Day, Gregory S.

Abstract We present a comprehensive global analysis of genetic variants associated with autosomal-dominant Alzheimer’s disease (ADAD). A total of 550 variants in the APP, PSEN1 and PSEN2 genes were identified, of which 279 were classified as pathogenic or likely pathogenic based on American College of Medical Genetics and Genomics and the Association for Molecular Pathology criteria, utilizing data from the Dominantly Inherited Alzheimer Network (DIAN), literature and public databases. Symptomatic age at onset (AAO) data were estimated for 227 of these variants, allowing detailed characterization of their frequency, pathogenicity and AAO. Importantly, 226 variants met eligibility criteria for inclusion in disease-modifying clinical trials. Furthermore, we demonstrated the predictive value of mean variant AAO and parental AAO in predicting symptomatic AAO, validated against converters who became symptomatic during follow-up in the DIAN Observational Study. This dataset provides critical insights into the global landscape of ADAD and reveals the genetic and AAO heterogeneity of ADAD variants while refining variant trial eligibility criteria.

Importance Depressive symptoms are associated with cognitive decline in older individuals. Uncertainty about underlying mechanisms hampers diagnostic and therapeutic efforts. This large-scale study aimed to elucidate the association between depressive symptoms and amyloid pathology. Objective To examine the association between depressive symptoms and amyloid pathology and its dependency on age, sex, education, and APOE genotype in older individuals without dementia. Design, Setting, and Participants Cross-sectional analyses were performed using data from the Amyloid Biomarker Study data pooling initiative. Data from 49 research, population-based, and memory clinic studies were pooled and harmonized. The Amyloid Biomarker Study has been collecting data since 2012 and data collection is ongoing. At the time of analysis, 95 centers were included in the Amyloid Biomarker Study. The study included 9746 individuals with normal cognition (NC) and 3023 participants with mild cognitive impairment (MCI) aged between 34 and 100 years for whom data on amyloid biomarkers, presence of depressive symptoms, and age were available. Data were analyzed from December 2022 to February 2024. Main Outcomes and Measures Amyloid-β1-42 levels in cerebrospinal fluid or amyloid positron emission tomography scans were used to determine presence or absence of amyloid pathology. Presence of depressive symptoms was determined on the basis of validated depression rating scale scores, evidence of a current clinical diagnosis of depression, or self-reported depressive symptoms. Results In individuals with NC (mean [SD] age, 68.6 [8.9] years; 5664 [58.2%] female; 3002 [34.0%] APOE ε4 carriers; 937 [9.6%] had depressive symptoms; 2648 [27.2%] had amyloid pathology), the presence of depressive symptoms was not associated with amyloid pathology (odds ratio [OR], 1.13; 95% CI, 0.90-1.40; P = .29). In individuals with MCI (mean [SD] age, 70.2 [8.7] years; 1481 [49.0%] female; 1046 [44.8%] APOE ε4 carriers; 824 [27.3%] had depressive symptoms; 1668 [55.8%] had amyloid pathology), the presence of depressive symptoms was associated with a lower likelihood of amyloid pathology (OR, 0.73; 95% CI 0.61-0.89; P = .001). When considering subgroup effects, in individuals with NC, the presence of depressive symptoms was associated with a higher frequency of amyloid pathology in APOE ε4 noncarriers (mean difference, 5.0%; 95% CI 1.0-9.0; P = .02) but not in APOE ε4 carriers. This was not the case in individuals with MCI. Conclusions and Relevance Depressive symptoms were not consistently associated with a higher frequency of amyloid pathology in participants with NC and were associated with a lower likelihood of amyloid pathology in participants with MCI. These findings were not influenced by age, sex, or education level. Mechanisms other than amyloid accumulation may commonly underlie depressive symptoms in late life.

