Craig Ritchie

The University of Edinburgh | UoE · Centre for Clinical Brain Sciences

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...

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 i...

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...

Introduction: The levels of many blood proteins are associated with Alzheimer's disease (AD) or its pathological hallmarks. Elucidating the molecular factors that control circulating levels of these proteins may help to identify proteins associated with disease risk mechanisms. Methods: Genome-wide and epigenome-wide studies (nindividuals ≤1064)...

Background The need for preventive therapies that interrupt the progression of Alzheimer’s disease (AD) before the onset of symptoms or when symptoms are emerging is urgent and has spurred the ongoing development of disease-modifying therapies (DMTs) in preclinical and early AD (mild cognitive impairment [MCI] to mild dementia). Assessing the meani...

Alzheimer's Disease (AD) is a growing global public health challenge. The development of new therapies is urgently needed, and a complex ecosystem of organizations has grown to facilitate AD drug discovery and development. Masterfully collating information on the drug development ecosystem, this book emphasizes the contributions of each aspect in t...

It is now acknowledged that Alzheimers 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 midlife. We asked whether modifiable lifestyle activities impact cognition in middle aged individuals who are cognitively healthy, b...

Introduction Identifying cost-effective, non-invasive biomarkers of Alzheimer’s disease (AD) is a clinical and research priority. Speech data are easy to collect, and studies suggest it can identify those with AD. We do not know if speech features can predict AD biomarkers in a preclinical population. Methods and analysis The Speech on the Phone A...

A biomarker associated with cognition in neurodegenerative dementias would aid in the early detection of disease progression, complement clinical staging, and act as a surrogate endpoint in clinical trials. The current systematic review evaluates the association between cerebrospinal fluid protein markers of synapse loss and neuronal injury, and co...

Background: Markers of cerebrovascular disease are common in dementia, and may be present before dementia onset. However, their clinical relevance in midlife adults at risk of future dementia remains unclear. We investigated whether the Cardiovascular Risk Factors, Ageing and Dementia (CAIDE) risk score was associated with markers of cerebral smal...

Background Metrics derived from the human eye are increasingly used as biomarkers and endpoints in studies of cardiovascular, cerebrovascular and neurological disease. In this context, it is important to account for potential confounding that can arise from differences in ocular dimensions between individuals, for example, differences in globe size...

Introduction Regulatory bodies recommend that outcome measures used in Alzheimer’s disease (AD) clinical trials capture clinically meaningful changes for the trial participant. However, commonly used outcome measures do not reflect the individual’s views on what matters to them individually. The aim of the electronic Person-Specific Outcome Measure...

Background Mild cognitive impairment (MCI) is a condition that exists between normal healthy ageing and dementia with an uncertain aetiology and prognosis. This uncertainty creates a complex dynamic between the clinicians’ conception of MCI, what is communicated to the individual about their condition, and how the individual responds to the informa...

Sex differences exist in the prevalence, prognosis, and clinical manifestation of cerebral small vessel disease (SVD) and dementia. Given the role of SVD in cognitive impairment – both directly and through accelerating neurodegenerative pathology – understanding sex differences in SVD risk factors could inform targeted intervention strategies. In t...

Hypothalamic‐pituitary‐adrenal axis (HPAa) dysfunction is associated with progression of cognitive decline in Alzheimer's disease (AD). HPAa abnormalities are also associated with diabetes, obesity, anxiety, depression and traumatic life events, all risk factors for AD. We hypothesised that these risk factors would be associated with AD biomarkers...

Liraglutide is a glucagon‐like peptide‐1 (GLP‐1) analogue licensed for the treatment of type 2 diabetes. Preclinical evidence in transgenic models of Alzheimer’s disease suggests that liraglutide exerts neuroprotective effects by reducing amyloid oligomers, normalising synaptic plasticity and cerebral glucose uptake, and increasing the proliferatio...

Alzheimer disease (AD) is a complex disorder involving biological, clinical, and lifestyle aspects. Assessing all these aspects simultaneously allows to better disentangle the position of CSF marker abnormalities across AD stages. Here, we employ a novel statistical method specifically developed to reveal meaningful associations across multiple asp...

Promising memory markers for Alzheimer´s dementia (AD) tap into either relational (face‐name) or conjunctive (object‐colour) functions (Rentz et al., 2013). Whereas relational functions appear affected in the early symptomatic stages of AD, conjunctive functions have been found impaired in the pre‐symptomatic stages. Relational but not conjunctive...

Mild cognitive impairment (MCI) is a state between normal healthy ageing and dementia with an uncertain prognosis. This uncertainty creates a complex dynamic between the clinicians’ conception of MCI, what is communicated to the individual about their condition, and how the individual perceives the information conveyed to them. The aim of this stud...

Functional decline is a gradual process occurring along the Alzheimer’s disease (AD) continuum, starting years before dementia onset. Different instruments, such as the ADCS‐ADL and the Amsterdam Instrumental Activities of Daily Living Questionnaire (A‐IADL‐Q) aim to capture early functional changes. In the current study, we compared measurement in...

