Craig Ritchie

University of Edinburgh | UoE · Centre for Clinical Brain Sciences

Brain Age Gap has been associated with dementia in old age. Less is known relating brain age gap to dementia risk-factors or cognitive performance in middle-age. Cognitively healthy, middle-aged subjects from PREVENT-Dementia had comprehensive neuropsychological, neuroimaging and genetic assessments. Brain Ages were predicted from T1-weighted 3T MR...

Background Females have a higher age-adjusted incidence of Alzheimer’s Disease (AD) than males, even when accounting for longer lifespan and, therefore, stand to benefit the most from dementia prevention efforts. As exposure to many modifiable risk factors for dementia begins in mid-life, interventions must be implemented from middle-age. Building...

The apolipoprotein (APOE) e4 allele is associated with brain changes in healthy carriers that are similar to changes observed in patients with Alzheimers Disease, including abnormalities in functional connectivity. The trajectory of these changes across the lifespan, specifically in early adulthood is still not clear. This study explores the link b...

INTRODUCTION We tested associations between two retinal measures (optic disc pallor, peripapillary retinal nerve fiber layer [pRNFL] thickness) and four magnetic resonance imaging markers of cerebral small vessel disease (SVD; lacunes, microbleeds, white matter hyperintensities, and enlarged perivascular spaces [ePVSs]). METHODS We used PallorMetr...

Importance Traumatic brain injuries (TBI) represent an important, potentially modifiable risk factor for dementia. Despite frequently observed vascular imaging changes in individuals with TBI, the relationships between TBI-associated changes in brain imaging and clinical outcomes have largely been overlooked in community cases of TBI. Objective To...

Brain atrophy and cortical thinning are typically observed in people with Alzheimer's disease (AD) and, to a lesser extent, in those with mild cognitive impairment. In asymptomatic middle‐aged apolipoprotein ε4 (ΑPOE4) carriers, who are at higher risk of future AD, study reports are discordant with limited evidence of brain structural differences b...

The trace element selenium is known to protect against oxidative damage which is known to contribute to cognitive impairment with ageing (1,2) . The aim of this study was to explore the association between selenium status (serum selenium and selenoprotein P (SELENOP)) and global cognitive performance at baseline and after 5 years in 85-year-olds li...

Background There is good evidence that elevated amyloid-β (Aβ) positron emission tomography (PET) signal is associated with cognitive decline in clinically normal (CN) individuals. However, it is less well established whether there is an association between the Aβ burden and decline in daily living activities in this population. Moreover, Aβ-PET Ce...

PREVENT is a multi-centre prospective cohort study in the UK and Ireland that aims to examine midlife risk factors for dementia and identify and describe the earliest indices of disease development. The PREVENT dementia programme is one of the original epidemiological initiatives targeting midlife as a critical window for intervention in neurodegen...

Background and purpose The Mediterranean diet (MedDiet) has been associated with reduced dementia incidence in several studies. It is important to understand if diet is associated with brain health in midlife, when Alzheimer's disease and related dementias are known to begin. Methods This study used data from the PREVENT dementia programme. Three...

Introduction There is emerging evidence that speech may be a potential indicator and manifestation of early Alzheimer’s disease (AD) pathology. Therefore, the University of Edinburgh and Sony Research have partnered to create the Speech for Intelligent cognition change tracking and DEtection of Alzheimer’s Disease (SIDE-AD) study, which aims to dev...

Background As clinical trials increasingly focus on the earliest stages of Alzheimer’s disease (AD), there is a need for reliable and valid functional measures in these stages. The National Institute of Aging and Alzheimer’s Association (NIA‐AA) defined six clinical stages of AD, with stages 1 and 2 covering preclinical AD with normal cognitive and...

Background CSF and imaging biomarkers are needed for the etiological diagnosis of neurocognitive disorders, but evidence is incomplete on their rational use in the clinic. Since October 2020, a European task force has been defining an evidence‐based diagnostic workflow, where incomplete evidence is filled by the opinion of experts. Herein, we repor...

