The PREVENT-AD cohort: accelerating Alzheimer's disease research and treatment in Canada and beyond.

The PREVENT-AD is an investigator-driven study that was created in 2011 and enrolled cognitively normal older adults with a family history of sporadic AD. Participants are deeply phenotyped and have now been followed annually for more than 12 years [median follow-up 8.0 years,SD 3.

Brain and CSF Alzheimer's Biomarkers Are Associated with SERPINE1 Gene Expression.

Background: SERPINE1, also known as plasminogen activator inhibitor (PAI), has been proposed as a potential blood biomarker for the early detection and diagnosis of Alzheimer's disease (AD). Expanding on previous studies, this research contrasted SERPINE1 levels in CSF and brain tissue of AD patients and those at risk for AD with established AD biomarkers.

Methods: Utilizing OLINK and immunoassay methods, CSF SERPINE1 protein levels were quantified across two separate cohorts: PREVENT-AD and ADNI.

Tau PET positivity in individuals with and without cognitive impairment varies with age, amyloid-β status, APOE genotype and sex.

Tau positron emission tomography (PET) imaging allows in vivo detection of tau proteinopathy in Alzheimer's disease, which is associated with neurodegeneration and cognitive decline. Understanding how demographic, clinical and genetic factors relate to tau PET positivity will facilitate its use for clinical practice and research. Here we conducted an analysis of 42 cohorts worldwide (N = 12,048), including 7,394 cognitively unimpaired (CU) participants, 2,177 participants with mild cognitive impairment (MCI) and 2,477 participants with dementia.

Characterizing spatiotemporal white matter hyperintensity pathophysiology in vivo to disentangle vascular and neurodegenerative contributions.

White matter hyperintensities (WMHs) are neuroimaging markers widely interpreted as caused by cerebral small vessel disease, yet emerging evidence suggests that a subset may have a neurodegenerative etiology. Current imaging methods have lacked the specificity to disentangle biological processes underlying WMHs . Here, we used voxel-level normative modeling and seven microstructural MRI markers with complementary biophysical sensitivities to generate single-subject high-resolution WMH pathophysiology maps in a large cohort (=32,526).

Frequency and Clinical Outcomes Associated With Tau Positron Emission Tomography Positivity.

Importance: Tau positron emission tomography (PET) allows in vivo detection of neurofibrillary tangles, a core neuropathologic feature of Alzheimer disease (AD).

Objective: To provide estimates of the frequency of tau PET positivity and its associated risk of clinical outcomes.

Design, Setting, And Participants: Longitudinal study using data pooled from 21 cohorts, comprising a convenience sample of 6514 participants from 13 countries, collected between January 2013 and June 2024.

Associations Between Changes in Levels of Phosphorylated Tau and Severity of Cognitive Impairment in Early Alzheimer Disease.

Background And Objectives: Aligning biomarker evidence with clinical presentation in early Alzheimer disease (AD) is essential for improving diagnosis, prognosis, and interventions. This study evaluates the relationship between cognitive impairment, future decline, and phosphorylated tau levels in plasma and CSF in predementia AD.

Methods: This longitudinal observational study included predementia cases and controls from 2 independent cohorts: the Norwegian Dementia Disease Initiation (DDI) and Canadian Pre-Symptomatic Evaluation of Experimental or Novel Treatments for Alzheimer's Disease (PREVENT-AD).

Longitudinal relationships among cerebrospinal fluid biomarkers, cerebral blood flow, and grey matter volume in individuals with a familial history of Alzheimer's disease.

Alzheimer's disease (AD) is a complex disease that involves complex interactions between protein biomarkers such as amyloid beta (Aβ) and tau, neurodegeneration, cerebrovascular health and inflammation. However, how these factors interact, especially in the early phases of disease development remain unclear. To address this, this study analyzed four-year longitudinal data from 110 cognitively unimpaired older adults with a family history of AD in the PreventAD cohort.

