John C.S. Breitner

• McGill University

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 1.01–10.47). METHODS We included 215 participants from the PREVENT−AD cohort with plasma Aβ42/40 and p‐tau...

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. Thr...

Background PET biomarkers have proven valuable for identifying cognitively unimpaired (CU) individuals at‐risk of near‐term clinical progression. Given the increasing interest in plasma biomarkers to detect Alzheimer’s pathology, we assessed levels of amyloid (Aß42/40) and tau (p‐tau217 and p‐tau181) biomarkers in plasma (A+T+plasma) in CU individu...

Background Synapse loss in Alzheimer’s disease (AD) is correlates closely with cognitive impairment. Recent evidence suggests that synapse loss is promoted by amyloid‐beta, leading in turn to the spread of tau pathology. We sought to assess: 1) the association in positron emission tomography (PET) between several cerebrospinal fluid (CSF) synaptic...

Background Synapse loss in Alzheimer’s disease (AD) is correlates closely with cognitive impairment. Recent evidence suggests that synapse loss is promoted by amyloid‐beta, leading in turn to the spread of tau pathology. We sought to assess: 1) the association in positron emission tomography (PET) between several cerebrospinal fluid (CSF) synaptic...

Background PET biomarkers have proven valuable for identifying cognitively unimpaired (CU) individuals at‐risk of near‐term clinical progression. Given the increasing interest in plasma biomarkers to detect Alzheimer’s pathology, we assessed levels of amyloid (Aβ42/40) and tau (p‐tau217 and p‐tau181) biomarkers in plasma (A+T+plasma) in CU individu...

Background The heterogeneous etiology of “sporadic” Alzheimer’s disease (sAD) includes genetic influences. To better understand synaptic dysfunction in AD pathogenesis, we used protein quantitative train loci (pQTL) assessments and a polygenic risk score (PRS) to examine the relationship between synaptic integrity and longitudinal cognitive perform...

Background The immune complement system is key to the elimination of redundant neural connections in the brain through a process called synaptic pruning. In neurodegenerative diseases such as Alzheimer's disease (AD), this system may result in excessive synapse loss, leading to brain atrophy and cognitive impairment. While increased cerebrospinal f...

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., 2021). To understand the importance of these phenomena, exploration of individu...

Genetic analysis results for synaptic proteins and cognitive performance show a promising connection between synaptic gene regulation and cognitive ability. CSF synaptic protein levels show promising correlations with emerging cognitive deficits and provide insights toward a possible compensatory mechanism in the early presymptomatic phase of the d...

Study Objectives Although short sleep could promote neurodegeneration, long sleep may be a marker of ongoing neurodegeneration, potentially as a result of neuroinflammation. The objective was to evaluate sleep patterns with age of expected Alzheimer’s disease (AD) onset and neuroinflammation. Methods We tested 203 dementia-free participants (68.5...

INTRODUCTION Measuring day‐to‐day sleep variability might reveal unstable sleep‐wake cycles reflecting neurodegenerative processes. We evaluated the association between Alzheimer's disease (AD) fluid biomarkers with day‐to‐day sleep variability. METHODS In the PREVENT‐AD cohort, 203 dementia‐free participants (age: 68.3 ± 5.4; 78 males) with a par...

The accumulation of tau abnormality in sporadic Alzheimer’s disease is believed typically to follow neuropathologically defined Braak staging. Recent in-vivo PET evidence challenges this belief, however, as accumulation patterns for tau appear heterogeneous among individuals with varying clinical expressions of Alzheimer’s disease. We, therefore, s...

White matter hyperintensities (WMHs) are radiological abnormalities reflecting cerebrovascular dysfunction detectable using magnetic resonance imaging (MRI). WMHs are often present in individuals at the later stages of the lifespan and in prodromal stages in the Alzheimer’s Disease spectrum. Tissue alterations underlying WMHs may include demyelinat...

Background: Synaptic proteins in the cerebrospinal fluid (CSF) may reveal changes in the pre-symptomatic stages of Alzheimer’s disease (AD), thus may be candidate biomarkers for early detection of the disease. Method: The PREVENT-AD cohort includes symptom-free (upon enrolment) elderly participants who are at risk of developing AD from their family...

