Association of African Ancestry-Specific APOE Missense Variant R145C With Risk of Alzheimer Disease.

Importance: Numerous studies have established the association of the common APOE ε2 and APOE ε4 alleles with Alzheimer disease (AD) risk across ancestries. Studies of the interaction of these alleles with other amino acid changes on APOE in non-European ancestries are lacking and may improve ancestry-specific risk prediction. Objective: To determine whether APOE amino acid changes specific to individuals of African ancestry modulate AD risk. Design, Setting, and Participants: Case-control study including 31 929 participants and using a sequenced discovery sample (Alzheimer Disease Sequencing Project; stage 1) followed by 2 microarray imputed data sets derived from the Alzheimer Disease Genetic Consortium (stage 2, internal replication) and the Million Veteran Program (stage 3, external validation). This study combined case-control, family-based, population-based, and longitudinal AD cohorts, which recruited participants (1991-2022) in primarily US-based studies with 1 US/Nigerian study. Across all stages, individuals included in this study were of African ancestry. Exposures: Two APOE missense variants (R145C and R150H) were assessed, stratified by APOE genotype. Main Outcomes and Measures: The primary outcome was AD case-control status, and secondary outcomes included age at AD onset. Results: Stage 1 included 2888 cases (median age, 77 [IQR, 71-83] years; 31.3% male) and 4957 controls (median age, 77 [IQR, 71-83] years; 28.0% male). In stage 2, across multiple cohorts, 1201 cases (median age, 75 [IQR, 69-81] years; 30.8% male) and 2744 controls (median age, 80 [IQR, 75-84] years; 31.4% male) were included. In stage 3, 733 cases (median age, 79.4 [IQR, 73.8-86.5] years; 97.0% male) and 19 406 controls (median age, 71.9 [IQR, 68.4-75.8] years; 94.5% male) were included. In ε3/ε4-stratified analyses of stage 1, R145C was present in 52 individuals with AD (4.8%) and 19 controls (1.5%); R145C was associated with an increased risk of AD (odds ratio [OR], 3.01; 95% CI, 1.87-4.85; P = 6.0 × 10-6) and was associated with a reported younger age at AD onset (ß, -5.87 years; 95% CI, -8.35 to -3.4 years; P = 3.4 × 10-6). Association with increased AD risk was replicated in stage 2 (R145C was present in 23 individuals with AD [4.7%] and 21 controls [2.7%]; OR, 2.20; 95% CI, 1.04-4.65; P = .04) and was concordant in stage 3 (R145C was present in 11 individuals with AD [3.8%] and 149 controls [2.7%]; OR, 1.90; 95% CI, 0.99-3.64; P = .051). Association with earlier AD onset was replicated in stage 2 (ß, -5.23 years; 95% CI, -9.58 to -0.87 years; P = .02) and stage 3 (ß, -10.15 years; 95% CI, -15.66 to -4.64 years; P = 4.0 × 10-4). No significant associations were observed in other APOE strata for R145C or in any APOE strata for R150H. Conclusions and Relevance: In this exploratory analysis, the APOE ε3[R145C] missense variant was associated with an increased risk of AD among individuals of African ancestry with the ε3/ε4 genotype. With additional external validation, these findings may inform AD genetic risk assessment in individuals of African ancestry.

Common X-Chromosome Variants Are Associated with Parkinson Disease Risk.

