in brain structure and cognition. Thus, how PA levels change over longer periods of aging may be an important contributor to cognitive and neural protection.

ObjectiveTo identify the shared neuroimaging signature of gait slowing and cognitive impairment.MethodsWe assessed a cohort of older adults (n = 175, mean age 73 years, 57% female, 65% white) with repeated measures of gait speed over 14 years, MRI for gray matter volume (GMV) at year 10 or 11, and adjudicated cognitive status at year 14. Gait slowing was calculated by bayesian slopes corrected for intercepts, with higher values indicating faster decline. GMV was normalized to intracranial volume, with lower values indicating greater atrophy for 10 regions of interest (hippocampus, anterior and posterior cingulate, primary and supplementary motor cortices, posterior parietal lobe, middle frontal lobe, caudate, putamen, pallidum). Nonparametric correlations adjusted for demographics, comorbidities, muscle strength, and knee pain assessed associations of time to walk with GMV. Logistic regression models calculated odds ratios (ORs) of gait slowing with dementia or mild cognitive impairment with and without adjustment for GMV.ResultsGait slowing was associated with cognitive impairment at year 14 (OR per 0.1 s/y slowing 1.47; 95% confidence interval 1.04-2.07). The right hippocampus was the only region that was related to both gait slowing (ρ = -0.16, p = 0.03) and cognitive impairment (OR 0.17, p = 0.009). Adjustment for right hippocampal volume attenuated the association of gait slowing with cognitive impairment by 23%.ConclusionsThe association between gait slowing and cognitive impairment is supported by a shared neural substrate that includes a smaller right hippocampus. This finding underscores the value of long-term gait slowing as an early indicator of dementia risk.

INTRODUCTION: Late‐onset Alzheimer's disease (LOAD) has a strong genetic component. Participants in Long‐Life Family Study (LLFS) exhibit delayed onset of dementia, offering a unique opportunity to investigate LOAD genetics. METHODS: We conducted a whole genome sequence analysis of 3475 LLFS members. Genetic associations were examined in six independent studies (N = 14,260) with a wide range of LOAD risk. Association analysis in a sub‐sample of the LLFS cohort (N = 1739) evaluated the association of LOAD variants with beta amyloid (Aβ) levels. RESULTS: We identified several single nucleotide polymorphisms (SNPs) in tight linkage disequilibrium within the MTUS2 gene associated with LOAD (rs73154407, p = 7.6 × 10−9). Association of MTUS2 variants with LOAD was observed in the five independent studies and was significantly stronger within high levels of Aβ42/40 ratio compared to lower amyloid. DISCUSSION: MTUS2 encodes a microtubule associated protein implicated in the development and function of the nervous system, making it a plausible candidate to investigate LOAD biology. Highlights: Long‐Life Family Study (LLFS) families may harbor late onset Alzheimer's dementia (LOAD) variants.LLFS whole genome sequence analysis identified MTUS2 gene variants associated with LOAD.The observed LLFS variants generalized to cohorts with wide range of LOAD risk.The association of MTUS2 with LOAD was stronger within high levels of beta amyloid.Our results provide evidence for MTUS2 gene as a novel LOAD candidate locus. [ABSTRACT FROM AUTHOR]

BackgroundWhite matter hyperintensities (WMH), a common marker of cerebral small vessel disease, and lower microstructural integrity of normal-appearing white matter are associated with slower gait. How these cerebral measures interact in relation to slower gait is unknown. We assessed whether microstructural integrity of normal-appearing white matter, measured by fractional anisotropy (FA), moderates the association of higher WMH with slower gait.MethodsWMH, FA, and gait speed were acquired for 265 community-dwelling older adults (average age = 82.9 years).ResultsThe inverse association between WMH and gait was robust to adjustment for age, gender, muscle strength, obesity, stroke, and hypertension (fully adjusted model: βs = -0.19, p = .001). The interaction between WMH and FA was significant; analyses stratified by FA showed that the inverse association between WMH and gait speed was significant only for those with low FA (FA < median, fully adjusted model: βs = -0.28, p = .001). Voxel-based results were similar for participants with FA less than median, there was an inverse association between gait speed and WMH which extended throughout the white matter (genu and body of corpus callosum, anterior limb of internal capsule, corona radiata, and superior longitudinal and fronto-occipital fasciculus). In contrast, for participants with FA ≥ median, the association was limited to the genu of corpus callosum, the cingulum, and the inferior longitudinal fasciculus.ConclusionsMicrostructural integrity is a moderating factor in the association between WMH and gait. Future studies should examine whether higher microstructural integrity represents a source of compensation in those with greater WMH burden to maintain function in late life.

