Women are at greater risk of developing sporadic Alzheimer's disease (AD). While their longer lifespans contribute to AD-risk, this factor does not fully explain the observed sex differences. Increased glial activation and neuroinflammation associated with female-sex may play a role. Glial fibrillary acidic protein (GFAP), a marker of astrocyte activation and neuroinflammation, has been linked to AD- risk. In preclinical and prodromal AD, higher brain GFAP levels are associated with cognitive decline, Aβ deposition, tau spread, and neurodegeneration associated with AD. Studies have reported that plasma GFAP levels are higher in women compared to men, but few have thoroughly examined this influence. This prompted us to examine sex-differences in plasma GFAP in cognitively unimpaired older adults and its relationship to cognitive performance and other plasma AD biomarkers, both at baseline and longitudinally. Participants were enrolled in the Memory Education and Research Initiative (MERI) program and completed a neuropsychological battery, clinical and psychiatric evaluation, and blood draw. Plasma GFAP, Aβ42, Aβ40 concentrations were measured using single-molecule array (SIMOA) platform. Participants were included if they gave blood (2+ timepoints), MMSE>23 at Baseline, and age 50-85. Analysis of covariance (ANCOVA) was conducted to assess for sex differences, and longitudinal analyses using linear mixed models were conducted to examine associations with cognition. A total 325 MERI (mean age=72 years; 59% females) were included in the analysis. ANCOVA, controlling for age, showed significantly higher plasma GFAP levels in females compared to males ( p  = 0.001). Longitudinal analysis of 229 MERI revealed that higher baseline GFAP is associated with lower MMSE scores over time (Figure 1, p  = 0.002). When stratified by sex, these associations remained significant in females but not males ( p  = 0.002). GFAP was also inversely associated with Aβ42/40 over time (Figure 2, p  <0.001) in females. Cognitively unimpaired females had higher levels of plasma GFAP compared to males. Moreover, elevated GFAP levels associated with greater decline in global cognition and lower Aβ42/40 in females but not males. These findings suggest increased astrocytic activation that may lead to cognitive decline in females. More studies are needed to understand how sex-differences in neuroinflammation may impact future AD-risk. Potential mechanisms will be discussed.

BACKGROUND:Alzheimer's disease (AD) detection with blood-based biomarkers promises to revolutionise dementia diagnosis. However, blood testing is still a challenge in remote settings. Cognitive testing that is sensitive to plasma biomarker levels can be a useful proxy. A common test for dementia assessment is the logical memory test (LMT) - where a story is read out loud to the individual and then freely recalled. Alongside standard metrics, item-based metrics, such as recall of proper names and serial positions, are effective at detecting AD-related pathology. We set out to compare a range of LMT metrics against plasma AD biomarkers, and examine differences between men and women. METHODS:The Wisconsin Registry for Alzheimer's Prevention cohort was used for analysis: participants (n = 1195, 69% women; mean age = 67.2, SD = 7.7) were free from dementia. Data included logical memory performance, demographics, clinical and genetic information, and plasma biomarkers. Analyses were cross-sectional with a maximum of two years between assessment and biomarker extraction. We carried out multiverse analyses to allow comparison of alternative models with permutations of covariates. RESULTS:In the full sample, associations were most stable between LMT scores and p-tau217, and were significant across all models, while associations with other plasma biomarkers were generally less reliable. In the stratified analyses, associations were overall more robust and consistent in women than in men. DISCUSSION:Current findings show LMT metrics are consistently associated with in vivo levels of pathology as measured by plasma p-tau217. The discrepancies observed between men and women require further investigation.

INTRODUCTION:Astrocyte reactivity may contribute to increased Alzheimer's disease (AD) risk in women. Although higher plasma glial fibrillary acidic protein (GFAP) levels have been reported in women, few studies have investigated sex-specific relationships with other plasma AD biomarkers and cognition. METHODS:Participants were enrolled in the Memory Education and Research Initiative, a longitudinal community-based cohort, and underwent evaluation including blood biomarker sampling. The Alzheimer's Disease Neuroimaging Initiative (ADNI) was included as a replication cohort. RESULTS:Unimpaired women exhibited higher plasma GFAP levels than men (N=584). Higher baseline GFAP was associated with worse longitudinal episodic memory, exclusively in women. In addition, both higher baseline and increasing GFAP levels over time were associated with lower longitudinal plasma Aβ42/40 ratio. The key results were replicated in the ADNI cohort. DISCUSSION:These findings suggest that astrocytic reactivity is more pronounced in women and may contribute to sex-specific vulnerability to AD-related pathology and cognitive decline.

