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The biological mechanisms underlying the increased prevalence of Alzheimer’s disease (AD) in women remain undefined. While previous case/control studies have identified sex-biased molecular pathways, the sex-specific relationships between gene expression and AD endophenotypes, particularly involving sex chromosomes, are underexplored. With bulk transcriptomic data across 3 brain regions from 767 decedents, we investigated sex-specific associations between gene expression and post-mortem β-amyloid and tau, as well as antemortem longitudinal cognition. Among 23,118 significant gene associations, 10% were sex-specific, with 73% of these identified in females and primarily associated with tau tangles and longitudinal cognition (90%). Notably, four X-linked genes, MCF2 , HDAC8 , FTX , and SLC10A3 , demonstrated significant sex differences in their associations with AD endophenotypes (i.e., significant sex x gene interaction). Our results also uncovered sex-specific biological pathways, including a female-specific role of neuroinflammation and neuronal development, underscoring the importance of sex-aware analyses to advance precision medicine approaches in AD. The genetic basis of sex differences in Alzheimer’s disease (AD) is not well characterized. Here, authors report 2,320 sex-specific gene associations with 3 AD endophenotypes using bulk RNAseq data from 3 brain regions in ROS/MAP.

Objectives There is a lack of consensus regarding what constitutes cognitively normal performance on the Montreal Cognitive Assessment (MoCA) based on demographic characteristics. Further, research regarding normative data on the MoCA for middle‐aged individuals is relatively limited. The current study sought to provide age‐ and education‐corrected normative data for the MoCA in a large epidemiological cohort of cognitively healthy middle‐aged and older adults with characteristics similar to the original validation sample of the MoCA. Methods Participants were from Generation 3 and Omni 2 cohorts of the Framingham Heart Study (n = 2637; 91.43% non‐Hispanic White) who were determined to be cognitively unimpaired at the time of MoCA assessment (Mean age = 53.56 years, age range = 32–83 years, 63.71% ≥ college‐educated). Normative data were generated by age in 10‐year intervals and education (≤ high school, some college, or ≥ college degree). Analysis of variance was used to examine the relationship between MoCA performance, age, and education. Results The average MoCA score across all participants was close to the revised MCI cutoff of 23 (M = 24.69, SD = 3.03). The average MoCA score for individuals over the age of 60 was below the recently suggested MCI cutoff score of 23 points. Similarly, individuals above the age of 70 scored below the revised cutoff score of 23 points, irrespective of level of education. Further, performance of participants below the age of 40 who were college educated was similar to the frequently used original MCI cutoff score of 26 (M = 26.28, SD = 2.41). Conclusions Results are consistent with previous literature suggesting that the original MoCA cutoff score of 26 may result in a high rate of false positives. Findings indicate that the recently suggested MCI cutoff score of 23 on the MoCA may also be artificially high. Using inappropriate normative data for the MoCA can impact diagnostic accuracy as well as misclassification in research settings. These findings highlight the need for the use of demographically appropriate, population‐based normative data for the MoCA in clinical and research settings.

Abstract Introduction Subjective cognitive decline (SCD) may indicate unhealthy cognitive changes, but no standardized SCD measurement exists. This pilot study aimed to identify reliable SCD questions. Methods A total of 112 cognitively normal (NC; 76 ± 8 years; 63% female), 43 mild cognitive impairment (MCI; 77 ± 7 years; 51% female), and 33 diagnostically ambiguous participants (79 ± 9 years; 58% female) were recruited from a research registry and completed 57 self-report SCD questions. Psychometric methods were used for item reduction. Results Factor analytic models assessed unidimensionality of the latent trait (SCD); 19 items were removed with extreme response distribution or trait-fit. Item response theory (IRT) provided information about question utility; 17 items with low information were dropped. Post hoc simulation using computerized adaptive test (CAT) modeling selected the most commonly used items (n = 9 of 21 items) that represented the latent trait well ( r  = 0.94) and differentiated NC from MCI participants ( F [1, 146] = 8.9, P  = .003). Discussion IRT and CAT modeling identified nine reliable SCD items. This pilot study is a first step toward refining SCD assessment in older adults. Replication of these findings and validation with Alzheimer's disease biomarkers will be an important next step for the creation of a SCD screener.

