New insights into atypical Alzheimer's disease in the era of biomarkers

Disruption of the default mode network is a hallmark of Alzheimer's disease, which has not been extensively examined in atypical phenotypes. We investigated cross-sectional and 1-year longitudinal changes in default mode network sub-systems in the visual and language variants of Alzheimer's disease, in relation to age and tau. Sixty-one amyloid-positive Alzheimer's disease participants diagnosed with posterior cortical atrophy (n = 33) or logopenic progressive aphasia (n = 28) underwent structural MRI, resting-state functional MRI and [18F]flortaucipir PET. One-hundred and twenty-two amyloid-negative cognitively unimpaired individuals and 60 amyloid-positive individuals diagnosed with amnestic Alzheimer's disease were included as controls and as a comparison group, respectively, and had structural and resting-state functional MRI. Forty-one atypical Alzheimer's disease participants, 26 amnestic Alzheimer's disease participants and 40 cognitively unimpaired individuals had one follow-up functional MRI ∼1-2 years after the baseline scan. Default mode network connectivity was calculated using the dual regression method for posterior, ventral, anterior ventral and anterior dorsal sub-systems derived from independent component analysis. A global measure of default mode network connectivity, the network failure quotient, was also calculated. Linear mixed-effects models and voxel-based analyses were computed for each connectivity measure. Both atypical and amnestic Alzheimer's disease participants had lower cross-sectional posterior and ventral and higher anterior dorsal connectivity and network failure quotient relative to cognitively unimpaired individuals. Age had opposite effects on connectivity in Alzheimer's disease participants and cognitively unimpaired individuals. While connectivity declined with age in cognitively unimpaired individuals, younger Alzheimer's disease participants had lower connectivity than the older ones, particularly in the ventral default mode network. Greater baseline tau-PET uptake was associated with lower ventral and anterior ventral default mode network connectivity in atypical Alzheimer's disease. Connectivity in the ventral default mode network declined over time in atypical Alzheimer's disease, particularly in older participants, with lower tau burden. Voxel-based analyses validated the findings of higher anterior dorsal default mode network connectivity, lower posterior and ventral default mode network connectivity and decline in ventral default mode network connectivity over time in atypical Alzheimer's disease. Visuospatial symptoms were associated with default mode network connectivity disruption. In summary, default mode connectivity disruption was similar between atypical and amnestic Alzheimer's disease variants, and discriminated Alzheimer's disease from cognitively unimpaired individuals, with decreased posterior and increased anterior connectivity and with disruption more pronounced in younger participants. The ventral default mode network declined over time in atypical Alzheimer's disease, suggesting a shift in default mode network connectivity likely related to tau pathology.

Posterior cortical atrophy and logopenic progressive aphasia are atypical clinical presentations of Alzheimer's disease. Resting-state functional connectivity studies have shown functional network disruptions in both phenotypes, particularly involving the language network in logopenic progressive aphasia and the visual network in posterior cortical atrophy. However, little is known about how connectivity differs both within and between brain networks in these atypical Alzheimer's disease phenotypes. A cohort of 144 patients was recruited by the Neurodegenerative Research Group at Mayo Clinic, Rochester, MN, USA, and underwent structural and resting-state functional MRI. Spatially preprocessed data were analysed to explore the default mode network and the salience, sensorimotor, language, visual and memory networks. The data were analysed at the voxel and network levels. Bayesian hierarchical linear models adjusted for age and sex were used to analyse within- and between-network connectivity. Reduced within-network connectivity was observed in the language network in both phenotypes, with stronger evidence of reductions in logopenic progressive aphasia compared to controls. Only posterior cortical atrophy showed reduced within-network connectivity in the visual network compared to controls. Both phenotypes showed reduced within-network connectivity in the default mode and sensorimotor networks. No significant change was noted in the memory network, but a slight increase in the salience within-network connectivity was seen in both phenotypes compared to controls. Between-network analysis in posterior cortical atrophy showed evidence of reduced visual-to-language network connectivity, with reduced visual-to-salience network connectivity, compared to controls. An increase in visual-to-default mode network connectivity was noted in posterior cortical atrophy compared to controls. Between-network analysis in logopenic progressive aphasia showed evidence of reduced language-to-visual network connectivity and an increase in language-to-salience network connectivity compared to controls. Findings from the voxel-level and network-level analysis were in line with the Bayesian hierarchical linear model analysis, showing reduced connectivity in the dominant network based on diagnosis and more crosstalk between networks in general compared to controls. The atypical Alzheimer's disease phenotypes were associated with disruptions in connectivity, both within and between brain networks. Phenotype-specific differences in connectivity patterns were noted in the visual network for posterior cortical atrophy and the language network for logopenic progressive aphasia.

