Petersen, Ronald

Abstract Studies assessing genetic associations with neuropathological features in Lewy body disease (LBD) have been limited to candidate gene investigations, and therefore, information is lacking regarding the genetic architecture of the neuropathology of LBD. In the current study, we examined a large series of neuropathologically confirmed LBD cases (n = 980 in the discovery series, n = 503 in the replication series) and performed genome-wide association studies of 11 different neuropathological outcome measures. The 11 neuropathological outcomes included Braak neurofibrillary tangle (NFT) stage, Thal amyloid phase, LBD subtype, Lewy body (LB) counts in five different brain regions, dorsolateral and ventromedial putaminal tyrosine hydroxylase immunoreactivity and neuronal loss in the ventrolateral part of the substantia nigra. Associations between variants and outcomes were assessed using regression models appropriate for the nature of the given neuropathological outcome and that were adjusted for age at death, sex and top principal components of genetic data. In the discovery series, APOE rs429358 (i.e. APOE ε4) was associated with a greater severity of each of Braak NFT stage [odds ratio (OR) = 3.07, P = 2.34 × 10−32], Thal amyloid phase (OR = 3.57, P = 3.28 × 10−29) and LBD subtype (OR = 1.78, P = 9.85 × 10−9), with similar findings observed in the independent replication series (Braak NFT stage, OR = 2.30, P = 2.70 × 10−11; Thal amyloid phase, OR = 3.17, P = 6.39 × 10−18; LBD subtype, OR = 2.68, P = 3.85 × 10−10). In the subgroup of cases with lower levels of Alzheimer's disease pathology (Braak NFT stage ≤ III and Thal amyloid phase ≤2), there was a strong association between APOE rs429358 and LBD subtype even when adjusting for Braak stage and Thal phase in the discovery series (n = 218, OR = 2.47, P = 0.007) and the replication series (n = 141, OR = 3.60, P = 0.006). Although additional genome-wide significant associations were identified in the discovery series between LINC01581/MCTP2 rs547411734 and lower middle frontal LB counts, between TLE3 rs3743309 and lower cingulate LB counts, and between GRIN2A/ATF7IP2 rs1097915 and lower parahippocampal LB counts, these findings were not observed in the replication series. Our results indicate that the APOE ε4 allele is the most prominent genetic determinant of severity of neuropathology in LBD. These findings represent a key step forward in our understanding of genetic drivers of neuropathological features in LBD. Future studies utilizing meta-analytical approaches will be important to more precisely assess other associations that were not quite genome-wide significant in the discovery series.

Abstract INTRODUCTION We aimed to compare gait between individuals with Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and cognitively unimpaired (CU) individuals and to evaluate the association between gait and regional amyloid beta (Aβ) burden in AD and DLB. METHODS We included 420 participants (70 AD, 70 DLB, 280 CU) in the Mayo Clinic Study of Aging (MCSA). Gait was assessed using a pressure‐sensor walkway. Aβ deposition was analyzed with Pittsburgh compound B (PiB) positron emission topography (PET). RESULTS The DLB group had reduced stride velocity, step length, and stride width variability, as well as increased double support percentage (%DS) and variability in step length, swing time, and step time compared to the AD and CU groups. Aβ burden was not associated with any gait outcomes. DISCUSSION This study provides additional evidence that gait differs between AD and DLB. Larger studies are needed to investigate associations between Aβ burden and gait outcomes in dementia. Highlights Gait was more impaired in dementia than in cognitively unimpaired (CU) controls. Compared with Alzheimer's disease (AD), Dementia with Lewy bodies (DLB) had more impaired pace, variability, and postural control. Step length and double support (%) distinguished DLB and AD with moderate accuracy.

