WASHINGTON – Plasma levels of β-amyloid may be low in elderly patients at risk for mild cognitive impairment or even Alzheimer's disease in the near term, according to research presented at an international conference sponsored by the Alzheimer's Association.
β-Amyloid is secreted as a 40-amino acid species (Aβ40) and a 42-amino acid species (Aβ42), both of which are found in the blood and cerebrospinal fluid (CSF). While Aβ40 is the most prevalent species, Aβ42 forms the plaques that are one of the pathological hallmarks of Alzheimer's disease (AD).
“Our results in this study indicate that the ratio of these two proteins [Aβ42:Aβ40] is a good biomarker for identifying those normal elderly subjects, who will develop Alzheimer's disease and mild cognitive impairment in the next 3–5 years,” said Neill Graff-Radford, M.D., a professor of neurology at the Mayo Clinic in Jacksonville, Fla.
The researchers followed 565 cognitively normal individuals (median age 78 years; 62% female) yearly using the Mattis Dementia Rating Scale (DRS). Patients were followed for 2–12 years (median 3.7 years) after baseline plasma Aβ42 and Aβ40 levels were measured.
Over the course of the study, 54 individuals converted to AD or amnestic mild cognitive impairment (MCI), as diagnosed using the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Association and Mayo criteria.
The researchers compared baseline Aβ42:Aβ40 ratios in subjects who developed either AD or MCI with those who did not, after adjusting for age and apoE genotype–two risk factors for AD. They found that subjects with Aβ42:Aβ40 ratios in the lowest quartile had three times the risk of developing MCI or AD, compared with those in the highest quartile.
Subjects with the lowest ratios of Aβ42:Aβ40 also were significantly more likely to show declined on DRS, even after adjustment for age and apolipoprotein E genotype.
Those with ratios in the lowest quartile developed AD or MCI earlier than those in the other groups, too. Participants in the lowest quartile started developing AD or MCI around 2 years' follow-up, while those with ratios in the next lowest quartile began around 4 years, and those in the upper half began at 6–8 years.
In those older than 80 years and with ratios in the lower half, 20% developed AD in 5 years, compared with 5% of those in the upper half.
“We have pretty convincing evidence and many of us believe that Aβ42 is a very important therapeutic target,” Dr. Graff-Radford said. High plasma levels of Aβ42 have been associated with the early-onset genetic form of AD, Down syndrome, the aging process, and with being a relative of someone with AD. However, low Aβ42 levels have been found in the cerebrospinal fluid of patients with MCI or AD. Data from animal models suggest that low plasma and CSF levels may be a consequence of Aβ42 deposition in the brain.
A biomarker for the disease could spur research into drugs and other preventive measures.
“To develop preventive therapies for Alzheimer's … it's essential to have biomarkers related to Alzheimer's that identify the people at risk before they get the disease–kind of like a cholesterol test,” Dr. Graff-Radford said.