Inflammation-associated risk factors for Alzheimer's disease and dementia

Abstract

Alzheimer's disease (AD) is the leading cause of dementia worldwide and a highly debilitating, and deadly, disease. For the majority of AD cases, the cause of the disease is not known. Chronic inflammation has been implicated in AD pathology. The overall objective of this thesis was to study indices of altered peripheral inflammation as risk factors for dementia in general and Alzheimer s disease in particular. The four studies included in this thesis are observational epidemiological studies based on data from the Swedish Twin Registry. Identifying inflammation-associated risk factors for AD could not only provide clues to the etiology of AD but also lead to novel strategies for combating the disease.

In Study I, the atopic inflammatory disorders asthma, eczema and rhinitis were assessed (prior to dementia follow-up) through questionnaires in the 1960s or 1970s. Dementia was ascertained in two different study designs, longitudinally (n = 22,188) and cross-sectionally (n = 7,800). A history of atopy conferred a 16% increased risk of dementia (Hazard Ratio [HR] 1.16, 95% confidence interval 1.01 1.33) in the longitudinal study but could not be replicated in the cross-sectional study, perhaps due to poorer survival in atopic individuals.

In Study II, manifest cardiovascular diseases other than stroke (CVD) were investigated as proxies for a burden of atherosclerosis (i.e. vascular inflammation). CVD information was collected from national registries and dementia was ascertained by clinical evaluations or register-linkage. Results showed that CVD increases the risk of dementia in general, but also of AD specifically, in carriers (but not non-carriers) of the APOE4 allele (HR 2.39, 1.15-4.96). By analyzing twin pairs, we could also show that the association between CVD and dementia is not explained by genetic or early life environmental factors in common to both disorders.

In Study III, we investigated serum levels of antibodies against phosphorylcholine (anti-PC), a novel marker with anti-atherogenic and anti-inflammatory effects. A nested case-control study of incident dementia (serum collected before onset of dementia) was performed to estimate the relative risk of dementia and AD. In addition, a case-control study of prevalent dementia cases (serum collected after dementia onset) was conducted to investigate differences in anti-PC between dementia cases and controls. We found no increased risk of developing AD or dementia due to lower anti-PC levels whereas patients with AD were more likely to belong to the lowest quartile of anti-PC than age- and sex-matched controls, OR 2.70, 1.45-4.99.

In Study IV, we sought to perform a comprehensive study of the inflammatory markers C-reactive protein (CRP) and interleukin-6 (IL6). Almost 4,000 elderly Swedes (1,265 AD cases) were genotyped for a total of 22 tagSNPs. A sub-set of the population had serum measurements of CRP and IL6 and was included in A) a nested case-control study of incident dementia cases, and B) a case-control study of prevalent dementia cases. None of the SNPs or haplotypes were associated with AD or dementia, nor were there associations between CRP or IL6 levels and the risk of future AD or dementia. However, AD cases were more likely to belong to the highest quartile of IL6 (measured on average 5.5 years after dementia onset) than age- and sexmatched controls, OR 2.24 (1.27-3.95).

In conclusion, this thesis shows that there are significant immune alterations in AD and dementia patients compared to non-demented controls. However, indicators of inflammatory burden, other than CVD, appear to have a limited association with the risk of developing dementia and AD late in life.