AbstractBackgroundTransactive response DNA‐binding protein of 43 kDa (TDP‐43) is implicated in numerous neurodegenerative diseases, including Alzheimer’s disease (AD). Immunohistochemically stained TDP‐43 is linked to faster rates of hippocampal atrophy (HA) in AD. However, it is unclear whether phosphorylated TDP‐43 (pTDP‐43) measured using an immunoassay is also associated with HA. We explored associations between pTDP‐43 levels, TDP‐43 immunohistochemistry, and annual rate of HA in AD. We hypothesized that higher pTDP‐43 levels would be associated with positive TDP‐43 immunohistochemistry, and faster rates of HA.MethodThirty‐seven cognitively impaired participants from the Mayo Clinic Alzheimer’s Disease Research Center underwent serial brain MRIs and brain autopsy. Hippocampal TDP‐43 was detected histochemically, and pTDP‐43 was quantified using biochemical assay. Hippocampal volumes were measured using the longitudinal pipeline in FreeSurfer‐7 and annualized HA rates were calculated. Linear regression analyzed the relationship between HA and pTDP‐43 biochemical assay levels. pTDP‐43 was categorized as positive (≥400) or negative (<400), and logistic regression tested the association of these levels with HA rates. The correlation between TDP‐43 immunohistochemistry status and biochemical assay levels was evaluated using descriptive statistics. All analyses were adjusted for potential confounders.ResultsThe mean age at death was 83.5 (±9.9) years with 49% females. Median scan interval was 3‐years. A negative relationship was observed between age at death and annual HA rate (β=‐3.1; 95% CI [‐5.3,‐0.9]; p=0.007), and a positive relationship was observed between pTDP‐43 level and annual HA rate (β=0.02; 95% CI [0.003,0.03]; p=0.015). A one‐unit increase in HA rate was associated with a 3% increase in the odds of being pTDP‐43 positive (≥400) (odds ratio=1.03; CI [1.007,1.05]; p=0.014). Cases that tested positive for Immunohistochemistry TDP‐43 had significantly higher mean pTDP‐43 immunoassay levels (1508 ± 2072 vs. 202 ± 131; p=0.008). More cases with positive IHC TDP‐43 surpassed the pTDP‐43 immunoassay cut‐off level of 400 vs the negative participants (p=0.003).ConclusionHigher pTDP‐43 levels in the hippocampus are linked to faster HA in AD and correlated with immunohistochemistry TDP‐43 positivity. These findings underscore the role of TDP‐43 in AD neurodegeneration. The biological and clinical implications of these observations necessitate further exploration in subsequent studies.

AbstractBackgroundTransactive response DNA‐binding protein of 43 kDa (TDP‐43) is implicated in numerous neurodegenerative diseases, including Alzheimer’s disease (AD). Immunohistochemically stained TDP‐43 is linked to faster rates of hippocampal atrophy (HA) in AD. However, it is unclear whether phosphorylated TDP‐43 (pTDP‐43) measured using an immunoassay is also associated with HA. We explored associations between pTDP‐43 levels, TDP‐43 immunohistochemistry, and annual rate of HA in AD. We hypothesized that higher pTDP‐43 levels would be associated with positive TDP‐43 immunohistochemistry, and faster rates of HA.MethodThirty‐seven cognitively impaired participants from the Mayo Clinic Alzheimer’s Disease Research Center underwent serial brain MRIs and brain autopsy. Hippocampal TDP‐43 was detected histochemically, and pTDP‐43 was quantified using biochemical assay. Hippocampal volumes were measured using the longitudinal pipeline in FreeSurfer‐7 and annualized HA rates were calculated. Linear regression analyzed the relationship between HA and pTDP‐43 biochemical assay levels. pTDP‐43 was categorized as positive (=400) or negative (<400), and logistic regression tested the association of these levels with HA rates. The correlation between TDP‐43 immunohistochemistry status and biochemical assay levels was evaluated using descriptive statistics. All analyses were adjusted for potential confounders.ResultsThe mean age at death was 83.5 (±9.9) years with 49% females. Median scan interval was 3‐years. A negative relationship was observed between age at death and annual HA rate (ß=‐3.1; 95% CI [‐5.3,‐0.9]; p=0.007), and a positive relationship was observed between pTDP‐43 level and annual HA rate (ß=0.02; 95% CI [0.003,0.03]; p=0.015). A one‐unit increase in HA rate was associated with a 3% increase in the odds of being pTDP‐43 positive (=400) (odds ratio=1.03; CI [1.007,1.05]; p=0.014). Cases that tested positive for Immunohistochemistry TDP‐43 had significantly higher mean pTDP‐43 immunoassay levels (1508 ± 2072 vs. 202 ± 131; p=0.008). More cases with positive IHC TDP‐43 surpassed the pTDP‐43 immunoassay cut‐off level of 400 vs the negative participants (p=0.003).ConclusionHigher pTDP‐43 levels in the hippocampus are linked to faster HA in AD and correlated with immunohistochemistry TDP‐43 positivity. These findings underscore the role of TDP‐43 in AD neurodegeneration. The biological and clinical implications of these observations necessitate further exploration in subsequent studies.