OBJECTIVE: The objective of this study was to identify genetic variants on the X-chromosome associated with Parkinson disease (PD) risk. METHODS: We performed an X-chromosome-wide association study (XWAS) of PD risk by meta-analyzing results from sex-stratified analyses. To avoid spurious associations, we designed a specific harmonization pipeline for the X-chromosome and focused on a European ancestry sample. We included 11,142 cases, 280,164 controls, and 5,379 proxy cases, based on parental history of PD. Additionally, we tested the association of significant variants with (1) PD risk in an independent replication with 1,561 cases and 2,465 controls and (2) putamen volume in 33,360 individuals from the UK Biobank. RESULTS: In the discovery meta-analysis, we identified rs7066890 (odds ratio [OR] = 1.10, 95% confidence interval [CI] = 1.06-1.14, p = 2.2 × 10-9 ), intron of GPM6B, and rs28602900 (OR = 1.10, 95% CI = 1.07-1.14, p = 1.6 × 10-8 ) in a high gene density region including RPL10, ATP6A1, FAM50A, and PLXNA3. The rs28602900 association with PD was replicated (OR = 1.16, 95% CI = 1.03-1.30, p = 0.016) and shown to colocalize with a significant expression quantitative locus (eQTL) regulating RPL10 expression in the putamen and other brain tissues in the Genotype-Tissue Expression Project. Additionally, the rs28602900 locus was found to be associated with reduced brain putamen volume. No results reached genome-wide significance in the sex-stratified analyses. INTERPRETATION: We report the first XWAS of PD and identify 2 genome-wide significant loci. The rs28602900 association was replicated in an independent PD dataset and showed concordant effects in its association with putamen volume. Critically, rs26802900 is a significant eQTL of RPL10. These results support a role for ribosomal proteins in PD pathogenesis and show that the X-chromosome contributes to PD genetic risk. ANN NEUROL 2021;90:22-34.

True ultra-low-dose amyloid PET/MRI enhanced with deep learning for clinical interpretation.

PURPOSE: While sampled or short-frame realizations have shown the potential power of deep learning to reduce radiation dose for PET images, evidence in true injected ultra-low-dose cases is lacking. Therefore, we evaluated deep learning enhancement using a significantly reduced injected radiotracer protocol for amyloid PET/MRI. METHODS: Eighteen participants underwent two separate 18F-florbetaben PET/MRI studies in which an ultra-low-dose (6.64 ± 3.57 MBq, 2.2 ± 1.3% of standard) or a standard-dose (300 ± 14 MBq) was injected. The PET counts from the standard-dose list-mode data were also undersampled to approximate an ultra-low-dose session. A pre-trained convolutional neural network was fine-tuned using MR images and either the injected or sampled ultra-low-dose PET as inputs. Image quality of the enhanced images was evaluated using three metrics (peak signal-to-noise ratio, structural similarity, and root mean square error), as well as the coefficient of variation (CV) for regional standard uptake value ratios (SUVRs). Mean cerebral uptake was correlated across image types to assess the validity of the sampled realizations. To judge clinical performance, four trained readers scored image quality on a five-point scale (using 15% non-inferiority limits for proportion of studies rated 3 or better) and classified cases into amyloid-positive and negative studies. RESULTS: The deep learning-enhanced PET images showed marked improvement on all quality metrics compared with the low-dose images as well as having generally similar regional CVs as the standard-dose. All enhanced images were non-inferior to their standard-dose counterparts. Accuracy for amyloid status was high (97.2% and 91.7% for images enhanced from injected and sampled ultra-low-dose data, respectively) which was similar to intra-reader reproducibility of standard-dose images (98.6%). CONCLUSION: Deep learning methods can synthesize diagnostic-quality PET images from ultra-low injected dose simultaneous PET/MRI data, demonstrating the general validity of sampled realizations and the potential to reduce dose significantly for amyloid imaging.

APOE effects on regional tau in preclinical Alzheimer's disease.