Background Previous work has shown that proper name recall from the Logical Memory (LM) task is sensitive to PET and cerebrospinal fluid biomarkers of Alzheimer's disease (AD) in older adult populations. These findings indicate potential utility in identifying preclinical AD. Objective The purpose of this study is to validate previous findings of the association of proper name recall and blood-based plasma pTau217. Methods Participants came from the Wisconsin Registry for Alzheimer's Prevention study. We fit linear mixed effects models of longitudinal LM and proper name recall as a function of most recent pTau217 values. Follow-up analyses added interaction terms to models for group differences in sex and APOE ε4 allele carriage. As an exploratory aim, logistic regression models were used to examine if proper name recall aided in predicting clinical diagnosis. Results Participants with higher concentrations of pTau217 showed a steeper decline on both conventional LM and proper name recall. APOE ε4 allele carriers with higher concentrations of pTau217 showed a greater decline in longitudinal task performance, while there was no significant interaction for sex, indicating that men and women with high pTau217 show similar rates of decline. Conclusions Our findings validate that proper name recall is sensitive to blood-based pTau217. Measuring proper name recall may be an efficient marker assessing early cognitive change that could be leveraged when designing future cognitive tests.

Objective: Blood-based biomarkers are valued for their lower cost and less invasive nature, though issues with widespread implementation and accessibility remain. Process-based scores from story recall have been shown to detect neuronal network disturbances typical of Alzheimer's disease (AD) pathology more effectively than traditional metrics. This study examined the associations between process-based scores and concurrent plasma AD biomarkers in older adults without dementia, while also comparing them to traditional metrics. Additionally, it also investigated the diagnostic utility of these metrics in detecting plasma p-tau217 positivity. Methods: Data from 416 participants (mean age = 66.6 ± 7) free of dementia were extracted from the Wisconsin Registry for Alzheimer's Prevention (WRAP). Logical Memory Test (LMT) and plasma p-tau217, p-tau181, p-tau231, Aβ42/Aβ40 ratio, GFAP and NfL levels were analyzed. Bayesian regression models assessed associations between plasma biomarkers and both process-based and traditional LMT scores, controlling for the covariates. Results: The best-fitting model for plasma p-tau217 included Total ratio (Tr) and Immediate recall (BF10=573), but Tr showed stronger evidence of association (mean coefficient = 0.208; BFinclusion=14.4) than Immediate recall (mean coefficient=-0.007; BFinclusion=1.7). Tr was also the best predictor of plasma p-tau181 (mean coefficient = 0.144; BF10=10.5) and GFAP (mean coefficient = 0.141; BF10=5.8), outperforming traditional LMT scores. No memory scores were associated with plasma p-tau231 or Aβ42/40 ratio levels. Tr score was the strongest single predictor of p-tau217 positivity (BF10=38). Conclusions: These findings suggest that process-based memory scores might be useful in enhancing the detection of neuronal network disturbances associated with AD pathology, especially in settings where biomarker testing is unavailable.

BACKGROUND:Early detection of Alzheimer disease (AD) is crucial; however, standard neuropsychological tests often lack sensitivity. Process scores, such as proper name (PN) recall from Logical Memory, may improve the detection of AD-related biomarker positivity. We examined whether baseline PN recall predicted future cerebrospinal fluid (CSF) amyloid (Aβ42/Aβ40) and tau (pTau 181 ) status, and whether biomarker status predicted PN recall trajectories. METHODS:We analyzed 271 cognitively unimpaired BIOCARD participants (mean age=57.3, 60.3% female, mean follow-up=15.5) using logistic regression and mixed-effects models to examine the associations between PN recall and CSF biomarkers. RESULTS:Higher baseline PN recall predicted lower amyloid positivity [odds ratio (OR)=0.72, P =0.015]. Amyloid and tau positivity have been linked to a faster decline in PN. Biomarker-positive participants in the biomarker-negative group lacked practice effects. CONCLUSIONS:PN recall predicts future AD biomarker positivity and may enhance early detection of AD-related cognitive decline.

