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Studies Identify Early Changes In Familial Alzheimer’s Disease

November 11, 2012

Young adult carriers of the presenilin gene mutation that invariably induces Alzheimer’s disease around the age of 45 years already show distinctive changes on functional and structural brain MRI and in amyloid-beta biomarkers when they are in their 20s and are still asymptomatic. However, amyloid-beta deposition in the grey matter of the brain does not appear until age 30 years, according to findings from two cross-sectional studies of the same cohort.

More than 2 decades before the median age of onset for familial Alzheimer’s disease (AD), functional and structural MRI changes were detectable in young adult carriers of the presenilin-1 (PSEN1) E280A mutation, “along with CSF [cerebrospinal fluid] and plasma biomarker findings consistent with amyloid-beta overproduction,” wrote investigators led by Dr. Eric M. Reiman of Banner Alzheimer’sInstitute, Phoenix.

Dr. Eric M. Reiman

Dr. Reiman was lead author of the amyloid-beta biomarkers and MRI study and coauthor of a second study; both were published online Nov. 6 in Lancet Neurology. The studies involved members of the largest known kindred of familial AD, located in Medellín, Antioquia, Colombia, as a part of the Alzheimer’s Prevention Initiative.

“Our study shows some of the earliest known brain changes in autosomal dominant AD mutation carriers,” Dr. Reiman and his associates noted. Because the changes appear to be present before amyloid-beta plaque deposition begins, the findings don’t fit with the current AD model in which amyloid plaque deposition precedes markers of downstream neurodegeneration.

The investigators assessed changes in biomarkers and brain imaging studies among 20 young adults (aged 18-26 years). They first performed CSF and plasma assays in 10 carriers of the PSEN1 E280A mutation and 10 noncarriers who were matched for demographic characteristics.

Carriers had significantly higher CSF concentrations of amyloid-beta than did noncarriers, but they did not differ in CSF total tau or phosphorylated tau concentrations. Carriers also had significantly higher plasma levels of amyloid-beta.

Both findings are consistent with overproduction of amyloid-beta in the earliest stages of AD. In contrast, CSF and plasma levels of amyloid-beta are reduced in later stages of the disease, likely because the excess is being deposited in the diffuse and neuritic plaques that characterize those stages, Dr. Reiman and his colleagues said.

Sixteen of the study subjects (eight carriers and eight noncarriers of the presenilin mutation) underwent brain MRI while performing memory encoding and novel viewing tasks. The mutation carriers showed significantly greater activation in the hippocampal and parahippocampal regions than did noncarriers, as well as significantly reduced volumes of grey matter in bilateral parietal regions.

These MRI abnormalities are similar to those found in the later stages of familial AD and in late-onset AD. But in this case, the MRI abnormalities were present before any evidence of plaque accumulation, the investigators said (Lancet Neurol. 2012 Nov. 6 [doi:10.1016/S1474-4422(12)70228-4]).

“We postulate that the reductions in regional grey matter are related to a very early age-related or neurodevelopmental reduction in the density of terminal neuronal fields innervating the implicated regions. … Regardless of whether these reductions begin before or after amyloid-beta plaque deposition, increases in hippocampal activity during a memory encoding and novel viewing task could be a result of the effort to compensate for neuronal or synaptic impairments or an inefficient inhibition of synaptic functions,” Dr. Reiman and his associates wrote.

The study findings highlight the need to clarify our understanding of the earliest brain changes in AD. They also suggest that clinical trials of potential treatments, such as anti-amyloid therapies, should begin at much earlier ages than previously recognized.

Because this study was cross-sectional rather than longitudinal, we cannot know how long the high concentrations of amyloid-beta have been present, when they will begin to fall, or even whether they may have begun to fall already, wrote Dr. Nick Fox of theDementia Research Centre in the Institute of Neurology at University College London.

Similarly, we can’t tell whether the reduced volume of grey matter and the altered synaptic function on MRI are part of a neurodegenerative process or have always been present and are developmental. Either way, “we must treat the results with great caution” because of the small study sample and cross-sectional design, Dr. Fox wrote (Lancet Neurol. 2012 Nov. 6 [doi:10.1016/s1474-4422(12)70256-9]).

The second study, led by Dr. Adam S. Fleisher (also of the Banner Alzheimer’s Institute), involved florbetapir (Amyvid) PET scan assessments of members of the familial AD kindred aged 20-56 years. A total of 11 subjects were carriers of the mutation who were already symptomatic, 19 were carriers who had not yet developed symptoms, and 20 were asymptomatic noncarriers of the mutation.

In the grey matter of the brain, florbetapir binding with amyloid-beta was evident in all the mutation carriers who were aged 30 years or older, regardless of whether they were symptomatic. In contrast, there was no such binding in the noncarriers or in the carriers who were younger than 30 years.

The cerebral pattern of this deposition was similar to that seen in patients with other forms of AD, primarily affecting the posterior cingulate, precuneus, parietotemporal, frontal, and basal ganglial regions, the researchers said (Lancet Neurol. 2012 Nov. 6 [doi:10.1016/S1474-4422(12)70227-2]).

Based on their findings, Dr. Fleisher and his associates estimated that fibrillar amyloid-beta begins to accumulate in the brain about 16 years before the typical onset of mild cognitive impairment and about 21 years before the typical onset of full dementia in familial AD. It seems to peak during the following decade, then plateau just a few years before symptoms start to appear.

It is important to note that the findings of Dr. Fleisher and his colleagues concerning people with autosomal-dominant AD may not be generalizable to more common forms of the disease, Dr. William Jagust wrote in an editorial accompanying the study.

Autosomal-dominant disease is thought to be related to the overproduction of amyloid-beta. In contrast, AD related to the apolipoprotein E genotype “is more closely associated with reduced clearance of amyloid-beta.” It is still unclear whether these different mechanisms will respond the same way to amyloid-lowering therapies, said Dr. Jagust of the Helen Wills Neuroscience Instituteand the School of Public Health at the University of California, Berkeley (Lancet Neurol. 2012 Nov. 6 [doi:10.1016/S1474-4422(12)70255-7]).

Both studies were funded in part by the Banner Alzheimer’s Foundation, Colciencias, the National Institute on Aging, and the state of Arizona. The florbetapir-PET scan study was funded in part by Avid Pharmaceuticals. The biomarker assay and MRI study also was funded in part by Boston University and the National Institute of Neurological Disorders and Stroke.

Dr. Fleisher reported ties to Eli Lilly and Avid Pharmaceuticals, and his associates reported ties to numerous industry sources. Dr. Jagust reported having served as a consultant to Synarc, TauRx, Genentech, and Siemens. Dr. Fox reported receiving institutional research support from Alzheimer’s Research UK, the Alzheimer’s Society, Bristol-Myers Squibb, Eisai, Elan, GE Healthcare, Janssen, Lilly, Lundbeck, the National Institute for Health Research, the U.K. Medical Research Council, Pfizer/Wyeth, and the Wolfson Foundation.



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