Browsing by Subject "Early‐Onset Alzheimer’s Disease (EOAD)"

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    Association Between Age and Cognitive Severity in Early‐Onset AD: Extension of preliminary findings in the Longitudinal Early‐Onset Alzheimer’s Disease Study (LEADS)
    (Wiley, 2025-01-03) Hammers, Dustin B.; Eloyan, Ani; Taurone, Alexander; Thangarajah, Maryanne; Kirby, Kala; Wong, Bonnie; Dage, Jeffrey L.; Nudelman, Kelly N.; Carrillo, Maria C.; Rabinovici, Gil D.; Dickerson, Bradford C.; Apostolova, Liana G.; LEADS Consortium; Neurology, School of Medicine
    Background: Widespread cognitive impairments have previously been documented in Early‐Onset Alzheimer’s Disease (EOAD) relative to cognitively normal (CN) same‐aged peers or those with cognitive impairment without amyloid pathology (Early‐Onset non‐Alzheimer’s Disease; EOnonAD; Hammers et al., 2023). Prior preliminary work has similarly observed worse cognitive performance being associated with earlier ages in EOAD participants enrolled in the Longitudinal Early‐Onset Alzheimer’s Disease Study (LEADS; Apostolova et al., 2019). It is unclear, however, if these age effects are seen across early‐onset conditions, and whether cognitive discrepancies among diagnostic groups are uniform across the age spectrum. The objective of the current study is to more‐extensively examine the impact of age‐at‐baseline on cognition within LEADS, with emphasis placed on the influence of diagnostic group on these associations. Method: Expanded cross‐sectional baseline cognitive data from 573 participants (CN, n = 97; EOAD, n = 364; EOnonAD, n = 112) enrolled in the LEADS study (aged 40‐64) were analyzed. Multiple linear regression analyses were conducted to investigate associations between age‐at‐baseline and cognition for each diagnostic group – and their interaction among diagnoses – controlling for gender, education, APOE ε4 status, and disease severity. Result: See Table 1 for demographic characteristics of our sample. Linear regression showed a significant interaction effect for the cognitive domain of Executive Functioning (p = .002). Specifically, while the EOAD group displayed a positive relationship between age‐at‐baseline and Executive Functioning performance (β = 0.08, p = .02; Figure 1), the CN group displayed a negative relationship (β = ‐0.04, p = .008) and the EOnonAD group displayed no relationship (β = ‐0.01, p = .50). A similar main‐effect for age was observed for the EOAD group when examining Visuospatial Skills (β = 0.12, p = .04), however no other age effects were evident across other diagnostic groups or cognitive domains (Episodic Memory, Language, or Speed/Attention; Table 2). Conclusion: Building off preliminary work, our results suggest that executive functioning may be disproportionately impacted earlier in the disease course in participants with EOAD relative to other diagnostic groups. This finding appears to be unique to executive functioning, as it was absent in other cognitive domains and remained after accounting for disease severity. This highlights the need for further investigation into executive dysfunction early in the course of EOAD.
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    Effects of BDNF and COMT variants on cognitive decline in Early‐Onset Alzheimer’s Disease
    (Wiley, 2025-01-03) Hammers, Dustin B.; Foroud, Tatiana M.; Kim, Hee Jin; Musema, Jane; Dage, Jeffrey L.; Eloyan, Ani; Carrillo, Maria C.; Dickerson, Bradford C.; Rabinovici, Gil D.; Apostolova, Liana G.; Nudelman, Kelly N.; LEADS Consortium; Medical and Molecular Genetics, School of Medicine
    Background: Early‐Onset Alzheimer’s Disease (EOAD) is a rare condition that affects only 5% of patients with Alzheimer’s Disease (AD). At present, only basic information is known about the impact of AD risk variants on EOAD, and the effects of more subtle genetic contributions to cognitive decline have yet to be investigated. Genetic variants for brain derived neurotrophic factor (BDNF) and catechol‐O‐methyltransferase (COMT) have both been implicated in cognitive change (Fiocco et al., 2010; Ferrer et al., 2019), consequently the aim of the current study was to examine the role of these genetic variants on cognitive decline in EOAD. Method: Data from 88 amyloid‐positive EOAD participants enrolled in the Longitudinal Early Onset Alzheimer’s Disease Study (LEADS; aged 40‐64) were analyzed. Exploratory multivariate analyses of covariance (MANCOVA) were conducted to investigate differences in 12‐month cognitive decline as a function of BDNF rs6265 (p.V66M) and COMT rs4680 (p.V158M) variants using dominant genetic models (Val/Val versus Val/Met or Met/Met). Cox Regression analyses were also conducted to consider the effect of genetic variants on age of onset. Result: See Table 1 for demographic characteristics of our sample. MANCOVA, controlling for age, education, sex, and race/ethnicity, showed significant effects for BDNF p.V66M on domains of Memory (p<0.001) and Executive Functioning (p = 0.04; Table 2). Specifically, greater 12‐month cognitive decline was observed for the CRAFT Immediate and Delayed Story Memory, with worse performance associated with BDNF minor alleles (ps. = 0.007 to 0.02). Conversely, worse decline was observed for the reference group for RAVLT Immediate Memory (p<0.006) and Digit Span Backwards (p<0.02). No significant effects were evident for domains of Language, Speed/Attention, or Visuospatial skills (ps = 0.34‐0.97), nor for any analyses of COMT carrier status (ps = 0.26‐0.87). Cox Regression analyses, controlling for race and ethnicity, were not significant for BDNF or COMT carrier status (ps = 0.59‐0.64; Figure 1). Conclusion: Results suggest subtle effects of BDNF p.V66M carrier status on memory decline in EOAD participants, which was not observed for disease progression/age‐of‐onset. No effects for COMT p.V158M carrier status were observed. Future investigation will replicate these effects in larger samples, permitting stratification of additional covariates including APOE genotype.