Recent evidence suggests that Alzheimer’s disease (AD) genetic risk variants (rs1582763 and rs6591561) of the MS4A locus are genome-wide significant regulators of soluble TREM2 levels such that the minor allele of the protective variant (rs1582763) is associated with higher sTREM2 and lower AD risk while the minor allele of (rs6591561) relates to lower sTREM2 and higher AD risk. Our group previously found that higher sTREM2 relates to higher Aβ 40 , worse blood–brain barrier (BBB) integrity (measured with the CSF/plasma albumin ratio), and higher CSF tau, suggesting strong associations with amyloid abundance and both BBB and neurodegeneration complicate interpretation. We expand on this work by leveraging these common variants as genetic tools to tune the interpretation of high CSF sTREM2, and by exploring the potential modifying role of these variants on the well-established associations between CSF sTREM2 as well as TREM2 transcript levels in the brain with AD neuropathology. Biomarker analyses leveraged data from the Vanderbilt Memory & Aging Project ( n  = 127, age = 72 ± 6.43) and were replicated in the Alzheimer’s Disease Neuroimaging Initiative ( n  = 399, age = 73 ± 7.39). Autopsy analyses were performed leveraging data from the Religious Orders Study and Rush Memory and Aging Project ( n  = 577, age = 89 ± 6.46). We found that the protective variant rs1582763 attenuated the association between CSF sTREM2 and Aβ 40 (β = -0.44, p -value = 0.017) and replicated this interaction in ADNI (β = -0.27, p = 0.017). We did not observe this same interaction effect between TREM2 mRNA levels and Aβ peptides in brain (Aβ total β = -0.14, p =  0.629; Aβ 1-38 , β = 0.11, p =  0.200). In contrast to the effects on Aβ, the minor allele of this same variant seemed to enhance the association with blood–brain barrier dysfunction (β = 7.0e-4, p =  0.009), suggesting that elevated sTREM2 may carry a much different interpretation in carriers vs. non-carriers of this allele. When evaluating the risk variant (rs6591561) across datasets, we did not observe a statistically significant interaction against any outcome in VMAP and observed opposing directions of associations in ADNI and ROS/MAP on Aβ levels. Together, our results suggest that the protective effect of rs1582763 may act by decoupling the associations between sTREM2 and amyloid abundance, providing important mechanistic insight into sTREM2 changes and highlighting the need to incorporate genetic context into the analysis of sTREM2 levels, particularly if leveraged as a clinical biomarker of disease in the future.

Neuroaxonal damage may contribute to cognitive changes preceding clinical dementia. Accessible biomarkers are critical for detecting such damage. Plasma and cerebrospinal fluid (CSF) neurofilament light (NFL) were related to neuropsychological performance among Vanderbilt Memory & Aging Project participants (plasma n = 333, 73 ± 7 years; CSF n = 149, 72 ± 6 years) ranging from normal cognition (NC) to mild cognitive impairment (MCI). Models adjusted for age, sex, race/ethnicity, education, apolipoprotein E ε4 carriership, and Framingham Stroke Risk Profile. Plasma NFL was related to all domains (P values ≤ .008) except processing speed (P values ≥ .09). CSF NFL was related to memory and language (P values ≤ .04). Interactions with cognitive diagnosis revealed widespread plasma associations, particularly in MCI participants, which were further supported in head-to-head comparison models. Plasma and CSF NFL (reflecting neuroaxonal injury) relate to cognition among non-demented older adults albeit with small to medium effects. Plasma NFL shows particular promise as an accessible biomarker with relevance to cognition in MCI. •Plasma and cerebrospinal fluid neurofilament light (NFL) were moderately correlated.•Cerebrospinal fluid NFL was related to language and memory functions.•Plasma NFL exhibited widespread cognitive associations.•Plasma NFL associations were particularly robust in mild cognitive impairment.

