A generalizable data-driven model of atrophy heterogeneity and progression in memory clinic settings.

Memory clinic patients are a heterogeneous population representing various aetiologies of pathological aging. It is unknown if divergent spatiotemporal progression patterns of brain atrophy, as previously described in Alzheimer's disease (AD) patients, are prevalent and clinically meaningful in this group of older adults. To uncover distinct atrophy subtypes, we applied the Subtype and Stage Inference (SuStaIn) algorithm to baseline structural MRI data from 813 participants enrolled in the DELCODE cohort (mean ± SD age = 70.67 ± 6.07 years, 52% females). Participants were cognitively unimpaired (CU; n = 285) or fulfilled diagnostic criteria for subjective cognitive decline (SCD; n = 342), mild cognitive impairment (MCI; n = 118), or dementia of the Alzheimer's type (n = 68). Atrophy subtypes were compared in baseline demographics, fluid AD biomarker levels, the Preclinical Alzheimer Cognitive Composite (PACC-5), as well as episodic memory and executive functioning. PACC-5 trajectories over up to 240 weeks were examined. To test if baseline atrophy subtype and stage predicted clinical trajectories before manifest cognitive impairment, we analysed PACC-5 trajectories and MCI conversion rates of CU and SCD participants. Limbic-predominant and hippocampal-sparing atrophy subtypes were identified. Limbic-predominant atrophy first affected the medial temporal lobes, followed by further temporal and, finally, the remaining cortical regions. At baseline, this subtype was related to older age, more pathological AD biomarker levels, APOE ε4 carriership, and an amnestic cognitive impairment. Hippocampal-sparing atrophy initially occurred outside the temporal lobe with the medial temporal lobe spared up to advanced atrophy stages. This atrophy pattern also affected individuals with positive AD biomarkers and was associated with more generalised cognitive impairment. Limbic-predominant atrophy, in all and in only unimpaired participants, was linked to more negative longitudinal PACC-5 slopes than observed in participants without or with hippocampal-sparing atrophy and increased the risk of MCI conversion. SuStaIn modelling was repeated in a sample from the Swedish BioFINDER-2 cohort. Highly similar atrophy progression patterns and associated cognitive profiles were identified. Cross-cohort model generalizability, both on the subject and group level, were excellent, indicating reliable performance in previously unseen data. The proposed model is a promising tool for capturing heterogeneity among older adults at early at-risk states for AD in applied settings. The implementation of atrophy subtype- and stage-specific end-points may increase the statistical power of pharmacological trials targeting early AD.

Speech patterns during memory recall relates to early tau burden across adulthood.

INTRODUCTION: Early cognitive decline may manifest in subtle differences in speech. METHODS: We examined 238 cognitively unimpaired adults from the Framingham Heart Study (32-75 years) who completed amyloid and tau PET imaging. Speech patterns during delayed recall of a story memory task were quantified via five speech markers, and their associations with global amyloid status and regional tau signal were examined. RESULTS: Total utterance time, number of between-utterance pauses, speech rate, and percentage of unique words significantly correlated with delayed recall score although the shared variance was low (2%-15%). Delayed recall score was not significantly different between ß-amyoid-positive (Aß+) and -negative (Aß-) groups and was not associated with regional tau signal. However, longer and more between-utterance pauses, and slower speech rate were associated with increased tau signal across medial temporal and early neocortical regions. DISCUSSION: Subtle speech changes during memory recall may reflect cognitive impairment associated with early Alzheimer's disease pathology. HIGHLIGHTS: Speech during delayed memory recall relates to tau PET signal across adulthood. Delayed memory recall score was not associated with tau PET signal. Speech shows greater sensitivity to detecting subtle cognitive changes associated with early tau accumulation. Our cohort spans adulthood, while most PET imaging studies focus on older adults.

Anxiety in late-life depression: Associations with brain volume, amyloid beta, white matter lesions, cognition, and functional ability.