Importance Although 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) is a well-established cross-sectional biomarker of brain metabolism in dementia with Lewy bodies (DLB), the longitudinal change in FDG-PET has not been characterized. Objective To investigate longitudinal FDG-PET in prodromal DLB and DLB, including a subsample with autopsy data, and report estimated sample sizes for a hypothetical clinical trial in DLB. Design, Setting, and Participants Longitudinal case-control study with mean (SD) follow-up of 3.8 (2.3) years. Cases were recruited consecutively between 2007 and 2022 at a referral center and among the population. Patients with probable DLB or mild cognitive impairment with Lewy bodies (MCI-LB) were included. Individuals without cognitive impairment were included from a population-based cohort balanced on age and sex for comparison. All participants completed at least 1 follow-up assessment by design. Exposure Patients with MCI-LB and DLB. Main Outcomes and Measures Rate of change in FDG-PET was assessed as standardized uptake value ratios (SUVr). Clinical progression was assessed with the Clinical Dementia Rating Sum of Boxes (CDR-SB) score. Results Thirty-five patients with probable DLB, 37 patients with MCI-LB, and 100 individuals without cognitive impairment were included. The mean (SD) age of the DLB and MCI-LB groups combined (n = 72) was 69.6 (8.2) years; 66 patients (92%) were men and 6 (8%) were women. At follow-up, 18 participants (49%) with MCI-LB had progressed to probable DLB. Patients with MCI-LB had a faster decline in FDG-SUVr, compared with that of participants without cognitive impairment, in the posterior cingulate, occipital, parietal, temporal, and lateral frontal cortices. The same regions showed greater metabolic decline in patients with DLB than in participants without cognitive impairment, with the addition of anterior-middle cingulate, insula, and medial frontal orbital cortices. Rates of change in FDG-PET in these brain regions were combined into a region of interest (ROI) labeled longitudinal FDG-PET LB meta-ROI. The rate of change in FDG-SUVr in the meta-ROI correlated with the rate of change in CDR-SB, and sample size estimates were reported for potential clinical trials in DLB. Findings were confirmed in the subsample with neuropathologic confirmation (n = 20). Conclusions and Relevance This study found that brain hypometabolism begins to evolve during the prodromal stages of DLB with changes paralleling symptomatic progression. These data may inform clinical practice and trials planning to use FDG-PET for biologic staging, monitoring disease progression, and potentially assessing treatment response.

AbstractBackgroundSAAs represent a promising biomarker of Lewy Body disease (LBD), with high sensitivity (87.3%, 95%CI: 0.755‐0.947) and specificity (97.2%, 95%CI: 0.922‐0.994) for detection of patients in the Parkinson’s Progression Markers Initiative repository with positive DaT SPECT; and reasonable sensitivity (78.7%, 95%CI: 0.66‐0.88) and specificity (89.5%, 95%CI: 0.78‐0.96 referencing clinical diagnoses in participants included within national research repositories. However, test performance in heterogeneous clinical cohorts is unknown.MethodPatients with typical (n=122) and rapid progressive dementia (n=76) consented to banking of CSF at the time of clinically‐indicated diagnostic lumbar puncture. Clinical data were deidentified and uploaded to a secure research database and clinical (etiologic) diagnoses established by two neurologists following independent review of available records. SAA (SYNTap™) were run on stored CSF by Amprion Diagnostics (San Diego, CA).ResultMedian participant age was 69.1 years (18.4‐86.1); 56.3% were female. CSF was sampled median 1.4 years (0‐10.3) after symptom onset. Pathological alpha‐synuclein was detected in 28/122 patients with typically progressive dementia (including 6/18 patients with presumed LBD; sensitivity 33%, specificity 79%) and 11/76 patients with rapid progressive dementia (including 3/9 patients with presumed LBD; sensitivity 33%, specificity 88%). “Positive” SAA was associated with tremor (OR=3.2, 95%CI: 1.3‐7.8), visual hallucinations (OR=6.14, 95%CI 1.6‐23.6), and REM behavior disorder (OR=3.7, 95%CI: 1.4‐9.5) in patients with typical but not rapid progressive dementia. Brain autopsies were completed in 17 patients: Lewy bodies were detected in 2/3 patients with positive SAA and no patients with negative SAA.Conclusion“Positive” SAA demonstrated reasonable specificity but low sensitivity for the diagnosis of LBD. Additional studies in heterogeneous cohorts with neuropathologic data are needed to optimize clinical applications of SAA.

