scholarly journals Associations between plasma p‐tau217, in vivo brain pathology and cognition in individuals with autosomal‐dominant Alzheimer’s disease: Findings from the Colombia‐Boston (COLBOS) biomarker study

2021 ◽  
Vol 17 (S5) ◽  
Author(s):  
David Aguillon ◽  
Clara Vila‐Castelar ◽  
Yinghua Chen ◽  
Yi Su ◽  
Kewei Chen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Autosomal Dominant ◽  
Brain Pathology ◽  
Autosomal Dominant Alzheimer’S Disease

scholarly journals Plasma Aβ ratios in autosomal dominant Alzheimer’s disease: the influence of genotype

2021 ◽  
Author(s):  
Antoinette O’Connor ◽  
Josef Pannee ◽  
Teresa Poole ◽  
Charles Arber ◽  
Erik Portelius ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Autosomal Dominant ◽  
Age At Onset ◽  
Cross Sectional ◽  
Autosomal Dominant Alzheimer’S Disease ◽  
Liquid Chromatography Tandem Mass ◽  
The Relationship

AbstractIn-vitro studies of autosomal dominant Alzheimer’s disease (ADAD) implicate longer Aβ peptides in pathogenesis, however less is known about the behaviour of ADAD mutations in-vivo. In this cross-sectional cohort study, we used liquid chromatography-tandem mass spectrometry to analyse 66 plasma samples from ADAD family members who were at-risk of inheriting a mutation or were already symptomatic. We tested for differences in plasma Aβ42:38, 38:40 and 42:40 ratios between Presenilin1 (PSEN1) and Amyloid Precursor Protein (APP) carriers. We examined the relationship between plasma and in-vitro models of Aβ processing and, among PSEN1 carriers, tested for associations with parental age at onset (AAO). 39 participants were mutation carriers (28 PSEN1 and 11 APP). Age- and sex-adjusted models showed marked differences in plasma Aβ between APP and PSEN1: higher Aβ42:38 in PSEN1 versus APP (p<0.001) and non-carriers (p<0.001); higher Aβ38:40 in APP versus PSEN1 (p<0.001) and non-carriers (p<0.001), while Aβ42:40 was higher in APP and PSEN1 compared to non-carriers (both p<0.001). Aβ profiles were reasonably consistent in plasma and cell lines. Within PSEN1, sex-adjusted models demonstrated negative associations between (i)Aβ42:40 (ii)Aβ42:38 and parental AAO. In-vivo differences in Aβ processing between APP and PSEN1 provide insights into ADAD pathophysiology which can inform therapy development.

scholarly journals Reduced thalamic volume is associated with early brain pathology in preclinical autosomal dominant Alzheimer’s disease

2020 ◽  
Vol 16 (S4) ◽  
Author(s):  
Enmanuelle Pardilla‐Delgado ◽  
Heirangi Torrico‐Teave ◽  
Liliana A Ramirez‐Gomez ◽  
Ana Baena ◽  
Yamile Bocanegra ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Autosomal Dominant ◽  
Brain Pathology ◽  
Autosomal Dominant Alzheimer’S Disease

scholarly journals Lower MR-indexed locus coeruleus integrity in autosomal-dominant Alzheimer’s disease is related to cortical tau burden and memory deficits

2020 ◽  
Author(s):  
Martin J. Dahl ◽  
Mara Mather ◽  
Markus Werkle-Bergner ◽  
Briana L. Kennedy ◽  
Yuchuan Qiao ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
High Resolution ◽  
Locus Coeruleus ◽  
Autosomal Dominant ◽  
Brain Regions ◽  
Cognitive Testing ◽  
Autosomal Dominant Alzheimer’S Disease