OBJECTIVES: Late-life depression (LLD) is common and frequently co-occurs with neurodegenerative diseases of aging. Little is known about how heterogeneity within LLD relates to factors typically associated with neurodegeneration. Varying levels of anxiety are one source of heterogeneity in LLD. We examined associations between anxiety symptom severity and factors associated with neurodegeneration, including regional brain volumes, amyloid beta (Aß) deposition, white matter disease, cognitive dysfunction, and functional ability in LLD. PARTICIPANTS AND MEASUREMENTS: Older adults with major depression (N = 121, Ages 65-91) were evaluated for anxiety severity and the following: brain volume (orbitofrontal cortex [OFC], insula), cortical Aß standardized uptake value ratio (SUVR), white matter hyperintensity (WMH) volume, global cognition, and functional ability. Separate linear regression analyses adjusting for age, sex, and concurrent depression severity were conducted to examine associations between anxiety and each of these factors. A global regression analysis was then conducted to examine the relative associations of these variables with anxiety severity. RESULTS: Greater anxiety severity was associated with lower OFC volume (ß = -68.25, t = -2.18, p = .031) and greater cognitive dysfunction (ß = 0.23, t = 2.46, p = .016). Anxiety severity was not associated with insula volume, Aß SUVR, WMH, or functional ability. When examining the relative associations of cognitive functioning and OFC volume with anxiety in a global model, cognitive dysfunction (ß = 0.24, t = 2.62, p = .010), but not OFC volume, remained significantly associated with anxiety. CONCLUSIONS: Among multiple factors typically associated with neurodegeneration, cognitive dysfunction stands out as a key factor associated with anxiety severity in LLD which has implications for cognitive and psychiatric interventions.

Hoarding Symptoms in Late Life Depression are Associated With Greater Executive Dysfunction and Disability and Poorer Response to Depression Treatment.

OBJECTIVES: Late life depression (LLD) and hoarding disorder (HD) are common in older adults and characterized by executive dysfunction and disability. We aimed to determine the frequency of co-occurring HD in LLD and examine hoarding severity as an additional contributor to executive dysfunction, disability, and response to psychotherapy for LLD. DESIGN: Cross-sectional. SETTING: Outpatient psychiatry program. PARTICIPANTS: Eighty-three community-dwelling adults ages 65-90 with LLD. INTERVENTION: Problem-solving therapy. MEASUREMENTS: Measures of executive function, disability, depression, and hoarding severity were completed at post-treatment. Pearson's chi-squared tests evaluated group differences in rates of cognitive impairment, disability, and depression treatment response between participants with HD (LLD+HD) and LLD only. Separate linear regressions assessed associations between hoarding severity and executive function, disability, and psychotherapy response. Covariates included age, education, gender, and depression severity. RESULTS: 30.1% (25/83) of LLD participants met HD criteria. Relative to LLD, LLD+HD participants demonstrated greater impairment rates on measures of executive function (Letter-Number-Sequencing, X2(1)=4.0, p = 0.045; Stroop-Interference, X2(1) = 4.8, p = 0.028). Greater hoarding severity was associated with poorer executive functioning performance (Letter-Number-Sequencing (t[70] = -2.1, ß = -0.05, p = 0.044), Digit-Span (t[71] = -2.4, ß = -0.07, p = 0.019), Letter-Fluency (t[ 71] = -2.8, ß = -0.24, p = 0.006)). Rates of disability were significantly higher for LLD+HD (88.0%) than LLD (62.3%), (X2[1] = 5.41, p = 0.020) and higher hoarding severity was related to greater disability (t[72] = 2.97, ß = 0.13, p = 0.004). Depression treatment response rates were significantly lower for LLD+HD (24.0%) compared to LLD (48.3%), X2(1) = 4.26, p = 0.039, and HD status predicted psychotherapy response, t(67) = -2.15, ß = -15.6, p = 0.035. CONCLUSIONS: We found 30.1% co-occurrence of HD in LLD, which was accompanied by greater executive dysfunction, disability, and poorer response to depression treatment. Results underscore the need for increased screening of hoarding behaviors in LLD and tailored interventions for this LLD+HD group.

Relationship of Hoarding and Depression Symptoms in Older Adults.

