Sex differences in associations between APOE ε2 and longitudinal cognitive decline.

INTRODUCTION: We examined whether sex modifies the association between APOE ε2 and cognitive decline in two independent samples. METHODS: We used observational data from cognitively unimpaired non-Hispanic White (NHW) and non-Hispanic Black (NHB) adults. Linear mixed models examined interactive associations of APOE genotype (ε2 or ε4 carrier vs. ε3/ε3) and sex on cognitive decline in NHW and NHB participants separately. RESULTS: In both Sample 1 (N = 9766) and Sample 2 (N = 915), sex modified the association between APOE ε2 and cognitive decline in NHW participants. Specifically, relative to APOE ε3/ε3, APOE ε2 protected against cognitive decline in men but not women. Among APOE ε2 carriers, men had slower decline than women. Among APOE ε3/ε3 carriers, cognitive trajectories did not differ between sexes. There were no sex-specific associations of APOE ε2 with cognition in NHB participants (N = 2010). DISCUSSION: In NHW adults, APOE ε2 may protect men but not women against cognitive decline. HIGHLIGHTS: We studied sex-specific apolipoprotein E (APOE) ε2 effects on cognitive decline. In non-Hispanic White (NHW) adults, APOE ε2 selectively protects men against decline. Among men, APOE ε2 was more protective than APOE ε3/ε3. In women, APOE ε2 was no more protective than APOE ε3/ε3. Among APOE ε2 carriers, men had slower decline than women. There were no sex-specific APOE ε2 effects in non-Hispanic Black (NHB) adults.

Biofluid markers of blood-brain barrier disruption and neurodegeneration in Lewy body spectrum diseases: A systematic review and meta-analysis.

BACKGROUND: Mixed evidence supports blood-brain barrier (BBB) dysfunction in Lewy body spectrum diseases. METHODS: We compare biofluid markers in people with idiopathic Parkinson's disease (PD) and people with PD dementia (PDD) and/or dementia with Lewy bodies (DLB), compared with healthy controls (HC). Seven databases were searched up to May 10, 2021. Outcomes included cerebrospinal fluid to blood albumin ratio (Qalb), and concentrations of 7 blood protein markers that also reflect BBB disruption and/or neurodegenerative co-pathology. We further explore differences between PD patients with and without evidence of dementia. Random-effects models were used to obtain standardized mean differences (SMD) with 95% confidence interval. RESULTS: Of 13,949 unique records, 51 studies were meta-analyzed. Compared to HC, Qalb was higher in PD (NPD/NHC = 224/563; SMD = 0.960 [0.227-1.694], p = 0.010; I2 = 92.2%) and in PDD/DLB (NPDD/DLB/NHC = 265/670; SMD = 1.126 [0.358-1.893], p < 0.001; I2 = 78.2%). Blood neurofilament light chain (NfL) was higher in PD (NPD/NHC = 1848/1130; SMD = 0.747 [0.442-1.052], p < 0.001; I2 = 91.9%) and PDD/DLB (NPDD/DLB/NHC = 183/469; SMD = 1.051 [0.678-1.423], p = 0.004; I2 = 92.7%) than in HC. p-tau 181 (NPD/NHC = 276/164; SMD = 0.698 [0.149-1.247], p = 0.013; I2 = 82.7%) was also higher in PD compared to HC. In exploratory analyses, blood NfL was higher in PD without dementia (NPDND/NHC = 1005/740; SMD = 0.252 [0.042-0.462], p = 0.018; I2 = 71.8%) and higher in PDD (NPDD/NHC = 100/111; SMD = 0.780 [0.347-1.214], p < 0.001; I2 = 46.7%) compared to HC. Qalb (NPDD/NPDND = 63/191; SMD = 0.482 [0.189-0.774], p = 0.010; I2<0.001%) and NfL (NPDD/NPDND = 100/223; SMD = 0.595 [0.346-0.844], p < 0.001; I2 = 3.4%) were higher in PDD than in PD without dementia. CONCLUSIONS: Biofluid markers suggest BBB disruption and neurodegenerative co-pathology involvement in common Lewy body diseases. Greater evidence of BBB breakdown was seen in Lewy body disease with cognitive impairment.

Relationships between memory decline and the use of metformin or DPP4 inhibitors in people with type 2 diabetes with normal cognition or Alzheimer's disease, and the role APOE carrier status.

INTRODUCTION: Few studies have examined memory decline among patients with type 2 diabetes using different oral hypoglycemic drugs. METHODS: Participants with normal cognition (NC) or Alzheimer's disease (AD) dementia using a hypoglycemic medication (2005 to 2019) were identified from the National Alzheimer's Coordinating Center database. Delayed memory was assessed using the Wechsler Memory Scale Revised-Logical Memory test. Associations between oral drug classes and memory over time were examined using mixed-effects models with inverse probability treatment weights. RESULTS: In NC (n = 1192), metformin use was associated with better memory performance over time, whereas in AD (n = 807), dipeptidyl peptidase-4 (DPP4) inhibitor use was associated with a slower rate of memory decline. Interaction effects suggested greater benefit associated with DPP4 inhibitor use among APOE ε4 carriers. DISCUSSION: Associations between different oral hypoglycemic drugs and memory change were not consistent between cognitively normal elderly and those with AD dementia. APOE ε4 genotype modified some relationships.