Touch has been shown to regulate emotions, stress responses, and physical pain. However, its impact on cognitive functions, such as inhibitory control, remains relatively understudied. In this experiment, we explored the effects of low-force, slow-moving touch-designed to optimally activate unmyelinated cutaneous low-threshold mechanoreceptor C-tactile (CT) afferents in human hairy skin-on inhibitory control and its psychophysiological correlates using the Stroop Task, a classic paradigm commonly employed to assess inhibitory control capacity. The Stroop Task was repeated twice before and once after receiving either gentle touch or no-touch. Participants were assigned to two groups: the touch group (n = 36), which received low-force, slow-moving touch on their forearms at a stroking velocity of ~3 cm/s, and the no-touch group (n = 36), which did not receive any touch stimulation. Changes in autonomic nervous system activity were also assessed by measuring heart rate variability (HRV) and skin conductance levels before and during cognitive performance. Compared to the no-touch group, participants who received gentle, low-force, slow-moving touch demonstrated faster responses and higher HRV during the Stroop Task. Additionally, within the touch group, individuals with higher HRV exhibited even quicker performance on the cognitive task. While we cannot draw definitive conclusions regarding the CT velocity-specific effect, these results provide preliminary evidence that low-force, slow-moving touch may influence cognitive processes involved in the inhibitory control of goal-irrelevant stimuli.

Cognitive assessment and analysis of plasma biomarkers are lower-cost options for the early assessment of Alzheimer's disease (AD). In this study, we examined whether serial position markers in the Rey's AVLT were sensitive to plasma AD biomarkers in cognitively unimpaired older individuals. Participants (n = 327; mean age = 70.4, SD = 10.4) were free of dementia (MMSE = 24+) at baseline and recruited as part of the Memory Evaluation Research Initiative (MERI; Nathan Kline Institute, NY, USA). Data included plasma p-tau231, Aβ40 and Aβ42, AVLT scores and demographics. Bayesian linear and logistic regression analyses were carried out with plasma biomarkers as outcomes (including the Aβ42/40 ratio); memory scores, including traditional metrics and serial position scores, were predictors; and age, years of education, APOE ε4-status and reported gender were control variables. Results indicated that plasma p-tau231 was associated primarily with delayed primacy recall (first four words): the more primacy words were recalled, the lower the plasma p-tau231 levels were. This study confirms that serial position analysis of word-list recall data, and particularly delayed primacy, is a valuable tool for the identification of in vivo AD-related pathology in cognitively unimpaired individuals.

Stage II pre-clinical Alzheimer's disease is defined by the presence of increased amyloid-beta evidenced by fluid and/or imaging biomarkers, in the absence of clinical signs and symptoms. Previous research suggests that pre-clinical sex differences exist on measures of story recall, such as the Wechsler memory scale-revised logical memory test total score. However, sex differences on a composite metric of proper names from that test have not been investigated, and the relationships between sex and amyloid positivity on longitudinal logical memory measures are unclear. We examined longitudinal trajectories of total score and proper names by sex (Aim 1), and by the combination of sex and amyloid status (Aim 2). N = 457 Wisconsin registry for Alzheimer's prevention participants with PET Pittsburgh compound B-assessed amyloid status (+/−) were included. Linear mixed-effects models were used to examine the interaction between sex and age at visit (the time variable), and sex and amyloid+/− on longitudinal total and proper name scores. Aim 1 analyses showed a main effect such that female participants, on average, scored higher than males on both total and proper name recall. The interaction between sex and age was not statistically significant, indicating that both sexes experienced a similar average rate of annual decline. Aim 2 analyses showed that amyloid positive participants, regardless of sex, showed steeper declines compared to amyloid negative, female participants (reference group). Thus, while female participants generally outperformed males on story recall measures, the impact of amyloid burden on longitudinal story recall trajectories was not significantly more pronounced in females. Results emphasize the need for further exploration into sex-specific cognitive reserve mechanisms in the context of Alzheimer's disease biomarker burden, as well as in the assessment and understanding of cognitive decline trajectories.