BACKGROUND: APOE variants are strongly associated with abnormal amyloid aggregation and additional direct effects of APOE on tau aggregation are reported in animal and human cell models. The degree to which these effects are present in humans when individuals are clinically unimpaired (CU) but have abnormal amyloid (Aß+) remains unclear. METHODS: We analyzed data from CU individuals in the Anti-Amyloid Treatment in Asymptomatic AD (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies. Amyloid PET data were available for 4486 participants (3163 Aß-, 1323 Aß+) and tau PET data were available for a subset of 447 participants (55 Aß-, 392 Aß+). Linear models examined APOE (number of e2 and e4 alleles) associations with global amyloid and regional tau burden in medial temporal lobe (entorhinal, amygdala) and early neocortical regions (inferior temporal, inferior parietal, precuneus). Consistency of APOE4 effects on regional tau were examined in 220 Aß + CU and mild cognitive impairment (MCI) participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). RESULTS: APOE2 and APOE4 were associated with lower and higher amyloid positivity rates, respectively. Among Aß+ CU, e2 and e4 were associated with reduced (-12 centiloids per allele) and greater (+15 centiloids per allele) continuous amyloid burden, respectively. APOE2 was associated with reduced regional tau in all regions (-0.05 to -0.09 SUVR per allele), whereas APOE4 was associated with greater regional tau (+0.02 to +0.07 SUVR per allele). APOE differences were confirmed by contrasting e3/e3 with e2/e3 and e3/e4. Mediation analyses among Aß+ s showed that direct effects of e2 on regional tau were present in medial temporal lobe and early neocortical regions, beyond an indirect pathway mediated by continuous amyloid burden. For e4, direct effects on regional tau were only significant in medial temporal lobe. The magnitude of protective e2 effects on regional tau was consistent across brain regions, whereas detrimental e4 effects were greatest in medial temporal lobe. APOE4 patterns were confirmed in Aß+ ADNI participants. CONCLUSIONS: APOE influences early regional tau PET burden, above and beyond effects related to cross-sectional amyloid PET burden. Therapeutic strategies targeting underlying mechanisms related to APOE may modify tau accumulation among Aß+ individuals.

Confirming Pathogenicity of the F386L PSEN1 Variant in a South Asian Family With Early-Onset Alzheimer Disease.

OBJECTIVES: The F386L PSEN1 variant has been reported in 1 Japanese family with limited clinical information. We aimed to prove that F386L is pathogenic by demonstrating that it segregates with early-onset Alzheimer disease (AD). METHODS: Eight individuals in a South Asian family provided DNA for genetic testing and underwent a neurologic examination. RESULTS: The female proband was diagnosed with AD at age 45 years and died at age 49 years. She had a CSF biomarker profile consistent with AD, and her florbetaben PET scan was amyloid positive with high uptake in the striatum. Her MRI showed no prominent white matter disease. Her affected relatives had an age at onset range of 38-57 years and had imaging and biomarker profiles similar to hers. DISCUSSION: The results presented here, in conjunction with the prior report, confirm the pathogenicity of F386L. Furthermore, our study highlights the importance of studying families from underrepresented populations to identify or confirm the pathogenicity of rare variants that may be specific to certain genetic ancestries.

Performance of a fully-automated Lumipulse plasma phospho-tau181 assay for Alzheimer's disease.

BACKGROUND: The recent promise of disease-modifying therapies for Alzheimer's disease (AD) has reinforced the need for accurate biomarkers for early disease detection, diagnosis and treatment monitoring. Advances in the development of novel blood-based biomarkers for AD have revealed that plasma levels of tau phosphorylated at various residues are specific and sensitive to AD dementia. However, the currently available tests have shortcomings in access, throughput, and scalability that limit widespread implementation. METHODS: We evaluated the diagnostic and prognostic performance of a high-throughput and fully-automated Lumipulse plasma p-tau181 assay for the detection of AD. Plasma from older clinically unimpaired individuals (CU, n = 463) and patients with mild cognitive impairment (MCI, n = 107) or AD dementia (n = 78) were obtained from the longitudinal Stanford University Alzheimer's Disease Research Center (ADRC) and the Stanford Aging and Memory Study (SAMS) cohorts. We evaluated the discriminative accuracy of plasma p-tau181 for clinical AD diagnosis, association with amyloid ß peptides and p-tau181 concentrations in CSF, association with amyloid positron emission tomography (PET), and ability to predict longitudinal cognitive and functional change. RESULTS: The assay showed robust performance in differentiating AD from control participants (AUC 0.959, CI: 0.912 to 0.990), and was strongly associated with CSF p-tau181, CSF Aß42/Aß40 ratio, and amyloid-PET global SUVRs. Associations between plasma p-tau181 with CSF biomarkers were significant when examined separately in Aß+ and Aß- groups. Plasma p-tau181 significantly increased over time in CU and AD diagnostic groups. After controlling for clinical diagnosis, age, sex, and education, baseline plasma p-tau181 predicted change in MoCA overall and change in CDR Sum of Boxes in the AD group over follow-up of up to 5 years. CONCLUSIONS: This fully-automated and available blood-based biomarker assay therefore may be useful for early detection, diagnosis, prognosis, and treatment monitoring of AD.

