Basic Science and Pathogenesis.

Background: Inflammation is central to Alzheimer Disease (AD), as astrocyte reactivity accompanies the appearance of Aβ and phosphorylated tau (Bellaver et al., 2023). As expected, therefore, AD patients have elevated levels of CSF inflammatory cytokines (Onyango et al.

Basic Science and Pathogenesis.

Background: ApoE4 is the strongest genetic risk factor for late onset Alzheimer's Disease (AD). However, ApoE4 has also been suggested to exhibit antagonistic pleiotropy, a phenomenon by which some allelic variations of a gene promote fitness during certain periods of life but may be detrimental in others. Previous work suggests that ApoE4 carriers exhibit superior performance on executive function tasks in early and middle age, while later in life (>70 years) ApoE4 carriers experience greater cognitive decline across multiple domains.

Basic Science and Pathogenesis.

Background: Clusterin is a major cholesterol transporter in the central nervous system (CNS) and different SNPs in the CLU gene have been associated with Alzheimer's disease (AD) risk. The rs11136000_T variant in the CLU gene has been shown to decrease the risk of AD. In this work, we investigate the role of the CLU rs11136000_T protective variant and of the clusterin protein throughout different phases of the AD spectrum.

Basic Science and Pathogenesis.

Background: Scavenger receptors (SR) are a group of receptors involved in the endocytosis of various ligands, such as modified LDL and soluble β-amyloid, which connects them to Alzheimer's disease (AD). SCARF2 (SREC-II) is part of the SR family, but unlike other scavenger receptors, internalizes a low amount of modified LDL. Its main function revolves around the binding of Aβ (Vo et al.

Midlife physical activity engagement is associated with later-life brain health.

The relationship between midlife physical activity (PA), and cognition and brain health in later life is poorly understood with conflicting results from previous research. Investigating the contribution of midlife PA to later-life cognition and brain health in high-risk populations will propel the development of health guidance for those most in need. The current study examined the association between midlife PA engagement and later-life cognition, grey matter characteristics and resting-state functional connectivity in older individuals at high-risk for Alzheimer's disease.

Resting-state MRI functional connectivity as a neural correlate of multidomain lifestyle adherence in older adults at risk for Alzheimer's disease.

Prior research has demonstrated the importance of a healthy lifestyle to protect brain health and diminish dementia risk in later life. While a multidomain lifestyle provides an ecological perspective to voluntary engagement, its association with brain health is still under-investigated. Therefore, understanding the neural mechanisms underlying multidomain lifestyle engagement, particularly in older adults at risk for Alzheimer's disease (AD), gives valuable insights into providing lifestyle advice and intervention for those in need.

Sex differences in associations between APOE ε2 and longitudinal cognitive decline.

Introduction: We examined whether sex modifies the association between APOE ε2 and cognitive decline in two independent samples.

Methods: We used observational data from cognitively unimpaired non-Hispanic White (NHW) and non-Hispanic Black (NHB) adults. Linear mixed models examined interactive associations of APOE genotype (ε2 or ε4 carrier vs.

Unified epigenomic, transcriptomic, proteomic, and metabolomic taxonomy of Alzheimer's disease progression and heterogeneity.

Alzheimer's disease (AD) is a heterogeneous disorder with abnormalities in multiple biological domains. In an advanced machine learning analysis of postmortem brain and in vivo blood multi-omics molecular data ( = 1863), we integrated epigenomic, transcriptomic, proteomic, and metabolomic profiles into a multilevel biological AD taxonomy. We obtained a personalized multilevel molecular index of AD dementia progression that predicts severity of neuropathologies, and identified three robust molecular-based subtypes that explain much of the pathologic and clinical heterogeneity of AD.

Spatial Extent of Amyloid-β Levels and Associations With Tau-PET and Cognition.

Importance: Preventive trials of anti-amyloid agents might preferably recruit persons showing earliest biologically relevant β-amyloid (Aβ) binding on positron emission tomography (PET).

Objective: To investigate the timing at which Aβ-PET binding starts showing associations with other markers of Alzheimer disease.

Design, Setting, And Participants: This longitudinal multicentric cohort study included 3 independent cohorts: Presymptomatic Evaluation of Experimental or Novel Treatments for Alzheimer Disease (PREVENT-AD) (data collected from 2012-2020), Alzheimer Disease Neuroimaging Initiative (ADNI) (data collected from 2005-2019), and Harvard Aging Brain Study (HABS) (data collected from 2011-2019).

Plasma p-tau231, p-tau181, PET Biomarkers, and Cognitive Change in Older Adults.

Objective: The objective of this study was to evaluate novel plasma p-tau231 and p-tau181, as well as Aβ and Aβ assays as indicators of tau and Aβ pathologies measured with positron emission tomography (PET), and their association with cognitive change, in cognitively unimpaired older adults.

Methods: In a cohort of 244 older adults at risk of Alzheimer's disease (AD) owing to a family history of AD dementia, we measured single molecule array (Simoa)-based plasma tau biomarkers (p-tau231 and p-tau181), Aβ and Aβ with immunoprecipitation mass spectrometry, and Simoa neurofilament light (NfL). A subset of 129 participants underwent amyloid-β ( F-NAV4694) and tau ( F-flortaucipir) PET assessments.

Cerebral white matter diffusion properties and free-water with obstructive sleep apnea severity in older adults.

Characterizing the effects of obstructive sleep apnea (OSA) on the aging brain could be key in our understanding of neurodegeneration in this population. Our objective was to assess white matter properties in newly diagnosed and untreated adults with mild to severe OSA. Sixty-five adults aged 55 to 85 were recruited and divided into three groups: control (apnea-hypopnea index ≤5/hr; n = 18; 65.

