Cortical thickness across the lifespan in a Colombian cohort with autosomal‐dominant Alzheimer's disease: A cross‐sectional study

Fox‐Fuller, Joshua T; Torrico‐Teave, Heirangi; Uquillas, Federico d’Oleire; Chen, Kewei; Su, Yi; Chen, Yinghua; Brickhouse, Michael; Sanchez, Justin S.; Agüero, Cinthya; Jacobs, Heidi I.L.; Hampton, Olivia L.; Guzmán-Vélez, Edmarie; Vila‐Castelar, Clara; Aguirre–Acevedo, Daniel Camilo; Baena, Ana; Artola, Arabiye; Martinez, Jean-Louis; Pluim, Celina F.; Álvarez, Sergio; Ochoa-Escudero, Martin; Reiman, Eric M.; Sperling, Reisa A.; Lopera, Francisco; Johnson, Keith A.; Dickerson, Bradford C.; Quiroz, Yakeel T.

doi:10.1002/dad2.12233

Cited by 4 publications

(2 citation statements)

References 44 publications

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“…This is also consistent with a study in seven PSEN1 mutation carriers, distinct from the Colombian kindred, who showed accelerated hippocampus atrophy with transition to a symptomatic stage, but did not differ from controls in hippocampus volumes before this transition 18 . Similarly, in a cross-sectional analysis, cortical thickness in PSEN1 E280A carriers was higher in children and adolescent mutation carriers compared to agematched noncarriers 40 . The underlying mechanisms of the volume increases in young asymptomatic individuals with PSEN1 mutations are currently unresolved.…”

Section: Discussionmentioning

confidence: 78%

Basal forebrain volume and metabolism in carriers of the Colombian mutation for autosomal dominant Alzheimer’s disease

Teipel,

Grazia,

Dyrba

et al. 2024

Sci Rep

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We aimed to study atrophy and glucose metabolism of the cholinergic basal forebrain in non-demented mutation carriers for autosomal dominant Alzheimer's disease (ADAD). We determined the level of evidence for or against atrophy and impaired metabolism of the basal forebrain in 167 non-demented carriers of the Colombian PSEN1 E280A mutation and 75 age- and sex-matched non-mutation carriers of the same kindred using a Bayesian analysis framework. We analyzed baseline MRI, amyloid PET, and FDG-PET scans of the Alzheimer’s Prevention Initiative ADAD Colombia Trial. We found moderate evidence against an association of carrier status with basal forebrain volume (Bayes factor (BF10) = 0.182). We found moderate evidence against a difference of basal forebrain metabolism (BF10 = 0.167). There was only inconclusive evidence for an association between basal forebrain volume and delayed memory and attention (BF10 = 0.884 and 0.184, respectively), and between basal forebrain volume and global amyloid load (BF10 = 2.1). Our results distinguish PSEN1 E280A mutation carriers from sporadic AD cases in which cholinergic involvement of the basal forebrain is already detectable in the preclinical and prodromal stages. This indicates an important difference between ADAD and sporadic AD in terms of pathogenesis and potential treatment targets.

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Section: Discussionmentioning

confidence: 78%

Basal forebrain volume and metabolism in carriers of the Colombian mutation for autosomal dominant Alzheimer’s disease

Teipel,

Grazia,

Dyrba

et al. 2024

Sci Rep

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show abstract

“…Our study only considered age-related cognitive trajectories in adult carriers; however, it is possible that APOE e4 may provide some biological or cognitive benefit in younger PSEN1 carriers (i.e., childhood, akin to young adults in sporadic AD). In fact, PSEN1 carriers in this kindred have greater cortical thickness in childhood than non-carriers, followed by atrophy in adulthood 37 . Studying the influence of both APOE and PSEN1 across the lifespan will enhance our knowledge of the effects of these genes, and, hopefully, provide mechanisms for disease prevention and treatment in the future.…”

Section: Discussionmentioning

confidence: 78%

Effect of apolipoprotein genotype and educational attainment on cognitive function in autosomal dominant Alzheimer’s disease

Langella,

Barksdale,

Vasquez

et al. 2023

Nat Commun

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Autosomal dominant Alzheimer’s disease (ADAD) is genetically determined, but variability in age of symptom onset suggests additional factors may influence cognitive trajectories. Although apolipoprotein E (APOE) genotype and educational attainment both influence dementia onset in sporadic AD, evidence for these effects in ADAD is limited. To investigate the effects of APOE and educational attainment on age-related cognitive trajectories in ADAD, we analyzed data from 675 Presenilin-1 E280A mutation carriers and 594 non-carriers. Here we show that age-related cognitive decline is accelerated in ADAD mutation carriers who also have an APOE e4 allele compared to those who do not and delayed in mutation carriers who also have an APOE e2 allele compared to those who do not. Educational attainment is protective and moderates the effect of APOE on cognition. Despite ADAD mutation carriers being genetically determined to develop dementia, age-related cognitive decline may be influenced by other genetic and environmental factors.

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Cholinergic-like neurons and cerebral spheroids bearing the PSEN1 p.Ile416Thr variant mirror Alzheimer's disease neuropathology

Gomez-Sequeda,

Mendivil-Perez,

Jimenez-Del-Rio

et al. 2023

Sci Rep

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Familial Alzheimer’s disease (FAD) is a complex neurodegenerative disorder for which there are no therapeutics to date. Several mutations in presenilin 1 (PSEN 1), which is the catalytic component of γ-secretase complex, are causal of FAD. Recently, the p.Ile416Thr (I416T) PSEN 1 mutation has been reported in large kindred in Colombia. However, cell and molecular information from I416T mutation is scarce. Here, we demonstrate that menstrual stromal cells (MenSCs)-derived planar (2D) PSEN 1 I416T cholinergic-like cells (ChLNS) and (3D) cerebral spheroids (CSs) reproduce the typical neuropathological markers of FAD in 4 post-transdifferentiating or 11 days of transdifferentiating, respectively. The models produce intracellular aggregation of APPβ fragments (at day 4 and 11) and phosphorylated protein TAU at residue Ser202/Thr205 (at day 11) suggesting that iAPPβ fragments precede p-TAU. Mutant ChLNs and CSs displayed DJ-1 Cys106-SO3 (sulfonic acid), failure of mitochondria membrane potential (ΔΨm), and activation of transcription factor c-JUN and p53, expression of pro-apoptotic protein PUMA, and activation of executer protein caspase 3 (CASP3), all markers of cell death by apoptosis. Moreover, we found that both mutant ChLNs and CSs produced high amounts of extracellular eAβ42. The I416T ChLNs and CSs were irresponsive to acetylcholine induced Ca2+ influx compared to WT. The I416T PSEN 1 mutation might work as dominant-negative PSEN1 mutation. These findings might help to understanding the recurring failures of clinical trials of anti-eAβ42, and support the view that FAD is triggered by the accumulation of other intracellular AβPP metabolites, rather than eAβ42.

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Cortical thickness across the lifespan in a Colombian cohort with autosomal‐dominant Alzheimer's disease: A cross‐sectional study

Cited by 4 publications

References 44 publications

Basal forebrain volume and metabolism in carriers of the Colombian mutation for autosomal dominant Alzheimer’s disease

Basal forebrain volume and metabolism in carriers of the Colombian mutation for autosomal dominant Alzheimer’s disease

Effect of apolipoprotein genotype and educational attainment on cognitive function in autosomal dominant Alzheimer’s disease

Cholinergic-like neurons and cerebral spheroids bearing the PSEN1 p.Ile416Thr variant mirror Alzheimer's disease neuropathology

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