Background Increasing evidence shows that Alzheimer’s Disease (AD) pathology, i.e., the Aß peptide, tau tangles and the APOEε4 allele, have all been associated with disrupted sleep and change in circadian rhythms. However, objective sleep measurements are often assessed over a single night. Measures of day‐to‐day variability might reveal unstable s...

Background Both short and long sleep duration have been associated with increased risk of developing Alzheimer’s Disease (AD). While short sleep has been hypothesized to be a risk factor promoting neurodegenerative processes. Long sleep has been viewed as a marker of ongoing neurodegeneration, potentially as a result of neuroinflammation. The objec...

Introduction: Plasma biomarkers are altered years prior to Alzheimer's disease (AD) clinical onset. Methods: We measured longitudinal changes in plasma amyloid-beta (Aβ)42/40 ratio, pTau181, pTau231, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) in a cohort of older adults at risk of AD (n = 373 total, n = 229 with...

Importance: National Institute on Aging-Alzheimer's Association (NIA-AA) workgroups have proposed biological research criteria intended to identify individuals with preclinical Alzheimer disease (AD). Objective: To assess the clinical value of these biological criteria to identify older individuals without cognitive impairment who are at near-te...

Importance National Institute on Aging-Alzheimer’s Association (NIA-AA) workgroups have proposed biological research criteria intended to identify individuals with preclinical Alzheimer’s disease (AD). Objective Assess the clinical value of these biological criteria for prediction of near-term cognitive impairment in cognitively unimpaired older i...

Objective: To evaluate novel plasma p-tau231, p-tau181 as well as Aβ40 and Aβ42 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 AD owing to a family history of A...

BACKGROUND Mindfulness, defined as non-judgmental awareness of the present moment, has been associated with an array of mental and physical health benefits. Mindfulness may also represent a protective factor for Alzheimer’s disease (AD). Here, we tested the potential protective effect of trait mindfulness on cognitive decline and AD pathology in ol...

Resting state functional connectivity (rs-fMRI) is impaired early in persons who subsequently develop Alzheimer’s disease (AD) dementia. This impairment may be leveraged to aid investigation of the pre-clinical phase of AD. We developed a model that predicts brain age from resting state (rs)-fMRI data, and assessed whether genetic determinants of A...

To move Alzheimer Disease (AD) research forward it is essential to collect data from large cohorts, but also make such data available to the global research community. We describe the creation of an open science dataset from the PREVENT-AD (PResymptomatic EValuation of Experimental or Novel Treatments for AD) cohort, composed of cognitively unimpai...

BACKGROUND AND OBJECTIVES Mindfulness, defined as non-judgmental awareness of the present moment, has been associated with an array of mental and physical health benefits, including improved cognitive functioning and changes to brain structure and function. Mindfulness may also represent a protective factor for Alzheimer’s disease (AD). Here, we te...

Resting-state functional connectivity is suggested to be cross-sectionally associated with both vascular burden and Alzheimer's disease (AD) pathology. However, evidence is lacking regarding longitudinal changes in functional connectivity. This study includes 247 cognitively unimpaired individuals with a family history of sporadic AD (185 women/ 62...

Beta-amyloid (Aβ) and tau proteins, the pathological hallmarks of Alzheimer's disease (AD), are believed to spread through connected regions. Combining diffusion imaging and positron emission tomography, we investigated associations between Aβ, tau and white matter microstructure specifically in bundles connecting brain regions in which AD patholog...

Objective To determine whether years of education and the ε4 risk allele at APOE influence β-amyloid pathology similarly in asymptomatic individuals with a family history of sporadic Alzheimer’s disease (AD) and pre-symptomatic autosomal dominant AD mutation carriers. Methods We analyzed cross-sectional data from 106 asymptomatic individuals with...

We aimed at developing a model able to predict brain aging from resting state functional connectivity (rs-fMRI) and assessing whether genetic risk/determinants of Alzheimer's disease (AD) and amyloid (Aβ) pathology contributes to accelerated brain aging. Using data collected in 1340 cognitively unimpaired participants from 18 to 94 years old select...

