Increasing evidence supports a role of vascular risk factors and markers in the development and etiology of Alzheimer disease (AD). Most major vascular risk factors, including hypertension,^1-4 diabetes,⁵ smoking,^3,6 and hypercholesterolemia,^4,7 particularly when measured in midlife, have been associated with risk of dementia generally and AD specifically. Whether these risk factors directly increase the neurodegeneration specifically associated with AD (such as through increasing amyloid deposition) or lead to other cerebral changes that, in conjunction with ongoing neurodegeneration, might worsen cognitive performance is not yet known.

Dopamine D₂ receptor occupancy (D₂RO) is a key feature of all currently approved antipsychotic medications. However, antipsychotic efficacy associated with high D₂RO is often limited by side effects such as motor disturbances and hyperprolactinemia. Lumateperone (ITI-007) is a first-in-class selective and simultaneous modulator of serotonin, dopamine and glutamate in development for the treatment of schizophrenia and other disorders. The primary objective of the present study was to determine D₂RO at plasma steady state of 60 mg ITI-007, a dose that previously demonstrated antipsychotic efficacy in a controlled trial, administered orally open-label once daily in the morning for two weeks in patients with schizophrenia (N = 10) and after at least a two-week washout period from standard of care antipsychotics. D₂RO was determined using positron emission tomography with ¹¹C-raclopride as the radiotracer. Mean peak dorsal striatal D₂RO was 39% at 60 mg ITI-007 occurring 1 h post-dose. Lumateperone was well-tolerated with a favorable safety profile in this study. There were no clinically significant changes in vital signs, ECGs, or clinical chemistry laboratory values, including prolactin levels. There were no adverse event reports of akathisia or other extrapyramidal motor side effects; mean scores on motor function scales indicated no motor disturbances with lumateperone treatment. This level of occupancy is lower than most other antipsychotic drugs at their efficacious doses and likely contributes to the favorable safety and tolerability profile of lumateperone with reduced risk for movement disorders and hyperprolactinemia. If approved, lumateperone may provide a new and safe treatment option for individuals living with schizophrenia.

The strongest genetic risk factor for Alzheimer's disease (AD) is the Apolipoprotein E type 4 allele (ApoE ε4). The interaction between sex and ApoE ε4 carrier status on AD risk remains an area of intense investigation. We hypothesized that sex modulates the relationship between ApoE ε4 carrier status and brain tau deposition (a quantitative endophenotype in AD) in individuals with mild cognitive impairment (MCI). Methods: Preprocessed 18F-AV-1451 tau and 18F-AV-45 amyloid PET images, T1-weighted structural magnetic resonance imaging (MRI) scans, demographic information, and cerebrospinal fluid (CSF) total tau (t-tau) and phosphorylated tau (p-tau) measurements from 108 MCI subjects in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database were included. After downloading pre-processed images from ADNI, an iterative reblurred Van Cittertiteration partial volume correction (PVC) method was applied to all PET images. MRIs were used for PET spatial normalization. Regions of interest (ROIs) were defined in standard space, and standardized uptake value ratio (SUVR) images relative to cerebellum were computed. ApoE ε4 by sex interaction analyses on 18F-AV-1451 and CSF tau (t-tau, p-tau) were assessed using generalized linear models. The association between 18F-AV-1451 SUVR and CSF tau (t-tau, p-tau) was assessed. Results: After applying PVC and controlling for age, education level and global cortical 18F-AV-45 SUVR, we found that the entorhinal cortex, amygdala, parahippocampal gyrus, posterior cingulate, and occipital ROIs exhibited a significant ApoE ε4 by sex interaction effect (false discovery rate P < 0.1) among MCI individuals. We also found a significant ApoE ε4 by sex interaction effect on CSF t-tau and p-tau. 18F-AV-1451 SUVR in the 5 ROIs with ApoE ε4 by sex interaction was significantly correlated with CSF p-tau and t-tau. Conclusions: Our findings suggest that women are more susceptible to ApoE ε4-associated accumulation of neurofibrillary tangles in MCI compared to males. Both CSF tau (p-tau, t-tau) and brain tau PET are robust quantitative biomarkers for studying ApoE ε4 by sex effects on brain tau deposition in MCI participants.

Recent studies in cognitively unimpaired elderly individuals suggest that the APOE ε4 allele exerts a dosage-dependent effect on brain tau deposition. The aim of this study was to investigate sex differences in APOE ε4 gene dosage effects on brain tau deposition in cognitively impaired individuals using quantitative ¹⁸F-flortaucipir PET. Preprocessed ¹⁸F-flortaucipir tau PET images, T₁-weighted structural MRI, demographic information, global cortical amyloid-β burden measured by ¹⁸F-florbetapir PET, CSF total tau and phosphorylated tau measurements were obtained from the Alzheimer’s Disease Neuroimaging Initiative database. Two hundred and sixty-eight cognitively impaired individuals with 146 APOE ε4 non-carriers and 122 carriers (85 heterozygotes and 37 homozygotes) were included in the study. An iterative reblurred Van Cittert iteration partial volume correction method was applied to all downloaded PET images. Magnetic resonance images were used for PET spatial normalization. Twelve regional standardized uptake value ratios relative to the cerebellum were computed in standard space. APOE ε4 dosage × sex interaction effect on ¹⁸F-flortaucipir standardized uptake value ratios was assessed using generalized linear models and sex-stratified analysis. We observed a significant APOE ε4 dosage × sex interaction effect on tau deposition in the lateral temporal, posterior cingulate, medial temporal, inferior temporal, entorhinal cortex, amygdala, parahippocampal gyrus regions after adjusting for age and education level (P < 0.05). The medial temporal, entorhinal cortex, amygdala and parahippocampal gyrus regions retained a significant APOE ε4 dosage × sex interaction effect on tau deposition after adjusting for global cortical amyloid-β (P < 0.05). In sex-stratified analysis, there was no significant difference in tau deposition between female homozygotes and heterozygotes (P > 0.05). In contrast, male homozygotes standardized uptake value ratios were significantly greater than heterozygotes or non-carriers throughout all 12 regions of interest (P < 0.05). Female heterozygotes exhibited significantly increased tau deposition compared to male heterozygotes in the orbitofrontal, posterior cingulate, lateral temporal, inferior temporal, entorhinal cortex, amygdala and parahippocampal gyrus (P < 0.05). Results from voxel-wise analysis were similar to the ones obtained from regions of interest analysis. Our findings indicate that an APOE ε4 dosage effect on brain region-specific tau deposition exists in males, but not females. These results have important clinical implications towards developing sex and genotype-guided therapeutics in Alzheimer’s disease and uncovers a potential explanation underlying differential APOE ε4-associated Alzheimer’s risk in males and females.