Macrostructural brain alterations at midlife are connected to cardiovascular and not inherited risk of future dementia: the PREVENT-Dementia study

Maria-Eleni Douvani, Coco Newton, Elijah Mak, Audrey Low, Graciela Muniz Terrera, Guy B. Williams, Brian Lawlor, Lorina Naci, Paresh Malhotra, Clare E. Mackay, Ivan Koychev, Karen Ritchie, Craig W. Ritchie, Li Su, John T O’Brien.

Journal of Neurology (2022)



Structural brain alterations such as volume loss in brain structures like the hippocampus, or thinning of the brain cortex typically occur  before cognitive symptomatology in people who will later develop dementia. In this study we investigated whether middle-aged participants in the PREVENT-Dementia study at risk of future dementia based on their genetic or cardiovascular risk demonstrated prominent structural brain alterations. Genetic risk was not associated with changes in brain volume even in the hippocampal subfields or with cortical thinning. A higher cardiovascular risk though (CAIDE dementia risk score) incorporating information on age, sex, education, blood pressure, cholesterol, body mass index and activity was associated with cortical thinning. This study highlights that in midlife, cardiovascular risk and not genetic risk for dementia is related to patterns of brain changes which are reminiscent of the patterns observed in dementia.​

CAIDE dementia risk score relates to severity and progression of cerebral small vessel disease in healthy midlife adults: the PREVENT-Dementia study

Audrey Low, Maria A Prats-Sedano, James D Stefaniak, Elizabeth Frances McKiernan, Stephen F Carter, Maria-Eleni Douvani, Elijah Mak, Li Su, Olivia Stupart, Graciela Muniz Terrera, Karen Ritchie, Craig W Ritchie, Hugh S Markus, John Tiernan O’Brien

Journal of Neurology, Neurosurgery & Psychiatry (2022)


Cerebral small vessel disease (SVD) refers to abnormalities of the small vessels of the brain. Importantly, SVD is linked to increased risk of cognitive impairment and dementia, and can appear decades before dementia onset. To understand the contribution of SVD to dementia at midlife, we examined whether a well-established dementia risk score (Cardiovascular Risk Factors, Ageing and Dementia; CAIDE) was related to SVD in healthy middle-aged volunteers in the PREVENT study. Results showed that the CAIDE dementia risk score, which is predictive of dementia 20 years later, was linked to greater midlife severity of all four SVD markers assessed, and 2-year progression of white matter lesions and systemic inflammation. While age was a strong risk factor of SVD, a higher CAIDE score amplified the effect of age on SVD. Findings highlight the value of the CAIDE score as both a prognostic and predictive marker in the context of cerebrovascular disease and related vascular cognitive impairment, and in identifying at-risk individuals who might benefit most from managing dementia risk through lifestyle modifications.

Measuring axial length of the eye from magnetic resonance brain imaging

Stewart J. Wiseman, Andrew J. Tatham, Rozanna Meijboom, Graciela Muniz Terrera, Charlene Hamid, Fergus N. Doubal, Joanna M. Wardlaw, Craig Ritchie, Baljean Dhillon, Tom MacGillivray
BMC Opthamology (2022)

The human eye supplies measurements that are increasingly used as biomarkers in studies of cardiovascular, cerebrovascular and neurological disease. One such measurement is “axial length” that essentially represents the size of the eye. Often, the length of the human eye is measured using an ophthalmological instrument, but not all studies have access to such specialized equipment. Studies of brain disease typically have access to brain scan data. The PREVENT Dementia programme has access to both. Hence, in 93 cognitively-healthy individuals from the programme (age 40 to 59 years), we measured axial length from brain MRI scans using three different image analysis software tools and compared results of our measurements to the gold standard measurements from the ophthalmic instrument. We concluded that axial length of the eye obtained from brain MRI is not a replacement for the precision of specialized ophthalmic equipment, but, in its absence, it could provide sufficient accuracy to act as a proxy.

Proximity to dementia onset and multi-modal neuroimaging changes: The prevent-dementia study.

Elijah Mak, Maria-Eleni Dounavi, Audrey Low, Stephen F Carter, Elizabeth McKiernan, Guy B Williams, Simon Jones, Isabelle Carriere, Graciela Muniz-Terrera, Karen Ritchie, Craig Ritchie, Li Su, John T O’Brien.