Differential effects of aging, Alzheimer's pathology, and APOE4 on longitudinal functional connectivity and episodic memory in older adults.

Background: Both aging and Alzheimer's disease (AD) affect brain networks, with early disruptions occurring in regions involved in episodic memory. Few studies have, however, focused on distinguishing region-specific effects of AD-biomarker negative "normal" aging and early amyloid- and tau pathology on functional connectivity. Further, longitudinal studies combining imaging, biomarkers, and cognition are rare.

Amyloid and Tau Pathology in Cognitively Unimpaired Individuals With a Parental History of Alzheimer Disease: Role of Sex and Parent's Sex.

Background And Objectives: Female sex and a parental history of Alzheimer disease (AD), especially maternal, confer increased risk of AD. Associations between sex, or affected AD parent's sex, and biomarkers of AD are less clear. We examined whether sex or affected AD parent's sex influences (1) β-amyloid (Aβ) and tau burden/accumulation, (2) the association between Aβ and tau burden, and (3) brain and cognitive resilience to Aβ and tau burden.

Plasma p-tau217 and tau-PET predict future cognitive decline among cognitively unimpaired individuals: implications for clinical trials.

Plasma p-tau217 and tau positron emission tomography (PET) are strong prognostic biomarkers in Alzheimer's disease (AD), but their relative performance in predicting future cognitive decline among cognitively unimpaired (CU) individuals is unclear. In a head-to-head comparison study including nine cohorts and 1,474 individuals, we show that plasma p-tau217 and medial temporal lobe tau-PET signal display similar associations with cognitive decline on a global cognitive composite test (R = 0.34 versus R = 0.

Uncovering atrophy progression pattern and mechanisms in individuals at risk of Alzheimer's disease.

Alzheimer's disease is associated with pre-symptomatic changes in brain morphometry and accumulation of abnormal tau and amyloid-beta pathology. Studying the development of brain changes prior to symptoms onset may lead to early diagnostic biomarkers and a better understanding of Alzheimer's disease pathophysiology. Alzheimer's disease pathology is thought to arise from a combination of protein accumulation and spreading via neural connections, but how these processes influence brain atrophy progression in the pre-symptomatic phases remains unclear.

Sex and APOE4-specific links between cardiometabolic risk factors and white matter alterations in individuals with a family history of Alzheimer's disease.

Early detection of pathological changes in Alzheimer's disease (AD) has garnered significant attention in the last few decades as interventions aiming to prevent progression will likely be most effective when initiated early. White matter (WM) alterations are among the earliest changes in AD, yet limited work has comprehensively characterized the effects of AD risk factors on WM. In older adults with a family history of AD, we investigated the sex-specific and APOE genotype-related relationships between WM microstructure and risk factors.

Protocol for an intergenerational randomized controlled trial to enhance physical activity in older adults at risk for Alzheimer's disease.

Background: Physical inactivity is one of the most important modifiable risk factors for Alzheimer's disease in North America. Despite this, most older adults are physically inactive. It is currently unknown how to successfully motivate physical activity behavior in older adults at risk for Alzheimer's disease, and this knowledge is crucial for early and effective disease prevention.

Plasma p-tau217 identifies cognitively normal older adults who will develop cognitive impairment in a 10-year window.

Introduction: We assessed the prognostic accuracy of plasma p-tau217 in predicting the progression to mild cognitive impairment (MCI) in cognitively unimpaired (CU) individuals over a mean follow-up of 5.65 years after plasma collection (range 1.01-10.

Frontotemporal dementia subtyping using machine learning, multivariate statistics and neuroimaging.

Frontotemporal dementia (FTD) is a prevalent form of early-onset dementia characterized by progressive neurodegeneration and encompasses a group of heterogeneous disorders. Due to overlapping symptoms, diagnosis of FTD and its subtypes still poses a challenge. Magnetic resonance imaging (MRI) is commonly used to support the diagnosis of FTD.

