Studies shake up Alzheimer’s hypotheses

Nov 6 2012

By Eleanor McDermid, Senior medwireNews Reporter

Two studies in people at genetic risk for Alzheimer's disease (AD) reveal very early changes in brain structure and function that may actually precede amyloid beta (Aβ) deposition.

Both studies are published in The Lancet Neurology, and involve people in the Colombian Alzheimer's Prevention Initiative Registry. This includes patients with the PSEN1 E280A mutation - who develop cognitive impairment at a median of 44 years and dementia at 49 years - and their unaffected relatives.

In one of the studies, Eric Reiman (Banner Alzheimer's Institute, Phoenix, Arizona, USA) and team found that 20 carriers of the mutation had significantly greater right hippocampal and parahippocampal activation than 24 noncarriers, detected by magnetic resonance imaging. They also had significantly less precuneus and posterior cingulate deactivation, as well as significantly reduced gray matter in several regions, with the reduction in right parietal lobe gray matter remaining significant after correction for multiple comparisons.

The participants were 22 years old, on average, and dementia ratings and neuropsychologic test scores did not differ between those with and without the E280A mutation.

In a commentary accompanying the paper, Nick Fox (University College London, UK) calls the finding a "remarkable result," which "questions our models of Alzheimer's disease on several fronts."

He says that the findings "do not fit with models that suggest that amyloid plaque deposition precedes markers of downstream neurodegeneration, such as increased cerebral atrophy."

Indeed, the E280A mutation carriers actually had higher levels of Aβ_1‑42 in the plasma and cerebrospinal fluid than the noncarriers, whereas build-up of Aβ in the brain is associated with reduced soluble levels.

The other study used florbetapir positron emission tomography to look specifically at Aβ deposition in E280A mutation carriers (19 presymptomatic and 11 with cognitive impairment or mild dementia) and 20 noncarriers, aged between 20 and 56 years.

Adam Fleisher (Banner Alzheimer's Institute) and team report that fibrillar Aβ began to appear in patients at an average age of 28 years, which was about 16 years before the age at which mutation carriers were expected to show the first signs of cognitive impairment. Aβ accumulated rapidly in patients up to the age of about 38 years, after which it plateaued.

In a commentary on this study, William Jagust (University of California, Berkeley, USA) points out that the findings may be less applicable to patients with sporadic AD. Like Fox, he believes the findings support the existence of a very long presymptomatic period of AD, during which intervention may be possible. But the result also raises questions about the potential effectiveness of targeting Aβ deposition and when best to intervene.

Fox says: "Pragmatically, we might need to balance potential benefits of very early treatment against greater feasibility of trials in presymptomatic individuals nearer to clinical onset. These are difficult choices but ones with substantial implications for future trials in Alzheimer's disease."

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