We describe the creation of an open science dataset from a cohort of cognitively unimpaired aging individuals with a parental or multiple-sibling history of Alzheimer′s disease (AD). Our purpose was to enable PResymptomatic EValuation of Novel or Experimental Treatments for AD (PREVENT-AD). To characterize this population, possibly progressing in t...

Importance Vascular risk factors are associated with increased risk of Alzheimer disease (AD), but it is unclear whether there is a direct association of these risk factors with AD pathogenesis. Objectives To assess the associations of vascular risk factors with AD pathogenesis in asymptomatic individuals, and to test whether this association is m...

Background Major prevention trials for Alzheimer’s disease (AD) are now focusing on multi-domain lifestyle interventions. However, the exact combination of behavioral factors related to AD pathology remains unclear. In two cohorts of cognitively unimpaired individuals at risk of AD, we examined which combinations of personality traits, neuropsychia...

Age being the main risk factor for Alzheimer's disease, it is particularly challenging to disentangle structural changes related to normal brain ageing from those specific to Alzheimer's disease. Most studies aiming to make this distinction focused on older adults only and on a priori anatomical regions. Drawing on a large, multi-cohort dataset ran...

IMPORTANCE Fluid and imaging biomarkers of Alzheimer disease (AD) are often used interchangeably, but some biomarkers may reveal earlier stages of disease. OBJECTIVE To characterize individuals with tau abnormality indicated by cerebrospinal fluid (CSF) assay or positron emission tomography (PET). DESIGN, SETTING, AND PARTICIPANTS Between 2010...

While numerous studies have used magnetic resonance imaging (MRI) to elucidate normative age‐related trajectories in subcortical structures across the human lifespan, there exists substantial heterogeneity among different studies. Here, we investigated the normative relationships between age and morphology (i.e., volume and shape), and microstructu...

We studied 78 participants having a parental or multiple‐sibling history of Alzheimer’s disease (AD) in a two‐year randomized placebo‐controlled trial of naproxen 220 mg b.i.d. for mitigation of early AD pathogenesis. Naproxen was detected in cerebrospinal fluid at concentrations ~100 times lower than in plasma, but produced negligible change in im...

It remains unclear which grey matter (GM) changes are associated with Alzheimer's disease (AD), and how these changes might differ from normal brain aging. Using independent component analysis of GM maps on a large, multi-cohort dataset, we derived morphometric networks and investigated GM volume in such networks in young, old adulthood, and AD. GM...

Objective: To evaluate the safety and efficacy of low-dose naproxen for prevention of progression in presymptomatic Alzheimer disease (AD) among cognitively intact persons at risk. Methods: Investigation of Naproxen Treatment Effects in Pre-symptomatic Alzheimer's Disease (INTREPAD), a 2-year double-masked pharmaco-prevention trial, enrolled 195...

Objective: To investigate relationships between tau-PET binding and in vivo Alzheimer’s disease (AD) markers in adults at increased risk of sporadic AD. Methods: One-hundred-nineteen cognitively normal older adults with a family history of sporadic AD (PREVENT-AD cohort, mean age=67±5) underwent tau-PET ([18F]AV-1451), Aβ-PET ([18F]NAV4694) and c...

Objective The Alzheimer's Disease Anti‐Inflammatory Prevention Trial (ADAPT) and Follow‐up Study (ADAPT‐FS) examined effects of naproxen and celecoxib on cognition in the elderly. We report here results describing trajectories of cognitive evaluation test scores. Methods A total of 2356 participants completed baseline and at least one follow‐up co...

Although the use of antihypertensive medications has been associated with reduced risk of Alzheimer's disease (AD), it remains unclear which class provides the most benefit. The Cache County Study of Memory Health and Aging is a prospective longitudinal cohort study of dementing illnesses among the elderly population of Cache County, Utah. Using wa...