Exploring morphological and microstructural signatures across the Alzheimer's spectrum and risk factors.

Neural alterations, including myelin degeneration and inflammation-related iron burden, may accompany early Alzheimer's disease (AD) pathophysiology. This study aims to identify multi-modal signatures associated with MRI-derived atrophy and quantitative MRI (qMRI) measures of myelin and iron in a unique dataset of 158 participants across the AD spectrum, including those without cognitive impairment, at familial risk for AD, with mild cognitive impairment, and with AD dementia. Our results revealed a brain pattern with decreased cortical thickness, indicating increased neuronal death, and compromised hippocampal integrity due to reduced myelin content.

Depressive Symptoms and Amyloid Pathology.

Importance: Depressive symptoms are associated with cognitive decline in older individuals. Uncertainty about underlying mechanisms hampers diagnostic and therapeutic efforts. This large-scale study aimed to elucidate the association between depressive symptoms and amyloid pathology.

Novel synaptic markers predict early tau pathology and cognitive deficit in an asymptomatic population at risk of Alzheimer's disease.

Cognitive dysfunction in Alzheimer's disease (AD) correlates closely with pathology in the neuronal microtubule-associated protein tau. Tau pathology may spread via neural synapses. In a population of cognitively unimpaired elderly at elevated risk of AD, we investigated four cerebrospinal (CSF) markers of synaptic dysfunction and degeneration.

Precuneus Activity during Retrieval Is Positively Associated with Amyloid Burden in Cognitively Normal Older 4 Carriers.

The precuneus is a site of early amyloid-beta (Aβ) accumulation. Previous cross-sectional studies reported increased precuneus fMRI activity in older adults with mild cognitive deficits or elevated Aβ. However, longitudinal studies in early Alzheimer's disease (AD) are lacking and the relationship to the Apolipoprotein-E () genotype is unclear.

Synergistic association of Aβ and tau pathology with cortical neurophysiology and cognitive decline in asymptomatic older adults.

Animal and computational models of Alzheimer's disease (AD) indicate that early amyloid-β (Aβ) deposits drive neurons into a hyperactive regime, and that subsequent tau depositions manifest an opposite, suppressive effect as behavioral deficits emerge. Here we report analogous changes in macroscopic oscillatory neurophysiology in the human brain. We used positron emission tomography and task-free magnetoencephalography to test the effects of Aβ and tau deposition on cortical neurophysiology in 104 cognitively unimpaired older adults with a family history of sporadic AD.

Osteopontin: A novel marker of pre-symptomatic sporadic Alzheimer's disease.

Introduction: We investigate the role of osteopontin (OPN) in participants with Pre-symptomatic Alzheimer's disease (AD), mild cognitive impairment (MCI), and in AD brains.

Methods: Cerebrospinal fluid (CSF) OPN, AD, and synaptic biomarker levels were measured in 109 cognitively unimpaired (CU), parental-history positive Pre-symptomatic Evaluation of Experimental or Novel Treatments for Alzheimer's Disease (PREVENT-AD) participants, and in 167 CU and 399 participants with MCI from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. OPN levels were examined as a function of amyloid beta (Aβ) and tau positivity.

Neurochemical organization of cortical proteinopathy and neurophysiology along the Alzheimer's disease continuum.

Introduction: Despite parallel research indicating amyloid-β accumulation, alterations in cortical neurophysiological signaling, and multi-system neurotransmitter disruptions in Alzheimer's disease (AD), the relationships between these phenomena remains unclear.

Methods: Using magnetoencephalography, positron emission tomography, and an atlas of 19 neurotransmitters, we studied the alignment between neurophysiological alterations, amyloid-β deposition, and the neurochemical gradients of the cortex.

Results: In patients with mild cognitive impairment and AD, changes in cortical rhythms were topographically aligned with cholinergic, serotonergic, and dopaminergic systems.