We need more sensitive cognitive screening tests – could neural processing speed be the answer?

We know that the neuropathological hallmarks of Alzheimer’s disease can be found in the brain years before the onset of noticeable cognitive impairment.  The beta-amyloid plaques start to appear as much as 20 years before while the tau-containing neurofibrillary tangles start to form later, several years before memory problems become a problem. It has become increasingly clear that by the time a person has significant cognitive impairment, it may be too late to intervene with medications aimed at removing the amyloid plaques and/or neurofibrillary tangles. The horses may already be out of the barn. Commonly used cognitive screening tests like the Mini Mental Status Exam (MMSE) are very insensitive for identifying subtle, early changes in cognition, but comprehensive neuropsychological testing can be expensive, time consuming, and impractical for screening. With the shift to thinking that early, pre-symptomatic treatment of Alzheimer’s may be an effective strategy, there is an urgent need for new screening tests sensitive enough to identify those at risk.

A recent paper in Neurology along with an accompanying editorial report important new information that may help design such tests. Longitudinal observations were made in clinically normal participants with an average age of 72 ± 6 years-old over approximately seven years with multiple amyloid and tau PET scans and annual, comprehensive cognitive testing.  As beta-amyloid became detectable in the PET scans, cognitive tests such as the Digital Symbol Substitution Test (DSST) and the Trail Making Test Part A showed evidence of slowing of neural processing speed while tests of memory remained normal.  When tau PET scans later turned positive, memory problems became apparent.  One possible explanation is that amyloid interferes with synaptic transmission thus slowing the speed of neural processing. Tau appears later when neurons start to die off. PET scans are wonderful research tools, but they are too expensive and cumbersome to be practical for screening.  Sensitive and specific blood tests for beta-amyloid and tau should be commercially available soon and should reduce the need for PET scans except in research settings.  The development of cognitive test batteries that focus on assessment of neural processing speed may expand our ability to define those who, though seemingly cognitively normal, may be on the Alzheimer’s trajectory and benefit from timely treatment with anti-amyloid and/or anti-tau therapies.