Objectives: The Alzheimer's Disease Anti-inflammatory Prevention Trial Follow-up Study (ADAPT-FS) was designed to evaluate the efficacy of naproxen and celecoxib for the primary prevention of Alzheimer's disease (AD) several years after cessation of treatment in ADAPT. Methods: ADAPT was a randomized, double-masked, multicenter clinical trial of...

For more than 2,000 years cognitive decline and dementia were considered a part of aging, like graying of hair, wrinkling of skin, or (more recently) reduction of pulmonary capacity or glomerular filtration rate. Thus, our recent predecessors considered "senile dementia" a normal consequence of the aging process. Their confidence increased after Ma...

Compared with in-person assessment methods, telephone screening for dementia and other cognitive syndromes may improve efficiency of large population studies or prevention trials. We used data from the Alzheimer's Disease Anti-Inflammatory Prevention Trial to compare performance of a four-test Telephone Assessment Battery (TAB) that included the Te...

Background: Single-nucleotide polymorphisms (SNPs) located in the gene encoding the regulatory subunit of the protein phosphatase 2B (PPP3R1, rs1868402) and the microtubule-associated protein tau (MAPT, rs3785883) gene were recently associated with higher cerebrospinal fluid (CSF) tau levels in samples from the Knight Alzheimer's Disease Research...

Objectives: Observational studies suggest reduced risk of Alzheimer disease (AD) in users of hormone therapy (HT), but trials show higher risk. We examined whether the association of HT with AD varies with timing or type of HT use. Methods: Between 1995 and 2006, the population-based Cache County Study followed 1,768 women who had provided a det...

We sought to identify possible subgroups of elders that varied in depressive symptomatology and to examine symptom patterns and health status differences between subgroups. The Cache County Memory Study is a population-based epidemiological study of dementia with 5092 participants. Depressive symptoms were measured with a modified version of the Di...

1) To report rates of neuropsychiatric symptoms (NPS) in cognitive impairment, no dementia (CIND). 2) To compare the 30-day prevalence of NPS in CIND with that in dementia and cognitively normal individuals. 3) To compare the prevalence of NPS in amnestic MCI (aMCI) with other predementia syndromes. Comparison of prevalence proportions among severa...

To identify distinct behavioral patterns of diet, exercise, social interaction, church attendance, alcohol consumption, and smoking and to examine their association with subsequent dementia risk. Longitudinal, population-based dementia study. Rural county in northern Utah, at-home evaluations. Two thousand four hundred ninety-one participants witho...

Early parental death is associated with lifelong tendencies toward depression and chronic stress. We tested the hypothesis that early parental death is associated with higher risk for Alzheimer disease (AD) in offspring. A population-based epidemiological study of dementia with detailed clinical evaluations, linked to one of the world's richest sou...

To determine whether atrial fibrillation (AF) is associated with risk of incident dementia or Alzheimer's disease (AD), beyond its effect on stroke. Prospective cohort study. An integrated healthcare delivery system. A population-based sample of 3,045 community-dwelling adults aged 65 and older without dementia or clinical stroke followed from 1994...

Epidemiologic evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) delay onset of Alzheimer's dementia (AD), but randomized trials show no benefit from NSAIDs in patients with symptomatic AD. The Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) randomized 2,528 elderly persons to naproxen or celecoxib versus placebo fo...

Progression of Alzheimer dementia (AD) is highly variable. Most estimates derive from convenience samples from dementia clinics or research centers where there is substantial potential for survival bias and other distortions. In a population-based sample of incident AD cases, we examined progression of impairment in cognition, function, and neurops...

We examined the effects of non-steroidal anti-inflammatory drugs on cognitive decline as a function of phase of pre-clinical Alzheimer disease. Given recent findings that cognitive decline accelerates as clinical diagnosis is approached, we used rate of decline as a proxy for phase of pre-clinical Alzheimer disease. We fit growth mixture models of...

To examine the association of engagement in cognitively stimulating activities with cognitive and functional decline in a population-based sample of incident Alzheimer's disease (AD). After diagnosis, 187 participants (65% females) were followed semiannually for a mean 2.7 (SD = 0.4) years. Mean age and education were 84.6 (SD = 5.8) and 13.2 (SD =...

