Because of the complexity of Alzheimer’s Disease (AD) clinical presentations across bio-psycho-social domains of functioning, data-reduction approaches, such as latent profile analysis (LPA), can be useful for studying profiles rather than individual symptoms. Previous LPA research has resulted in more precise characterization and understanding of patients, better clarity regarding the probability and rate of disease progression, and an empirical approach to identifying those who might benefit most from early intervention. Whereas previous LPA research has revealed useful cognitive, neuropsychiatric, or functional subtypes of patients with AD, no study has identified patient profiles that span the domains of health and functioning and that also include motor and sensory functioning.

LPA was conducted with data from the Advancing Reliable Measurement in Alzheimer’s Disease and cognitive Aging study. Participants were 209 older adults with amnestic mild cognitive impairment (aMCI) or mild dementia of the Alzheimer’s type (DAT). LPA indicator variables were from the NIH Toolbox® and included cognitive, emotional, social, motor, and sensory domains of functioning.

The data were best modeled with a 4-profile solution. The latent profiles were most differentiated by indices of social and emotional functioning and least differentiated by motor and sensory function.

These multi-domain patient profiles support and extend previous findings on single-domain profiles and highlight the importance of social and emotional factors for understanding patient experiences of aMCI/DAT. Future research should investigate these profiles further to better understand risk and resilience factors, the stability of these profiles over time, and responses to intervention.

Depressive symptoms are common in mild cognitive impairment (MCI). These may be associated with poorer cognitive function and increased risks of dementia transition.

We aimed to examine the cognitive patterns associated with variations in depressive symptoms in neurodegenerative MCI without a primary mood disorder.

Individuals with MCI (n = 123), including MCI due to Alzheimer’s disease (n = 54) and MCI with Lewy bodies (n = 69), underwent repeated annual assessment of cognitive function and concurrent depressive symptoms using the Addenbrooke’s Cognitive Examination-Revised and the Geriatric Depression Scale-15, respectively.

Between- and within-person differences in depressive symptoms were disaggregated and related to between- and within-person cognitive differences and modification of cognitive performance trajectories over time.

There was strong evidence of a state-based association between depressive symptoms and cognitive function. Intra-individual differences in depressive symptoms were negatively associated with concurrent cognitive performance such that a 2-point increase in depressive score explained a 1-point decrease in cognitive score, on average (point estimate −0.56, 95% credibile interval (CrI) −1.05 to −0.08).

The data did not support a trait-based association between depressive symptoms and cognitive performance (point estimate 0.10, 95% CrI −0.42 to 0.59), nor any between- or within-person trajectory modification associated with depressive symptoms.

Within-person variations in depressive symptom severity are associated with acute cognitive performance differences. Cognitive scores derived during active depressive periods may underestimate longer-term cognitive capabilities. Treating depressive symptoms in MCI may clarify underlying cognitive performance capacity, and help maintain optimal cognitive function for longer.

Cognitive intra-individual variability (IIV) is a neuropsychological marker reflecting divergent performance across cognitive domains. In this brief communication, we examined whether clinical severity, apolipoprotein E (APOE) ε4 carriers, and higher polygenic risk were associated with higher cognitive IIV, and whether higher polygenic risk and cognitive IIV synergistically influence clinical severity.

This large study involved up to 24,248 participants (mean age = 72) from the National Alzheimer’s Coordinating Center (NACC) and multiple regression controlling for age, sex, and education was used to analyze the data.

We found that disease severity (B = 0.055, SE = 0.001, P < 0.001), APOE ε4 carriers (B = 0.02, SE = 0.003, P < 0.001), and higher polygenic risk (B = 0.02, SE = 0.004, P < 0.001) were associated with higher cognitive IIV. Polygenic risk and cognitive IIV also interacted to influence clinical severity, beyond APOE ε4 (B = 0.11, SE = 0.05, P = 0.02), such that individuals with high polygenic risk and cognitive IIV had the greatest clinical severity.

Heightened polygenic risk and increased cross-domain cognitive variation are implicated in dementia and may impact clinical decline in tandem.

Post-traumatic stress disorder (PTSD) and hypertension are highly prevalent among Veterans. Cognitive dispersion, indicating within-person variability across neuropsychological measures at one time point, is associated with increased risk of dementia. We examined interactive effects of PTSD symptom severity and hypertension on cognitive dispersion among older Veterans.

We included 128 Vietnam-era Veterans from the Department of Defense-Alzheimer’s Disease Neuroimaging Initiative (DoD-ADNI) with a history of PTSD. Regression models examined interactions between PTSD symptom severity and hypertension on cognitive dispersion (defined as the intraindividual standard deviation across eight cognitive measures) adjusting for demographics and comorbid vascular risk factors.

There was an interaction between PTSD symptom severity and hypertension on cognitive dispersion (p = .026) but not on mean cognitive performance (p = .543). Greater PTSD symptom severity was associated with higher cognitive dispersion among those with hypertension (p = .002), but not among those without hypertension (p = .531). Results remained similar after adjusting for mean cognitive performance.

