Risk factors and blood biomarkers for  pre-clinical and clinical dementia

Identifying candidate plasma biomarkers associated with pre-clinical amyloid and tau PET deposition, vascular brain injury (VBI), and subsequent clinical dementia could illuminate underlying mechanistic pathways of disease and identify potential novel biomarkers for risk prediction. In addition, a greater understanding of the relationship between dietary and vascular factors, namely mid-life vitamin D and blood pressure across early to late mid-life, and preclinical dementia can inform population-based approaches to preclinical disease prediction and early disease modification. This thesis explores the association between candidate plasma proteins (including markers of vascular dysfunction and neurodegeneration), vitamin D and blood pressure trajectories in the mid-life period with neuroimaging markers of preclinical dementia as well as clinical dementia in the multi-generational, community-based, Framingham Heart Study. In the relatively young (mean age 39, standard deviation [SD] 8) Framingham Generation 3 cohort, vitamin D, blood pressure at mid-life, nerve growth factor (NGF) and candidate plasma proteins (n=125) were related to positron emission tomography (PET) and magnetic resonance imaging (MRI) measures performed approximately 13-16 years later. Following this, candidate biomarkers (n=55) identified as demonstrating significant associations with neuroimaging markers of preclinical dementia were validated for the outcomes of clinical all- cause and AD dementia in the older Framingham Generation 2 (Offspring) cohort. In this series of chapters, a steep decline in diastolic blood pressure (DBP) from early to late midlife was associated with greater tau-PET deposition in the entorhinal cortex, one of the earliest cortical regions affected in AD, highlighting how maintaining normotension across the ~15-16y mid-life period may confer protection against subsequent pathological tau accumulation in the brain. Higher vitamin D in mid-life was associated with lower subsequent tau-PET deposition on average 16 years later, but was not associated with amyloid burden in the brain, highlighting how mid-life vitamin D may represent a potentially modifiable target to mitigate the risk of neuroimaging markers of preclinical dementia. Higher nerve growth factor (NGF), a marker of neuroprotection and neural repair, was associated with a reduced risk of VBI, namely clinical stroke and covert brain infarcts, indicating its potential as a predictor of ischemic stroke risk. In the exploratory, ‘development’ chapter to identify potential candidate plasma protein biomarkers for neuroimaging markers of pre-clinical dementia, we identified 55 candidate proteins (many markers of systemic vascular dysfunction) associated with 19 Risk Factors and Blood Biomarkers for Pre-Clinical Dementia neuroimaging markers of preclinical dementia. Proteins reflecting endothelial dysfunction and fibrinolysis (such as growth differentiation factor-15 [GDF-15], plasminogen activator inhibitor-1 [PAI-1], leptin, and proinsulin) were associated with white-matter vascular brain injury (VBI), while markers of inflammation and blood–brain barrier disruption (including tau, butyrylcholinesterase [BChE], insulin-like growth factor binding protein-3 [IGFBP-3], bikunin, melanoma cell adhesion molecule [MCAM], and soluble glycoprotein 130 [sGP130]) were associated with amyloid deposition. Proteins involved in perfusion, purine metabolism, and excitability (such as N-terminal pro-B-type natriuretic peptide [NT- proBNP], purine nucleoside phosphorylase [PNP] and insulin-like growth factor-1 [IGF-1]) were associated with tau burden in the entorhinal cortex and medial temporal lobe. These findings suggest that systemic vascular dysfunction may contribute to both white- and gray-matter pathologies, highlighting candidate biomarkers for VBI that could strengthen dementia risk prediction and support the vascular ‘V’ component expansion of the ATNIVS+ (amyloid [A], tau [T], neurodegeneration [N], inflammation [I], vascular [V], and synaptic dysfunction [S]) classification framework. In the final chapter (validation study), the 55 biomarkers that were previously associated with neuroimaging outcomes were validated in the older Framingham Offspring cohort with clinical dementia outcomes. A total of 14 midlife plasma proteins were associated with future dementia outcomes; higher levels of insulin-like growth factor binding protein-2 (IGFBP-2), stromal cell-derived factor-1 (SDF-1), PAI-1, matrix metalloproteinase-8 (MMP- 8), intercellular adhesion molecule-1 (ICAM-1), and total tau were associated with an increased dementia risk, while IGFBP-3 and amyloid-beta 42 (Aβ42) were associated with decreased dementia risk. These results highlight systemic pathways linking vascular dysfunction and subsequent neurodegeneration with clinical dementia. This thesis offers an integrated, ‘mid to late-life’ lifespan perspective on the role of select dietary, vascular and candidate blood biomarkers in the risk of preclinical and clinical dementia. Across two generations and four decades of follow-up, midlife systemic changes in DBP, vitamin D, NGF, and plasma protein biomarkers were associated with downstream amyloid and tau deposition, white matter injury, and ultimately clinical dementia.

Funder

Irish Research Council
Health Research Board, Ireland

Publisher

University of Galway

Rights

CC BY-NC-ND

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University of Galway Theses (PhD Theses)