AbstractBackgroundThere is a strong link between tau and progression of Alzheimer’s disease (AD), necessitating an understanding of tau spreading mechanisms. Prior research, predominantly in typical AD, suggested that tau propagates from epicenters (regions with earliest tau) to functionally connected regions. However, given the constrained spatial heterogeneity of tau in typical AD, validating this connectivity‐based tau spreading model in AD variants with distinct tau deposition patterns is crucial.MethodWe included 269 amyloid‐β‐positive (PET/CSF) individuals with clinically diagnosed atypical AD (113 posterior cortical atrophy, PCA‐AD; 83 logopenic variant primary progressive aphasia, lvPPA‐AD; 33 behavioural variant AD, bvAD; 40 corticobasal syndrome, CBS‐AD) and 68 with typical AD from 12 international cohorts, who underwent tau‐PET (54% [18F]AV1451/[18F]flortaucipir/Tauvid, 27% [18F]MK6240, 19% [18F]PI2620). Using Gaussian mixture modeling including amyloid‐β‐negative controls, cross‐sectional tau‐PET standardized uptake value ratios within Schaefer‐200 atlas regions were transformed to tau positivity probabilities. Tau epicenters were defined as the 5% regions with highest tau positivity probabilities. For each variant, the association between functional connectivity‐based distance (using the 30% strongest positive region‐to‐region connections of a group‐average connectivity matrix from ADNI elderly controls) and tau‐PET covariance (group‐average correlation per region pair) was assessed through linear regression, adjusting for age, sex, site, and Euclidean distance. Regions were categorized based on functional proximity to the epicenter (quartiles 1‐4) and tau positivity probabilities were assessed accordingly.ResultTau positivity probabilities matched clinical variants, with a posterior pattern in PCA‐AD, left‐hemispheric dominant pattern in lvPPA‐AD, widespread pattern in bvAD, sensorimotor cortex involvement in CBS‐AD, and temporo‐parietal predominance in typical AD (Figure 1). In line with this, tau epicenters were highly heterogeneous across variants (Figure 1). In all variants, greater tau‐PET covariance was associated with shorter functional connectivity‐based distance (Figure 2). We observed that regions in closer functional proximity to the epicenter exhibited higher tau positivity probabilities than regions functionally further away (p<0.05, Figure 3).ConclusionThis multi‐center study shows that the brain’s functional architecture serves as a universal predictor of tau spreading in AD. Since tau is a key driver of neurodegeneration and cognitive decline in AD, this finding holds potential for personalized medicine and defining participant‐specific endpoints in clinical trials.

AbstractBackgroundParkinson’s disease and dementia with Lewy bodies are characterized by abnormal iron deposition in the substantia nigra, which can be measured with quantitative susceptibility mapping (QSM) on MRI. However, neuropathologic validation of the increased QSM in the substantia nigra associated with Lewy body disease (LBD) is lacking. We compared substantia nigra QSM on antemortem MRI between patients with and without Lewy‐related pathology which was confirmed by autopsy in all cases.MethodWe studied cases with antemortem QSM who underwent autopsy from the Mayo Clinic Alzheimer’s Disease Research Center and Mayo Clinic Study of Aging (n=54). Immunohistochemistry was performed with rabbit NACP antibody against the amino acids 98‐115 of the α‐synuclein protein to detect Lewy‐related pathology. After neuropathologic evaluation, cases were classified as LBD‐present (n=13) if they had Lewy‐related pathology and LBD‐absent (n=42) if they did not have Lewy‐related pathology. Alzheimer’s disease co‐pathology was present in 9 of the LBD‐present cohort (70%). QSM was calculated for the whole substantia nigra and the two sub‐regions: pars compacta and pars reticulata. Non‐parametric Wilcoxon rank‐sum test was used to compare substantia nigra QSM values between LBD‐present and LBD‐absent cases. Area under the curve (AUC) analyses tested the accuracy of QSM to distinguish the two groups.ResultsLBD‐present group had higher QSM values in the substantia nigra than LBD‐absent group. Furthermore, sub‐regional analyses showed that the LBD‐present group had higher QSM in the substantia nigra pars compacta (p=0.008) but not in the pars reticulata than the LBD‐absent group (Figure 1). QSM of the substantia nigra pars compacta distinguished LBD‐present and LBD‐absent cases with good accuracy (AUC=0.74; p=0.006; Figure 2).ConclusionThis study provides neuropathologic insight into the relevance of QSM of substantia nigra pars compacta as an in‐vivo biomarker of autopsy‐confirmed LBD. These findings indicate that imaging evidence of abnormal iron deposition in the substantia nigra may serve as a biomarker of Lewy‐related pathology in patients with primary LBD (i.e., Parkinson disease, dementia with Lewy bodies) and patients with potential LBD co‐pathology (e.g., patients with Alzheimer disease).

