CSF proteomics related to the neurovascular unit are associated with white matter hyperintensity volumes and cerebral microhemorrhages in autosomal dominant Alzheimer disease.

Background: Autosomal dominant Alzheimer disease (ADAD) is characterized by genetic mutations affecting the beta‐amyloid (Aβ) pathway. However, vascular and immune factors play important roles which are not completely understood. Understanding the function of the neurovascular unit (NVU) comprised of neurons, glial cells, and vasculature, at different disease stages appears ideal to developing and evaluating therapeutics.

Left frontoparietal control network connectivity moderates the effect of amyloid on cognitive decline in preclinical Alzheimer’s disease.

Background: Stronger default mode (DMN) and bilateral frontoparietal control network (FPCN) resting‐state functional connectivity are associated with reduced β‐amyloid (Aβ)‐related cognitive decline in cognitively unimpaired older adults, who were predominantly Aβ negative. This suggests that these networks might support cognitive resilience in the face of early AD pathology but it remains unclear whether these effects are apparent in preclinical AD. We investigated whether left‐FPCN, right‐FPCN, and DMN connectivity moderated the effect of Aβ on cognitive decline using a large multi‐site dataset from the Anti‐Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) study.

Plasma N‐terminal tau fragment is associated with cognitive status and AD biomarkers of tau and neurodegeneration in older adults.

Background: The emergence of blood‐based biomarkers offers a cost‐effective and less invasive alternative to established neuroimaging and cerebrospinal fluid biomarkers. Newly developed fluid biomarkers, including N‐terminal tau fragment (NT1), have shown promise for identifying individuals at risk for Alzheimer’s disease (AD). Evidence has shown NT1 may be more abundant than full‐length tau across the AD continuum and has high sensitivity and specificity to separate cognitively normal (CN) individuals from those with mild cognitive impaired (MCI) and AD in discovery and replication cohorts.

Elevated baseline white matter hyperintensity volume is related to the emergence of microhemorrhages in preclinical Alzheimer’s disease: the A4 Trial.

Background: Increased white matter hyperintensity volume (WMH) visible on MRI is a common finding in Alzheimer’s disease (AD) and is often attributed to small vessel ischemic changes. We hypothesized that WMH in preclinical AD is associated with worsening of vessel amyloidosis manifested as microhemorrhages (mH, ARIA‐H). We examine this hypothesis using cross‐sectional and longitudinal data over 4.

Examining the impact of hormone therapy and Alzheimer’s disease risk factors on depressive symptoms in the Harvard Aging Brain Study.

Background: Hormone therapy (HT) is often used to manage symptoms related to menopause, but its longer‐term effects on depressive symptoms in older women remains unclear. Previous literature reports inconclusive results on whether HT use is protective against or associated with increased depressive symptoms over time in older women. The objective of this study was to examine the associations of self‐reported HT use with baseline and longitudinal later life depressive symptoms.

CSF proteomics related to the neurovascular unit are associated with white matter hyperintensity volumes and cerebral microhemorrhages in autosomal dominant Alzheimer disease.

Background: Autosomal dominant Alzheimer disease (ADAD) is characterized by genetic mutations affecting the beta‐amyloid (Aß) pathway. However, vascular and immune factors play important roles which are not completely understood. Understanding the function of the neurovascular unit (NVU) comprised of neurons, glial cells, and vasculature, at different disease stages appears ideal to developing and evaluating therapeutics.

Left frontoparietal control network connectivity moderates the effect of amyloid on cognitive decline in preclinical Alzheimer’s disease.

Background: Stronger default mode (DMN) and bilateral frontoparietal control network (FPCN) resting‐state functional connectivity are associated with reduced ß‐amyloid (Aß)‐related cognitive decline in cognitively unimpaired older adults, who were predominantly Aß negative. This suggests that these networks might support cognitive resilience in the face of early AD pathology but it remains unclear whether these effects are apparent in preclinical AD. We investigated whether left‐FPCN, right‐FPCN, and DMN connectivity moderated the effect of Aß on cognitive decline using a large multi‐site dataset from the Anti‐Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) study.