AbstractBackground and AimsPhysical activity (PA) is associated with higher gait speed. We aimed to examine the associations between PA and change in spatial and temporal gait measures as well as fall risk in community‐dwelling individuals free of dementia.MethodsLongitudinal study among 4173 individuals aged ≥50 years (mean age 71 years; 2078 males; median follow‐up 4 years) enrolled in the Mayo Clinic Study of Aging. Self‐reported late‐life PA was used to calculate overall PA and moderate‐vigorous PA (MVPA) scores. Gait was assessed using GAITRite® and Zeno™ systems. Incident falls information was based on diagnostic codes retrieved from medical records. We ran linear mixed effects models to examine associations between z‐scored PA variables and longitudinal gait parameters, adjusted for age, sex, education, body mass index (BMI), medical comorbidities, and including interactions between PA and time since baseline. In secondary analyses, we calculated Cox Proportional hazard models with age as time scale predicting incident falls by PA, adjusting for sex, education, BMI, medical comorbidities, and falls history.ResultsAt baseline, higher PA was associated with higher velocity (overall PA: estimate 2.9935; MVPA: 2.2961; p < 0.001), higher cadence (overall PA: 1.0665; MVPA: 0.9073; p < 0.001), greater stride length (overall PA: 2.0805; MVPA: 1.4726; p < 0.001), shorter double support time (overall PA: −0.0257; MVPA: −0.0205; p < 0.001), and lower stance time variability (overall PA: −0.0204, p < 0.001; MVPA: −0.0152; p = 0.006). Overall PA was longitudinally associated with less decline in cadence, and MVPA with less increase in intraindividual stance time variability. Overall PA (Hazard ratio 0.892, 95% confidence interval 0.828–0.961, p = 0.003) and MVPA (HR 0.901; 95% CI 0.835–0.973, p = 0.008) were associated with a decreased risk of incident falls.ConclusionLate‐life PA was associated with favorable gait outcomes and decreased risk of incident falls. Thus, late‐life PA may help to maintain gait performance and decrease fall risk in old age.

Abstract Obstructive sleep apnoea (OSA) is associated with an increased risk for cognitive impairment and dementia, which likely involves Alzheimer’s disease pathology. Non-rapid eye movement slow-wave activity (SWA) has been implicated in amyloid clearance, but it has not been studied in the context of longitudinal amyloid accumulation in OSA. This longitudinal retrospective study aims to investigate the relationship between polysomnographic and electrophysiological SWA features and amyloid accumulation. From the Mayo Clinic Study of Aging cohort, we identified 71 participants ≥60 years old with OSA (mean baseline age = 72.9 ± 7.5 years, 60.6% male, 93% cognitively unimpaired) who had at least 2 consecutive Amyloid Pittsburgh Compound B (PiB)-PET scans and a polysomnographic study within 5 years of the baseline scan and before the second scan. Annualized PiB-PET accumulation [global ΔPiB(log)/year] was estimated by the difference between the second and first log-transformed global PiB-PET uptake estimations divided by the interval between scans (years). Sixty-four participants were included in SWA analysis. SWA was characterized by the mean relative spectral power density (%) in slow oscillation (SO: 0.5–0.9 Hz) and delta (1–3.9 Hz) frequency bands and by their downslopes (SO-slope and delta-slope, respectively) during the diagnostic portion of polysomnography. We fit linear regression models to test for associations among global ΔPiB(log)/year, SWA features (mean SO% and delta% or mean SO-slope and delta-slope), and OSA severity markers, after adjusting for age at baseline PiB-PET, APOE ɛ4 and baseline amyloid positivity. For 1 SD increase in SO% and SO-slope, global ΔPiB(log)/year increased by 0.0033 (95% CI: 0.0001; 0.0064, P = 0.042) and 0.0069 (95% CI: 0.0009; 0.0129, P = 0.026), which were comparable to 32% and 59% of the effect size associated with baseline amyloid positivity, respectively. Delta-slope was associated with a reduction in global ΔPiB(log)/year by −0.0082 (95% CI: −0.0143; −0.0021, P = 0.009). Sleep apnoea severity was not associated with amyloid accumulation. Regional associations were stronger in the pre-frontal region. Both slow-wave slopes had more significant and widespread regional associations. Annualized PiB-PET accumulation was positively associated with SO and SO-slope, which may reflect altered sleep homeostasis due to increased homeostatic pressure in the setting of unmet sleep needs, increased synaptic strength, and/or hyper-excitability in OSA. Delta-slope was inversely associated with PiB-PET accumulation, suggesting it may represent residual physiological activity. Further investigation of SWA dynamics in the presence of sleep disorders before and after treatment is necessary for understanding the relationship between amyloid accumulation and SWA physiology.

