David Holtzman on Do Two APOE4 Alleles Always Mean Alzheimer's?

COMMENT studies and comment that: “Findings revealed that almost all APOE4 homozygotes exhibited AD pathology and

David Holtzman on First Whole-Genome Sequencing of PSP Nets Six New Risk Loci

COMMENT This GWA study shows that APOE2 is associated with higher risk and E4 with lower risk for PSP, a 4R tauopathy. That said, I don’t think we can say from this genetic analysis that it means that with PSP, E2 increases and E4 decreases tauopathy. Further bio

David Holtzman on The APOE-R136S mutation protects against APOE4-driven Tau pathology, neurodegeneration and neuroinflammation.

COMMENT In 2019, a rare variant on an APOE3 background (APOE3-R136S), Christchurch mutation, when present in the homozygous state, was found to be associated with a marked delay in cognitive decline in an individual with the PSEN1-E280A mutation that causes autos

Jason Ulrich, David Holtzman on New Therapeutic Strategy—Mimic the ApoE Christchurch Mutation?

COMMENT The identification of rare variants in APOE that appear to protect against Alzheimer’s disease, such as V236E (Jacksonville) and R136S (Christchurch), present an exciting opportunity to better understand the mechanisms by which APOE may influence differen

Xiaoying Chen, David Holtzman on In 3D Cell Model of AD, Microglia and CD8+ T Cells Gang Up on Neurons

COMMENT In this study, the authors developed a three-dimensional human neuroimmune axis model, which includes human stem-cell-derived neurons, astrocytes, and microglia, together with human peripheral immune cells, to model AD pathology and progression. They foun

David Holtzman on Ridding Microglia of a MicroRNA Compacts Amyloid, Protects Synapses

COMMENT I agree that the ablation of miR-155 in microglia promotes their transition into an IFN-γ responsive state in a mouse model of amyloidosis. I also agree that the data show that mIR-155 ablation in microglia leads to the cells being more adept at phagocyto

David Holtzman, Yun Chen, Michael Strickland on Catch and Release: Cryo-EM Reveals How LRP2 Receptor Recycles Cargo

COMMENT In this landmark paper, Andrew Beenken et al. used cryoEM to solve the structure of LRP2, which is part of the LDL-receptor-related family of proteins, at both extracellular and endosomal pH. This family of proteins is able to bind ApoE isoforms, which gr

Yun Chen, David Holtzman on Healthy, Drug-Resistant Microglia Reinvigorate Mouse Brain

COMMENT In this paper, Chadarevian et al. have shown that an intriguing, single-point mutation in human CSF1R, G795A, resists inhibition by PLX3397. They have demonstrated successful transplantation of microglia expressing CSF1R with the G795A mutation both in a

David Holtzman on In AD, CSF Immune Cells Hint at Mounting Mayhem in the Brain

COMMENT In this interesting resource paper by Piehl et al. from the lab of David Gate, the authors assess the CSF immune cell profiles of 45 cognitively normal subjects and 14 cognitively impaired subjects who likely had very mild to mild Alzheimer’s disease. Usi

David Holtzman on Meddling Medin: A Vascular Amyloid That Promotes CAA?

COMMENT I think this is a very nice paper and shows good evidence that medin does influence CAA formation and would be a potential novel target for CAA treatment. The effect of knocking out medin on CAA is not nearly as strong as knocking out ApoE, which, in simi

David Holtzman on Finally: Big Win on All Outcomes for Lecanemab in Phase 3 Topline Results

COMMENT The press release indicating that lecanemab hit its primary and secondary endpoints in slowing cognitive decline in very mild to mild AD is incredibly exciting. This is very encouraging for the field, and it will be very interesting to see the clinical da

David Holtzman, Yang Shi on Sans Microglia, Mice Develop CAA and Die Young

COMMENT Many studies have used CSF1R antagonists to deplete myeloid cells, including microglia in amyloid or tauopathy mouse models, and many have observed protective effects against pathology and neurodegeneration. This is a very interesting and well-done study

David Holtzman on Two ApoE Mutations Decrease Risk for Alzheimer's Disease

COMMENT In this manuscript, Le Guen and colleagues report that two missense variants in APOE were associated with a twofold to threefold decreased AD risk: APOE ε4 (R251G) (odds ratio, 0.44; 95 percent CI, 0.33-0.59; P = 4.7 × 10−8) and APOE ε3 (V236E) (odds rati

David Holtzman on Alzheimer disease neuropathology in a patient previously treated with aducanumab.

COMMENT In this paper, the authors assess the neuropathology of a woman who had received 32 monthly doses of Aducanumab after first being in the placebo arm of the Phase Ib study. Longitudinal amyloid imaging during life revealed that she initially had a very hig

David Holtzman on Tau-PET Imaging Brings Braak Staging to Life

COMMENT Therriault and colleagues assessed biomarkers in 324 individuals who were cognitively normal or had mild cognitive impairment at baseline and longitudinally. They were assessed clinically, cognitively, and for several biomarkers including with amyloid ima