Early Metazoan Origin and Multiple Losses of a Novel Clade of RIM Presynaptic Calcium Channel Scaffolding Protein Homologs.

The precise localization of CaV2 voltage-gated calcium channels at the synapse active zone requires various interacting proteins, of which, Rab3-interacting molecule or RIM is considered particularly important. In vertebrates, RIM interacts with CaV2 channels in vitro via a PDZ domain that binds to the extreme C-termini of the channels at acidic ligand motifs of D/E-D/E/H-WC-COOH, and knockout of RIM in vertebrates and invertebrates disrupts CaV2 channel synaptic localization and synapse function. Here, we describe a previously uncharacterized clade of RIM proteins bearing domain architectures homologous to those of known RIM homologs, but with some notable differences including key amino acids associated with PDZ domain ligand specificity. This novel RIM emerged near the stem lineage of metazoans and underwent extensive losses, but is retained in select animals including the early-diverging placozoan Trichoplax adhaerens, and molluscs. RNA expression and localization studies in Trichoplax and the mollusc snail Lymnaea stagnalis indicate differential regional/tissue type expression, but overlapping expression in single isolated neurons from Lymnaea. Ctenophores, the most early-diverging animals with synapses, are unique among animals with nervous systems in that they lack the canonical RIM, bearing only the newly identified homolog. Through phylogenetic analysis, we find that CaV2 channel D/E-D/E/H-WC-COOH like PDZ ligand motifs were present in the common ancestor of cnidarians and bilaterians, and delineate some deeply conserved C-terminal structures that distinguish CaV1 from CaV2 channels, and CaV1/CaV2 from CaV3 channels.

Comparison of transcriptomes from two chemosensory organs in four decapod crustaceans reveals hundreds of candidate chemoreceptor proteins.

Crustaceans express genes for at least three classes of putative chemosensory proteins. These are: Ionotropic Receptors (IRs), derived from the heterotetrameric ionotropic glutamate receptors (iGluRs); Transient Receptor Potential (TRP) channels, a diverse set of sensor-channels that include several families of chemoreceptor channels; and Gustatory Receptor Like receptors (GRLs), ionotropic receptors that are homologues of Gustatory Receptors (GRs) of insects and are expressed sparingly in most crustaceans so far studied. IRs are typically numerically the most dominant of these receptor proteins in crustaceans and include two classes: co-receptor IRs, which are necessary for making a functional receptor-channel; and tuning IRs, whose specific combination in the IR subunits in the heterotetramer confers chemical specificity. Previous work showed that the transcriptomes from two major chemosensory organs-the lateral flagellum of the antennule (LF) and the tips of the legs (dactyls)-of the Caribbean spiny lobster Panulirus argus express four co-receptor IRs and over 100 tuning IRs. In this paper, we examined and compared the transcriptomes from the LF and dactyls of P. argus and three other decapod crustaceans-the clawed lobster Homarus americanus, red swamp crayfish Procambarus clarkii, and the blue crab Callinectes sapidus. Each species has at least ca. 100 to 250 IRs, 1 to 4 GRLs, and ca. 15 TRP channels including those shown to be involved in chemoreception in other species. The IRs show different degrees of phylogenetic conservation: some are arthropod-conserved, others are pancrustacean-conserved, others appear to be crustacean-conserved, and some appear to be species-specific. Many IRs appear to be more highly expressed in the LF than dactyl. Our results show that decapod crustaceans express an abundance of genes for chemoreceptor proteins of different types, phylogenetic conservation, and expression patterns. An understanding of their functional roles awaits determining their expression patterns in individual chemosensory neurons and the central projections of those neurons.

Evolutionary insights into T-type Ca2+ channel structure, function, and ion selectivity from the Trichoplax adhaerens homologue.

Four-domain voltage-gated Ca2+ (Cav) channels play fundamental roles in the nervous system, but little is known about when or how their unique properties and cellular roles evolved. Of the three types of metazoan Cav channels, Cav1 (L-type), Cav2 (P/Q-, N- and R-type) and Cav3 (T-type), Cav3 channels are optimized for regulating cellular excitability because of their fast kinetics and low activation voltages. These same properties permit Cav3 channels to drive low-threshold exocytosis in select neurons and neurosecretory cells. Here, we characterize the single T-type calcium channel from Trichoplax adhaerens (TCav3), an early diverging animal that lacks muscle, neurons, and synapses. Co-immunolocalization using antibodies against TCav3 and neurosecretory cell marker complexin labeled gland cells, which are hypothesized to play roles in paracrine signaling. Cloning and in vitro expression of TCav3 reveals that, despite roughly 600 million years of divergence from other T-type channels, it bears the defining structural and biophysical features of the Cav3 family. We also characterize the channel's cation permeation properties and find that its pore is less selective for Ca2+ over Na+ compared with the human homologue Cav3.1, yet it exhibits a similar potent block of inward Na+ current by low external Ca2+ concentrations (i.e., the Ca2+ block effect). A comparison of the permeability features of TCav3 with other cloned channels suggests that Ca2+ block is a locus of evolutionary change in T-type channel cation permeation properties and that mammalian channels distinguish themselves from invertebrate ones by bearing both stronger Ca2+ block and higher Ca2+ selectivity. TCav3 is the most divergent metazoan T-type calcium channel and thus provides an evolutionary perspective on Cav3 channel structure-function properties, ion selectivity, and cellular physiology.