Background Polypharmacy, the concurrent use of multiple medicines, is increasing. Population‐wide studies of its association with dementia are lacking. We examined this relationship longitudinally, at a national level. Method We used National Health Service community prescribing data from all adults in Scotland aged ≥50 years who received at least...

Background Evidence suggests that the early detection and management of modifiable risk factors can reduce, or partially prevent, incidence of neurodegenerative diseases. While there is consensus that risk factors should be addressed as early as possible, research has largely focused on childhood or mid‐ and later‐life. As a result, there is a sign...

Introduction As the global population ages, the economic, societal, and personal burdens associated with worsening cognition and dementia onset are growing. It is therefore becoming ever more critical to understand the factors associated with cognitive decline. One such factor is sleep. Adequate sleep has been shown to maintain cognitive function a...

Background The Eatwell guide reflects the UK government’s recommendations for a healthy and balanced diet. Previous research has identified associations between healthy eating patterns and both cardiovascular and brain health, although there is little evidence specifically focusing on the Eatwell Guide. To date no research has investigated associat...

Cerebral hemodynamic alterations have been observed in apolipoprotein ε4 (APOE4) carriers at midlife, however the physiological underpinnings of this observation are poorly understood. Our goal was to investigate cerebral blood flow (CBF) and its spatial coefficient of variation (CoV) in relation to APOE4 and a measure of erythrocyte anisocytosis (...

It is well acknowledged that the pathological processes of Alzheimer′s disease (AD) start decades before clinical manifestations, but early indicators of AD in midlife remain unclear. Functional segregation of brain networks has recently emerged as a key indicator of brain health. In this study, we investigated the vulnerability of intrinsic brain...

Growing evidence supports the use of plasma levels of tau phosphorylated at threonine 181 (p-tau181), amyloid-β, neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) as promising biomarkers for Alzheimer’s disease. While these blood biomarkers are promising for distinguishing people with Alzheimer’s disease from healthy controls, t...

Background: In the absence of preventative pharmacological interventions for Alzheimer's Disease dementia, there is a growing interest in modifiable risk factors associated with AD. Such risk factors are thought to contribute up to 40% of the risk of dementia. The Lifestyle for Brain Health (LIBRA) index, a dementia risk score which focuses exclus...

Amyloid-β accumulation starts in highly connected brain regions and is associated with functional connectivity alterations in the early stages of Alzheimer’s disease. This regional vulnerability is related to the high neuronal activity and strong fluctuations typical of these regions. Recently, dynamic functional connectivity was introduced to inve...

Background The identification of effective dementia prevention strategies is a major public health priority, due to the enormous and growing societal cost of this condition. Consumption of a Mediterranean diet (MedDiet) has been proposed to reduce dementia risk. However, current evidence is inconclusive and is typically derived from small cohorts w...

Observational population studies indicate that prevention of dementia and cognitive decline is being accomplished, possibly as an unintended result of better vascular prevention and healthier lifestyles. Population aging in the coming decades requires deliberate efforts to further decrease its prevalence and societal burden. Increasing evidence sup...

The entorhinal cortex (EC) is the first cortical region to exhibit neurodegeneration in Alzheimer’s disease (AD), associated with EC grid cell dysfunction. Given the role of grid cells in path integration, we predicted that path integration impairment would represent the first behavioural change in adults at-risk of AD. Using immersive virtual real...

Background Speech impairments are an early feature of Alzheimer’s disease (AD) and consequently, analysing speech performance is a promising new digital biomarker for AD screening. Future clinical AD trials on disease modifying drugs will require a shift to very early identification of individuals at risk of dementia. Hence, digital markers of lang...