Hoarding disorder (HD) is a debilitating neuropsychiatric condition that affects 2%-6% of the population and increases in incidence with age. Major depressive disorder (MDD) co-occurs with HD in approximately 50% of cases and leads to increased functional impairment and disability. However, only one study to date has examined the rate and trajectory of hoarding symptoms in older individuals with a lifetime history of MDD, including those with current active depression (late-life depression; LLD). We therefore sought to characterize this potentially distinct phenotype. We determined the incidence of HD in two separate cohorts of participants with LLD (n = 73) or lifetime history of MDD (n = 580) and examined the reliability and stability of hoarding symptoms using the Saving Inventory-Revised (SI-R) and Hoarding Rating Scale-Self Report (HRS), as well as the co-variance of hoarding and depression scores over time. HD was present in 12% to 33% of participants with MDD, with higher rates found in those with active depressive symptoms. Hoarding severity was stable across timepoints in both samples (all correlations >0.75), and fewer than 30% of participants in each sample experienced significant changes in severity between any two timepoints. Change in depression symptoms over time did not co-vary with change in hoarding symptoms. These findings indicate that hoarding is a more common comorbidity in LLD than previously suggested, and should be considered in screening and management of LLD. Future studies should further characterize the interaction of these conditions and their impact on outcomes, particularly functional impairment in this vulnerable population.

Genetic Moderation of the Association of ß-Amyloid With Cognition and MRI Brain Structure in Alzheimer Disease.

BACKGROUND AND OBJECTIVES: There is considerable heterogeneity in the association between increasing ß-amyloid (Aß) pathology and early cognitive dysfunction in preclinical Alzheimer disease (AD). At this stage, some individuals show no signs of cognitive dysfunction, while others show clear signs of decline. The factors explaining this heterogeneity are particularly important for understanding progression in AD but remain largely unknown. In this study, we examined an array of genetic variants that may influence the relationships among Aß, brain structure, and cognitive performance in 2 large cohorts. METHODS: In 2,953 cognitively unimpaired participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer disease (A4) study, interactions between genetic variants and 18F-Florbetapir PET standardized uptake value ratio (SUVR) to predict the Preclinical Alzheimer Cognitive Composite (PACC) were assessed. Genetic variants identified in the A4 study were evaluated in the Alzheimer Disease Neuroimaging Initiative (ADNI, N = 527) for their association with longitudinal cognition and brain atrophy in both cognitively unimpaired participants and those with mild cognitive impairment. RESULTS: In the A4 study, 4 genetic variants significantly moderated the association between Aß load and cognition. Minor alleles of 3 variants were associated with additional decreases in PACC scores with increasing Aß SUVR (rs78021285, ß = -2.29, SE = 0.40, p FDR = 0.02, nearest gene ARPP21; rs71567499, ß = -2.16, SE = 0.38, p FDR = 0.02, nearest gene PPARD; and rs10974405, ß = -1.68, SE = 0.29, p FDR = 0.02, nearest gene GLIS3). The minor allele of rs7825645 was associated with less decrease in PACC scores with increasing Aß SUVR (ß = 0.71, SE = 0.13, p FDR = 0.04, nearest gene FGF20). The genetic variant rs76366637, in linkage disequilibrium with rs78021285, was available in both the A4 and ADNI. In the A4, rs76366637 was strongly associated with reduced PACC scores with increasing Aß SUVR (ß = -1.01, SE = 0.21, t = -4.90, p < 0.001). In the ADNI, rs76366637 was associated with accelerated cognitive decline (χ2 = 15.3, p = 0.004) and atrophy over time (χ2 = 26.8, p < 0.001), with increasing Aß SUVR. DISCUSSION: Patterns of increased cognitive dysfunction and accelerated atrophy due to specific genetic variation may explain some of the heterogeneity in cognition in preclinical and prodromal AD. The genetic variant near ARPP21 associated with lower cognitive scores in the A4 and accelerated cognitive decline and brain atrophy in the ADNI may help to identify those at the highest risk of accelerated progression of AD.

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.

Natural cubic splines for the analysis of Alzheimer's clinical trials.

Mixed model repeated measures (MMRM) is the most common analysis approach used in clinical trials for Alzheimer's disease and other progressive diseases measured with continuous outcomes over time. The model treats time as a categorical variable, which allows an unconstrained estimate of the mean for each study visit in each randomized group. Categorizing time in this way can be problematic when assessments occur off-schedule, as including off-schedule visits can induce bias, and excluding them ignores valuable information and violates the intention to treat principle. This problem has been exacerbated by clinical trial visits which have been delayed due to the COVID19 pandemic. As an alternative to MMRM, we propose a constrained longitudinal data analysis with natural cubic splines that treats time as continuous and uses test version effects to model the mean over time. Compared to categorical-time models like MMRM and models that assume a proportional treatment effect, the spline model is shown to be more parsimonious and precise in real clinical trial datasets, and has better power and Type I error in a variety of simulation scenarios.

