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Alzheimer's disease (AD) is associated with heterogeneous atrophy patterns. We employed a semi-supervised representation learning technique known as Surreal-GAN, through which we identified two latent dimensional representations of brain atrophy in symptomatic mild cognitive impairment (MCI) and AD patients: the "diffuse-AD" (R1) dimension shows widespread brain atrophy, and the "MTL-AD" (R2) dimension displays focal medial temporal lobe (MTL) atrophy. Critically, only R2 was associated with widely known sporadic AD genetic risk factors (e.g., APOE ε4) in MCI and AD patients at baseline. We then independently detected the presence of the two dimensions in the early stages by deploying the trained model in the general population and two cognitively unimpaired cohorts of asymptomatic participants. In the general population, genome-wide association studies found 77 genes unrelated to APOE differentially associated with R1 and R2. Functional analyses revealed that these genes were overrepresented in differentially expressed gene sets in organs beyond the brain (R1 and R2), including the heart (R1) and the pituitary gland, muscle, and kidney (R2). These genes were enriched in biological pathways implicated in dendritic cells (R2), macrophage functions (R1), and cancer (R1 and R2). Several of them were "druggable genes" for cancer (R1), inflammation (R1), cardiovascular diseases (R1), and diseases of the nervous system (R2). The longitudinal progression showed that APOE ε4, amyloid, and tau were associated with R2 at early asymptomatic stages, but this longitudinal association occurs only at late symptomatic stages in R1. Our findings deepen our understanding of the multifaceted pathogenesis of AD beyond the brain. In early asymptomatic stages, the two dimensions are associated with diverse pathological mechanisms, including cardiovascular diseases, inflammation, and hormonal dysfunction-driven by genes different from APOE-which may collectively contribute to the early pathogenesis of AD. All results are publicly available at https://labs-laboratory.com/medicine/ ., (© 2024. The Author(s).)

Infections have been associated with the incidence of Alzheimer disease and related dementias, but the mechanisms responsible for these associations remain unclear. Using a multicohort approach, we found that influenza, viral, respiratory, and skin and subcutaneous infections were associated with increased long-term dementia risk. These infections were also associated with region-specific brain volume loss, most commonly in the temporal lobe. We identified 260 out of 942 immunologically relevant proteins in plasma that were differentially expressed in individuals with an infection history. Of the infection-related proteins, 35 predicted volumetric changes in brain regions vulnerable to infection-specific atrophy. Several of these proteins, including PIK3CG, PACSIN2, and PRKCB, were related to cognitive decline and plasma biomarkers of dementia (Aβ 42/40 , GFAP, NfL, pTau-181). Genetic variants that influenced expression of immunologically relevant infection-related proteins, including ITGB6 and TLR5, predicted brain volume loss. Our findings support the role of infections in dementia risk and identify molecular mediators by which infections may contribute to neurodegeneration., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Although blood-based biomarkers have been identified as cost-effective and scalable alternatives to PET and CSF markers of neurodegenerative disease, little is known about how these biomarkers predict future brain atrophy and cognitive decline in cognitively unimpaired individuals. Using data from the Baltimore Longitudinal Study of Aging (BLSA), we examined whether plasma biomarkers of Alzheimer's disease (AD) pathology (amyloid-β [Aβ 42/40 ], phosphorylated tau [pTau-181]), astrogliosis (glial fibrillary acidic protein [GFAP]), and neuronal injury (neurofilament light chain [NfL]) were associated with longitudinal brain volume loss and cognitive decline. Additionally, we determined whether sex, APOEε4 status, and plasma amyloid-β status modified these associations., Methods: Plasma biomarkers were measured using Quanterix SIMOA assays. Regional brain volumes were measured by 3T MRI, and a battery of neuropsychological tests assessed five cognitive domains. Linear mixed effects models adjusted for demographic factors, kidney function, and intracranial volume (MRI analyses) were completed to relate baseline plasma biomarkers to baseline and longitudinal brain volume and cognitive performance., Results: Brain volume analyses included 622 participants (mean age ± SD: 70.9 ± 10.2) with an average of 3.3 MRI scans over 4.7 years. Cognitive performance analyses included 674 participants (mean age ± SD: 71.2 ± 10.0) with an average of 3.9 cognitive assessments over 