Atypical Alzheimer's dementia: Addressing the subtypes, epidemiology, atypical presentations, diagnostic biomarkers, and treatment updates.

Bridging the Gap between Psychiatry and Neurology: Alzheimer's disease- symptoms beyond memory impairment

Recent studies have evaluated Alzheimer's disease (AD) associated with cerebrovascular and cardiovascular risk factors. Stroke history mediates association between late-onset AD and cardiovascular disease risk factors (Tosto et al., 2016). Our research investigated stroke as a potential moderator between polygenic risk score (PRS) and Alzheimer's disease. Participants were enrolled in the multi-ethnic Washington Heights-Inwood Columbia Aging Project (WHICAP). 653 non-Hispanic white and 2285 Caribbean Hispanic participants were included based on GWAS data and stroke status (self-reported history of stroke or MRI-visualized stroke). A concordance analysis assessed stroke group agreement. PRS from GWAS statistics was calculated for both populations. Following calculation of moderators by stroke status on population-specific PRS, binomial logistic regression models were conducted. Model outcome was Alzheimer's disease, which incorporated four diagnoses: Pure Alzheimer's disease, Probable Alzheimer's disease with Stroke, Alzheimer's disease with Parkinsonism, and Atypical Alzheimer's disease. Another set of models was conducted for the Caribbean Hispanic population towards a general outcome of Alzheimer's disease alone. Concordance analyses among all 4987 WHICAP participants showed Cohen's kappa of -0.033 and p of 0.001* (p* < 0.05), indicating no concordance between self-reported and MRI-visualized stroke groups; this is consistent with observation by Reitz et al., 2009. Within the Caribbean Hispanic population, MRI-visualized stroke models for Alzheimer's disease (four types) showed moderator significance (p of 0.002*, 0.007*, and 0.001* for Models 1, 2, 3 respectively) and MRI-visualized stroke models towards generalized Alzheimer's disease showed moderator significance (p of 0.152, 0.041*, and 0.020* for Models 1, 2, 3 respectively). Stroke is likely to be an important moderator of PRS and Alzheimer's disease risk in MRI-visualized stroke models, while a self-reported history of stroke was not related.

Baseline multimodal imaging to predict longitudinal clinical decline in atypical Alzheimer's disease

Alzheimer’s disease-related atrophy in the posterior cingulate cortex, a key node of the default mode network, is present in the early stages of disease progression across clinical phenotypic variants of the disease. In the typical amnestic variant, posterior cingulate cortex neuropathology has been linked with disrupted connectivity of the posterior default mode network, but it remains unclear if this relationship is observed across atypical variants of Alzheimer’s disease. In the present study, we first sought to determine if tau pathology is consistently present in the posterior cingulate cortex and other posterior nodes of the default mode network across the atypical Alzheimer’s disease syndromic spectrum. Second, we examined functional connectivity disruptions within the default mode network and sought to determine if tau pathology is related to functional disconnection within this network. We studied a sample of 25 amyloid-positive atypical Alzheimer’s disease participants examined with high-resolution MRI, tau (18F-AV-1451) PET, and resting-state functional MRI. In these patients, high levels of tau pathology in the posteromedial cortex and hypoconnectivity between temporal and parietal nodes of the default mode network were observed relative to healthy older controls. Furthermore, higher tau signal and reduced grey matter density in the posterior cingulate cortex and angular gyrus were associated with reduced parietal functional connectivity across individual patients, related to poorer cognitive scores. Our findings converge with what has been reported in amnestic Alzheimer’s disease, and together these observations offer a unifying mechanistic feature that relates posterior cingulate cortex tau deposition to aberrant default mode network connectivity across heterogeneous clinical phenotypes of Alzheimer’s disease.