The genetic regulation of protein expression in cerebrospinal fluid.

Studies of the genetic regulation of cerebrospinal fluid (CSF) proteins may reveal pathways for treatment of neurological diseases. 398 proteins in CSF were measured in 1,591 participants from the BioFINDER study. Protein quantitative trait loci (pQTL) were identified as associations between genetic variants and proteins, with 176 pQTLs for 145 CSF proteins (P < 1.25 × 10-10 , 117 cis-pQTLs and 59 trans-pQTLs). Ventricular volume (measured with brain magnetic resonance imaging) was a confounder for several pQTLs. pQTLs for CSF and plasma proteins were overall correlated, but CSF-specific pQTLs were also observed. Mendelian randomization analyses suggested causal roles for several proteins, for example, ApoE, CD33, and GRN in Alzheimer's disease, MMP-10 in preclinical Alzheimer's disease, SIGLEC9 in amyotrophic lateral sclerosis, and CD38, GPNMB, and ADAM15 in Parkinson's disease. CSF levels of GRN, MMP-10, and GPNMB were altered in Alzheimer's disease, preclinical Alzheimer's disease, and Parkinson's disease, respectively. These findings point to pathways to be explored for novel therapies. The novel finding that ventricular volume confounded pQTLs has implications for design of future studies of the genetic regulation of the CSF proteome.

Tau positron emission tomography in preclinical Alzheimer's disease.

Rates of tau accumulation in cognitively unimpaired older adults are subtle, with magnitude and spatial patterns varying in recent reports. Regional accumulation also likely varies in the degree to which accumulation is amyloid-ß-dependent. Thus, there is a need to evaluate the pattern and consistency of tau accumulation across multiple cognitively unimpaired cohorts and how these patterns relate to amyloid burden, in order to design optimal tau end points for clinical trials. Using three large cohorts of cognitively unimpaired older adults, the Anti-Amyloid Treatment in Asymptomatic Alzheimer's and companion study, Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (n = 447), the Alzheimer's Disease Neuroimaging Initiative (n = 420) and the Harvard Aging Brain Study (n = 190), we attempted to identify regions with high rates of tau accumulation and estimate how these rates evolve over a continuous spectrum of baseline amyloid deposition. Optimal combinations of regions, tailored to multiple ranges of baseline amyloid burden as hypothetical clinical trial inclusion criteria, were tested and validated. The inferior temporal cortex, fusiform gyrus and middle temporal cortex had the largest effect sizes of accumulation in both longitudinal cohorts when considered individually. When tau regions of interest were combined to find composite weights to maximize the effect size of tau change over time, both longitudinal studies exhibited a similar pattern-inferior temporal cortex, almost exclusively, was optimal for participants with mildly elevated amyloid ß levels. For participants with highly elevated baseline amyloid ß levels, combined optimal composite weights were 53% inferior temporal cortex, 31% amygdala and 16% fusiform. At mildly elevated levels of baseline amyloid ß, a sample size of 200/group required a treatment effect of 0.40-0.45 (40-45% slowing of tau accumulation) to power an 18-month trial using the optimized composite. Neither a temporal lobe composite nor a global composite reached 80% power with 200/group with an effect size under 0.5. The focus of early tau accumulation on the medial temporal lobe has resulted from the observation that the entorhinal cortex is the initial site to show abnormal levels of tau with age. However, these abnormal levels do not appear to be the result of a high rate of accumulation in the short term, but possibly a more moderate rate occurring early with respect to age. While the entorhinal cortex plays a central role in the early appearance of tau, it may be the inferior temporal cortex that is the critical region for rapid tau accumulation in preclinical Alzheimer's disease.

Cognitive outcomes are differentially associated with depression severity trajectories during psychotherapy treatment for late life major depressive disorder.

