Browsing by Subject "Early-onset Alzheimer's disease"

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    APOE ε4 carrier status and sex differentiate rates of cognitive decline in early- and late-onset Alzheimer's disease
    (Wiley, 2023) Polsinelli, Angelina J.; Logan, Paige E.; Lane, Kathleen A.; Manchella, Mohit K.; Nemes, Sára; Sanjay, Apoorva Bharthur; Gao, Sujuan; Apostolova, Liana G.; Neurology, School of Medicine
    Background: We studied the effect of apolipoprotein E (APOE) ε4 status and sex on rates of cognitive decline in early- (EO) and late- (LO) onset Alzheimer's disease (AD). Method: We ran mixed-effects models with longitudinal cognitive measures as dependent variables, and sex, APOE ε4 carrier status, and interaction terms as predictor variables in 998 EOAD and 2562 LOAD participants from the National Alzheimer's Coordinating Center. Results: APOE ε4 carriers showed accelerated cognitive decline relative to non-carriers in both EOAD and LOAD, although the patterns of specific cognitive domains that were affected differed. Female participants showed accelerated cognitive decline relative to male participants in EOAD only. The effect of APOE ε4 was greater in EOAD for executive functioning (p < 0.0001) and greater in LOAD for language (p < 0.0001). Conclusion: We found APOE ε4 effects on cognitive decline in both EOAD and LOAD and female sex in EOAD only. The specific patterns and magnitude of decline are distinct between the two disease variants. Highlights: Apolipoprotein E (APOE) ε4 carrier status and sex differentiate rates of cognitive decline in early-onset (EO) and late-onset (LO) Alzheimer's disease (AD). APOE ε4 in EOAD accelerated decline in memory, executive, and processing speed domains. Female sex in EOAD accelerated decline in language, memory, and global cognition. The effect of APOE ε4 was stronger for language in LOAD and for executive function in EOAD. Sex effects on language and executive function decline differed between EOAD and LOAD.
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    APOE-ε4 is associated with earlier symptom onset in LOAD but later symptom onset in EOAD
    (Wiley, 2023) Polsinelli, Angelina J.; Lane, Kathleen A.; Manchella, Mohit K.; Logan, Paige E.; Gao, Sujuan; Apostolova, Liana G.; Neurology, School of Medicine
    Background: We studied the effect of apolipoprotein E (APOE) ε4 status and sex on age of symptom onset (AO) in early- (EO) and late- (LO) onset Alzheimer's disease (AD). Method: A total of 998 EOAD and 2562 LOAD participants from the National Alzheimer's Coordinating Center (NACC) were included. We used analysis of variance to examine AO differences between sexes and APOE genotypes and the effect of APOE ε4, sex, and their interaction on AO in EOAD and LOAD, separately. Results: APOE ε4 carriers in LOAD had younger AO and in EOAD had older AO. Female EOAD APOE ε4 carriers had older AO compared to non-carriers (P < 0.0001). There was no difference for males. Both male and female LOAD APOE ε4 carriers had younger AO relative to non-carriers (P < 0.0001). Conclusion: The observed earlier AO in EOAD APOE ε4 non-carriers relative to carriers, particularly in females, suggests the presence of additional AD risk variants.
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    Learning slopes in early-onset Alzheimer's disease
    (Wiley, 2023) Hammers, Dustin B.; Nemes, Sára; Diedrich, Taylor; Eloyan, Ani; Kirby, Kala; Aisen, Paul; Kramer, Joel; Nudelman, Kelly; Foroud, Tatiana; Rumbaugh, Malia; Atri, Alireza; Day, Gregory S.; Duara, Ranjan; Graff-Radford, Neill R.; Honig, Lawrence S.; Jones, David T.; Masdeu, Joseph C.; Mendez, Mario F.; Musiek, Erik; Onyike, Chiadi U.; Riddle, Meghan; Rogalski, Emily; Salloway, Steve; Sha, Sharon J.; Turner, Raymond Scott; Weintraub, Sandra; Wingo, Thomas S.; Wolk, David A.; Wong, Bonnie; Carrillo, Maria C.; Dickerson, Bradford C.; Rabinovici, Gil D.; Apostolova, Liana G.; LEADS Consortium; Neurology, School of Medicine
    Objective: Investigation of learning slopes in early-onset dementias has been limited. The current study aimed to highlight the sensitivity of learning slopes to discriminate disease severity in cognitively normal participants and those diagnosed with early-onset dementia with and without β-amyloid positivity. METHOD: Data from 310 participants in the Longitudinal Early-Onset Alzheimer's Disease Study (aged 41 to 65) were used to calculate learning slope metrics. Learning slopes among diagnostic groups were compared, and the relationships of slopes with standard memory measures were determined. RESULTS: Worse learning slopes were associated with more severe disease states, even after controlling for demographics, total learning, and cognitive severity. A particular metric-the learning ratio (LR)-outperformed other learning slope calculations across analyses. CONCLUSIONS: Learning slopes appear to be sensitive to early-onset dementias, even when controlling for the effect of total learning and cognitive severity. The LR may be the learning measure of choice for such analyses. Highlights: Learning is impaired in amyloid-positive EOAD, beyond cognitive severity scores alone. Amyloid-positive EOAD participants perform worse on learning slopes than amyloid-negative participants. Learning ratio appears to be the learning metric of choice for EOAD participants.