Plasma N‐terminal tau fragment is associated with cognitive status and AD biomarkers of tau and neurodegeneration in older adults.

Background: The emergence of blood‐based biomarkers offers a cost‐effective and less invasive alternative to established neuroimaging and cerebrospinal fluid biomarkers. Newly developed fluid biomarkers, including N‐terminal tau fragment (NT1), have shown promise for identifying individuals at risk for Alzheimer’s disease (AD). Evidence has shown NT1 may be more abundant than full‐length tau across the AD continuum and has high sensitivity and specificity to separate cognitively normal (CN) individuals from those with mild cognitive impaired (MCI) and AD in discovery and replication cohorts.

γ-Secretase activity, clinical features, and biomarkers of autosomal dominant Alzheimer's disease: cross-sectional and longitudinal analysis of the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS).

Background: Genetic variants that cause autosomal dominant Alzheimer's disease are highly penetrant but vary substantially regarding age at symptom onset (AAO), rates of cognitive decline, and biomarker changes. Most pathogenic variants that cause autosomal dominant Alzheimer's disease are in presenilin 1 (PSEN1), which encodes the catalytic core of γ-secretase, an enzyme complex that is crucial in production of amyloid β. We aimed to investigate whether the heterogeneity in AAO and biomarker trajectories in carriers of PSEN1 pathogenic variants could be predicted on the basis of the effects of individual PSEN1 variants on γ-secretase activity and amyloid β production.

Vascular contributions to cognitive decline: Beyond amyloid and tau in the Harvard Aging Brain Study.

In addition to amyloid and tau pathology, elevated systemic vascular risk, white matter injury, and reduced cerebral blood flow contribute to late-life cognitive decline. Given the strong collinearity among these parameters, we proposed a framework to extract the independent latent features underlying cognitive decline using the Harvard Aging Brain Study (N = 166 cognitively unimpaired older adults at baseline). We used the following measures from the baseline visit: cortical amyloid, inferior temporal cortex tau, relative cerebral blood flow, white matter hyperintensities, peak width of skeletonized mean diffusivity, and Framingham Heart Study cardiovascular disease risk.

Presenilin-1 mutation position influences amyloidosis, small vessel disease, and dementia with disease stage.

Introduction: Amyloidosis, including cerebral amyloid angiopathy, and markers of small vessel disease (SVD) vary across dominantly inherited Alzheimer's disease (DIAD) presenilin-1 (PSEN1) mutation carriers. We investigated how mutation position relative to codon 200 (pre-/postcodon 200) influences these pathologic features and dementia at different stages.

Methods: Individuals from families with known PSEN1 mutations (n = 393) underwent neuroimaging and clinical assessments.

Plasma VEGFA and PGF impact longitudinal tau and cognition in preclinical Alzheimer's disease.

Vascular dysfunction is increasingly recognized as an important contributor to the pathogenesis of Alzheimer's disease. Alterations in vascular endothelial growth factor (VEGF) pathways have been implicated as potential mechanisms. However, the specific impact of VEGF proteins in preclinical Alzheimer's disease and their relationships with other Alzheimer's disease and vascular pathologies during this critical early period remain to be elucidated.

Etiology of White Matter Hyperintensities in Autosomal Dominant and Sporadic Alzheimer Disease.

Importance: Increased white matter hyperintensity (WMH) volume is a common magnetic resonance imaging (MRI) finding in both autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD), but it remains unclear whether increased WMH along the AD continuum is reflective of AD-intrinsic processes or secondary to elevated systemic vascular risk factors.

Objective: To estimate the associations of neurodegeneration and parenchymal and vessel amyloidosis with WMH accumulation and investigate whether systemic vascular risk is associated with WMH beyond these AD-intrinsic processes.

Design, Setting, And Participants: This cohort study used data from 3 longitudinal cohort studies conducted in tertiary and community-based medical centers-the Dominantly Inherited Alzheimer Network (DIAN; February 2010 to March 2020), the Alzheimer's Disease Neuroimaging Initiative (ADNI; July 2007 to September 2021), and the Harvard Aging Brain Study (HABS; September 2010 to December 2019).