To examine whether histamine-2 receptor antagonist medications (H2RAs) are associated with a lower incidence of all-cause dementia or Alzheimer's disease (AD), as some studies have suggested. Prospective population-based cohort Group Health, an integrated health maintenance organization, Seattle, Washington. Two thousand nine hundred twenty-three p...

In this article, the challenges faced by several noted population studies for Alzheimer dementia in operationalizing current clinical diagnostic criteria for Alzheimer's disease (AD) have been reviewed. Differences in case ascertainment, methodological biases, cultural and educational influences on test performance, inclusion of special populations...

Summary“The etiology of Alzheimer's Disease, the most common form of dementia in late-life, is unknown. There are no therapies that effectively ameliorate the symptoms, nor stop the eventual deterioration of cognition, function, and behavior. Research over the past several decades has identified a number of modifiable factors that increase the risk...

Observational and experimental studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) may protect against Alzheimer disease (AD); however, clinical trials and other observational studies, including the Adult Changes in Thought (ACT) study, show no protection or promotion of AD. The objective of this study is to determine the relationshi...

To determine whether risk reduction of statins for Alzheimer's disease (AD) varies by age or presence of apolipoprotein E (APOE) epsilon4 allele. A cohort of cognitively intact elderly participants was assessed biennially for dementia and AD. Community based. Three thousand three hundred ninety-two members of a health maintenance organization (HMO)...

OBJECTIVES: To determine whether risk reduction of statins for Alzheimer's disease (AD) varies by age or presence of apolipoprotein E (APOE) ɛ4 allele.DESIGN: A cohort of cognitively intact elderly participants was assessed biennially for dementia and AD.SETTING: Community based.PARTICIPANTS: Three thousand three hundred ninety-two members of a hea...

To examine the effects of caring for a spouse with dementia on the caregiver's risk for incident dementia. Population-based study of incident dementia in spouses of persons with dementia. Rural county in northern Utah. Two thousand four hundred forty-two subjects (1,221 married couples) aged 65 and older. Incident dementia was diagnosed in 255 subj...

The APOE epsilon4 allele is an established risk factor for Alzheimer's disease, but reports of its association with vascular dementia (VaD) have been inconsistent. We examined the relationship between APOE epsilon4 allele and the risk of incident VaD in a large, population-based cohort of elderly adults with up to 10 years of follow-up between 1995...

Among the major impediments to the design of clinical trials for the prevention of Alzheimer's disease (AD), the most critical is the lack of validated biomarkers, assessment tools, and algorithms that would facilitate identification of asymptomatic individuals with elevated risk who might be recruited as study volunteers. Thus, the Leon Thal Sympo...

Results from prevention trials, including the Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT), have fueled discussion about the cardiovascular (CV) risks associated with non-steroidal anti-inflammatory drugs (NSAIDs). We tested the hypotheses that (i) adverse CV events reported among ADAPT participants (aged 70 years and older) are a...

Given the magnitude of the public health problem of dementia in the elderly, there is a pressing need for research, development, and timely application of biomarkers that will identify latent and prodromal illness as well as dementia. Although identification of risk factors and neuroimaging measures will remain key to these efforts, this review foc...

To evaluate the influences of a family history of Alzheimer dementia (FHxAD) and the apolipoprotein E epsilon4 genotype (APOE epsilon4) on cognitive decline. Residents of Cache County, Utah, aged 65 years or older, were invited to participate. At baseline, 2957 participants provided DNA for genotyping of APOE and a detailed FHxAD. They also complet...

Given the magnitude of the public health problem of dementia in the elderly, there is a pressing need for research, development, and timely application of biomarkers that will identify latent and prodromal illness as well as dementia. Although identification of risk factors and neuroimaging measures will remain key to these efforts, this review foc...

Applying Rusbult's investment model of dyadic relationships, we examined the effect of caregiver–care recipient relationship closeness (RC) on cognitive and functional decline in Alzheimer's disease. After diagnosis, 167 participants completed up to six visits, observed over an average of 20 months. Participants were 64% women, had a mean age of 86...