We have previously characterised functional brain abnormalities in young adults at
genetic risk for late-onset Alzheimer's disease. To gain further knowledge on the
preclinical phase of Alzheimer's disease, we sought to characterise structural and
functional MRI, CSF, and plasma biomarkers in a cohort of young adults carrying a
high-penetrance autosomal dominant mutation that causes early-onset Alzheimer's disease.
Between January and August, 2010, 18-26-year-old presenilin 1 (PSEN1) E280A mutation
carriers and non-carriers from the Colombian Alzheimer's Prevention Initiative Registry
in Medellín Antioquia, Colombia, had structural MRI, functional MRI during associative
memory encoding and novel viewing and control tasks, and cognitive assessments. Consenting
participants also had lumbar punctures and venepunctures. Outcome measures were task-dependent
hippocampal or parahippocampal activations and precuneus or posterior cingulate deactivations,
regional grey matter reductions, CSF Aβ(1-42), total tau and phospho-tau(181) concentrations,
and plasma Aβ(1-42) concentrations and Aβ(1-42):Aβ(1-40) ratios. Structural and functional
MRI data were compared using automated brain mapping algorithms and search regions
related to Alzheimer's disease. Cognitive and fluid biomarkers were compared using
Mann-Whitney tests.
44 participants were included: 20 PSEN1 E280A mutation carriers and 24 non-carriers.
The carrier and non-carrier groups did not differ significantly in their dementia
ratings, neuropsychological test scores, or proportion of apolipoprotein E (APOE)
ɛ4 carriers. Compared with non-carriers, carriers had greater right hippocampal and
parahippocampal activation (p=0·001 and p<0·014, respectively, after correction for
multiple comparisons), less precuneus and posterior cingulate deactivation (all p<0·010
after correction), and less grey matter in several parietal regions (all p<0·002 uncorrected
and corrected p=0·009 in the right parietal search region). In the 20 participants
(ten PSEN1 E280A mutation carriers and ten non-carriers) who had lumbar punctures
and venepunctures, mutation carriers had higher CSF Aβ(1-42) concentrations (p=0·008)
and plasma Aβ(1-42) concentrations (p=0·01) than non-carriers.
Young adults at genetic risk for autosomal dominant Alzheimer's disease have functional
and structural MRI findings and CSF and plasma biomarker findings consistent with
Aβ(1-42) overproduction. Although the extent to which the underlying brain changes
are either neurodegenerative or developmental remain to be determined, this study
shows the earliest known biomarker changes in cognitively normal people at genetic
risk for autosomal dominant Alzheimer's disease.
Banner Alzheimer's Foundation, Nomis Foundation, Anonymous Foundation, Forget Me Not
Initiative, Boston University Department of Psychology, Colciencias, National Institute
on Aging, National Institute of Neurological Disorders and Stroke, and the State of
Arizona.
Copyright © 2012 Elsevier Ltd. All rights reserved.