Sleep-wake disturbances are a prominent feature of Alzheimer's disease (AD). Atypical (non-amnestic) AD syndromes have different patterns of cortical vulnerability to AD. We hypothesized that atypical AD also shows differential vulnerability in subcortical nuclei that will manifest as different patterns of sleep dysfunction. Overnight electroencephalography monitoring was performed on 48 subjects, including 15 amnestic, 19 atypical AD, and 14 controls. AD was defined based on neuropathological or biomarker confirmation. We compared sleep architecture by visual scoring and spectral power analysis in each group. Overall, AD cases showed increased sleep fragmentation and N1 sleep compared to controls. Compared to atypical AD groups, typical AD showed worse N3 sleep dysfunction and relatively preserved rapid eye movement (REM) sleep. Results suggest differing effects of amnestic and atypical AD variants on slow wave versus REM sleep, respectively, corroborating the hypothesis of differential selective vulnerability patterns of the subcortical nuclei within variants. Optimal symptomatic treatment for sleep dysfunction in clinical phenotypes may differ. Alzheimer's disease (AD) variants show distinct patterns of sleep impairment. Amnestic/typical AD has worse N3 slow wave sleep (SWS) impairment compared to atypical AD. Atypical AD shows more rapid eye movement deficits than typical AD. Selective vulnerability patterns in subcortical areas may underlie sleep differences. Relatively preserved SWS may explain better memory scores in atypical versus typical AD.

This presentation will first provide an overview of the rationale behind this Perspective Session bringing the Atypical Alzheimer's disease (AD) and Clinical Trials ISTAART Professional Interest Area (PIAs) together. We will then highlight foundational notions about atypical forms of Alzheimer's disease (AD) and critical shortcomings in current clinical trial designs that fail to address the unique needs of these populations. We will first briefly describe the distinct clinical and biological features of atypical AD variants, including posterior cortical atrophy (PCA), logopenic variant primary progressive aphasia (lvPPA), dysexecutive AD (dAD), and behavioral AD (bvAD). These variants are typically characterized by early‐onset symptoms and predominant non‐memory impairments, factors that have contributed to the significant underrepresentation of these patients in large‐scale clinical trials. Special attention will be given to recent FDA‐approved amyloid‐targeting therapies, which have largely focused on the “typical” amnestic, late‐onset presentation of AD, further underscoring the urgent need for inclusive research efforts for the broader phenotypic spectrum of the disease. We will identify critical gaps in clinical trial design for atypical AD and propose early strategic avenues to address these challenges. Key considerations include optimizing enrollment strategies, developing syndrome‐specific biological and clinical endpoints, and fostering advocacy to promote accurate diagnosis, equitable representation, and improved outcomes for these underrepresented populations.

Investigation of frailty as a moderator of the relationship between neuropathology and dementia in Alzheimer's disease: a cross-sectional analysis of data from the Rush Memory and Aging Project

BRIDGING THE GAP BETWEEN NEUROLOGY AND PSYCHIATRY-ATYPICAL PRESENTATION OF COMMON NEURODEGENERATIVE DISORDERS: Session 418

Given the challenges posed by the clinical diagnosis of atypical Alzheimer's disease (AD) variants and the limited imaging evidence available in the prodromal phases of atypical AD, we assessed brain hypometabolism patterns at the single-subject level in the AD variants spectrum. Specifically, we tested the accuracy of [18F]FDG-PET brain hypometabolism, as a biomarker of neurodegeneration, in supporting the differential diagnosis of atypical AD variants in individuals with dementia and mild cognitive impairment (MCI). We retrospectively collected N = 67 patients with a diagnosis of typical AD and AD variants according to the IWG-2 criteria (22 typical-AD, 15 frontal variant-AD, 14 logopenic variant-AD and 16 posterior variant-AD). Further, we included N = 11 MCI subjects, who subsequently received a clinical diagnosis of atypical AD dementia at follow-up (21 ± 11months). We assessed brain hypometabolism patterns at group- and single-subject level, using W-score maps, measuring their accuracy in supporting differential diagnosis. In addition, the regional prevalence of cerebral hypometabolism was computed to identify the most vulnerable core regions. W-score maps pointed at distinct, specific patterns of hypometabolism in typical and atypical AD variants, confirmed by the assessment of core hypometabolism regions, showing that each variant was characterized by specific regional vulnerabilities, namely in occipital, left-sided, or frontal brain regions. ROC curves allowed discrimination among AD variants and also non-AD dementia (i.e., dementia with Lewy bodies and behavioral variant of frontotemporal dementia), with high sensitivity and specificity. Notably, we provide preliminary evidence that, even in AD prodromal phases, these specific [18F]FDG-PET patterns are already detectable and predictive of clinical progression to atypical AD variants at follow-up. The AD variant-specific patterns of brain hypometabolism, highly consistent at single-subject level and already evident in the prodromal stages, represent relevant markers of disease neurodegeneration, with highly supportive diagnostic and prognostic role.