Background Amyloid-β (Aβ) accumulation is considered the earliest pathological change in Alzheimer's disease (AD). The Amyloid Imaging to Prevent Alzheimer's Disease (AMYPAD) consortium is a collaborative European framework across European Federation of Pharmaceutical Industries Associations (EFPIA), academic, and ‘Small and Medium-sized enterprise...

Importance Individuals who are amyloid-positive with subjective cognitive decline and clinical features increasing the likelihood of preclinical Alzheimer disease (SCD+) are at higher risk of developing dementia. Some individuals with SCD+ undergo amyloid-positron emission tomography (PET) as part of research studies and frequently wish to know the...

Purpose: Retinal microvascular abnormalities measured on retinal images are a potential source of prognostic biomarkers of vascular changes in the neurodegenerating brain. We assessed the presence of these abnormalities in Alzheimer's dementia and mild cognitive impairment (MCI) using ultra-widefield (UWF) retinal imaging. Methods: UWF images fr...

Background The risk of dementia is higher in women than men. The metabolic consequences of estrogen decline during menopause accelerate neuropathology in women. The use of hormone replacement therapy (HRT) in the prevention of cognitive decline has shown conflicting results. Here we investigate the modulating role of APOE genotype and age at HRT in...

It is now acknowledged that Alzheimer's Disease (AD) processes are present decades before the onset of clinical symptoms, but whether lifestyle activities can protect against these early AD processes in mid-life remains poorly understood. Furthermore, the impact of sex as a biological variable on associations between dementia risk, protective lifes...

Blood‐based biomarker tests are critical tools with the potential to change pathways for dementia diagnosis and care. These tests are less invasive than PET scan or lumbar puncture, potentially more affordable, and thus more accessible across more care settings and in more countries. Utilization in primary care settings together with brief cognitiv...

Adherence to the Mediterranean diet (MedDiet) has been associated with better cognitive performance, lower incidence of dementia, stroke and lower Alzheimer’s disease (AD) biomarker burden (Scarmeas et al, 2018). Improving dietary patterns in at‐risk populations may improve brain health, reducing incidence of dementia and stroke (Lewis et al, 2014;...

The AMYPAD Prognostic and Natural History Study aims to evaluate the value of (semi‐) quantitative amyloid PET imaging for predicting progression within an Alzheimer’s disease risk probability spectrum. The project is actively recruiting non‐demented participants from 17 sites across Europe, with a particular interest in those with emerging amyloid...

Early amyloid deposition results in functional and structural brain alterations in predementia stages of Alzheimer's disease (AD). However, how early functional and structural brain changes are related to each other remains unclear. Investigating the simultaneous disruptions of functional‐structural brain features within individuals in relation to...

The Mediterranean diet (MedDiet) is a primarily plant‐based eating pattern. High adherence to a MedDiet has been associated with a 10‐40% lower incidence of dementia. There is limited evidence exploring associations between the MedDiet and Alzheimer’s disease (AD) pathology. Our study explored cross‐sectional associations between MedDiet and AD out...

Early amyloid deposition results in functional and structural brain alterations in predementia stages of Alzheimer's disease (AD). However, how early functional and structural brain changes are related to each other remains unclear. Investigating the simultaneous disruptions of functional‐structural brain features within individuals in relation to...

The AMYPAD Prognostic and Natural History Study aims to evaluate the value of (semi‐)quantitative amyloid PET imaging for predicting progression within an Alzheimer’s disease risk probability spectrum. The project is actively recruiting non‐demented participants from 17 sites across Europe, with a particular interest in those with emerging amyloid...

In preclinical Alzheimer’s disease (AD), amyloid accumulates in highly‐functionally connected brain regions. This selective vulnerability is related to the high neuronal fluctuations, typical of these regions. Dynamic functional connectivity (FC) was introduced to investigate network organization over time, with high network variations indicating r...