AbstractAbnormally phosphorylated tau, an indicator of Alzheimer’s disease, begins to accumulate in the first decades of life in the locus coeruleus (LC), the primary source of cortical norepinephrine. Ensuing dysfunction in noradrenergic neuromodulation is hypothesized to contribute to Alzheimer’s progression. However, research into the role of the LC has been impeded by a lack of effective ways of assessing it in vivo. Advances in high-resolution brainstem magnetic resonance imaging (MRI) hold potential to investigate the association of locus coeruleus integrity and Alzheimer’s-related neuropathological markers in vivo.Leveraging a meta-analytical approach, we first synthesized LC localizations and dimensions across previously published studies to improve the reliability and validity of MR-based locus coeruleus detection. Next, we applied this refined volume of interest to determine whether MR-indexed LC integrity can serve as a marker for noradrenergic degeneration in early-onset Alzheimer’s disease. Eighteen participants (34.7±10.1 years; 9♀) with or known to be at-risk for mutations in genes associated with autosomal-dominant Alzheimer’s disease (ADAD) were investigated. Genotyping confirmed mutations in seven participants (PSEN1, n = 6; APP, n = 1), of which four were symptomatic. Participants underwent 3T-MRI, flortaucipir positron emission tomography (PET), and cognitive testing. LC MRI intensity, a non-invasive proxy for neuronal density, was semi-automatically extracted from high-resolution brainstem scans across the rostrocaudal extent of the nucleus.Relative to healthy controls, symptomatic participants showed lower LC intensity. This effect was pronounced in rostral segments of the nucleus that project to the mediotemporal lobe and other memory-relevant areas. Among carriers of ADAD-causing mutations, closer proximity to the mutation-specific median age of dementia diagnosis was associated with lower LC intensity. Leveraging a multivariate statistical approach, we revealed a pattern of LC-related tau pathology in occipito-temporo-parietal brain regions. Finally, higher locus intensity was closely linked to memory performance across a variety of neuropsychological tests.Our finding of diminished MR-indexed LC integrity in autosomal-dominant Alzheimer’s disease suggest a role of the noradrenergic system in this neurodegenerative disease.

scholarly journals BIOLOGICAL AND COGNITIVE MARKERS OF PRESENILIN1 E280A AUTOSOMAL DOMINANT ALZHEIMER’S DISEASE: A COMPREHENSIVE REVIEW OF THE COLOMBIAN KINDRED

2019 ◽  
pp. 1-9
Author(s):  
J.T. Fuller ◽  
A. Cronin-Golomb ◽  
J.R. Gatchel ◽  
D.J. Norton ◽  
E. Guzmán-Vélez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Autosomal Dominant ◽  
Clinical Symptoms ◽  
Age Of Onset ◽  
Single Mutation ◽  
Cognitive Changes ◽  
Cognitive Markers ◽  
Autosomal Dominant Alzheimer’S Disease

The study of individuals with autosomal dominant Alzheimer’s disease affords one of the best opportunities to characterize the biological and cognitive changes of Alzheimer’s disease that occur over the course of the preclinical and symptomatic stages. Unifying the knowledge gained from the past three decades of research in the world’s largest single-mutation autosomal dominant Alzheimer’s disease kindred — a family in Antioquia, Colombia with the E280A mutation in the Presenilin1 gene — will provide new directions for Alzheimer’s research and a framework for generalizing the findings from this cohort to the more common sporadic form of Alzheimer’s disease. As this specific mutation is virtually 100% penetrant for the development of the disease by midlife, we use a previously defined median age of onset for mild cognitive impairment for this cohort to examine the trajectory of the biological and cognitive markers of the disease as a function of the carriers’ estimated years to clinical onset. Studies from this cohort suggest that structural and functional brain abnormalities — such as cortical thinning and hyperactivation in memory networks — as well as differences in biofluid and in vivo measurements of Alzheimer’s-related pathological proteins distinguish Presenilin1 E280A mutation carriers from non-carriers as early as childhood, or approximately three decades before the median age of onset of clinical symptoms. We conclude our review with discussion on future directions for Alzheimer’s disease research, with specific emphasis on ways to design studies that compare the generalizability of research in autosomal dominant Alzheimer’s disease to the larger sporadic Alzheimer’s disease population.

Associations between physical activity and markers of brain pathology in autosomal dominant Alzheimer’s disease: A preliminary report

2020 ◽  
Vol 16 (S10) ◽  
Author(s):  
Edmarie Guzman‐Velez ◽  
Clara Vila‐Castelar ◽  
Enmanuelle Pardilla‐Delgado ◽  
Joshua T Fox‐Fuller ◽  
Yamile Bocanegra ◽  
...  
Keyword(s):  
Physical Activity ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Preliminary Report ◽  
Autosomal Dominant ◽  
Brain Pathology ◽  
Autosomal Dominant Alzheimer’S Disease
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