%0 Journal Article %J J Alzheimers Dis %D 2023 %T Type 2 Diabetes Comorbidity and Cognitive Decline in Patients with Alzheimer's Disease. %A Davidson, Skylar %A Allenback, Gayle %A Decourt, Boris %A Sabbagh, Marwan N %X

BACKGROUND: Although insulin dysregulation and resistance likely participate in Alzheimer's disease (AD) etiologies, little is known about the correlation between type 2 diabetes mellitus (T2DM) and the progression of cognitive decline in patients with AD.

OBJECTIVE: To determine whether AD patients with T2DM experience more rapid cognitive decline than those without T2DM.

METHODS: All cognitive performance data and the presence or absence of T2DM comorbidity in patients with AD were derived from the US National Alzheimer's Coordinating Center's (NACC) Uniform Data Set (UDS). A search of the UDS identified 3055 participants with AD who had more than one epoch completed. The data set culled clinically diagnosed AD dementia patients who were assessed for diabetes type identified during at least 1 visit. These patients were divided into 2 groups based on whether they had a diagnosis of T2DM. The data from these groups were then analyzed for differences in cognitive decline based on neuropsychological test battery scores and a Clinician Dementia Rating using a general linear model.

RESULTS: Comparisons of the mean scores for 16 selected tests from the neuropsychological test battery showed no significant differences in baseline scores and scores at subsequent visits between the T2DM and nondiabetic groups.

CONCLUSIONS: The results revealed no differences in cognitive decline metrics over the course of 5 visits in either study group. These data indicate that the presence of T2DM does not increase the rate of cognitive decline in AD. This finding contradicts expected disease burden and will need to be explored further.

%B J Alzheimers Dis %V 95 %P 1573-1584 %8 2023 Oct 10 %G eng %N 4 %R 10.3233/JAD-230489 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Deep Brain Stimulation Targeting the Fornix for Mild Alzheimer Dementia (the ADvance Trial): A Two Year Follow-up Including Results of Delayed Activation. %A Leoutsakos, Jeannie-Marie S %A Yan, Haijuan %A Anderson, William S %A Asaad, Wael F %A Baltuch, Gordon %A Burke, Anna %A Chakravarty, M Mallar %A Drake, Kristen E %A Foote, Kelly D %A Fosdick, Lisa %A Giacobbe, Peter %A Mari, Zoltan %A McAndrews, Mary Pat %A Munro, Cynthia A %A Oh, Esther S %A Okun, Michael S %A Pendergrass, Jo Cara %A Ponce, Francisco A %A Rosenberg, Paul B %A Sabbagh, Marwan N %A Salloway, Stephen %A Tang-Wai, David F %A Targum, Steven D %A Wolk, David %A Lozano, Andres M %A Smith, Gwenn S %A Lyketsos, Constantine G %X

BACKGROUND: Given recent challenges in developing new treatments for Alzheimer dementia (AD), it is vital to explore alternate treatment targets, such as neuromodulation for circuit dysfunction. We previously reported an exploratory Phase IIb double-blind trial of deep brain stimulation targeting the fornix (DBS-f) in mild AD (the ADvance trial). We reported safety but no clinical benefits of DBS-f versus the delayed-on (sham) treatment in 42 participants after one year. However, secondary post hoc analyses of the one-year data suggested a possible DBS-f benefit for participants≥65 years.

OBJECTIVE: To examine the long-term safety and clinical effects of sustained and delayed-on DBS-f treatment of mild AD after two years.

METHODS: 42 participants underwent implantation of DBS-f electrodes, with half randomized to active DBS-f stimulation (early on) for two years and half to delayed-on (sham) stimulation after 1 year to provide 1 year of active DBS-f stimulation (delayed on). We evaluated safety and clinical outcomes over the two years of the trial.

RESULTS: DBS-f had a favorable safety profile with similar rates of adverse events across both trial phases (years 1 and 2) and between treatment arms. There were no differences between treatment arms on any primary clinical outcomes. However, post-hoc age group analyses suggested a possible benefit among older (>65) participants.

CONCLUSION: DBS-f was safe. Additional study of mechanisms of action and methods for titrating stimulation parameters will be needed to determine if DBS has potential as an AD treatment. Future efficacy studies should focus on patients over age 65.

%B J Alzheimers Dis %V 64 %P 597-606 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29914028?dopt=Abstract %R 10.3233/JAD-180121 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Long-Term Follow Up of Patients with Mild-to-Moderate Alzheimer's Disease Treated with Bapineuzumab in a Phase III, Open-Label, Extension Study. %A Salloway, Stephen P %A Sperling, Reisa %A Fox, Nick C %A Sabbagh, Marwan N %A Honig, Lawrence S %A Porsteinsson, Anton P %A Rofael, Hany %A Ketter, Nzeera %A Wang, Daniel %A Liu, Enchi %A Carr, Stephen %A Black, Ronald S %A Brashear, H Robert %X

BACKGROUND: A 3-year extension of two Phase III parent studies of intravenous (IV) bapineuzumab in patients with mild-to-moderate Alzheimer's disease dementia (apolipoprotein (APOE) ɛ4 carriers and noncarriers) is summarized.

