Molecular and neuropsychological predictive markers of cognitive decline
Funding Source: National Health and Medical Research Council of Australia (NHMRC)
Aims
The primary aim of this study is to establish whether combining risk stratification based on symptomatology and cognitive function with the assessment of genotypic and phenotypic markers will allow for the determination of a risk profile for AD that could allow for accurate diagnosis prior to the onset of objective clinical symptoms. To test this hypothesis we will investigate whether:
- Individuals with subjective memory complaints show significantly more cognitive decline than healthy controls during a follow-up period of 24 months.
- Elevated levels of plasma apoE, APP and Aβ are associated with greater cognitive decline.
- An acute fat challenge enhances differences in the levels of protein biomarkers between individuals with/without cognitive decline.
- Polymorphisms in genes encoding pro-inflammatory cytokines and growth/neurotrophic factors are significantly associated with cognitive decline.
- Participants who carry a 'high-risk' profile display a higher frequency of neurological soft signs compared to those with a 'low-risk' profile.
Background
Current means for the definitive diagnosis of Alzheimer's disease (AD) is dependent upon post-mortem examination of the brain for evidence of the disease's characteristic neuropathology, namely extracellular and intracellular amyloid deposits. The recent therapeutic advances in AD research have given impetus to the importance of early diagnosis during the pre-dementia phase. Pre-dementia includes the continuum of normal aging, memory complaints without objective impairment and mild cognitive impairment (MCI). Pre-dementia syndromes may be purely subjective with no objective evidence of brain dysfunction. Subjective memory complaints (SMC) in the elderly population are fairly common with prevalence rates of between 22%-56% in community-based studies. However, SMC are frequently associated with depressive symptoms, especially in self-referrals to memory clinics or in clinical studies. Studies report that memory complaints in individuals with objective cognitive impairment were predictive for cognitive decline and dementia with odds ratios of 2.6 to 4.1, whilst complainers with no apparent cognitive impairment were 2.8 times more likely to develop AD than non-complainers.
Research Plan
This project will follow-up the individuals recruited by the McCusker AD Research Unit under a grant funded by the NHMRC (ID970094). At time zero (2005; Figure 1) the majority of individuals that participate in this study had been monitored for up to 6 years. This provides valuable information at time zero regarding changes in cognition and the levels of biomarkers such as plasma Aβ and apoE. Furthermore, the frequency of polymorphisms for further genetic markers associated with inflammation commenced at time zero. In addition to the genotyping procedures, all biochemistry, cognitive, clinical and fat consumption procedures started at time zero. To increase the number of participants additional recruitment took place (represented by striped boxes in time-line).
Study Outcomes
The major outcome will be to determine whether a 'high risk' biochemical and genetic profile exists in individuals that have a higher frequency of cognitive decline as determined by tests of delayed recall and selective attention. We will therefore determine whether specific biochemical and genetic factors correlate with cognitive decline.
Chief Investigators