Abstract INTRODUCTION We aimed to evaluate clinical interpretation cutpoints for two plasma phosphorylated tau (p‐tau)217 assays (ALZpath and Lumipulse) as predictors of amyloid status for implementation in clinical practice. METHODS Clinical performance of plasma p‐tau217 against amyloid positron emission tomography status was evaluated in participants with mild cognitive impairment or mild dementia ( n = 427). RESULTS Using a one‐cutpoint approach (negative/positive), neither assay achieved ≥ 90% in both sensitivity and specificity. A two‐cutpoint approach yielding 92% sensitivity and 96% specificity provided the desired balance of false positives and false negatives, while categorizing 20% and 39% of results as indeterminate for the Lumipulse and ALZpath assays, respectively. DISCUSSION This study provides a systematic framework for selection of assay‐specific cutpoints for clinical use of plasma p‐tau217 for determination of amyloid status. Our findings suggest that a two‐cutpoint approach may have advantages in optimizing diagnostic accuracy while minimizing potential harm from false positive results. Highlights Phosphorylated tau (p‐tau)217 cutpoints for detection of amyloid pathology were established. A two‐cutpoint approach exhibited the best performance for clinical laboratory use. p‐tau217 assays differed in the percentage of results categorized as intermediate.

ImportanceIncreased white matter hyperintensity (WMH) volume is a common magnetic resonance imaging (MRI) finding in both autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD), but it remains unclear whether increased WMH along the AD continuum is reflective of AD-intrinsic processes or secondary to elevated systemic vascular risk factors.ObjectiveTo estimate the associations of neurodegeneration and parenchymal and vessel amyloidosis with WMH accumulation and investigate whether systemic vascular risk is associated with WMH beyond these AD-intrinsic processes.Design, Setting, and ParticipantsThis cohort study used data from 3 longitudinal cohort studies conducted in tertiary and community-based medical centers—the Dominantly Inherited Alzheimer Network (DIAN; February 2010 to March 2020), the Alzheimer’s Disease Neuroimaging Initiative (ADNI; July 2007 to September 2021), and the Harvard Aging Brain Study (HABS; September 2010 to December 2019).Main Outcome and MeasuresThe main outcomes were the independent associations of neurodegeneration (decreases in gray matter volume), parenchymal amyloidosis (assessed by amyloid positron emission tomography), and vessel amyloidosis (evidenced by cerebral microbleeds [CMBs]) with cross-sectional and longitudinal WMH.ResultsData from 3960 MRI sessions among 1141 participants were included: 252 pathogenic variant carriers from DIAN (mean [SD] age, 38.4 [11.2] years; 137 [54%] female), 571 older adults from ADNI (mean [SD] age, 72.8 [7.3] years; 274 [48%] female), and 318 older adults from HABS (mean [SD] age, 72.4 [7.6] years; 194 [61%] female). Longitudinal increases in WMH volume were greater in individuals with CMBs compared with those without (DIAN: t = 3.2 [P = .001]; ADNI: t = 2.7 [P = .008]), associated with longitudinal decreases in gray matter volume (DIAN: t = −3.1 [P = .002]; ADNI: t = −5.6 [P &amp;lt; .001]; HABS: t = −2.2 [P = .03]), greater in older individuals (DIAN: t = 6.8 [P &amp;lt; .001]; ADNI: t = 9.1 [P &amp;lt; .001]; HABS: t = 5.4 [P &amp;lt; .001]), and not associated with systemic vascular risk (DIAN: t = 0.7 [P = .40]; ADNI: t = 0.6 [P = .50]; HABS: t = 1.8 [P = .06]) in individuals with ADAD and LOAD after accounting for age, gray matter volume, CMB presence, and amyloid burden. In older adults without CMBs at baseline, greater WMH volume was associated with CMB development during longitudinal follow-up (Cox proportional hazards regression model hazard ratio, 2.63; 95% CI, 1.72-4.03; P &amp;lt; .001).Conclusions and RelevanceThe findings suggest that increased WMH volume in AD is associated with neurodegeneration and parenchymal and vessel amyloidosis but not with elevated systemic vascular risk. Additionally, increased WMH volume may represent an early sign of vessel amyloidosis preceding the emergence of CMBs.