5.7 years. Higher baseline pTau-181 was associated with steeper declines in total gray matter volume and steeper regional declines in several medial temporal regions, whereas higher baseline GFAP was associated with greater longitudinal increases in ventricular volume. Baseline Aβ 42/40 and NfL levels were not associated with changes in brain volume. Lower baseline Aβ 42/40 (higher Aβ burden) was associated with a faster decline in verbal memory and visuospatial performance, whereas higher baseline GFAP was associated with a faster decline in verbal fluency. Results were generally consistent across sex and APOEε4 status. However, the associations of higher pTau-181 with increasing ventricular volume and memory declines were significantly stronger among individuals with higher Aβ burden, as was the association of higher GFAP with memory decline., Conclusions: Among cognitively unimpaired older adults, plasma biomarkers of AD pathology (pTau-181) and astrogliosis (GFAP), but not neuronal injury (NfL), serve as markers of future brain atrophy and cognitive decline., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Although liver dysfunction has been implicated in Alzheimer's disease (AD), it remains unknown how liver disease may influence the trajectory of brain and cognitive changes in older adults. We related self-reported liver disease to longitudinal measures of brain structure and cognition, as well as baseline measures of plasma AD/neurodegeneration biomarkers in the Baltimore Longitudinal Study of Aging. Liver disease was identified using ICD-9 classification codes. Brain volume and cognition were assessed serially using 3T-MRI and a cognitive battery. 1008, 2157, and 780 participants were included in the MRI, cognitive, and plasma biomarker analysis, respectively. After adjustment for confounders, liver disease was associated with accelerated decline in total brain and white matter volume, but not total gray matter or AD signature region volume. Although liver disease showed no relationship with domain-specific cognitive decline or plasma biomarkers, participants with a history of hepatitis demonstrated accelerated decline in verbal fluency and elevated neurofilament light. Results suggest all-cause liver disease may accelerate brain volume loss but does not appear to promote AD-specific neurocognitive changes., (Published by Elsevier Inc.)

Background and Objectives: Although an infectious etiology of Alzheimer disease (AD) has received renewed attention with a particular focus on herpes viruses, the longitudinal effects of symptomatic herpes virus (sHHV) infection on brain structure and cognition remain poorly understood, as does the effect of sHHV on AD/neurodegeneration biomarkers., Methods: We used a longitudinal, community-based cohort to characterize the association of sHHV diagnoses with changes in 3 T MRI brain volume and cognitive performance. In addition, we related sHHV to cross-sectional differences in plasma biomarkers of AD (β-amyloid [Aβ] 42/40 ), astrogliosis (glial fibrillary acidic protein [GFAP]), and neurodegeneration (neurofilament light [NfL]). Baltimore Longitudinal Study of Aging participants were recruited from the community and assessed with serial brain MRIs and cognitive examinations over an average of 3.4 (SD = 3.2) and 8.6 (SD = 7.7) years, respectively. sHHV classification used International Classification of Diseases, Ninth Revision codes documented at comprehensive health and functional screening evaluations at each study visit. Linear mixed-effects and multivariable linear regression models were used in analyses., Results: A total of 1,009 participants were included in the primary MRI analysis, 98% of whom were cognitively normal at baseline MRI (mean age = 65.7 years; 54.8% female). Having a sHHV diagnosis (N = 119) was associated with longitudinal reductions in white matter volume (annual additional rate of change -0.34 cm 3 /y; p = 0.035), particularly in the temporal lobe. However, there was no association between sHHV and changes in total brain, total gray matter, or AD signature region volumes. Among the 119 participants with sHHV, exposure to antiviral treatment attenuated declines in occipital white matter ( p = 0.04). Although the sHHV group had higher cognitive scores at baseline, sHHV diagnosis was associated with accelerated longitudinal declines in attention (annual additional rate of change -0.01 Z-score/year; p = 0.008). In addition, sHHV diagnosis was associated with elevated plasma GFAP, but not related to Aβ 42/40 and NfL levels., Discussion: These findings suggest an association of sHHV infection with white matter volume loss, attentional decline, and astrogliosis. Although the findings link sHHV to several neurocognitive features, the results do not support an association between sHHV and AD-specific disease processes., (© 2022 American Academy of Neurology.)