AbstractBackgroundPatients with rapid progressive Alzheimer disease and related dementias (rpAD/ADRD) develop dementia within 1 year or incapacitation within 2 years of symptom onset. We previously showed that selected CSF biomarkers of neuronal injury (NfL, VILIP‐1), AD neuropathology (p‐tau181), and neuroinflammation (GFAP, MCP‐1, sTREM2) measured at presentation associated with etiologic diagnoses and reliably differentiated patients with treatment‐responsive causes of rapid progressive dementia. However, no differences were identified between CSF biomarkers in patients with rapid and typical progressive forms of AD/ADRD, leaving key questions unanswered concerning the mechanisms that drive rpAD/ADRD. Blood‐based biomarkers may inform the systemic factors that contribute to rpAD/ADRD, including the systemic inflammation, metabolic function, and vascular injury.MethodsBiomarkers of systemic inflammation (Eotaxin‐3, IFN‐γ, IL‐1b, IL‐2, IL‐4, IL‐6, IL‐8, IL‐10, IL‐12p70, IL‐13, TARC, TNF‐α), metabolic function (A2M, B2M, FABP‐3, FVII, I‐309, IL‐18, PPY, TNC, TPO), and vascular injury (CRP, SAA, sICAM‐1, sVCAM‐1) were measured in plasma obtained at presentation from patients with rpAD/ADRD (n=29) and age‐ and sex‐ similar participants with typical progressive AD/ADRD (n=39) enrolled in prospective studies of memory and aging at Mayo Clinic in Florida. Biomarker measures were completed at the University of North Texas Institute for Translational Research using Meso Scale Discovery multiplexed assays. Biomarker concentrations were compared between groups using univariate analyses; potential predictors (p<0.05) were further evaluated via step‐wise multivariate logistic regression.ResultsMarkers of vascular injury (SAA, CRP, sICAM‐1), metabolic function (I‐309, TPO), and systemic inflammation (Eotaxin‐3, TARC, TNF‐α) were increased in patients with rapid versus typical progressive AD/ADRD (p<0.05). Eotaxin‐3, I‐309, and SAA were independently associated with rpAD/ADRD in multivariable model after controlling for age and sex. The overall model correctly characterized 86.8% of patients, with an area under the curve of 0.864 (95%CI: 0.777‐0.950; p<0.001).ConclusionBlood‐based biomarkers of systemic inflammation, metabolic function, and vascular injury were elevated at presentation in patients with rapid vs typical AD/ADRD. These findings may provide additional insights into the mechanisms that drive rpAD/ADRD. Longitudinal measures from larger cohorts are needed to decipher the relationship between candidate biomarkers and rpAD/ADRD.

AbstractBackgroundAlzheimer disease (AD) related cognitive decline occurs at relatively young ages in individuals with Down syndrome (DS, early‐mid 50s) and in those with autosomal dominant mutations (ADAD, 40‐50s). Both groups show similar patterns of amyloid accumulation. We examined if brain volumes are similarly affected by AD pathology in individuals with DS and ADAD.MethodData for cognitively stable and declining participants was obtained from the Alzheimer Biomarker Consortium‐Down Syndrome (ABC‐DS) and the Dominantly Inherited Alzheimer Network (DIAN). Stability/decline was identified based on cognitive testing and interview of individuals and caregivers by trained assessors. Cognitively stable family members without DS/ADAD mutations were recruited as controls from both studies. Participants underwent MRI and amyloid positron emission tomography (PET) scans from which brain volumes and amyloid (centiloids) were derived, respectively. Participants from DIAN had Pittsburgh Compound‐B (PIB) scans, ABC‐DS had PIB or florbetapir. Nonlinear cross‐sectional associations between regional brain volumes and estimated years to onset of cognitive decline (EYO, negative values before onset, positive after) and centiloid were evaluated using generalized additive models while controlling for sex and random effects of family. EYO was set to 52 for all participants with DS and based on parental decline/mutation type for participants with ADAD. EYO for controls was based on the EYO of their family member.ResultData from 239 participants with DS (47 declining), and 340 participants with ADAD (122 declining), and 263 familial controls were included. Higher EYO and centiloid values were associated with lower brain volumes in almost all regions. At earlier EYOs, individuals with DS typically had smaller regional volumes than ADAD or sibling controls, with volume declining linearly across the EYO range. By contrast, ADAD mutation carriers had similar volumes to non‐carriers at early EYOs, with volumes diverging as early as 10 years before decline. Brain volumes and centiloid values were inversely related in ADAD and DSAD. Volume in key cortical regions were similar by the expected year of onset in both groups.ConclusionADAD and DSAD demonstrated different temporal patterns of regional neurodegeneration prior to cognitive change despite being similarly affected by early onset amyloid.