The Global Alzheimer’s Platform Foundation® (GAP) was launched in 2015 in response to the critical need to improve the delivery of Alzheimer’s disease (AD) clinical trials. Over 80 AD sites have joined GAP’s growing network (GAP‐Net). While initial efforts were focused on North America, a top priority of the platform was to develop an international...

Regulatory bodies recommend that outcome measures used in Alzheimer’s disease (AD) clinical trials capture clinically meaningful changes for the trial participant. However, commonly used cognitive outcomes are limited in this regard. The aim of the electronic Person‐Specific Outcome Measure (ePSOM) programme is to better understand what outcomes ma...

Mild cognitive impairment (MCI) is a condition with slight decline in cognition, but unaffected daily functioning. Given its uncertain prognosis, communicating this in clinical consultations with patients is crucial. Our aim was to understand the impact of clinical risk reporting to individuals with newly identified MCI, focusing on changes in cogn...

In light of the COVID‐19 pandemic, it is increasingly likely that researchers will adopt home‐based remote administration of cognitive tests for the continuation of clinical studies. Yet, there are limited data on the reliability of remotely administered cognitive assessments compared to in‐person. Specifically, cross‐modal reliability of the RBANS...

As Alzheimer’s disease (AD) clinical trials move to an earlier phase in the neurodegenerative disease process, any outcome measures used to assess an intervention’s efficacy would need to be appropriate for the earlier pre‐clinical or prodromal study population. Evidence suggests that 40% of dementia cases could be prevented by targeting modifiable...

In the context of ageing and Alzheimer’s disease (AD), factors linked to reserve and resilience may confer protection against impact of underlying neuropathology on cognitive function. Such factors are differentially manifested in men and women, yet limited studies have explored potential divergence in their capacity to moderate cognitive outcomes,...

Neuroimaging biomarkers in large‐scale multimodal studies have proven effective for early diagnosis. Image‐derived phenotypes (IDPs) are summary features derived from modalities such as magnetic resonance imaging (MRI). We provide an overview of the IDPs computed from the European Prevention of Alzheimer Dementia (EPAD) cohort study, a multi‐center...

Structural MRI measurements can contribute to the prediction of amyloid pathology in cognitively unimpaired (CU) individuals. In this work, we aimed at studying the predictive capacity, robustness, and generalizability of ML techniques to predict amyloid‐β pathology in CU individuals, as well as identifying key brain regions contributing to this pr...

Understanding the role of amyloid imaging in the earliest stages of Alzheimer’s Disease (AD) becomes increasingly relevant for secondary prevention. In this context, the AMYPAD Prognostic and Natural History Study (PNHS) is an open‐label, prospective, multi‐centre cohort study (http://amypad.eu/) to determine the value of quantitative amyloid PET i...

Gray matter network (GMN) disruptions correlate with amyloid burden in the earliest stages of Alzheimer’s Disease (AD) pathology in cognitively unimpaired individuals. However, it remains unknown if and how hyperphosphorylated tau (p‐tau) influences GMNs. Here, we investigated the relation between GMNs and cerebrospinal fluid (CSF) p‐tau181 levels...

INTRODUCTION: Plasma phospho-tau 181 (p-tau181) is a promising blood biomarker for Alzheimer's disease. However, its predictive validity for age-related cognitive decline without dementia remains unclear. Several forms of p-tau have been shown to contribute to synapse degeneration, but it is unknown whether p-tau181 is present in synapses. Here, we...

We envisage the development of new Brain Health Services to achieve primary and secondary dementia prevention. These services will complement existing memory clinics by targeting cognitively unimpaired individuals, where the focus is on risk profiling and personalized risk reduction interventions rather than diagnosing and treating late-stage disea...

Although prevention of dementia and late-life cognitive decline is a major public health priority, there are currently no generally established prevention strategies or operational models for implementing such strategies into practice. This article is a narrative review of available evidence from multidomain dementia prevention trials targeting sev...

Dementia has a devastating impact on the quality of life of patients and families and comes with a huge cost to society. Dementia prevention is considered a public health priority by the World Health Organization. Delaying the onset of dementia by treating associated risk factors will bring huge individual and societal benefit. Empirical evidence s...

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 Functional cognitive disorders (FCD) are an important differential diagnosis of neurodegenerative disease. The utility of suggested diagnostic features has not been prospectively explored in “real world” clinical populations. This study aimed to identify positive clinical markers of FCD. Methods Adults with cognitive complaints but not...

Characterising associations between the epigenome, proteome and phenome may provide insight into molecular regulation of biological pathways governing health. However, epigenetic signatures for many neurologically-associated plasma protein markers remain uncharacterised. Here, we report an epigenome and phenome-wide association study of the circula...

Background: Communication difficulties are one of the primary symptoms associated with dementia, and mobile applications have shown promise as tools for facilitating communication in patients with dementia (PwD). The literature regarding mobile health (mHealth) applications, especially communications-based mHealth applications, is limited. Object...