Recently, it was shown that patients with Parkinson's disease (PD) who exhibit an "Alzheimer's disease (AD)-like" pattern of brain atrophy are at greater risk for future cognitive decline. This study aimed to investigate whether this association is domain-specific and whether atrophy associated with brain aging also relates to cognitive impairment in PD. SPARE-AD, an MRI index capturing AD-like atrophy, and atrophy-based estimates of brain age were computed from longitudinal structural imaging data of 178 PD patients and 84 healthy subjects from the LANDSCAPE cohort. All patients underwent an extensive neuropsychological test battery. Patients diagnosed with mild cognitive impairment or dementia were found to have higher SPARE-AD scores as compared to patients with normal cognition and healthy controls. All patient groups showed increased brain age. SPARE-AD predicted impairment in memory, language and executive functions, whereas advanced brain age was associated with deficits in attention and working memory. Data suggest that SPARE-AD and brain age are differentially related to domain-specific cognitive decline in PD. The underlying pathomechanisms remain to be determined., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Heterogeneity of brain diseases is a challenge for precision diagnosis/prognosis. We describe and validate Smile-GAN (SeMI-supervised cLustEring-Generative Adversarial Network), a semi-supervised deep-clustering method, which examines neuroanatomical heterogeneity contrasted against normal brain structure, to identify disease subtypes through neuroimaging signatures. When applied to regional volumes derived from T1-weighted MRI (two studies; 2,832 participants; 8,146 scans) including cognitively normal individuals and those with cognitive impairment and dementia, Smile-GAN identified four patterns or axes of neurodegeneration. Applying this framework to longitudinal data revealed two distinct progression pathways. Measures of expression of these patterns predicted the pathway and rate of future neurodegeneration. Pattern expression offered complementary performance to amyloid/tau in predicting clinical progression. These deep-learning derived biomarkers offer potential for precision diagnostics and targeted clinical trial recruitment., (© 2021. The Author(s).)

Background: Cognitive processing speed is important for performing everyday activities in persons with mild cognitive impairment (MCI). However, its role in daily function has not been examined while simultaneously accounting for contributions of Alzheimer's disease (AD) risk biomarkers. We examine the relationships of processing speed and genetic and neuroimaging biomarkers to composites of daily function, mobility, and driving., Method: We used baseline data from 103 participants on the MCI/mild dementia spectrum from the Applying Programs to Preserve Skills trial. Linear regression models examined relationships of processing speed, structural magnetic resonance imaging (MRI), and genetic risk alleles for AD to composites of performance-based instrumental activities of daily living (IADLs), community mobility, and on-road driving evaluations., Results: In multivariable models, processing speed and the brain MRI neurodegeneration biomarker Spatial Pattern of Abnormality for Recognition of Early Alzheimer's disease (SPARE-AD) were significantly associated with functional and mobility composite performance. Better processing speed and younger age were associated with on-road driving ratings. Genetic risk markers, left hippocampal atrophy, and white matter lesion volumes were not significant correlates of these abilities. Processing speed had a strong positive association with IADL function (p < .001), mobility (p < .001), and driving (p = .002)., Conclusions: Cognitive processing speed is strongly and consistently associated with critical daily functions in persons with MCI in models including genetic and neuroimaging biomarkers of AD risk. SPARE-AD scores also significantly correlate with IADL performance and mobility. Results highlight the central role of processing speed in everyday task performance among persons with MCI/mild dementia., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: Meta-analyses of randomized clinical trials have indicated that improved hypertension control reduces the risk for cognitive impairment and dementia. However, it is unclear to what extent pathways reflective of Alzheimer disease (AD) pathology are affected by hypertension control., Objective: To evaluate the association of intensive blood pressure control on AD-related brain biomarkers., Design, Setting, and Participants: This is a substudy of the Systolic Blood Pressure Intervention Trial (SPRINT MIND), a multicenter randomized clinical trial that compared the efficacy of 2 different blood pressure-lowering strategies. Potential participants (n = 1267) 50 years or older with hypertension and without a history of diabetes or stroke were approached for a brain magnetic resonance imaging (MRI) study. Of these, 205 participants were deemed ineligible and 269 did not agree to participate; 673 and 454 participants completed brain MRI at baseline and at 4-year follow-up, respectively; the final follow-up date was July 1, 2016. Analysis began September 2019 and ended November 2020., Interventions: Participants were randomized to either a systolic blood pressure goal of less than 120 mm Hg (intensive treatment: n = 356) or less than 140 mm Hg (standard treatment: n = 317)., Main Outcomes and Measures: Changes in hippocampal volume, measures of AD regional atrophy, posterior cingulate cerebral blood flow, and mean fractional anisotropy in the cingulum bundle., Results: Among 673 recruited patients who had baseline MRI (mean [SD] age, 67.3 [8.2] years; 271 women [40.3%]), 454 completed the follow-up MRI at a median (interquartile range) of 3.98 (3.7-4.1) years after randomization. In the intensive treatment group, mean hippocampal volume decreased from 7.45 cm3 to 7.39 cm3 (difference, -0.06 cm3; 95% CI, -0.08 to -0.04) vs a decrease from 7.48 cm3 to 7.46 cm3 (difference, -0.02 cm3; 95% CI, -0.05 to -0.003) in the standard treatment group (between-group difference in change, -0.033 cm3; 95% CI, -0.062 to -0.003; P = .03). There were no significant treatment group differences for measures of AD regional atrophy, cerebral blood flow, or mean fractional anisotropy., Conclusions and Relevance: Intensive treatment was associated with a small but statistically significant greater decrease in hippocampal volume compared with standard treatment, consistent with the observation that intensive treatment is associated with greater decreases in total brain volume. However, intensive treatment was not associated with changes in any of the other MRI biomarkers of AD compared with standard treatment., Trial Registration: ClinicalTrials.gov Identifier: NCT01206062.