Previous studies have found connections between recall of proper names (PN) and amyloid positivity in cognitively unimpaired (CU) adults at risk for Alzheimer’s Disease (AD; Mueller et al., 2020). Given the promising prospect of employing plasma-based biomarkers to determine amyloid burden, we looked at associations between longitudinal change in PN and total score recall from Logical Memory (LM) story recall test and plasma pTau217. Participants from the Wisconsin Registry for Alzheimer’s Prevention (WRAP) study, who were CU at baseline LM visit; had item-level, longitudinal LM and plasma pTau217 data from a recent blood draw (n=412; EDTA plasma samples analyzed using the ALZpath pTau217 Simoa assay on a Quanterix HD-X). Linear-mixed effects models were utilized to examine whether the last available plasma pTau217 measure moderated retrospective age (centered at mean=63) trajectories associated with LM Total Score and PN subscores; pTau217 interactions with quadratic age were removed if they were non-significant. Models included a person-level random intercept term, sex, practice effects, and WRAT-III reading standard scores as covariates. Sample characteristics overall and by last observed plasma pTau217 category (Ashton et al, 2023 pre-print) are shown in Table 1. The sample was mostly female (n=278, 67.5%), and white (n=393, 95.4%), with an average age of 58 (sd=6.44) at baseline visit. The interaction term of pTau217 was significant for all of the models for linear age (Table 2, β ranging from -0.50 through -0.08, p<0.001); the interaction of pTau217 was also significant for quadratic age in the PN delayed subscore (β=-0.00, p=0.010) and the LM delayed total score (β=-0.01, p=0.031). Change in LM total and PN subscores are sensitive to amyloid burden via plasma pTau217. Participants with high levels of pTau217 performed more poorly over time than those with intermediate or low levels (Figure 1). Despite being limited to only nine items on LM tasks, PN subscores continue to demonstrate their strength as a potential indicator of amyloid accumulation as measured by a quick and lower-burden blood test.

Social isolation (SI) and loneliness are related to several negative health outcomes, including cognitive decline and dementia. While both males and females experience increased SI as a function of age, studies have found that females experience greater loneliness than males, despite males reporting more physical isolation and smaller social networks. Females, independent of SI-status, are also at increased risk of Alzheimer’s disease (AD). These sex-related differences in SI and AD-risk prompted us to examine whether sex and loneliness influenced the plasma AD biomarkers in a cohort of elderly individuals. Participants were enrolled in the Memory Education and Research Initiative (MERI) program. MERI participants completed a neuropsychological battery, clinical and psychiatric evaluation, and blood draw. Plasma Aβ40, Aβ42, and PTau231 concentrations were determined using single-molecule array (SIMOA) platform. Plasma Aβ42/Aβ40 ratio was calculated. MERI participants were included if they gave blood, were cognitively-normal defined by MMSE>27, age 50 years older, and completed the Profile of Mood States scale (POMS). POMS-Loneliness item was coded to a dichotomous variable (0-Not Lonely; 1-Lonely). A total of 459 MERI participants (mean age=71 years; 59% females) were included. There were no significant differences between males and females for education, HAM-D total score, or MMSE, only age. A 2x2 analysis of covariance (ANCOVA) with sex (male, female) and loneliness (not lonely, lonely), and age as a covariate, revealed a significant interaction between sex and loneliness with Aβ42 (p=0.014). Lonely females had significantly lower Aβ42 than males who are lonely. The same analysis revealed a significant main effect of sex on Aβ40 (p=0.014) and PTau231 (p=0.007); females had higher Aβ40 and lower PTau231, respectively. There were no significant main effects or interactions for Plasma ratio Aβ42/Aβ40. Cognitively-normal females who reported being lonely, as compared with males, had lower levels of plasma Aβ42 but not lower levels of plasma Aβ42/Aβ40 ratio, a better predictor of a positive amyloid PET scan. Future studies should examine if the results reflect increased brain amyloid deposition in lonely females. If so, interventions that mitigate loneliness may reduce overall risk for AD in females.

