BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: 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.
"The discrepancies in the results can be due to small sample sizes and differences in the age of included subjects between studies. The studies by Fortea et al.  and Reiman et al.  mentioned above, respectively showing increased cortical thickness in MC and increased CSF A␤ 42 levels in MC, might reflect pathological changes appearing very early in the preclinical stage and therefore do not need to be in disagreement with results from other groups. Then there is a possibility that differences in the sequence of pathological events in different FAD mutations explain some of the variable observations. "
[Show abstract][Hide abstract] ABSTRACT: Objective: To compare cerebrospinal fluid (CSF) biomarkers and brain structure in preclinical mutation carriers (MC) and non-carriers (NC) from families with familial Alzheimer disease (FAD).
Methods: The study included members from four Swedish families at risk for carrying an APPswe, APParc, PSEN1 H163Y or PSEN1 I143T mutation. Magnetic resonance imaging (MRI) scans were obtained from 13 MC and 20 NC and analyzed using vertex-based analyses of cortical thickness and volume. CSF was collected from 10 MC and 12 NC and analyzed for Aβ42, tau-protein and phospho-tau.
Results: The MC had significantly lower levels of CSF Aβ42 and higher levels tau-protein and phospho-tau than the NC. There was a trend showing a decrease in Aβ42 15 – 20 years before expected onset of clinical symptoms, while a trend of increasing tau-protein and phospho-tau was observed closer to expected onset. The MC had decreased volume on MRI in the left precuneus, superior temporal gyrus and fusiform gyrus.
Conclusions: Aberrant biomarker levels in CSF as well as regional brain atrophy are present in preclinical FAD, several years before the expected onset of clinical symptoms.
"DS patients have decreased levels of CSF Ab1-42 already in mid life, likely reflecting sequestration of Ab monomers into plaques (Tamaoka et al. 1999; Tapiola et al. 2001). This is consistent with biomarker results from patients with other types of autosomal dominant early onset AD where the disease is believed to be caused by Ab overproduction or an increase in the Ab1-42/ Ab1-40 ratio (Karran et al. 2011; Reiman et al. 2012). However, besides the altered CSF Ab42 levels, little is known about APP and Ab metabolism in DS. "
[Show abstract][Hide abstract] ABSTRACT: Down's syndrome (DS) patients develop early Alzheimer's disease pathology with abundant cortical amyloid plaques, likely due to overproduction of the amyloid precursor protein (APP), which subsequently leads to amyloid β (Aβ) aggregation. This is reflected in cerebrospinal fluid (CSF) levels of the 42-amino acid long Aβ peptide (Aβ1-42), which are increased in young DS patients and decreases with age. However, it is unclear whether DS also affects other aspects of Aβ metabolism, including production of shorter C- and N-terminal truncated Aβ peptides, and production of peptides from the amyloid precursor-like protein 1 (APLP1), which is related to APP, and cleaved by the same enzymatic processing machinery. APLP1-derived peptides may be surrogate markers for Aβ1-42 production in the brain. Here, we used hybrid immunoaffinity-mass spectrometry and enzyme-linked immunosorbent assays to monitor several Aβ and APLP1 peptides in CSF from DS patients (n = 12) and healthy controls (n = 20). CSF levels of Aβ1-42 and three endogenous peptides derived from APLP1 (APL1β25, APL1β27 and APL1β28) were decreased in DS compared with controls, while a specific Aβ peptide, Aβ1-28, was increased in a majority of the DS individuals. This study indicates that DS causes previously unknown specific alterations of APP and APLP1 metabolism.
Neuromolecular medicine 04/2014; 16(2). DOI:10.1007/s12017-014-8302-1 · 3.68 Impact Factor
"Presently, there is a major effort investigating the promising novel approaches for AD early diagnosis by detecting the presence and accumulation of protein Aí µí»½. Brain scans such as magnetic resonance (MR) microscopy , positron emission tomography (PET) tracers   , and spinal fluid tests  are currently used by researchers to evaluate Alzheimer's-related changes and monitor disease course in living AD patients and animal models, but they are costly and impractical for widespread screening, and none of them have been approved for routine use  . There is a clear need to look for a reasonably priced technology capable of detecting the condition before symptoms occur with high resolution sensitivity and specificity that offers ease of use during the test. "
[Show abstract][Hide abstract] ABSTRACT: Alzheimer's disease (AD) is the most common form of dementia pathologically characterized by cerebral amyloid-beta (Aβ) deposition. Early and accurate diagnosis of the disease still remains a big challenge. There is evidence that Aβ aggregation starts to occur years before symptoms arise. Noninvasive monitoring of Aβ plaques is critical for both the early diagnosis and prognosis of AD. Presently, there is a major effort on looking for a reasonably priced technology capable of diagnosing AD by detecting the presence of Aβ. Studies suggest that AD is systemic rather than brain-limited focus diseases and the aggregation of the disease-causing proteins also takes place in lens except the brain. There is a possible relationship between AD and a specific subtype of age-related cataract (supranuclear cataract). If similar abnormal protein deposits are present in the lens, it would facilitate non-invasive diagnosis and monitoring of disease progression. However, there are controversies on the issues related to performance and validation of Aβ deposition in lens as biomarkers for early detection of AD. Here we review the recent findings concerning Aβ deposition in the lenses of AD patients and evaluate if the ocular lens can provide a biomarker for AD.
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