19 Feb 2008

One question in Alzheimer disease research is when in life the disease process actually begins. It clearly begins years before diagnosis, but how early no one knows. By contrast, a new study suggests that susceptibility to primary progressive aphasia (PPA), a related neurodegenerative disease, can even be traced to childhood. In this month’s Archives of Neurology, Marsel Mesulam and colleagues at Northwestern University, Chicago, report that there is a higher frequency of learning disability (LD), particularly dyslexia, among PPA patients and their first-degree relatives than among families with other forms of dementia. “We are not saying that everyone who has a learning disability should be concerned that they may get PPA, but we are finding that there is a relatively high presence of learning disabilities in this population,” said Emily Rogalski, the lead author on the paper. Larger epidemiological studies will be needed to determine how strong a risk factor early disabilities might be.

Primary progressive aphasia is a neurodegenerative disease that attacks the language center of the brain. The study grew out of anecdotal evidence from the clinic that people with PPA tend to complain more of learning disabilities, such as being bad at spelling. “We thought we should determine if there is any merit to those reports,” said Rogalski. To address the question, the researchers examined self-reported histories of learning disabilities in families with dementia in their AD center’s patient registry. The researchers looked at three different groups—patients with PPA, with Alzheimer disease, and with the behavioral variant of frontotemporal dementia (FTD)—and compared data from those groups with records from normal elderly controls.

Of 108 patients with PPA, almost 15 percent had a learning disability, while double that number had a first-degree relative with a learning disability. The results were statistically significant compared to the other groups. In the control group, only 1.5 and 6.8 percent of subjects reported a learning disability for themselves or a family member, respectively. The incidences of learning disability in the AD and FTD groups were higher than among controls, but at one-third and one-half that reported for PPA, respectively, were not statistically significant when compared with other groups. “The bottom line is that we found that learning disabilities are a risk factor for PPA,” said Rogalski.

What links learning disabilities to PPA is unclear, but the concordance is interesting given that this disease is a disorder of the language network, said Rogalski. She suggested that looking at subgroups of patients with learning disabilities may point to earlier diagnostic clues or genetic risk factors that may reveal more about the disease process itself. The researchers also suggest that learning disabilities may point to some inherent vulnerability that is compensated for during much of adulthood but that eventually manifests itself as a neurodegenerative process. “But it is way too early to speculate on how this might work,” said Rogalski.

Compensation for an underlying pathological process is a familiar concept to AD researchers. The temporary protection against AD that seems to come with higher educational achievement has been attributed to a greater cognitive reserve compensating for ongoing neurodegeneration (see ARF related news story). However, years of formal education do not seem to explain the link between learning disabilities and PPA in this study. The mean years of education in the PPA group (15.3) were not significantly different from the control (15.8) or even AD groups (14.0). “So far, our findings point to more differences than similarities between PPA and AD,” suggested Rogalski.—Tom Fagan