Alzheimer’s Disease, the leading cause of dementia, is over‐represented in females. The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late‐onset AD and is associated with aberrant cerebrospinal fluid levels (CSF) of total tau (t‐tau), phosphorylated tau (p‐tau), and amyloid‐β (Aβ). There is some evidence that sex may me...

In preclinical Alzheimer’s disease (AD), amyloid accumulates in highly‐functionally connected brain regions. This selective vulnerability is related to the high neuronal fluctuations, typical of these regions. Dynamic functional connectivity (FC) was introduced to investigate network organization over time, with high network variations indicating r...

Background: Adherence to the Mediterranean diet (MedDiet), a primarily plant-based eating pattern, has been associated with lower dementia incidence. Much of the research has focused on Alzheimer’s disease (AD) dementia and mild cognitive impairment (MCI), with less research looking at the preclinical symptomatically silent stages that pre-empt MCI...

Background: It is now acknowledged that Alzheimer's disease (AD) processes are present decades before the onset of clinical symptoms, but it remains unknown whether lifestyle factors can protect against these early AD processes in mid-life. Objective: We asked whether modifiable lifestyle activities impact cognition in middle-aged individuals wh...

Previous studies have demonstrated an association between adherence to the Mediterranean diet (MedDiet) and better cognitive performance, lower incidence of dementia and lower Alzheimer's disease biomarker burden. The aim of this systematic review was to evaluate the evidence base for MedDiet associations with hippocampal volume and white matter hy...

Despite implications of sleep disturbances in Alzheimer’s disease (AD) pathophysiology (e.g. cerebral amyloid accumulation, atrophy in AD‐pathology sensitive brain regions); contradictory findings on sleep/neuropathology relationships at preclinical‐AD stage exist, possibly due to sex‐differences and/or methodological disparities and inconsistencie...

The entorhinal cortex (EC) is the first cortical brain region to exhibit neurodegeneration in Alzheimer’s disease (AD). Given that the EC contains unique grid cells underpinning path integration, tests probing this aspect of navigation may have added value in detecting AD in its earliest preclinical stages. Building on our past work showing that a...

Introduction Tens of millions of people worldwide will develop Alzheimer's disease (AD), and only by intervening early in the preclinical disease can we make a fundamental difference to the rates of late-stage disease where clinical symptoms and societal burden manifest. However, collectively utilizing data, samples, and knowledge amassed by large-...

A general obligation to make aggregate research results available to participants has been widely supported in the bioethics literature. However, dementia research presents several challenges to this perspective, particularly because of the fear associated with developing dementia. The authors argue that considerations of respect for persons, benef...

Both research and clinical practice have traditionally centred on the dementia syndrome of Alzheimer's disease rather than its preclinical and prodromal stages. However, there is a strong scientific and ethical impetus to shift focus to earlier disease stages to improve brain health outcomes and help to keep affected individuals symptom-free (demen...

Both research and clinical practice have traditionally centred on the dementia syndrome of Alzheimer's disease rather than its preclinical and prodromal stages. However, there is a strong scientific and ethical impetus to shift focus to earlier disease stages to improve brain health outcomes and help to keep affected individuals symptom-free (demen...

Gray matter networks are altered with amyloid accumulation in the earliest stage of AD, and are associated with decline throughout the AD spectrum. It remains unclear to what extent gray matter network abnormalities are associated with hyperphosphorylated-tau (p-tau). We studied the relationship of cerebrospinal fluid (CSF) p-tau181 with gray matte...

Background Considerable overlap exists between the risk factors of dementia and cerebral small vessel disease (SVD). However, studies remain limited to older cohorts wherein pathologies of both dementia (e.g. amyloid) and SVD (e.g. white matter hyperintensities) already co-exist. In younger asymptomatic adults, we investigated differential associat...

Introduction: Etiological diagnosis of neurocognitive disorders of middle-old age relies on biomarkers, although evidence for their rational use is incomplete. A European task force is defining a diagnostic workflow where expert experience fills evidence gaps for biomarker validity and prioritization. We report methodology and preliminary results....