Sensitive screening for early Alzheimer’s disease (AD)-related cognitive decline are needed. Prior research links high beta-amyloid (Aβ) levels to reduced proper name (PN) retrieval in individuals without cognitive impairment. We examined whether language-related regional tau from PET associated with Logical Memory (LM) proper name recall, accounting for LM covariates. Participants included n = 396 from the Wisconsin Registry for Alzheimer’s Prevention (WRAP) with Logical Memory (LM) story recall, amyloid PET ([11C]Pittsburgh Compound-B, PiB), and [18F]-MK-6240 tau PET; all were unimpaired at LM baseline. Outcomes included z-scores for LM delayed total score (“total-LM”) and PN delayed LM subscore (“PN-score”) from the visit most adjacent to PET-tau imaging. Amyloid PET burden (visit adjacent to tau PET) was summarized as a global PIB DVR (PiB index, cerebellum GM reference region, graphical analysis). Left and right volume-weighted MK-6240 SUVR (inferior cerebellar GM reference regions) averages were calculated for regions previously associated with PN retrieval, including temporal pole, anterior temporal gyrus, anterior middle gyrus, and anterior inferior gyrus (“PN-regional-tau-network”). We compared results from two ANCOVA models (L vs. R regional network as predictors) for each outcome (PN-score, total-LM). Covariates in each model included age at LM, sex, WRAT-3 reading, and PiB index (to replicate prior analyses). To account for unexplained variance from global tau in entorhinal cortex, residuals from a regression of global tau on PN-regional-tau-network were also included. Table 1 displays demographics overall and by tau status (T+/T-). Overall mean age was 67 (SD = 7); n(%) = 80(20.2%) were T+. Left and right PN-regional-tau-networks were significant predictors of PN-score (β = -.06, R 2 = .190, β = -.08, R 2 = .192, respectively) and total-LM (β = -.08, R 2 = .201, β = -.09, R 2 = .202, respectively; Table 2, Fig 1). In sensitivity analyses removing n = 23 participants with MCI or dementia, Right-hemisphere PN-regional-tau (but not left) was still a significant predictor of PN-score (β = -.06, R 2 = .190), and L and R PN-regional-tau significantly predicted total-LM (β = -.06, R 2 = .134, β = -.07, R 2 = .136, respectively). Logical Memory story recall measures may be sensitive to tau burden in specific language regions; right hemisphere tau in the PN-regional-network may be particularly sensitive to early tau burden. Future directions include characterizing regional PET patterns and plasma-biomarker-related preclinical rates of change in these outcomes.

INTRODUCTION:Menopausal hormone therapy (MHT), along with the apolipoprotein E (APOE) ε4 allele, has been suggested as a possible risk factor for Alzheimer's disease (AD). However, the relationship between MHT and cerebrospinal fluid (CSF) biomarkers is unknown: we investigated this association, and whether APOE ε4 carrier status moderates it. METHODS:In an observational study of 136 cognitively unimpaired female participants (Mage = 66.0; standard deviation = 6.3), we examined whether MHT use alone or in interaction with APOE ε4 carrier status was associated with CSF levels of phosphorylated tau (p-tau), amyloid beta (Aβ)40, Aβ42, p-tau/Aβ42, and Aβ42/40 ratios. RESULTS:Significant interactions were found between APOE ε4 and MHT use for CSF biomarkers. APOE ε4 carriers who were MHT users showed worse levels of CSF p-tau/Aβ42 and Aβ42/40 ratios than all other users and non-users. DISCUSSION:The presence of both APOE ε4 and MHT may be associated with elevated amyloid deposition and AD pathology in this sample of participants who demonstrated high familial AD risk. HIGHLIGHTS:Significant interactions were found between apolipoprotein E (APOE) ε4 and menopausal hormone therapy (MHT) use for cerebrospinal fluid (CSF) phosphorylated tau (p-tau)/amyloid beta (Aβ)42 and Aβ42/40 ratios. APOE ε4 carriers who were MHT users showed worse levels of CSF biomarkers than non-users and non-carriers, both users and non-users. Younger age at MHT initiation was associated with worse levels of the p-tau/Aβ42 and Aβ42/40 ratios in carriers only. The presence of both APOE ε4 carriage and MHT use may be associated with elevated amyloid deposition and AD pathology. Further studies with larger sample sizes are necessary to confirm the differences observed in the current study.