Biomarker definitions for preclinical Alzheimer's disease (AD) have identified individuals with neurodegeneration (ND+) without β-amyloidosis (Aβ-) and labeled them with suspected non-AD pathophysiology (SNAP). We evaluated Apolipoprotein E (APOE) ε2 and ε4 allele frequencies across biomarker definitions-Aβ-/ND- (n = 268), Aβ+/ND- (n = 236), Aβ-/ND+ or SNAP (n = 78), Aβ+/ND+ (n = 204)-hypothesizing that SNAP would have an APOE profile comparable to Aβ-/ND-. Using AD Neuroimaging Initiative data (n = 786, 72±7 years, 48% female), amyloid status (Aβ+ or Aβ-) was defined by cerebrospinal fluid (CSF) Aβ-42 levels, and neurodegeneration status (ND+ or ND-) was defined by hippocampal volume from MRI. Binary logistic regression related biomarker status to APOE ε2 and ε4 allele carrier status, adjusting for age, sex, education, and cognitive diagnosis. Compared to the biomarker negative (Aβ-/ND-) participants, higher proportions of ε4 and lower proportions of ε2 carriers were observed among Aβ+/ND- (ε4: OR = 6.23, p<0.001; ε2: OR = 0.53, p = 0.03) and Aβ+/ND+ participants (ε4: OR = 12.07, p<0.001; ε2: OR = 0.29, p = 0.004). SNAP participants were statistically comparable to biomarker negative participants (p-values>0.30). In supplemental analyses, comparable results were observed when coding SNAP using amyloid imaging and when using CSF tau levels. In contrast to APOE, a polygenic risk score for AD that excluded APOE did not show an association with amyloidosis or neurodegeneration (p-values>0.15), but did show an association with SNAP defined using CSF tau (β = 0.004, p = 0.02). Thus, in a population with low levels of cerebrovascular disease and a lower prevalence of SNAP than the general population, APOE and known genetic drivers of AD do not appear to contribute to the neurodegeneration observed in SNAP. Additional work in population based samples is needed to better elucidate the genetic contributors to various etiological drivers of SNAP.

Physical activity has emerged as a modifiable behavioral factor to improve cognitive function. However, research on adherence to remote monitoring of physical activity in older adults is limited. This study aimed to assess adherence to remote monitoring of physical activity in older adults within a pilot cohort from objective user data, providing insights for the scalability of such monitoring approaches in larger, more comprehensive future studies. This study included 22 participants from the Boston University Alzheimer's Disease Research Center Clinical Core. These participants opted into wearing the Verisense watch as part of their everyday routine during 14-day intervals every 3 months. Eighteen continuous physical activity measures were assessed. Adherence was quantified daily and cumulatively across the follow-up period. The coefficient of variation was used as a key metric to assess data consistency across participants over multiple days. Day-to-day variability was estimated by calculating intraclass correlation coefficients using a 2-way random-effects model for the baseline, second, and third days. Adherence to the study on a daily basis outperformed cumulative adherence levels. The median proportion of adherence days (wearing time surpassed 90% of the day) stood at 92.1%, with an IQR spanning from 86.9% to 98.4%. However, at the cumulative level, 32% (7/22) of participants in this study exhibited lower adherence, with the device worn on fewer than 4 days within the requested initial 14-day period. Five physical activity measures have high variability for some participants. Consistent activity data for 4 physical activity measures might be attainable with just a 3-day period of device use. This study revealed that while older adults generally showed high daily adherence to the wearable device, consistent usage across consecutive days proved difficult. These findings underline the effectiveness of wearables in monitoring physical activity in older populations and emphasize the ongoing necessity to simplify usage protocols and enhance user engagement to guarantee the collection of precise and comprehensive data.