Background: Anemia and red cell distribution width (RDW) have been linked to poor cognitive performance, pending studies of underlying mechanisms., Objective: We examined cross-sectional relationships of initial RDW status (v1), RDW change (δ), and anemia with brain structural magnetic resonance imaging (sMRI) markers, including global and cortical brain and hippocampal and white matter lesion (WML) volumes, 5-6 years later., Methods: Data were used from three prospective visits within the Healthy Aging in Neighborhoods of Diversity Across the Life Span (HANDLS) study with complete v1 (2004-2009) and v2 (2009-2013) exposures and ancillary sMRI data at vscan (2011-2015, n = 213, mean v1 to vscan time: 5.7 years). Multivariable-adjusted linear regression models were conducted, overall, by sex, by race, and within non-anemics, correcting for multiple testing with q-values., Results: In minimally adjusted models (socio-demographics and follow-up time), anemiav1 and RDWv1 were consistently associated with smaller bilateral hippocampal volumes overall, and among females (q < 0.05), without significant sex differences. RDWv1 was related to smaller select regional cortical brain gray and white matter volumes in hematological measure-adjusted models; anemiav1 was associated with larger WML volumes only among whites., Conclusion: In summary, baseline anemia and RDW were consistently associated with smaller bilateral hippocampal volumes, particularly among females, while anemia was linked to larger WML volume among Whites. In hematological measure-adjusted models, baseline RDW was linked to smaller regional gray and white matter volumes. Pending studies with sMRI repeats, randomized controlled trials are needed, demonstrating associations of anemia and elevated RDW with reduced brain volumes and cognitive dysfunction.

Performance of instrumental activities of daily living (IADLs) can become compromised in older adults with mild cognitive impairment (MCI). Patients' level of insight into their everyday functioning varies both amongst individuals and across domains assessed, with some individuals exhibiting complete unawareness of deficits. The current cross-sectional study examined the neuroanatomical substrates of self-awareness in order to help explain the variability in this phenomenon in older adults across a continuum of cognitive impairment. Eighty-five participants (ages 54-88, mean age = 73 years, 57% female, 89% Caucasian) diagnosed with MCI or mild probable dementia underwent structural magnetic resonance imaging. Level of self-awareness was assessed by calculating the discrepancy between objective and subjective performance across six IADLs (Financial Management, Driving, Grocery Shopping, Nutrition Evaluation, Medication Management, and Telephone Use). Over-estimation of current abilities occurred in 13-31% of the sample depending on which IADL was evaluated. Poor awareness was significantly related to reduced volume in the bilateral medial prefrontal cortex, middle and posterior cingulate cortex, right insular cortex, and cerebellum. No associations were found with total white matter lesion load. These findings were broadly consistent across all functional domains assessed, supporting the theory that cortical midline and cerebellar structures are involved in self-referential processing across a variety of different cognitive and behavioral skills. Longitudinal studies are needed to confirm this association., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Effects of Alzheimer's disease (AD) risk factors on brain volume changes may partly explain what happens during the preclinical AD stage in people who develop subsequent cognitive impairment (SI). We investigated predictors of neurodegeneration, measured by MRI-based volume loss, in older adults before diagnosis of cognitive impairment. There were 623 cognitively normal and 65 SI Baltimore Longitudinal Study of Aging participants (age 55-92 years) enrolled in the neuroimaging substudy from 1994 to 2015. Mixed-effects regression was used to assess the associations of AD risk factors (age, APOE e4 carrier status, diabetes, hypertension, obesity, current smoking, and elevated cholesterol) with brain regional volume change among the overall sample and by diagnostic status. Older age, APOE e4 carrier status, hypertension, and HDL cholesterol were predictors of volumetric