Two Proteins Needed to Turn on Dementia
No change on the sum of boxes score was evident in p-tau-negative individuals (β1=-0.003, P=0.94).
Similarly, on the Alzheimer’s disease cognitive subscale, changes were seen only among those who had high levels of p-tau (β1=0.94, P=0.004).
The researchers then considered whether total tau, as opposed to the phosphorylated subtype, correlated with decline and found that the clinical dementia rating score among amyloid-beta-positive individuals was not associated with total tau, although associations were seen on the Alzheimer’s cognitive subscale.
Total tau is elevated in other degenerative neurologic disorders, but p-tau appears to be more specific for Alzheimer’s disease in that it “correlates with increased neurofibrillary pathology,” they observed.
“It is feasible that although amyloid-beta initiates the degenerative cascade, elevated levels of tau may represent a second phase of the [Alzheimer’s disease] pathologic process where neurodegenerative changes occur largely independent of amyloid-beta,” Desikan and colleagues suggested.
Accordingly, tau may represent a therapeutic target, and future clinical trials should consider participants’ levels of both amyloid-beta and p-tau.
Limitations of the study included its reliance on the two indirect biomarkers that may not represent the full extent of Alzheimer’s pathology, and the possibility that other markers such as visinin-like protein also may have a role in preclinical dementia.
Normal cognitive decline or dementia?
Cognitive speed, inhibitory function, and memory decline with age while crystallised, particularly verbal, abilities remain largely intact. Poor health, fewer years of education, lower activity, the presence of the APOE E4 allele, and high BP appear to predict faster cognitive decline. Dementia is diagnosed in the presence of objective cognitive impairment, both long- and short-term memory, plus at least one additional (cortical) cognitive deficit, such as dysphasia, dyspraxia, agnosia, or disturbance in executive functioning. In addition, patients have to show significant impairment in social or occupational functioning and a significant decline from previous levels. Both smoking and diabetes increase the risk of all types of dementia, not smoking or even stopping smoking reduces this risk, but better control of type 2 diabetes does not appear to have a measurable effect. Drinking small to moderate amounts of alcohol appears to confer some benefit in ameliorating cognitive decline. There is some evidence that HRT, DHEA, BP lowering in patients without prior cerebrovascular disease, statins, vitamin B6 and procaine are NOT helpful. There is insufficient evidence to establish or refute a beneficial effect for exercise, treatment of type 2 diabetes, omega-3 fatty acids, folic acid with/without vitamin B12, antioxidant vitamins, or ginkgo biloba. Depressive symptoms are more prevalent than dementia. Clinical (major) depression can present with cognitive deterioration, often associated with subjective complaints. Patients with subjective or objective memory impairment, but without functional deterioration, can be referred to the local memory clinic, while demented patients eligible for acetylcholinesterase inhibitor treatment, patients whose diagnosis is unclear and who may need some specific investigations, as well as patients who may benefit from a combined approach with psychotropic drugs and behavioural support should be referred to the local mental health team.
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Ebmeier KP.
University of Oxford.
Also, the findings need to be replicated in a representative cohort of community-dwelling elderly individuals.
In an editorial accompanying the article, David M. Holtzman, MD, of Washington University in St. Louis argued in favor of using these biomarkers in the design of Alzheimer’s prevention trials, because without markers indicating that individuals are at risk for dementia, “trial size would be enormous and cost prohibitive, and individuals may be subjected to treatments that have the potential for toxicity with no clear benefit.”
Clinical research into prevention of Alzheimer’s disease should follow the pattern established in cancer and cardiovascular disease, he stated.
“While it will not be easy, this is the most likely way to make a real, lasting, and important clinical impact,” Holtzman said.
The study was funded by the National Institutes of Health and the San Diego chapter of the Alzheimer’s Association.
Several of the researchers receive research support and act as consultants for various companies, including Eli Lilly, Esai, Wyeth, Roche, Amgen, Pfizer, Novartis, NeuroPhage, Merck, and Baxter International.
Primary source: Archives of Neurology
Source reference: Desikan R, et al “Amyloid-β-associated clinical decline occurs only in the presence of elevated p-tau” Arch Neurol 2012; DOI: 10.1001/archneurol.2011.3354.
Additional source: Archives of Neurology
Source reference: Holtzman D “CSF biomarkers for secondary prevention trials” Arch Neurol 2012; DOI: 10.1001/archneurol.2012.587.