Amyloid-β deposition and tau pathology are suggested to play a role in the emergence of depressive symptoms and cognitive decline in Parkinson's disease (PD). Additionally, studies have reported an association between presence of the APOE4 allele and poorer cognition in PD. The present study aims to investigate whether amyloid-β, tau pathology and APOE4 carrier status interact with depressive symptoms in predicting global cognition in PD.We analysed data from 348 persons with PD (PwPD) and 160 healthy controls (HCs). Linear mixed effects regression analyses were conducted to examine if CSF levels of Aβ42 and p-tau, and APOE4 carrier status did interact with depressive symptoms, as assessed by the Geriatric Depression Scale (GDS), in predicting cognition performance, as measured by Montreal Cognitive Assessment Test (MoCA) scores, over three years.Results of a first linear regression model conducted considering both PwPD and HC indicated that MoCA scores were significantly predicted by GDS, as well as by the interaction between GDS and p-tau, Group and p-tau, and between Group, p-tau and GDS. Results of the models conducted in the two groups separately indicated that, while in HC MoCA scores were predicted by age and time only, a significant interaction between GDS and CSF levels of p-tau emerged as a predictor of MoCA scores in PwPD. Specifically, post hoc analysis revealed a negative association between CSF levels of p-tau and cognitive performance that was significant only in PwPD with the highest GDS scores.Taken together, results of this study confirm that, in early stages of PD, depressive symptoms interact with CSF levels of p-tau in predicting cognitive performance. Findings highlight the importance of assessing and treating depression in PwPD as early as possible, as it might reduce the likelihood of future cognitive decline.

We introduce a special issue of the Journal of Neuropsychology dedicated to a recent paradigm shift in Alzheimer's disease diagnosis. Joint workgroups from the (US) National Institute on Aging and the Alzheimer's Association (NIA-AA) recently issued policy guidelines reclassifying Alzheimer's disease as a biological entity. These guidelines shift the onus of diagnosis in favour of protein biomarkers, relegating cognitive symptoms (e.g. subjective memory and language disorders) as supportive rather than core features. We invited experts in the study of Alzheimer's disease and Related Disorders (ADRDs) to express their views on this paradigmatic shift in dementia management. In this editorial, we synthesize some of the main points advanced in the commentaries. Contributors identified the promise of blood-based biomarker testing for improving equitable detection of dementia in large swathes of the world population. This enthusiasm was tempered by concerns about the biomarker-only diagnostic approach, including the potential for significant harm (e.g. stigma, depression, suicide) caused by labelling asymptomatic older adults who might otherwise never behaviourally express the underlying disease pathology.

Memory recall is subject to errors that can lead to the formation of false memories. Several factors affect memory processes, such as attention deficits or emotional distress. Additionally, cardiovascular diseases may lead to cognitive decline and memory loss, also increasing the occurrence of false events recall. Hypnosis has proved to affect the autonomic nervous system, positively impacting the cardiovascular response. Hypnosis has also been suggested as a tool to enhance memory and autobiographical events recall in both healthy and unhealthy individuals; however, this approach has led to several controversies. Particularly, the employment of hypnosis in autobiographical recall (hypnotic regression) has been accused of favoring the creation of false memories, leading to therapeutic fallacy. In this paper, we review the current literature on the mechanisms behind the creation of false memories and the role played by hypnosis in memory enhancement and false memory recall. The evidence here collected suggests that cardiovascular diseases affect brain health contributing to cognitive decline and memory impairments, also increasing the occurrence of false memories. Hypnosis induces an increase in parasympathetic activity and a decrease in sympathetic activity, suggesting a potential role in preventing some cardiovascular diseases, such as hypertension, which in turn may improve brain health. Additionally, hypnosis has been shown to have some effectiveness in enhancing memory functions, although contradictory findings reported by several studies make it difficult to draw proper conclusions. Hypnotic regression and guided imagery should be used with caution as they may unintentionally lead to false memory recall. Nevertheless, further studies are required to better understand the effects of hypnosis on the brain and the heart and how it can be used to enhance memory, especially in people with cognitive decline.