Imaging correlations of tau, amyloid, metabolism, and atrophy in typical and atypical Alzheimer's disease

Identifying individuals with early-stage Alzheimer's disease (AD) at greater risk of steeper clinical decline would enable better-informed medical, support and life planning decisions. Despite accumulating evidence on the clinical prognostic value of tau PET in typical late-onset amnestic AD, its utility in predicting clinical decline in individuals with atypical forms of AD remains unclear. Across heterogeneous clinical phenotypes, patients with atypical AD consistently exhibit abnormal tau accumulation in the posterior nodes of the default mode network of the cerebral cortex. This evidence suggests that tau burden in this functional network could be a common imaging biomarker for prognostication across the syndromic spectrum of AD. Here, we examined the relationship between baseline tau PET signal and the rate of subsequent clinical decline in a sample of 48 A+/T+/N+ patients with mild cognitive impairment or mild dementia due to AD with atypical clinical phenotypes: Posterior Cortical Atrophy (n = 16); logopenic variant Primary Progressive Aphasia (n = 15); and amnestic syndrome with multi-domain impairment and young age of onset < 65 years (n = 17). All patients underwent MRI, tau PET and amyloid PET scans at baseline. Each patient's longitudinal clinical decline was assessed by calculating the annualized change in the Clinical Dementia Rating Sum-of-Boxes (CDR-SB) scores from baseline to follow-up (mean time interval = 14.55 ± 3.97 months). Atypical early AD patients showed an increase in CDR-SB by 1.18 ± 1.25 points per year: t(47) = 6.56, P < 0.001, Cohen's d = 0.95. Across clinical phenotypes, baseline tau in the default mode network was the strongest predictor of clinical decline (R2 = 0.30), outperforming a simpler model with baseline clinical impairment and demographic variables (R2 = 0.10), tau in other functional networks (R2 = 0.11-0.26) and the magnitude of cortical atrophy (R2 = 0.20) and amyloid burden (R2 = 0.09) in the default mode network. Overall, these findings point to the contribution of default mode network tau to predicting the magnitude of clinical decline in atypical early AD patients 1 year later. This simple measure could aid the development of a personalized prognostic, monitoring and treatment plan, which would help clinicians not only predict the natural evolution of the disease but also estimate the effect of disease-modifying therapies on slowing subsequent clinical decline given the patient's tau burden while still early in the disease course.

BackgroundStudies suggest that plasma Alzheimer's disease (AD) biomarkers may aid in the overall diagnosis of AD, but their utility among patients with atypical clinical presentations of AD are unknown.ObjectiveThe main objective of this study was to determine the relationship between amyloid-β (Aβ) and tau plasma biomarkers and PET measures of both Aβ and tau in atypical AD. The secondary objective was to determine if plasma biomarkers could differentiate patients with different atypical AD phenotypes and whether they were related to measures of disease severity.MethodsWe assessed whether plasma p-tau 181 and Aβ42/40 were associated with Aβ and tau PET uptake, clinical phenotype and severity in 77 patients with PET biomarker-confirmed atypical AD.ResultsPlasma Aβ42/40 ratio showed positive associations with tau PET uptake, with higher (more normal) Aβ42/40 ratio associated with higher tau uptake; the ratio was not associated with Aβ PET. No associations were noted with plasma p-tau 181. Plasma Aβ42/40 ratio and p-tau 181 concentrations were not associated with AD phenotype or cognitive severity.ConclusionPlasma Aβ42/40 ratio and p-tau 181 concentrations are not associated with amyloid or tau PET or with clinical severity among individuals presenting with atypical AD.