OBJECTIVES: Late Life Depression (LLD) is associated with persistent cognitive dysfunction even after depression symptoms improve. The present study was designed to examine cognitive outcomes associated with the pattern of depression severity change during psychotherapy intervention for LLD. METHODS: 96 community-dwelling adults ages 65-91 with major depressive disorder completed 12 sessions of Problem-Solving Therapy at the University of California, San Francisco. Nonlinear trajectories of depression severity ratings using the Hamilton Depression Rating Scale were computed from multiple time points collected throughout the weekly psychotherapy intervention. Performance on measures of cognition (information processing speed, executive functioning, verbal learning, memory) was assessed at baseline and post-treatment. Linear mixed-effects models examined associations between nonlinear depression severity trajectories and post-treatment change in cognitive performance. RESULTS: Broadly, different patterns of depression change during treatment were associated with improved cognition post-treatment. Greater and more consistent interval improvements in depression ratings were differentially associated with improvements in aspects of verbal learning, memory, and executive function post-treatment, while no associations were found with information processing speed. CONCLUSIONS: The heterogeneity of depression trajectories associated with improved cognitive outcomes suggests that the temporal pattern of depression response may impact specific cognitive processes distinctly. Results suggest that use of nonlinear depression severity trajectories may help to elucidate complex associations between the time course of depression response and cognitive outcomes of psychotherapy in LLD. These findings have important implications for identifying treatment targets to enhance clinical and cognitive outcomes of psychotherapy in LLD.

Reliability and Validity of a Home-Based Self-Administered Computerized Test of Learning and Memory Using Speech Recognition.

INTRODUCTION: The objective of this study is to evaluate the reliability and validity of the ReVeReTM word list recall test (RWLRT), which uses speech recognition, when administered remotely and unsupervised. METHODS: Prospective cohort study. Participants included 249 cognitively intact community dwelling older adults. Measures included clinician administered neuropsychological assessments at baseline and unsupervised remotely administered tests of cognition from six time-points over six months. RESULTS: The RWLRT showed acceptable validity. Reliability coefficients varied across time points, with poor reliability between times 1 and 2 and fair-to-good reliability across the remaining five testing sessions. Practice effects were observed with repeated administration as expected. DISCUSSION: Unsupervised computerized tests of cognition, particularly word list learning and memory tests that use speech recognition, have significant potential for large scale early detection and long-term tracking of cognitive decline due to AD.

Association of Sleep and ß-Amyloid Pathology Among Older Cognitively Unimpaired Adults.

Importance: Disrupted sleep commonly occurs with progressing neurodegenerative disease. Large, well-characterized neuroimaging studies of cognitively unimpaired adults are warranted to clarify the magnitude and onset of the association between sleep and emerging ß-amyloid (Aß) pathology. Objective: To evaluate the associations between daytime and nighttime sleep duration with regional Aß pathology in older cognitively unimpaired adults. Design, Setting, and Participants: In this cross-sectional study, screening data were collected between April 1, 2014, and December 31, 2017, from healthy, cognitively unimpaired adults 65 to 85 years of age who underwent florbetapir F 18 positron emission tomography (PET), had APOE genotype information, scored between 25 and 30 on the Mini-Mental State Examination, and had a Clinical Dementia Rating of 0 for the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study. Data analysis was performed from December 1, 2019, to May 10, 2021. Exposures: Self-reported daytime and nighttime sleep duration. Main Outcomes and Measures: Regional Aß pathology, measured by florbetapir PET standardized uptake value ratio. Results: Amyloid PET and sleep duration information was acquired on 4425 cognitively unimpaired participants (mean [SD] age, 71.3 [4.7] years; 2628 [59.4%] female; 1509 [34.1%] tested Aß positive). Each additional hour of nighttime sleep was associated with a 0.005 reduction of global Aß standardized uptake value ratio (F1, 4419 = 5.0; P = .03), a 0.009 reduction of medial orbitofrontal Aß (F1, 4419 = 17.4; P < .001), and a 0.011 reduction of anterior cingulate Aß (F1, 4419 = 15.9; P < .001). When restricting analyses to participants who tested Aß negative, nighttime sleep was associated with a 0.006 reduction of medial orbitofrontal Aß (F1,2910 = 16.9; P < .001) and a 0.005 reduction of anterior cingulate Aß (F1,2910 = 7.6; P = .03). Daytime sleep was associated with a 0.013 increase of precuneus Aß (F1,2910 = 7.3; P = .03) and a 0.024 increase of posterior cingulate Aß (F1,2910 = 14.2; P = .001) in participants who tested Aß negative. Conclusions and Relevance: In this cross-sectional study, the increased risk of Aß deposition with reduced nighttime sleep duration occurred early, before cognitive impairment or significant Aß deposition. Daytime sleep may be associated with an increase in risk for early Aß accumulation and did not appear to be corrective for loss of nighttime sleep, demonstrating a circadian rhythm dependence of sleep in preventing Aß accumulation. Treatments that improve sleep may reduce early Aß accumulation and aid in delaying the onset of cognitive dysfunction associated with early Alzheimer disease.