BACKGROUND:Alzheimer's disease (AD) can be diagnosed by in vivo abnormalities of amyloid-β plaques (A) and tau accumulation (T) biomarkers. Previous studies have shown that analyses of serial position performance in episodic memory tests, and especially, delayed primacy, are associated with AD pathology even in individuals who are cognitively unimpaired. The earliest signs of cortical tau pathology are observed in medial temporal lobe (MTL) regions, yet it is unknown if serial position markers are also associated with early tau load in these regions. This study of cognitively unimpaired older individuals examined whether serial position scores in word-list recall cross-sectionally predicted tau PET load in the MTL, and were able to discriminate between biomarker profiles, based on AT classification. METHODS:Data from 490 participants (mean age = 68.8 ± 7.2) were extracted from two cohorts, which were merged into one sample. Linear regression analyses were carried out with regional volume-controlled tau (18F-MK-6240) PET SUVR of the entorhinal cortex (EC), parahippocampal cortex (PHC) and hippocampus (H) as outcomes, cross-sectional memory scores from the Rey Auditory Verbal Learning Test as predictors (total and delayed recall, along with serial position scores) and control variables, in separate analyses for each outcome and predictor. The sample was then stratified by biomarker profile and ANCOVAs were conducted with the strongest scores from the regression analyses, AT groups as fixed factor and the covariates. RESULTS:Higher delayed primacy significantly predicted lower tau PET in EC, PHC, and H, cross-sectionally. Higher total recall scores predicted lower EC tau, but delayed primacy showed the best model fit, as indicated by AICs. ANCOVAs showed that AVLT metrics did not significantly discriminate between A-T- and A+T+, after correcting for multiple comparisons. CONCLUSIONS:Serial position analysis of word-list recall, particularly delayed primacy, may be a valuable tool for identifying in vivo tau pathology in cognitively unimpaired individuals.

The East Boston memory test (EBMT) is a short story recall test that compares favorably to longer story recall tests like the logical memory test. However, little is known as to how well EBMT predicts postmortem Alzheimer's disease (AD) pathology, and whether item-based serial position analysis is applicable to it for this purpose. Data from 1699 individuals participating in three different Rush University study cohorts were examined (age = 79.7, SD = 7.1). The majority of the sample was comprised of women (69%). All participants completed the test in English and were free of dementia at baseline. Analyses were carried out with Bayesian and Frequentist statistics. Regression analyses were applied to predict overall postmortem AD pathology longitudinally from baseline. Predictors were immediate EBMT recall, delayed EBMT recall, and serial position metrics, i.e., the order in which story items were learned. Control variables were age at baseline, gender, years of education, time between baseline and death, and APOE e4 status. Inspection of q-q plots suggested the data were suitable for linear regressions. Results from the Bayesian analyses showed that the best fitting model included two predictors: immediate recall (BFinclusion = 4069) and delayed primacy recall (BFinclusion = 9), i.e., remembering the beginning of the story after a delay. The two predictors did not meaningfully interact. Frequentist tests confirmed that including either immediate recall (AIC = 2884; Figure 1) or delayed primacy (AIC = 2896; Figure 2) in the models improved fit over control variables (AIC = 2915). Further tests indicated that immediate and delayed primacy recalls predicted postmortem neuritic plaques and neurofibrillary tangles burdens, but not diffuse plaques burden. In summary, EBMT is suitable to use for early prediction of AD pathology from a cognitively healthy baseline, despite its brevity. Additionally, immediate recall and delayed primacy performance are independent contributors to the prediction of post-mortem AD-related neuropathology.

Objective: Process-based scores of episodic memory tests, such as the recency ratio (Rr), have been found to compare favourably to, or to be better than, most conventional or "traditional" scores employed to estimate memory ability in older individuals (Bock et al., 2021; Bruno et al., 2019). We explored the relationship between process-based scores and hippocampal volume in older adults, while comparing process-based to traditional story recall-derived scores, to examine potential differences in their predictive abilities.Methods: We analysed data from 355 participants extracted from the WRAP and WADRC databases, who were classified as cognitively unimpaired, or exhibited mild cognitive impairment (MCI) or dementia. Story Recall was measured with the Logical Memory Test (LMT) from the Weschler Memory Scale Revised, collected within twelve months of the magnetic resonance imaging scan. Linear regression analyses were conducted with left or right hippocampal volume (HV) as outcomes separately, and with Rr, Total ratio, Immediate LMT, or Delayed LMT scores as predictors, along with covariates.Results: Higher Rr and Tr scores significantly predicted lower left and right HV, while Tr showed the best model fit of all, as indicated by AIC. Traditional scores, Immediate LMT and Delayed LMT, were significantly associated with left and right HV, but were outperformed by both process-based scores for left HV, and by Tr for right HV.Conclusions: Current findings show the direct relationship between hippocampal volume and all the LMT scores examined here, and that process-based scores outperform traditional scores as markers of hippocampal volume.