OBJECTIVES: The primary and secondary objectives were to evaluate the long-term safety, tolerability, and maintenance of efficacy of bapineuzumab.

METHODS: A multicenter study in patients who had participated in double-blind placebo-controlled parent studies. Patients enrolled in the extension study were assigned to receive IV infusions of bapineuzumab (0.5 or 1.0 mg/kg) every 13 weeks until termination but were blinded to whether they had received bapineuzumab or placebo in the parent studies.

RESULTS: A total of 1,462 (688 were APOEɛ4 carriers and 774 were noncarriers) patients were enrolled. Extension-onset adverse events occurred in >81% of the patients in each dose group. Fall, urinary tract infection, agitation, and ARIA-E occurred in ≥10% of participants. The incidence proportion of ARIA-E was higher among carriers and noncarriers who received bapineuzumab for the first time in the extension study (11.8% and 5.4%, respectively) versus those who were previously exposed in the parent studies (5.1% and 1.3%, respectively). After 6 to 12 months exposure to bapineuzumab IV in the extension study, similar deterioration of cognition and function occurred with no significant differences between the dose groups.

CONCLUSIONS: Infusion of bapineuzumab 0.5 or 1.0 mg/kg every 13 weeks for up to 3 years was generally well tolerated, with a safety and tolerability profile similar to that in previous studies.

%B J Alzheimers Dis %V 64 %P 689-707 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29914022?dopt=Abstract %R 10.3233/JAD-171157 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Pathologically Confirmed Alzheimer's Disease in APOE ɛ2 Homozygotes is Rare but Does Occur. %A Stipho, Faissal %A Jackson, Robert %A Sabbagh, Marwan N %X

BACKGROUND: Homozygous APOEɛ4 status is a well-known risk factor in the development of Alzheimer's disease (AD). However, other genotypes of APOE have not yet been found to have equal clinical significance. There is a paucity of reports regarding clinically or pathologically described AD in APOEɛ2 homozygotes compared to the other alleles.

OBJECTIVE: To notify clinicians that patients with homozygous APOEɛ2 are also at risk of developing AD based on results from the largest prospectively gathered registry of brain samples to date.

METHODS: We queried the National Alzheimer's Coordinating Center (NACC) database for autopsy-confirmed AD cases. Of the Uniform Data Set (UDS) participants who are deceased, 5,779 were diagnosed with dementia at their last UDS visit prior to death, and autopsy data is available for 3,518.

RESULTS: Of the brains in the NACC database with pathologically confirmed dementia, seven were found to be homozygous for APOEɛ2, which represents only 0.2% of the autopsy-confirmed sample. Furthermore, pathology-confirmed AD represents 29% (2/7) of the APOEɛ2/ɛ2 patients diagnosed with dementia.

CONCLUSIONS: Although rare, autopsy-confirmed AD can be present in APOEɛ2/ɛ2 carriers.

%B J Alzheimers Dis %V 62 %P 1527-1530 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562509?dopt=Abstract %R 10.3233/JAD-171060 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Histopathology and Florbetaben PET in Patients Incorrectly Diagnosed with Alzheimer's Disease. %A Sabbagh, Marwan N %A Schäuble, Barbara %A Anand, Keshav %A Richards, Danielle %A Murayama, Shigeo %A Akatsu, Hiroyasu %A Takao, Masaki %A Rowe, Christopher C %A Masters, Colin L %A Barthel, Henryk %A Gertz, Hermann-Josef %A Peters, Oliver %A Rasgon, Natalie %A Jovalekic, Aleksandar %A Sabri, Osama %A Schulz-Schaeffer, Walter J %A Seibyl, John %X

Of 57 individuals diagnosed with Alzheimer's disease (AD) in a phase III study, 13 (23%) had amyloid-β (Aβ) levels on postmortem histopathology that did not explain the dementia. Based on postmortem histopathology, a wide range of different non-AD conditions was identified, including frontotemporal dementia, hippocampal sclerosis, and dementia with Lewy bodies. Of the histopathologically Aβ negative scored cases ante-mortem Florbetaben PET scans were classified as negative for Aβ in 11 patients based on visual analysis and in all 12 quantifiable cases based on composite standardized uptake value ratios. Thus, florbetaben PET can assist physicians in the differential diagnosis of neurodegenerative disorders by reliably excluding Aβ pathology.

%B J Alzheimers Dis %V 56 %P 441-446 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27983552?dopt=Abstract %R 10.3233/JAD-160821