Introduction: Progressive cognitive decline is the cardinal behavioral symptom in most dementia-causing diseases such as Alzheimer's disease. While most well-established measures for cognition might not fit tomorrow's decentralized remote clinical trials, digital cognitive assessments will gain importance. We present the evaluation of a novel digi...

Cerebrovascular changes associated with Alzheimer’s disease (AD) can occur years before the onset of symptoms. Studies have suggested that changes in the retina may act as a surrogate for cerebrovascular changes in the brain, hence the retina might be a source of biomarkers for declining vascular brain health. Optical Coherence Tomography Angiograp...

It is well acknowledged that Alzheimer′s Disease (AD) pathological processes start decades before clinical manifestations, but the brain mechanism of sporadic AD in midlife remains unclear. To address this gap, we examined whether risk factors for late-life AD are associated with disrupted connectivity between two key structures in AD pathophysiolo...

Background Alzheimer's Disease, the leading cause of dementia, is over-represented in females. The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late-onset AD and is associated with aberrant cerebrospinal fluid levels (CSF) of total tau (t-tau), phosphorylated tau (p-tau), and amyloid-β (Aβ). There is some evidence that...

Type 2 diabetes is a robust predictor of cognitive impairment. Impairment in allocentric processing may help identify those at increased risk for Alzheimer’s disease dementia. The objective of this study was to investigate the performance of participants with and without diabetes on a task of allocentric spatial processing. This was a cross‐section...

Characterising associations between the methylome, proteome and phenome may provide insight into biological pathways governing brain health. Here, we report an integrated DNA methylation and phenotypic study of the circulating proteome in relation to brain health. Methylome-wide association studies of 4058 plasma proteins are performed (N = 774), i...

Background Macrostructural brain alterations in the form of brain atrophy or cortical thinning typically occur during the prodromal Alzheimer’s disease stage. Mixed findings largely dependent on the age of the examined cohorts have been reported during the preclinical, asymptomatic disease stage. In the present study, our aim was to examine the ass...

Background Guanfacine is a α2A adrenergic receptor agonist approved for treating attention deficit hyperactivity disorder (ADHD). It is thought to act via postsynaptic receptors in the prefrontal cortex, modulating executive functions including the regulation of attention. Attention is affected early in Alzheimer’s disease (AD), and this may relate...

Background: The risk of dementia is higher in women than men. The metabolic consequences of estrogen decline during menopause accelerates neuropathology in women. The use of hormone replacement therapy (HRT) in the prevention of cognitive decline has shown conflicting results. Here we investigate the modulating role of APOE genotype and age at HRT...

The European Prevention of Alzheimer Dementia (EPAD) is a multi-center study that aims to characterize the preclinical and prodromal stages of Alzheimer’s Disease. The EPAD imaging dataset includes core (3D T1w, 3D FLAIR) and advanced (ASL, diffusion MRI, and resting-state fMRI) MRI sequences. Here, we give an overview of the semi-automatic multimo...

Background Despite its widespread use, the semi-quantitative standardized uptake value ratio (SUVR) may be biased compared with the distribution volume ratio (DVR). This bias may be partially explained by changes in cerebral blood flow (CBF) and is likely to be also dependent on the extent of the underlying amyloid-β (Aβ) burden. This study aimed t...

White matter hyperintensities are common radiological findings in ageing and a typical manifestation of cerebral small vessel disease. White matter hyperintensity burden is evaluated by quantifying their volume; however, subtle changes in the white matter may not be captured by white matter hyperintensity volumetry. In this cross-sectional study, w...

Biomarker testing is recommended for the accurate and timely diagnosis of Alzheimer's disease (AD). Using illustrative case narratives we consider how cerebrospinal fluid (CSF) biomarker tests may be used in different presentations of cognitive impairment to facilitate timely and differential diagnosis, improving diagnostic accuracy, providing prog...