NeuroImage. 2021.



First-degree relatives of people with dementia (FH+) are at increased risk of developing Alzheimer’s disease (AD). Here, we investigate “estimated years to onset of dementia” (EYO) as a surrogate marker of preclinical disease progression and assess its associations with multi-modal neuroimaging biomarkers. 89 FH+ participants in the PREVENT-Dementia study underwent longitudinal MR imaging over 2 years. EYO was calculated as the difference between the parental age of dementia diagnosis and the current age of the participant (mean EYO = 23.9 years). There were no significant effects of EYO on regional grey matter atrophy or white matter hyperintensities. However, a shorter EYO was associated with lower white matter Fractional Anisotropy and elevated Mean/Radial Diffusivity, particularly in the corpus callosum. The influence of EYO on white matter deficits were significantly stronger compared to that of normal ageing. APOE-ε4 carriers exhibited hyperperfusion with nearer proximity to estimated onset in temporo-parietal regions. There were no interactions between EYO and time, suggesting that EYO was not associated with accelerated imaging changes in this sample. Amongst cognitively normal midlife adults with a family history of dementia, a shorter hypothetical proximity to dementia onset may be associated with brain abnormalities, particularly amongst APOE-ε4 carriers. Our findings also confer biological validity to the construct of EYO as a potential stage marker of preclinical progression in the context of sporadic dementia. 

Inherited risk of dementia and the progression of cerebral small vessel disease and inflammatory markers in cognitively healthy midlife adults: the PREVENT-Dementia study.

Audrey Low, Li Su, James Stefaniak, Elijah Mak, Maria-Eleni Dounavi, Graciela Muniz-Terrera, Karen Ritchie, Craig W Ritchie, Hugh S Markus, John T O’Brien.

Neurobiology of Aging. 2020



Cerebral small vessel disease (SVD) and inflammation are increasingly recognized as key contributors to Alzheimer’s disease (AD),Therefore, to investigate very early-stage changes, we compared 158 healthy midlife adults with and without inherited AD predisposition (APOE4 carriership (38% positive), parental family history (FH) of dementia (54% positive)) on markers of SVD (white matter hyperintensities (WMH), cerebral microbleeds), and inflammation (C-reactive protein (CRP), fibrinogen), cross-sectionally and longitudinally over two years. While WMH severity was comparable between groups at baseline, longitudinal progression of WMH was greater in at-risk groups (APOE4+ and FH+). Topographically, APOE4 was associated exclusively with deep, but not periventricular, WMH progression after adjusting for FH. Conversely, APOE4 carriers displayed lower CRP levels than noncarriers, but not fibrinogen. Furthermore, interaction analysis showed that FH moderated the effect of SVD and inflammation on reaction time, an early feature of SVD, but not episodic memory or executive function. Findings suggest that vascular and inflammatory changes could occur decades before dementia onset, and may be of relevance in predicting incipient clinical progression.

Higher midlife CAIDE score is associated with increased brain atrophy in a cohort of cognitively healthy middle-aged individuals

Xulin Liu, Marialena Dounavi, Karen Ritchie, Katie Wells, Craig W Ritchie, Li Su, Graciela Muniz-Terrera, John T O’Brien.

Journal of Neurology. 2021.



Structural brain changes associated with Alzheimer’s disease (AD) can occur decades before the onset of symptoms. The Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) score has been suggested to be associated with accelerated brain atrophy in middle-aged subjects but the regional specificity of atrophic areas remains to be elucidated. MRI imaging brain scans of 160 cognitively healthy middle-aged participants in the PREVENT-Dementia cohort, from baseline and follow-up after 2 years, were examined. Compared to subjects with CAIDE score ≤ 6 (low risk), subjects with CAIDE score > 6 (high risk) showed lower volume in the temporal, occipital, and fusiform cortex and lingual gyrus at baseline, and greater percentage of loss over 2 years in the supramarginal gyrus, angular gyrus, precuneus, lateral occipital cortex, superior parietal lobule and cingulate gyrus. This study demonstrated accelerated atrophy concentrated in several AD signature cortical regions in healthy middle-aged subjects with high CAIDE scores.