Modifiable lifestyle factors as modulators of brain parameters and cognitive decline in ageing and Alzheimer's disease

Alzheimer’s disease (AD) is a progressive neurodegenerative condition associated with pathological accumulations of misfolded proteins, amyloid plaques and neurofibrillary tangles. AD manifests clinically with prominent memory complaints, deficits in other cognitive domains in addition to brain structural and functional deficits. Research in the recent decades has shifted its focus on the marked vascular dysfunction observed in AD and how the interaction between vascular senescence and vascular burden arising from modifiable lifestyle factors can change the course of the disease. It is unclear whether the presence of vascular comorbidities stemming from modifiable lifestyle factors can have an additive effect in AD or whether there is an interaction between ageing, AD and cardiovascular comorbidity-related mechanisms that can result in a worse AD phenotype. The current thesis thus aims to investigate how the additional vascular contributions from modifiable lifestyle factors can alter cerebral constituents and cognitive function in normal ageing and AD, using multi-modal neuroimaging. This was done by exploring the effects of three common cardiovascular risk factors on the brain, that are modifiable through interventions facilitating lifestyle changes, namely obesity, hypertension and type 2 diabetes, in cognitively normal individuals and patients across the AD spectrum.

With reference to obesity, it appears that having parameters within the healthy weight range could make the brain more resilient to age and AD-related effects in later stages of the disease. However, in the transitional mild cognitive impairment stage, being in the overweight category could contribute towards a worse prognostic profile of AD, while being in the obese weight range in cognitively healthy controls could be detrimental to a wide range of cerebral constituents and cognitive functions. The baseline differences in the weight categories of the different diagnostic groups could have been among the main drivers for the associations found, and these differences are also consistent with what is observed in the general population, due to age and disease related effects. When comparing AD patients medicated for hypertension (who had a medical history of hypertension) with AD patients unmedicated for hypertension, no differences were found with respect to neuroimaging parameters or cognitive function. However, in the medicated group, dividing the patients according to the class of antihypertensive drug treatment revealed a preservative effect of the use of beta-blockers only, on brain structure and cerebral blood flow. Moreover, on correlating values of pulse pressure (the difference between systolic and diastolic blood pressure) with neuroimaging parameters in the unmedicated AD patient group, a negative correlation was found between cerebral blood flow and pulse pressure in subcortical brain regions. On the other hand, when comparing AD patients with type 2 diabetes with AD patients without type 2 diabetes, AD patients with type 2 diabetes presented with a worse AD phenotype than their counterparts. On comparing AD patients with type 2 diabetes with age and sex-matched healthy controls, widespread differences were found in brain structure, cerebral blood flow and cognition between the two groups.

The work from the current thesis highlights that the additional burden from modifiable lifestyle factors is additive to the detrimental effects of AD and that these effects are exaggerated through the interaction of pathological mechanisms downstream of cardiovascular comorbidities, vascular senescence and AD. The irreversible nature of these downstream mechanisms is a crucial point for the consideration of implementing primary prevention strategies to reduce the prevalence of cardiovascular risk factors as their presence can increase the severity of AD in patients and can also lower the threshold for AD onset in healthy individuals. Considering the fact that there are several non-modifiable risk factors for AD, that there is a paucity in effective treatments and early diagnostic criteria for AD, the modifiable nature of cardiovascular risk factors makes them the crux for preventing the clinical manifestations of AD and mitigating its severity. The findings from this thesis therefore highlight the need for early interventions recommending primary prevention to reduce the burden of cardiovascular risk factors to reduce the risk of AD onset in healthy individuals and to reduce the severity of the AD phenotype in patients through pharmacological interventions and lifestyle modifications.