Alzheimer’s disease likely begins far earlier than its hallmark cognitive impairments emerge. As a result, researchers have been attempting to pinpoint biomarkers that might predict disease development in advance of clinical symptoms. One form of Alzheimer’s disease, linked to the presinelin (PSEN1) 1 E280A mutation, is autosomal dominant. Offspring of parents with an autosomal dominant mutation linked to disease have a 50-50 chance of inheriting the mutation. Because people who carry the PSEN1 mutation will develop AD, researchers at the Banner Alzheimer’s Institute in Arizona led a multiorganization investigation into potential biomarkers for AD in a group of Columbian people with high autosomal dominant AD prevalence.1
The team tested 20 PSEN1 carriers and 24 noncarriers using cerebral spinal fluid and plasma analyses, as well as structural and functional MRI to see if they could identify differences between the two groups that may lead to a diagnostic test. All subjects were between 19 and 26 at testing, ages well in advance of the usual onset of clinical AD symptoms (age 44). All tested negative for cognitive impairments.1
When given memory tasks, in terms of performance, the two groups did not differ. However, on functional MRI investigation, PSEN1 carriers exhibited greater hippocampal and parahippocampal activation when performing memory-related tasks. Increases in hippocampal activity during a memory encoding task could result from an effort to compensate for either neuronal or synaptic impairments or may possibly be due to inefficient synaptic inhibition.1
Structural MRIs performed on the two groups revealed reductions in gray matter and cortical thickness among carriers. They exhibited significantly less gray matter in bilateral parietal and parietaltemporal regions.1 The parietal lobe has been shown to play a role in recollection of episodic memory.2
The PSEN1 carriers also tested for higher levels of amyloid beta (the major component of neuronal plaques) concentrations in both CSF and blood plasma assays. It has long been recognized that elevated amyloid beta is a precursor to AD.1 Pharmaceutical companies have been attempting to formulate BACE inhibitor-class drugs, which have the potential to slow down the production of amyloid beta in the brain.3 The other interesting result was that carriers did not show elevated tau phosphorylation associated with the fibrous tendrils characteristic in AD brains.
The results of this study indicate that more than 20 years prior to clinical AD onset, structural and functional brain and fluid alterations are associated with the PSEN1 mutation.1 Alzheimer’s researchers have long held the belief that physiological alterations occur well before clinical systems. Because early detection is key to treatment for all forms of Alzheimer’s, it is possible that this information from the PSEN1 study is true for other forms. For people with the PSEN1 mutation, treatment regimens might begin early in adulthood. And, in the future, the structural and functional targets may form targets for other interventions. Lastly, this study confirms that elevated AB is an accurate biomarker for AD much earlier than previously determined.1
1. Reiman, E., et al. (2012) ‘Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer’s disease in the presenilin 1 E280A kindred: A case-control study‘, The Lancet, Neurology, 11 (12), (pp. 1048-56)
2. Berryhill, M.E. (2007) ‘Parietal lobe and episodic memory: Bilateral damage causes impaired free recall of autobiographical memory‘, Journal of Neuroscience, 27 (52), (pp. 14415-14423)
3. Johnson, L. 2012 ‘New drug studies offer patients hope of treatment to slow Alzheimer’s within several years‘, The Vancouver Sun, December 4, 2012. 8:25 a.m.