Strategies to reduce sample sizes in Alzheimer's disease primary and secondary prevention trials using longitudinal amyloid PET imaging.

BACKGROUND: Detecting subtle-to-moderate biomarker changes such as those in amyloid PET imaging becomes increasingly relevant in the context of primary and secondary prevention of Alzheimer's disease (AD). This work aimed to determine if and when distribution volume ratio (DVR; derived from dynamic imaging) and regional quantitative values could improve statistical power in AD prevention trials. METHODS: Baseline and annualized % change in [11C]PIB SUVR and DVR were computed for a global (cortical) and regional (early) composite from scans of 237 cognitively unimpaired subjects from the OASIS-3 database ( www.oasis-brains.org ). Bland-Altman and correlation analyses were used to assess the relationship between SUVR and DVR. General linear models and linear mixed effects models were used to determine effects of age, sex, and APOE-ε4 carriership on baseline and longitudinal amyloid burden. Finally, differences in statistical power of SUVR and DVR (cortical or early composite) were assessed considering three anti-amyloid trial scenarios: secondary prevention trials including subjects with (1) intermediate-to-high (Centiloid > 20.1), or (2) intermediate (20.1 < Centiloid ≤ 49.4) amyloid burden, and (3) a primary prevention trial focusing on subjects with low amyloid burden (Centiloid ≤ 20.1). Trial scenarios were set to detect 20% reduction in accumulation rates across the whole population and in APOE-ε4 carriers only. RESULTS: Although highly correlated to DVR (ρ = .96), cortical SUVR overestimated DVR cross-sectionally and in annual % change. In secondary prevention trials, DVR required 143 subjects per arm, compared with 176 for SUVR. Both restricting inclusion to individuals with intermediate amyloid burden levels or to APOE-ε4 carriers alone further reduced sample sizes. For primary prevention, SUVR required less subjects per arm (n = 855) compared with DVR (n = 1508) and the early composite also provided considerable sample size reductions (n = 855 to n = 509 for SUVR, n = 1508 to n = 734 for DVR). CONCLUSION: Sample sizes in AD secondary prevention trials can be reduced by the acquisition of dynamic PET scans and/or by restricting inclusion to subjects with intermediate amyloid burden or to APOE-ε4 carriers only. Using a targeted early composite only leads to reductions of sample size requirements in primary prevention trials. These findings support strategies to enable smaller Proof-of-Concept Phase II clinical trials to better streamline drug development.

The Impact of Amyloid Burden and APOE on Rates of Cognitive Impairment in Late Life Depression.

BACKGROUND: Cognitive impairment (CI) is a key feature of late life depression (LLD), but the contribution of underlying neurodegenerative pathology remains unclear. OBJECTIVE: To evaluate cognitive dysfunction in LLD relative to a sample of nondepressed (ND) older adults with matched levels of memory impairment and amyloid-ß (Aß) burden. METHODS: Participants included 120 LLD and 240 ND older adults matched on age, education, sex, Mini-Mental State Exam, mild cognitive impairment diagnosis, and PET Aß burden. RESULTS: LLD showed higher rates of impairment relative to ND with 54.6% of the LLD sample demonstrating impairment in at least one cognitive domain compared to 42.9% of controls (H = 7.13, p = 0.008). LLD had poorer performance and higher rates of impairment on Rey Auditory Verbal Learning Test learning and memory compared to controls. In the overall sample, Aß positivity was associated with worse performance on Logical Memory I (p = 0.044), Logical Memory II (p = 0.011), and Trail Making Test -B (p = 0.032), and APOEɛ4 genotype was associated with worse performance on Logical Memory I (p = 0.022); these relationships did not differ between LLD and ND. CONCLUSION: LLD showed higher rates of CI driven by focal deficits in verbal learning and memory. Alzheimer's disease (AD) biomarkers were associated with worse performance on timed set-shifting and story learning and memory, and these relationships were not impacted by depression status. These findings suggest that AD may account for a portion of previously reported multi-domain CI in LLD and highlight the potential for AD to confound studies of cognition in LLD.