Progression of cerebral amyloid angiopathy: a pathophysiological framework.

Cerebral amyloid angiopathy, which is defined by cerebrovascular deposition of amyloid β, is a common age-related small vessel pathology associated with intracerebral haemorrhage and cognitive impairment. Based on complementary lines of evidence from in vivo studies of individuals with hereditary, sporadic, and iatrogenic forms of cerebral amyloid angiopathy, histopathological analyses of affected brains, and experimental studies in transgenic mouse models, we present a framework and timeline for the progression of cerebral amyloid angiopathy from subclinical pathology to the clinical manifestation of the disease. Key stages that appear to evolve sequentially over two to three decades are (stage one) initial vascular amyloid deposition, (stage two) alteration of cerebrovascular physiology, (stage three) non-haemorrhagic brain injury, and (stage four) appearance of haemorrhagic brain lesions.

Metabolic and Vascular Risk Factor Variability Over 25 Years Relates to Midlife Brain Volume and Cognition.

Background: Metabolic and vascular risk factors (MVRF) are associated with neurodegeneration and poor cognition. There is a need to better understand the impact of these risk factors on brain health in the decades that precede cognitive impairment. Longitudinal assessments can provide new insight regarding changes in MVRFs that are related to brain imaging features.

Tau Mediates Synergistic Influence of Vascular Risk and Aβ on Cognitive Decline.

Objective: Elevated vascular risk and beta-amyloid (Aβ) burden have been synergistically associated with cognitive decline in preclinical Alzheimer's disease (AD), although the underlying mechanisms remain unclear. We examined whether accelerated longitudinal tau accumulation mediates the vascular risk-Aβ interaction on cognitive decline.

Methods: We included 175 cognitively unimpaired older adults (age 70.

Elevated regional cerebral blood flow in adults with 22q11.2 deletion syndrome.

Objectives: Recurrent chromosome 22q11.2 deletions cause 22q11 deletion syndrome (22q11DS), a multisystem disorder associated with high rates of schizophrenia. Neuroanatomical changes on brain MRI have been reported in relation to 22q11DS.

Progressive White Matter Injury in Preclinical Dutch Cerebral Amyloid Angiopathy.

Autosomal-dominant, Dutch-type cerebral amyloid angiopathy (D-CAA) offers a unique opportunity to develop biomarkers for pre-symptomatic cerebral amyloid angiopathy (CAA). We hypothesized that neuroimaging measures of white matter injury would be present and progressive in D-CAA prior to hemorrhagic lesions or symptomatic hemorrhage. In a longitudinal cohort of D-CAA carriers and non-carriers, we observed divergence of white matter injury measures between D-CAA carriers and non-carriers prior to the appearance of cerebral microbleeds and >14 years before the average age of first symptomatic hemorrhage.

Associations of plant-based dietary patterns with cardiovascular risk factors in women.

Given that some plant-based foods, such as potatoes, adversely affect cardiovascular disease (CVD) risk factors, this study was performed to assess the association between plant dietary patterns and these risk factors. This cross-sectional study was conducted among 371 healthy 18 to 50 year-old Iranian women. Participant dietary intake was assessed using a validated food frequency questionnaire.

Associations of white matter hyperintensities with networks of gray matter blood flow and volume in midlife adults: A coronary artery risk development in young adults magnetic resonance imaging substudy.

White matter hyperintensities (WMHs) are emblematic of cerebral small vessel disease, yet effects on the brain have not been well characterized at midlife. Here, we investigated whether WMH volume is associated with brain network alterations in midlife adults. Two hundred and fifty-four participants from the Coronary Artery Risk Development in Young Adults study were selected and stratified by WMH burden into Lo-WMH (mean age = 50 ± 3.

Automated generation of cerebral blood flow and arterial transit time maps from multiple delay arterial spin-labeled MRI.

Purpose: Develop and evaluate a deep learning approach to estimate cerebral blood flow (CBF) and arterial transit time (ATT) from multiple post-labeling delay (PLD) ASL MRI.

Methods: ASL MRI were acquired with 6 PLDs on a 1.5T or 3T GE system in adults with and without cognitive impairment (N = 99).