Biomarkers of dementia in obstructive sleep apnea.

Epidemiologic and mechanistic evidence is increasingly supporting the notion that obstructive sleep apnea is a risk factor for dementia. Hence, the identification of patients at risk of cognitive decline due to obstructive sleep apnea may significantly improve preventive strategies and treatment decision-making. Cerebrospinal fluid and blood biomarkers obtained through genomic, proteomic and metabolomic approaches are improving the ability to predict incident dementia.

TLR4 Gene Expression and Pro-Inflammatory Cytokines in Alzheimer's Disease and in Response to Hippocampal Deafferentation in Rodents.

One important aspect in Alzheimer's disease pathology is the presence of chronic inflammation. Considering its role as a key receptor in the microglial innate immune system, TLR4 was shown to regulate the binding and phagocytosis of amyloid plaques by microglia in several mouse models of amyloidosis, as well as the production of pro-inflammatory cytokines. To our knowledge, TLR4 and its association with cytokines have not been thoroughly examined in the brains of subjects affected with Alzheimer's disease.

Healthy versus Entorhinal Cortical Atrophy Identification in Asymptomatic APOE4 Carriers at Risk for Alzheimer's Disease.

Early detection of Alzheimer's disease (AD) has been challenging as current biomarkers are invasive and costly. Strong predictors of future AD diagnosis include lower volume of the hippocampus and entorhinal cortex, as well as the ɛ4 allele of the Apolipoprotein E gene (APOE) gene. Therefore, studying functions that are critically mediated by the hippocampus and entorhinal cortex, such as spatial memory, in APOE ɛ4 allele carriers, may be key to the identification of individuals at risk of AD, prior to the manifestation of cognitive impairments.

Inhibiting tumor necrosis factor-α before amyloidosis prevents synaptic deficits in an Alzheimer's disease model.

Deficits in synaptic structure and function are likely to underlie cognitive impairments in Alzheimer's disease. While synaptic deficits are commonly found in animal models of amyloidosis, it is unclear how amyloid pathology may impair synaptic functions. In some amyloid mouse models of Alzheimer's disease, however, synaptic deficits are preceded by hyperexcitability of glutamate synapses.

BDNF Val66Met Polymorphism Interacts with Sleep Consolidation to Predict Ability to Create New Declarative Memories.

Unlabelled: It is hypothesized that a fundamental function of sleep is to restore an individual's day-to-day ability to learn and to constantly adapt to a changing environment through brain plasticity. Brain-derived neurotrophic factor (BDNF) is among the key regulators that shape brain plasticity. However, advancing age and carrying the BDNF Met allele were both identified as factors that potentially reduce BDNF secretion, brain plasticity, and memory.

Divergent regional patterns of cerebral hypoperfusion and gray matter atrophy in mild cognitive impairment patients.

Reductions of cerebral blood flow and gray matter structure have been implicated in early pathogenesis of Alzheimer's disease, potentially providing complementary information. The present study evaluated regional patterns of cerebral hypoperfusion and atrophy in patients with mild cognitive impairment and healthy older adults. In each participant, cerebral perfusion and gray matter structure were extracted within selected brain regions vulnerable to Alzheimer's disease using magnetic resonance imaging.

Rationale and Structure for a New Center for Studies on Prevention of Alzheimer's Disease (StoP-AD).

We describe events spanning over 20 years that have shaped our approach to identification of interventions that may delay symptoms in Alzheimer's disease (AD). These events motivated the development of a new Centre for Studies on Prevention of AD that includes an observational cohort of cognitively normal high-risk persons and INTREPAD, a nested two-year randomized placebo-controlled trial of the non-steroidal anti-inflammatory drug naproxen sodium. INTREPAD enrolled 217 persons and will follow 160 in a modified intent-to-treat analysis of persons who remained on-protocol through at least one follow-up evaluation.

'Alzheimer's Progression Score': Development of a Biomarker Summary Outcome for AD Prevention Trials.

Background: Alzheimer's disease (AD) prevention research requires methods for measurement of disease progression not yet revealed by symptoms. Preferably, such measurement should encompass multiple disease markers.

Objectives: Evaluate an item response theory (IRT) model-based latent variable Alzheimer Progression Score (APS) that uses multi-modal disease markers to estimate pre-clinical disease progression.

Effects of rs3846662 Variants on HMGCR mRNA and Protein Levels and on Markers of Alzheimer's Disease Pathology.

3-Hydroxy-3-methyglutaryl coenzyme A reductase (HMGCR) is a cholesterol-regulating gene with statin relevance. rs3846662 being involved in regulation of HMGCR alternative splicing, we explored its impact on HMGCR messenger RNA (mRNA) and protein levels in the brain and the associations between those levels and levels of Alzheimer's disease pathological markers. We used brain samples derived from a cohort of 33 non-demented controls and 90 Alzheimer's disease autopsied-confirmed cases.

Test-retest resting-state fMRI in healthy elderly persons with a family history of Alzheimer's disease.

We present a test-retest dataset of resting-state fMRI data obtained in 80 cognitively normal elderly volunteers enrolled in the "Pre-symptomatic Evaluation of Novel or Experimental Treatments for Alzheimer's Disease" (PREVENT-AD) Cohort. Subjects with a family history of Alzheimer's disease in first-degree relatives were recruited as part of an on-going double blind randomized clinical trial of Naproxen or placebo. Two pairs of scans were acquired ~3 months apart, allowing the assessment of both intra- and inter-session reliability, with the possible caveat of treatment effects as a source of inter-session variation.