AbstractBackgroundThe prevalence of dementia in populations that are underrepresented in research is projected to increase with population aging. Latino and Black individuals, the largest underrepresented populations in the US, experience a higher dementia burden than non‐Hispanic White individuals, which is not explained by ethnoracial biological factors. Disparities in structural and social determinants of health may contribute to the preponderance of medical conditions known to increase dementia risk, including potentially modifiable factors in Latino and Black communities. To assess the scope of this problem, we measured the frequency of common modifiable dementia risk factors in community‐dwelling, cognitively normal, Latino and Black adults.MethodCognitively normal community‐dwelling Latino and Black adults, ≥45‐years‐old, were enrolled within our longitudinal study of memory and aging at Mayo Clinic in Florida (Jacksonville, FL) and completed a baseline assessment between 3/2022 and 10/2023. Demographics, and self‐reported race/ethnicity and history of dementia risk factors were recorded. Dementia risk factors were objectively sampled through clinical interview (depression: Geriatric Depression Scale ≥5), examination (hypertension: BP >130/80 mmHg; obesity: BMI≥30), and serum analyses (hyperlipidemia: total cholesterol<200mg/dL, HDL>50mg/dL, LDL<100mg/dL, Triglycerides<150mg/dL; diabetes: HbA1C >5.6%, vitamin B12 deficiency: <350 ng/dL).Result86 participants (43 Latino, 43 Black), 65.8 (8.8) years‐old, female (62.8%), with 16 (2.4) years of education were assessed. Dementia risk factors were frequent in Latino and Black participants, including hypertension (63%, 90%; p = 0.005), hyperlipidemia (93%, 89%; p = 0.702), obesity (33%, 44%; p = 0.370), diabetes (60%, 47%; p = 0.370), vitamin B12 deficiency (21%, 21%; p = 0.989), and depression (5%, 24%; p = 0.781). These risk factors were unrecognized or suboptimally managed in a substantial proportion of Latino and Black participants: hypertension (56%, 73%; p = 0.170), hyperlipidemia (80%, 73%; p = 0.591), diabetes (57%, 47%; p = 0.502), vitamin B12 deficiency (21%, 21%; p = 0.789), and depression (5%, 3%; p>0.99).ConclusionPotentially modifiable dementia risk factors were detected in the majority of community‐dwelling Latino and Black cognitively normal older‐adults and were frequently unrecognized or suboptimally managed. Proactive screening for known dementia risk factors may provide opportunities for targeted interventions to improve brain health and decrease dementia disparities in underrepresented populations.

AbstractBackgroundThere is a strong link between tau and progression of Alzheimer’s disease (AD), necessitating an understanding of tau spreading mechanisms. Prior research, predominantly in typical AD, suggested that tau propagates from epicenters (regions with earliest tau) to functionally connected regions. However, given the constrained spatial heterogeneity of tau in typical AD, validating this connectivity‐based tau spreading model in AD variants with distinct tau deposition patterns is crucial.MethodWe included 269 amyloid‐ß‐positive (PET/CSF) individuals with clinically diagnosed atypical AD (113 posterior cortical atrophy, PCA‐AD; 83 logopenic variant primary progressive aphasia, lvPPA‐AD; 33 behavioural variant AD, bvAD; 40 corticobasal syndrome, CBS‐AD) and 68 with typical AD from 12 international cohorts, who underwent tau‐PET (54% [18F]AV1451/[18F]flortaucipir/Tauvid, 27% [18F]MK6240, 19% [18F]PI2620). Using Gaussian mixture modeling including amyloid‐ß‐negative controls, cross‐sectional tau‐PET standardized uptake value ratios within Schaefer‐200 atlas regions were transformed to tau positivity probabilities. Tau epicenters were defined as the 5% regions with highest tau positivity probabilities. For each variant, the association between functional connectivity‐based distance (using the 30% strongest positive region‐to‐region connections of a group‐average connectivity matrix from ADNI elderly controls) and tau‐PET covariance (group‐average correlation per region pair) was assessed through linear regression, adjusting for age, sex, site, and Euclidean distance. Regions were categorized based on functional proximity to the epicenter (quartiles 1‐4) and tau positivity probabilities were assessed accordingly.ResultTau positivity probabilities matched clinical variants, with a posterior pattern in PCA‐AD, left‐hemispheric dominant pattern in lvPPA‐AD, widespread pattern in bvAD, sensorimotor cortex involvement in CBS‐AD, and temporo‐parietal predominance in typical AD (Fig.1). In line with this, tau epicenters were highly heterogeneous across variants (Fig.1). In all variants, greater tau‐PET covariance was associated with shorter functional connectivity‐based distance (Fig.2). We observed that regions in closer functional proximity to the epicenter exhibited higher tau positivity probabilities than regions functionally further away (p<0.05, Fig.3).ConclusionThis multi‐center study shows that the brain’s functional architecture serves as a universal predictor of tau spreading in AD. Since tau is a key driver of neurodegeneration and cognitive decline in AD, this finding holds potential for personalized medicine and defining participant‐specific endpoints in clinical trials.