The neuroprotective effects of physical activity (PA) are consistently shown in older adults, but the neural substrates, particularly in white matter (WM), are understudied, especially in very old adults with the fastest growth rate and the highest risk of dementia. This study quantified the association between PA and WM integrity in adults over 80. The moderating effects of cardiometabolic conditions, physical functional limitations and WM hyperintensities were also examined, as they can affect PA and brain integrity. Fractional anisotropy (FA) from normal-appearing WM via diffusion tensor imaging and WM hyperintensities were obtained in 90 participants (mean age = 87.4, 51.1% female, 55.6% white) with concurrent objective measures of steps, active energy expenditure (AEE in kcal), duration (min), and intensity (metabolic equivalents, METs) via SenseWear Armband. Clinical adjudication of cognitive status, prevalence of stroke and diabetes, systolic blood pressure, and gait speed were assessed at time of neuroimaging. Participants were on average sedentary (mean ± SD/day: 1766 ± 1345 steps, 202 ± 311 kcal, 211 ± 39 min, 1.8 ± 1.1 METs). Higher steps, AEE and duration, but not intensity, were significantly associated with higher FA. Associations were localized in frontal and temporal areas. Moderating effects of cardiometabolic conditions, physical functional limitations, and WM hyperintensities were not significant. Neither FA nor PA was related to cognitive status. Older adults with a sedentary lifestyle and a wide range of cardiometabolic conditions and physical functional limitations, displayed higher WM integrity in relation to higher PA. Studies of very old adults to quantify the role of PA in reducing dementia burden via WM integrity are warranted.

A positive association between cardiorespiratory fitness (CRF) and white matter integrity has been consistently reported in older adults. However, it is unknown whether this association exists in adults over 80 with a range of chronic disease conditions and low physical activity participation, which can influence both CRF and brain health. This study examined whether higher CRF was associated with greater microstructural integrity of gray and white matter in areas related to memory and information processing in adults over 80 and examined moderating effects of chronic diseases and physical activity. CRF was measured as time to walk 400 m as quickly as possible with concurrent 3T diffusion tensor imaging in 164 participants (57.1% female, 40.3% black). Fractional anisotropy (FA) was computed for cingulum, uncinate and superior longitudinal fasciculi. Mean diffusivity (MD) was computed for dorsolateral prefrontal cortex, hippocampus, parahippocampus, and entorhinal cortex. Moderating effects were tested using hierarchical regression models. Higher CRF was associated with higher FA in cingulum and lower MD in hippocampus and entorhinal cortex (β, sex-adjusted p: -0.182, 0.019; 0.165, 0.035; and 0.220, 0.006, respectively). Hypertension attenuated the association with MD in entorhinal cortex. Moderating effects of chronic diseases and physical activity in walking and climbing stairs on these associations were not significant. The association of higher CRF with greater microstructural integrity in selected subcortical areas appears robust, even among very old adults with a range of chronic diseases. Intervention studies should investigate whether increasing CRF can preserve memory and information processing by improving microstructure and potential effects of hypertension management.

In older adults, depressive symptoms are associated with lower quality of life, high morbidity and mortality. This study aims to identify brain magnetic resonance imaging (MRI) features associated with late-life depressive symptoms in the population. Older community-dwelling adults (n=314) from the Health ABC study underwent brain MRI. Logistic regression was used to characterize the relationships between depressive symptoms (Center for Epidemiologic Studies of Depression scale, CES-D) and the following whole-brain variables: white matter hyperintensity (WMH) burden, fractional anisotropy (FA), and gray matter volume (GMV). Analyses examining possible regional differences between the CES-D groups controlled for Modified Mini-Mental State Examination score and diabetes status. The relative importance of localization of the markers was examined by comparing the distribution of significant peaks across the brain. Each whole-brain variable showed loss of integrity associated with high CES-D. For GMV, the odds ratio (OR)=0.84 (95% confidence interval (CI) 0.74, 0.96); for FA, OR=0.714 (95% CI 0.57, 0.88); for WMH, OR=1.89 (95%CI 1.33, 2.69). Voxel-wise analyses and patterns of peak significance showed non-specific patterns for white matter measures. Loss of GMV was most significant in the bilateral insula and anterior cingulate cortex. This study supports a cerebrovascular pattern for depressive symptoms in older adults. The localization of gray matter changes to the insula, a watershed area and a hub of affective circuits, suggests an etiological pathway from ischemia to increased depressive burden.