Early stages of tau pathology and its associations with functional connectivity, atrophy and memory.

In Alzheimer's disease, post-mortem studies have shown that the first cortical site where neurofibrillary tangles appear is the transentorhinal region, a subregion within the medial temporal lobe that largely overlaps with Brodmann area 35, and the entorhinal cortex. Here we used tau-PET imaging to investigate the sequence of tau pathology progression within the human medial temporal lobe and across regions in the posterior-medial system. Our objective was to study how medial temporal tau is related to functional connectivity, regional atrophy, and memory performance. We included 215 amyloid-ß- cognitively unimpaired, 81 amyloid-ß+ cognitively unimpaired and 87 amyloid-ß+ individuals with mild cognitive impairment, who each underwent 18F-RO948 tau and 18F-flutemetamol amyloid PET imaging, structural T1-MRI and memory assessments as part of the Swedish BioFINDER-2 study. First, event-based modelling revealed that the entorhinal cortex and Brodmann area 35 show the earliest signs of tau accumulation followed by the anterior and posterior hippocampus, Brodmann area 36 and the parahippocampal cortex. In later stages, tau accumulation became abnormal in neocortical temporal and finally parietal brain regions. Second, in cognitively unimpaired individuals, increased tau load was related to local atrophy in the entorhinal cortex, Brodmann area 35 and the anterior hippocampus and tau load in several anterior medial temporal lobe subregions was associated with distant atrophy of the posterior hippocampus. Tau load, but not atrophy, in these regions was associated with lower memory performance. Further, tau-related reductions in functional connectivity in critical networks between the medial temporal lobe and regions in the posterior-medial system were associated with this early memory impairment. Finally, in patients with mild cognitive impairment, the association of tau load in the hippocampus with memory performance was partially mediated by posterior hippocampal atrophy. In summary, our findings highlight the progression of tau pathology across medial temporal lobe subregions and its disease stage-specific association with memory performance. While tau pathology might affect memory performance in cognitively unimpaired individuals via reduced functional connectivity in critical medial temporal lobe-cortical networks, memory impairment in mild cognitively impaired patients is associated with posterior hippocampal atrophy.

Mild behavioral impairment and its relation to tau pathology in preclinical Alzheimer's disease.

Mild behavioral impairment (MBI) is suggested as risk marker for neurodegenerative diseases, such as Alzheimer's disease (AD). Recently, pathologic tau deposition in the brain has been shown closely related to clinical manifestations, such as cognitive deficits. Yet, associations between tau pathology and MBI have rarely been investigated. It is further debated if MBI precedes cognitive deficits in AD. Here, we explored potential mechanisms by which MBI is related to AD, this by studying associations between MBI and tau in preclinical AD. In all, 50 amyloid-ß-positive cognitively unimpaired subjects (part of the BioFINDER-2 study) underwent MBI-checklist (MBI-C) to assess MBI, and the Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-Cog) delayed word recall (ADAS-DR) to assess episodic memory. Early tau pathology was determined using tau-PET ([18F]RO948 retention in entorhinal cortex/hippocampus) and cerebrospinal fluid (CSF) P-tau181. Regression models were used to test for associations. We found that higher tau-PET signal in the entorhinal cortex/hippocampus and CSF P-tau181 levels were associated with higher MBI-C scores (ß = 0.010, SE = 0.003, p = 0.003 and ß = 1.263, SE = 0.446, p = 0.007, respectively). When MBI-C and ADAS-DR were entered together in the regression models, tau-PET (ß = 0.009, p = 0.009) and CSF P-tau181 (ß = 0.408, p = 0.006) were predicted by MBI-C, but not ADAS-DR. We conclude that in preclinical AD, MBI is associated with tau independently from memory deficits. This denotes MBI as an important early clinical manifestation related to tau pathology in AD.

Association Between Apolipoprotein E ε2 vs ε4, Age, and ß-Amyloid in Adults Without Cognitive Impairment.