A novel age-informed approach for genetic association analysis in Alzheimer's disease.

BACKGROUND: Many Alzheimer's disease (AD) genetic association studies disregard age or incorrectly account for it, hampering variant discovery. METHODS: Using simulated data, we compared the statistical power of several models: logistic regression on AD diagnosis adjusted and not adjusted for age; linear regression on a score integrating case-control status and age; and multivariate Cox regression on age-at-onset. We applied these models to real exome-wide data of 11,127 sequenced individuals (54% cases) and replicated suggestive associations in 21,631 genotype-imputed individuals (51% cases). RESULTS: Modeling variable AD risk across age results in 5-10% statistical power gain compared to logistic regression without age adjustment, while incorrect age adjustment leads to critical power loss. Applying our novel AD-age score and/or Cox regression, we discovered and replicated novel variants associated with AD on KIF21B, USH2A, RAB10, RIN3, and TAOK2 genes. CONCLUSION: Our AD-age score provides a simple means for statistical power gain and is recommended for future AD studies.

Association of Short and Long Sleep Duration With Amyloid-ß Burden and Cognition in Aging.

Importance: Disrupted sleep is common in aging and is associated with cognition. Age-related changes to sleep are associated with multiple causes, including early Alzheimer disease pathology (amyloid ß [Aß]), depression, and cardiovascular disease. Objective: To investigate the associations between self-reported sleep duration and brain Aß burden as well as the demographic, cognitive, and lifestyle variables in adults with normal cognition. Design, Setting, and Participants: This cross-sectional study obtained data from participants in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study, which is being conducted in 67 sites in the United States, Canada, Australia, and Japan. The sample for this analysis consisted of individuals aged 65 to 85 years who underwent an Aß positron emission tomography (PET) scan, had complete apolipoprotein E (APOE) genotype data, and were identified as clinically normal (per a Clinical Dementia Rating score of 0) and cognitively unimpaired (per a Mini-Mental State Examination score of 25 to 30 and Logical Memory Delayed Recall test score of 6 to 18). Data were analyzed from April 3, 2020, to June 20, 2021. Main Outcomes and Measures: The outcome was self-reported nightly sleep duration (grouped by short sleep duration: ≤6 hours, normal sleep duration: 7-8 hours, and long sleep duration: ≥9 hours) compared with demographic characteristics, Aß burden (as measured with a fluorine 18-labeled-florbetapir PET scan), objective and subjective cognitive function measures, and lifestyle variables. Results: The 4417 participants in the study included 2618 women (59%) and had a mean (SD) age of 71.3 (4.7) years. Self-reported shorter sleep duration was linearly associated with higher Aß burden (ß [SE] = -0.01 [0.00]; P = .005), and short sleep duration was associated with reduced cognition that was mostly in memory domains. No difference in Aß was found between long and normal sleep duration groups (ß [SE] = 0.00 [0.01]; P = .99). However, compared with normal sleep duration, both short and long sleep durations were associated with higher body mass index (short vs normal sleep duration: ß [SE] = 0.48 [0.17], P = .01; long vs normal sleep duration: ß [SE] = 0.97 [0.31], P = .002), depressive symptoms (short vs normal sleep duration: ß [SE] = 0.31 [0.05], P < .001; long vs normal sleep duration: ß [SE] = 0.39 [0.09], P < .001), and daytime napping (short vs normal sleep duration: ß [SE] = 2.66 [0.77], P = .001; long vs normal sleep duration: ß [SE] = 3.62 [1.38], P = .01). Long sleep duration was associated with worse performance across multiple cognitive domains. Conclusions and Relevance: In this cross-sectional study, both short and long sleep durations were associated with worse outcomes for older adults, such as greater Aß burden, greater depressive symptoms, higher body mass index, and cognitive decline, emphasizing the importance of maintaining adequate sleep.