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    Sex and APOE ε4 carrier effects on atrophy, amyloid PET, and tau PET burden in early-onset Alzheimer's disease
    (Wiley, 2023) Nemes, Sára; Logan, Paige E.; Manchella, Mohit K.; Mundada, Nidhi S.; La Joie, Renaud; Polsinelli, Angelina J.; Hammers, Dustin B.; Koeppe, Robert A.; Foroud, Tatiana M.; Nudelman, Kelly N.; Eloyan, Ani; Iaccarino, Leonardo; Dorsant-Ardón, Valérie; Taurone, Alexander; Thangarajah, Maryanne; Dage, Jeffery L.; Aisen, Paul; Grinberg, Lea T.; Jack, Clifford R., Jr.; Kramer, Joel; Kukull, Walter A.; Murray, Melissa E.; Rumbaugh, Malia; Soleimani-Meigooni, David N.; Toga, Arthur; Touroutoglou, Alexandra; Vemuri, Prashanthi; Atri, Alireza; Day, Gregory S.; Duara, Ranjan; Graff-Radford, Neill R.; Honig, Lawrence S.; Jones, David T.; Masdeu, Joseph; Mendez, Mario F.; Musiek, Erik; Onyike, Chiadi U.; Riddle, Meghan; Rogalski, Emily; Salloway, Stephen; Sha, Sharon J.; Turner, Raymond S.; Wingo, Thomas S.; Womack, Kyle B.; Wolk, David A.; Rabinovici, Gil D.; Carrillo, Maria C.; Dickerson, Bradford C.; Apostolova, Liana G.; LEADS Consortium; Neurology, School of Medicine
    Introduction: We used sex and apolipoprotein E ε4 (APOE ε4) carrier status as predictors of pathologic burden in early-onset Alzheimer's disease (EOAD). Methods: We included baseline data from 77 cognitively normal (CN), 230 EOAD, and 70 EO non-Alzheimer's disease (EOnonAD) participants from the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS). We stratified each diagnostic group by males and females, then further subdivided each sex by APOE ε4 carrier status and compared imaging biomarkers in each stratification. Voxel-wise multiple linear regressions yielded statistical brain maps of gray matter density, amyloid, and tau PET burden. Results: EOAD females had greater amyloid and tau PET burdens than males. EOAD female APOE ε4 non-carriers had greater amyloid PET burdens and greater gray matter atrophy than female ε4 carriers. EOnonAD female ε4 non-carriers also had greater gray matter atrophy than female ε4 carriers. Discussion: The effects of sex and APOE ε4 must be considered when studying these populations. Highlights: Novel analysis examining the effects of biological sex and apolipoprotein E ε4 (APOE ε4) carrier status on neuroimaging biomarkers among early-onset Alzheimer's disease (EOAD), early-onset non-AD (EOnonAD), and cognitively normal (CN) participants. Female sex is associated with greater pathology burden in the EOAD cohort compared to male sex. The effect of APOE ε4 carrier status on pathology burden was the most impactful in females across all cohorts.
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    The Sporadic Early-onset Alzheimer's Disease Signature Of Atrophy: Preliminary Findings From The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) Cohort
    (Wiley, 2023) Touroutoglou, Alexandra; Katsumi, Yuta; Brickhouse, Michael; Zaitsev, Alexander; Eckbo, Ryan; Aisen, Paul; Beckett, Laurel; Dage, Jeffrey L.; Eloyan, Ani; Foroud, Tatiana; Ghetti, Bernardino; Griffin, Percy; Hammers, Dustin; Jack, Clifford R., Jr.; Kramer, Joel H.; Iaccarino, Leonardo; La Joie, Renaud; Mundada, Nidhi S.; Koeppe, Robert; Kukull, Walter A.; Murray, Melissa E.; Nudelman, Kelly; Polsinelli, Angelina J.; Rumbaugh, Malia; Soleimani-Meigooni, David N.; Toga, Arthur; Vemuri, Prashanthi; Atri, Alireza; Day, Gregory S.; Duara, Ranjan; Graff-Radford, Neill R.; Honig, Lawrence S.; Jones, David T.; Masdeu, Joseph C.; Mendez, Mario F.; Musiek, Erik; Onyike, Chiadi U.; Riddle, Meghan; Rogalski, Emily; Salloway, Stephen; Sha, Sharon; Turner, R. Scott; Wingo, Thomas S.; Wolk, David A.; Womack, Kyle; Carrillo, Maria C.; Rabinovici, Gil D.; Apostolova, Liana G.; Dickerson, Bradford C.; LEADS Consortium; Neurology, School of Medicine
    Introduction: Magnetic resonance imaging (MRI) research has advanced our understanding of neurodegeneration in sporadic early-onset Alzheimer's disease (EOAD) but studies include small samples, mostly amnestic EOAD, and have not focused on developing an MRI biomarker. Methods: We analyzed MRI scans to define the sporadic EOAD-signature atrophy in a small sample (n = 25) of Massachusetts General Hospital (MGH) EOAD patients, investigated its reproducibility in the large longitudinal early-onset Alzheimer's disease study (LEADS) sample (n = 211), and investigated the relationship of the magnitude of atrophy with cognitive impairment. Results: The EOAD-signature atrophy was replicated across the two cohorts, with prominent atrophy in the caudal lateral temporal cortex, inferior parietal lobule, and posterior cingulate and precuneus cortices, and with relative sparing of the medial temporal lobe. The magnitude of EOAD-signature atrophy was associated with the severity of cognitive impairment. Discussion: The EOAD-signature atrophy is a reliable and clinically valid biomarker of AD-related neurodegeneration that could be used in clinical trials for EOAD. Highlights: We developed an early-onset Alzheimer's disease (EOAD)-signature of atrophy based on magnetic resonance imaging (MRI) scans. EOAD signature was robustly reproducible across two independent patient cohorts. EOAD signature included prominent atrophy in parietal and posterior temporal cortex. The EOAD-signature atrophy was associated with the severity of cognitive impairment. EOAD signature is a reliable and clinically valid biomarker of neurodegeneration.