Importance: Although the most common recent approach in Alzheimer disease drug discovery is to directly target the ß-amyloid (Aß) pathway, the high prevalence of apolipoprotein E ε4 (APOE ε4) in Alzheimer disease and the ease of identifying ε4 carriers make the APOE genotype and its corresponding protein (apoE) an appealing therapeutic target to slow Aß accumulation. Objective: To determine whether the ε2 allele is protective against Aß accumulation in the presence of the ε4 allele and evaluate how age and the APOE genotype are associated with emerging Aß accumulation and cognitive dysfunction. Design, Setting, and Participants: This cross-sectional study used screening data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease Study (A4 Study) collected from April 2014 to December 2017 and analyzed from November 2019 to July 2020. Of the 6943 participants who were a part of the multicenter clinical trial screening visit, 4432 were adults without cognitive impairment aged 65 to 85 years who completed a fluorine 18-labeled (18F)-florbetapir positron emission tomography scan, had APOE genotype information, and had a Clinical Dementia Rating of 0. Participants who were taking a prescription Alzheimer medication or had a current serious or unstable illness that could interfere with the study were excluded. Main Outcomes and Measures: Aß pathology, measured by 18F-florbetapir positron emission tomography and cognition, measured by the Preclinical Alzheimer Cognitive Composite. Results: A total of 4432 participants were included (mean [SD] age, 71.3 [4.7] years; 2634 women [59.4%]), with a mean (SD) of 16.6 (2.8) years of education and 1512 (34.1%) with a positive Aß level. APOE ε2 was associated with a reduction in both the overall (standardized uptake value ratio [SUVR], ε24, 1.11 [95% CI, 1.08-1.14]; ε34, 1.18 [95% CI, 1.17-1.19]) and the age-dependent level of Aß in the presence of ε4, with Aß levels in the APOE ε24 group (n = 115; ε24, 0.005 SUVR increase per year of age) increasing at less than half the rate with respect to increasing age compared with the APOE ε34 group (n = 1295; 0.012 SUVR increase per year of age; P = .04). The association between Aß and decreasing Preclinical Alzheimer Cognitive Composite scores did not differ by APOE genotype, and the reduced performance on the Preclinical Alzheimer Cognitive Composite in APOE ε4 carriers compared with noncarriers was completely mediated by Aß (unadjusted difference in composite scores between ε4 carriers and noncarriers = -0.084, P = .005; after adjusting for 18F-florbetapir = -0.006, P = .85; after adjusting for 18F-florbetapir and cardiovascular scores = -0.009, P = .78). Conclusions and Relevance: These findings suggest that the protective outcome of carrying an ε2 allele in the presence of an ε4 allele against Aß accumulation is important for potential treatments that attempt to biochemically mimic the function of the ε2 allele in order to facilitate Aß clearance in ε4 carriers. Such a treatment strategy is appealing, as ε4 carriers make up approximately two-thirds of patients with Alzheimer disease dementia. This strategy could represent an early treatment option, as many ε4 carriers begin to accumulate Aß in early middle age.

Late-Life Depression Is Associated With Reduced Cortical Amyloid Burden: Findings From the Alzheimer's Disease Neuroimaging Initiative Depression Project.

BACKGROUND: We evaluated the role of cortical amyloid deposition as a factor contributing to memory dysfunction and increased risk of dementia associated with late-life depression (LLD). METHODS: A total of 119 older adult participants with a current diagnosis of major depression (LLD) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) Depression Project study and 119 nondepressed (ND) cognitively unimpaired participants matched on age, sex, and APOE genotype were obtained from the ADNI database. RESULTS: Thirty-three percent of LLD participants met ADNI criteria for mild cognitive impairment. Compared with ND individuals, the LLD group exhibited less global amyloid beta (Aß) accumulation (p = .05). The proportion of amyloid positivity in the LLD group was 19.3% compared with 31.1% for the ND participants (p = .02). Among LLD participants, global Aß was not associated with lifetime number of depressive episodes, lifetime length of depression, length of lifetime selective serotonin reuptake inhibitor use, or lifetime length of untreated depression (p > .21 for all). Global Aß was associated with worse memory performance (p = .05). Similar results were found in secondary analyses restricting comparisons to the cognitively unimpaired LLD participants as well as when comparing the LLD group with an ND group that included participants with mild cognitive impairment. CONCLUSIONS: Contrary to expectation, the LLD group showed less Aß deposition than the ND group and Aß deposition was not associated with depression history characteristics. Aß was associated with memory, but this relationship did not differ between LLD and ND. Our results suggest that memory deficits and accelerated cognitive decline reported in previous studies of LLD are not due to greater cortical Aß accumulation.