change. Among SI participants only, hypertension, obesity, and APOE e4 carrier status were associated with greater declines in selected brain regions. SI individuals in the preclinical AD stage are vulnerable to risk factors that have either a protective or null effect in cognitively normal individuals., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Importance: There are currently no proven treatments to reduce the risk of mild cognitive impairment and dementia., Objective: To evaluate the effect of intensive blood pressure control on risk of dementia., Design, Setting, and Participants: Randomized clinical trial conducted at 102 sites in the United States and Puerto Rico among adults aged 50 years or older with hypertension but without diabetes or history of stroke. Randomization began on November 8, 2010. The trial was stopped early for benefit on its primary outcome (a composite of cardiovascular events) and all-cause mortality on August 20, 2015. The final date for follow-up of cognitive outcomes was July 22, 2018., Interventions: Participants were randomized to a systolic blood pressure goal of either less than 120 mm Hg (intensive treatment group; n = 4678) or less than 140 mm Hg (standard treatment group; n = 4683)., Main Outcomes and Measures: The primary cognitive outcome was occurrence of adjudicated probable dementia. Secondary cognitive outcomes included adjudicated mild cognitive impairment and a composite outcome of mild cognitive impairment or probable dementia., Results: Among 9361 randomized participants (mean age, 67.9 years; 3332 women [35.6%]), 8563 (91.5%) completed at least 1 follow-up cognitive assessment. The median intervention period was 3.34 years. During a total median follow-up of 5.11 years, adjudicated probable dementia occurred in 149 participants in the intensive treatment group vs 176 in the standard treatment group (7.2 vs 8.6 cases per 1000 person-years; hazard ratio [HR], 0.83; 95% CI, 0.67-1.04). Intensive BP control significantly reduced the risk of mild cognitive impairment (14.6 vs 18.3 cases per 1000 person-years; HR, 0.81; 95% CI, 0.69-0.95) and the combined rate of mild cognitive impairment or probable dementia (20.2 vs 24.1 cases per 1000 person-years; HR, 0.85; 95% CI, 0.74-0.97)., Conclusions and Relevance: Among ambulatory adults with hypertension, treating to a systolic blood pressure goal of less than 120 mm Hg compared with a goal of less than 140 mm Hg did not result in a significant reduction in the risk of probable dementia. Because of early study termination and fewer than expected cases of dementia, the study may have been underpowered for this end point., Trial Registration: ClinicalTrials.gov Identifier: NCT01206062.

Background and Purpose: Dementia in Parkinson's disease (PD) is common and disabling. Identification of modifiable risk factors for it is essential. Vascular risk factors (VRFs) may be associated with cognitive decline in early PD. Biomarkers that serve as surrogates of the long-term effect of VRFs on PD are needed. To that end, we aimed to quantitate white matter hyperintensities (WMH) in early PD, measure associations with VRFs and examine relationships between WMH and longitudinal cognition., Methods: Participants in the Parkinson's Progression Markers Initiative study (141 patients with PD, 63 healthy controls) with adequate baseline structural brain magnetic resonance imaging data were included. Hypertension and diabetes history, and body mass index were combined to create a vascular risk score. WMH were quantitated via automated methods. Cognition was assessed annually with a comprehensive test battery., Results: In the PD group, vascular risk score was associated with WMH for total brain (β = 0.210; P = 0.021), total white matter (β = 0.214; P = 0.013), frontal (β = 0.220; P = 0.002) and temporal (β = 0.212; P = 0.002) regions. Annual rate of change in global cognition was greater in those with higher vascular risk score (β = -0.040; P = 0.007) and greater WMH (β = -0.029; P = 0.049). Higher temporal WMH burden was associated with great decline over time in verbal memory (β = -0.034; P = 0.031)., Conclusions: In early PD, modifiable VRFs are associated with WMH on brain magnetic resonance imaging. Temporal WMH burden predicts decline in verbal memory. WMH may serve as a surrogate marker for the effect of VRFs on cognitive abilities in PD., (© 2018 EAN.)