Findings suggest, among older Veterans with PTSD, those with both hypertension and more severe PTSD symptoms may be at greater risk for cognitive difficulties. Further, cognitive dispersion may be a useful marker of subtle cognitive difficulties. Future research should examine these associations longitudinally and in a diverse sample.

Mild behavioural impairment (MBI) is a neurobehavioral prodrome to dementia with multiple phenotypic characteristics. To investigate the complex neurobiological substrate underlying MBI, we evaluated its association with a composite magnetic resonance imaging (MRI)-based measure of concomitant cerebrovascular disease (CeVD) and neurodegeneration; and the interaction effects of MBI and MRI scores on cognitive and clinical trajectory.

253 dementia-free participants (mean age = 71.9, follow-up period = 49.89 months) from 2 memory clinics were included in this study. 37 (14.6%) participants met clinical diagnostic criteria for MBI, ascertained by repeated neuropsychiatric inventory assessments. MRI scores were computed using a validated weighted sum of white matter hyperintensities volume, presence of infarct, hippocampal volume, and cortical thickness of known Alzheimer’s disease-associated regions. Clinical and cognitive outcomes were evaluated annually using the Clinical Dementia Rating sum-of-boxes (CDR-SB) and standardised global cognitive scores of a comprehensive neuropsychological battery respectively.

Lower MRI scores, indicating greater burden of comorbid CeVD and neurodegeneration, yielded a 3.8-fold likelihood of MBI compared to 1.5-fold with larger WMH volume or lower cortical thickness individually. Interaction analyses showed that MBI participants with low MRI scores had greater increase in CDR-SB (B = 0.05, SE = 0.01, p < 0.001) over time. All models involving the composite MRI measure yielded a better fit compared to reduced models with either pathology alone.

MBI is associated with a composite MRI measure that reflects mixed pathologies of dementia and their co-evaluation may improve risk profiling and identification of memory clinic patients without dementia who are at the highest risk of experiencing clinical decline.

Novel ultrasound neuromodulation techniques allow therapeutic brain stimulation with unmet precision and non-invasive targeting of deep brain areas. Transcranial pulse stimulation (TPS), a multifrequency sonication technique, is approved for the clinical treatment of Alzheimer’s disease (AD). Here, we present the largest real-world retrospective analysis of ultrasound neuromodulation therapy in dementia (AD, vascular, mixed) and mild cognitive impairment (MCI).

The consecutive sample involved 58 patients already receiving state-of-the-art treatment in an open-label, uncontrolled, retrospective study. TPS therapy typically comprises 10 sessions (range 8–12) with individualized MRI-based target areas defined according to brain pathology and individual pathophysiology. We compared the CERAD-Plus neuropsychological test battery results before and after treatment, with the CERAD Corrected Total Score ( CTS) as the primary outcome. Furthermore, we analyzed side effects reported by patients during the treatment period.

CERAD Corrected Total Score (CTS) significantly improved (p = .017, d = .32) after treatment (Baseline: M = 56.56, SD = 18.56; Post-treatment: M = 58.65, SD = 19.44). The group of top-responders (top quartile) improved even by 9.8 points. Fewer than one-third of all patients reported any sensation during treatment. Fatigue and transient headaches were the most common, with no severe adverse events.

The findings implicate TPS as a novel and safe add-on therapy for patients with dementia or MCI with the potential to further improve current state-of-the-art treatment results. Despite the individual benefits, further randomized, sham-controlled, longitudinal clinical trials are needed to differentiate the effects of verum and placebo.

Previous research has shown abnormal functional network gradients in Alzheimer’s disease (AD). Structural network gradient is capable of capturing continuous changes in brain morphology and has the ability to elucidate the underlying processes of neurodevelopment. However, it remains unclear whether structural network gradients are altered in AD and what associations exist between these changes and cognitive function, and gene expression profiles.

By constructing an individualized structural network gradient decomposition framework, we calculated the morphological similarity network (MSN) gradients for 404 subjects (186 AD patients and 218 normal controls). We investigated AD-related alterations in MSN gradients, along with the associations between MSN gradients and cognitive function, MSN topological properties, and gene expression profiles.

Our findings indicated that the principal MSN gradient alterations in AD were primarily characterized by an increase in the primary and secondary sensory cortices and a decrease in the association cortex 1. The primary and higher-order cortices exhibited opposite associations with cognition, including executive function, language skills, and memory processes. Moreover, the principal MSN gradients were found to significantly predict cognitive function in AD. The altered gradient pattern was 14.8% attributable to gene expression profiles, and the genes demonstrating the highest correlation are involved in metabolic activity and synaptic signaling.

Our results offered novel insights into the underlying mechanisms of structural brain network impairment in AD patients, enhancing our understanding of the neurobiological processes responsible for impaired cognition in patients with AD, and offering a new dimensional structural biomarker for AD.