Association of Alzheimer’s Disease Progression with White Matter Hyperintensities and Blood Biomarkers

Abstract

Alzheimer’s disease (AD) is the most common form of dementia affecting around 70% of dementia cases. The global prevalence of dementia is estimated to be 44.4 million people. The pathological hallmarks of AD are amyloid plaques and neurofibrillary tangles. AD impairs many cognitive functions including memory, language, abstract thinking, and spatial orientation and alters mood and behaviour. These symptoms become gradually more severe, affecting common daily activities until eventually full time care is required. There is currently no cure. A large number of promising drugs are being tested in clinical trials, but their effect on disease progression is difficult to assess using existing psychometric measures. New biomarkers, including cognitive-, MRI-, and blood-based measures could be combined to accurately predict disease progression. First, potential associations of 1-year cognitive decline with baseline volumes of MRI White Matter Hyperintensities (WMH) from the whole brain, were evaluated. Higher baseline WMH volumes were found to be significantly associated with greater AD-cognitive decline (number of subjects (n) =84, P<0.05), with a median, yearly, cognitive change of -1.2 points in the Minimal-Mental-State-Exam, 1.5 points in ADAS-cog, and 1.3 points in Clinical-Dementia-Rating. Second, WMH volume was associated with an identified panel of mRNAs (trainingset: n=53, P<0.001, R2=0.75; validationset: n=21, R2=0.11), and with proteins (trainingset: n=59, P<0.001, R2=0.76; validationset: n=30, R2=0.03), in individuals with AD. Disease progression, measured by AD-cognitive decline in CDR-SOB points, was associated with an identified panel of mRNA transcripts (trainingset: n=46, P<0.001, R2=0.86; validationset: n=16, R2=0.13). It can be suggested that WMH and cognitive disease progression affect mRNA expression and protein concentration in blood. A limitation was that there were only small independent validationsets. Future work could investigate the identified molecular candidates in larger subject groups, and if confirmed, they could contribute to defining a blood-based disease progression biomarker panel.

Date of Award	2015
Original language	English
Awarding Institution	King's College London
Supervisor	Angela Hodges (Supervisor) & Simon Lovestone (Supervisor)