INTRODUCTION Subjective cognitive complaints (SCC) can precede Alzheimer's disease and related dementias. SCC in the absence of objective impairment is termed subjective cognitive decline (SCD). This study aimed to characterize SCC and SCD among a sample of aging individuals with and without prior repetitive head impact (RHI) exposure, the former of whom are at risk for chronic traumatic encephalopathy (CTE). METHODS RHI‐exposed (N = 167) and non–RHI‐exposed (N = 317) Boston University Alzheimer's Disease Research Center (ADRC) participants and their informants completed subjective measures assessing memory and executive function. Participants completed objective tests of these domains. RESULTS RHI exposure was associated with greater self‐ and informant‐reported SCC and with over four‐fold increased odds of SCD among cognitively unimpaired participants (odds ratio = 4.10, p < 0.001). SCC was associated with objective measures in RHI and non‐RHI participants. DISCUSSION Among RHI‐exposed individuals, SCC align with objective cognitive performance. SCD warrants investigation as potential early indicator of RHI‐related neuropathologies. Highlights Subjective cognitive complaints (SCC) are common after repetitive head impacts (RHI). RHI status is associated with increased odds of subjective cognitive decline (SCD). Neuropsychiatric symptoms are associated with SCC in RHI‐exposed individuals. SCC may indicate underlying post‐traumatic neuropathology in RHI‐exposed individuals.

INTRODUCTION Plasma phosphorylated tau‐181 (p‐tau181) associations with global cognition and memory are clear, but the link between p‐tau181 with other cognitive domains and subjective cognitive decline (SCD) across the clinical spectrum of Alzheimer's disease (AD) and how this association changes based on genetic and demographic factors is poorly understood. METHODS Participants were drawn from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and included 1185 adults >55 years of age with plasma p‐tau181 and neuropsychological test data. Linear regression models related plasma p‐tau181 to neuropsychological composite and SCD scores with follow‐up models examining plasma p‐tau181 interactions with cognitive diagnosis, apolipoprotein E (APOE) ε4 carrier status, age, and sex on cognitive outcomes. RESULTS Higher plasma p‐tau181 level was associated with worse memory, executive functioning, and language abilities, and greater informant‐reported SCD. Visuospatial abilities and self‐report SCD were not associated with plasma p‐tau181. Associations were generally stronger in mild cognitive impairment (MCI) or dementia, APOE ε4 carriers, women, and younger participants. DISCUSSION Higher levels of plasma p‐tau181 are associated with worse neuropsychological test performance across multiple cognitive domains; however, these associations vary based on disease stage, genetic risk status, age, and sex. Highlights Greater plasma p‐tau181 was associated with lower cognition across most domains. Associations between p‐tau181 and cognition were modified by age and sex. Level of p‐tau181 was more strongly associated with cognition in people with mild cognitive impairment (MCI) and apolipoprotein E (APOE) ε4.

Introduction It is unclear how rates of white matter microstructural decline differ between normal aging and abnormal aging. Methods Diffusion MRI data from several well‐established longitudinal cohorts of aging (Alzheimer's Disease Neuroimaging Initiative [ADNI], Baltimore Longitudinal Study of Aging [BLSA], Vanderbilt Memory & Aging Project [VMAP]) were free‐water corrected and harmonized. This dataset included 1723 participants (age at baseline: 72.8 ± 8.87 years, 49.5% male) and 4605 imaging sessions (follow‐up time: 2.97 ± 2.09 years, follow‐up range: 1–13 years, mean number of visits: 4.42 ± 1.98). Differences in white matter microstructural decline in normal and abnormal agers was assessed. Results While we found a global decline in white matter in normal/abnormal aging, we found that several white matter tracts (e.g., cingulum bundle) were vulnerable to abnormal aging. Conclusions There is a prevalent role of white matter microstructural decline in aging, and future large‐scale studies in this area may further refine our understanding of the underlying neurodegenerative processes. HIGHLIGHTS Longitudinal data were free‐water corrected and harmonized. Global effects of white matter decline were seen in normal and abnormal aging. The free‐water metric was most vulnerable to abnormal aging. Cingulum free‐water was the most vulnerable to abnormal aging.