Prospective memory performance in veterans with and without histories of mild traumatic brain injury: effect of the apolipoprotein E (APOE) ε4 genotype.

OBJECTIVE: Identifying factors that moderate cognitive outcomes following mild traumatic brain injury (mTBI) is crucial. Prospective memory (PM) is a cognitive domain of interest in mTBI recovery as it may be especially sensitive to TBI-related changes. Since studies show that genetic status - particularly possession of the apolipoprotein E (APOE) ε4 allele - can modify PM performance, we investigated associations between mTBI status and APOE-ε4 genotype on PM performance in a well-characterized sample of Veterans with neurotrauma histories. METHODS: 59 Veterans (mTBI = 33, Military Controls [MCs] = 26; age range: 24-50; average years post-injury = 10.41) underwent a structured clinical interview, neuropsychological assessment, and genotyping. The Memory for Intentions Test (MIST) measured PM across multiple subscales. ANCOVAs, adjusting for age and posttraumatic stress symptoms, tested the effects of mTBI status (mTBI vs. MC) and ε4 status (ε4+ vs. ε4-) on MIST scores. RESULTS: Veterans with mTBI history performed more poorly compared to MCs on the MIST 15-min delay (p=.002, ηp2 =.160), Time Cue (p = .003, ηp2 =.157), and PM Total (p = .016, ηp2 =.102). Those with at least one copy of the ε4 allele performed more poorly compared to ε4- Veterans on the MIST 15-min delay (p = .011, ηp2 =.113) and PM Total (p = .048, ηp2 = .071). No significant interactions were observed between mTBI and APOE-ε4 status on MIST outcomes (ps>.25). Within the mTBI group, APOE-ε4+ Veterans performed worse than APOE-ε4- Veterans on the MIST 15-min delay subscale (p = .031, ηp2 = .150). CONCLUSIONS: mTBI history and APOE-ε4 genotype status were independently associated with worse PM performance compared to those without head injury histories or possession of the APOE-e4 genotype. Performance on the MIST 15-min delay was worse in Veterans with both risk factors (mTBI history and APOE-ε4 positivity). Findings suggest that genetic status may modify outcomes even in relatively young Veterans with mTBI histories. Future research examining longitudinal associations and links to neuroimaging and biomarker data are needed.

Characterizing cognitive profiles in diverse middle-aged and older Hispanics/Latinos: Study of Latinos-Investigation of Neurocognitive Aging (HCHS/SOL).

Introduction: We investigated cognitive profiles among diverse, middle-aged and older Hispanic/Latino adults in the Study of Latinos-Investigation of Neurocognitive Aging (SOL-INCA) cohort using a cross-sectional observational study design. Methods: Based on weighted descriptive statistics, the average baseline age of the target population was 56.4 years, slightly more than half were women (54.6%), and 38.4% reported less than a high school education. We used latent profile analysis of demographically adjusted z scores on SOL-INCA neurocognitive tests spanning domains of verbal memory, language, processing speed, and executive function. Results: Statistical fit assessment indices combined with clinical interpretation suggested five profiles: (1) a Higher Global group performing in the average-to-high-average range across all cognitive and instrumental activity of daily living (IADL) tests (13.8%); (2) a Higher Memory group with relatively high performance on memory tests but average performance across all other cognitive/IADL tests (24.6%); (3) a Lower Memory group with relatively low performance on memory tests but average performance across all other cognitive/IADL tests (32.8%); (4) a Lower Executive Function group with relatively low performance on executive function and processing speed tests but average-to-low-average performance across all other cognitive/IADL tests (16.6%); and (5) a Lower Global group performing low-average-to-mildly impaired across all cognitive/IADL tests (12.1%). Discussion: Our results provide evidence of heterogeneity in the cognitive profiles of a representative, community-dwelling sample of diverse Hispanic/Latino adults. Our analyses yielded cognitive profiles that may assist efforts to better understand the early cognitive changes that may portend Alzheimer's disease and related dementias among diverse Hispanics/Latinos. Highlights: The present study characterized cognitive profiles among diverse middle-aged and older Hispanic/Latino adults.Latent profile analysis of neurocognitive test scores was the primary analysis conducted.The target population consists of middle-aged and older Hispanic/Latino adults enrolled in the Hispanic Community Health Study/Study of Latinos and ancillary Study of Latinos - Investigation of Neurocognitive Aging.

News event memory in amnestic and non-amnestic MCI, heritable risk for dementia, and subjective memory complaints.

Robust and sensitive clinical measures are needed for more accurate and earlier detection of Alzheimer's disease (AD), for staging preclinical AD, and for gauging the efficacy of treatments. Mild impairment on episodic memory tests is thought to indicate a cognitive risk of developing AD and mild cognitive impairment (MCI), considered to be a transitional stage between normal aging and AD. Novel tests of semantic memory, such as memory for news events, are also impaired early on but have received little clinical attention even though they may provide a novel way to assess cognitive risk for AD. We examined memory for news events in older adults with normal cognition (NC, N = 34), amnestic MCI (aMCI, N = 27), or non-aMCI (N = 10) using the Retrograde Memory News Events Test (RM-NET). We asked if news event memory was sensitive to 1) aMCI and also non-aMCI, which has rarely been examined, 2) genetic risk for dementia (positive family history of any type of dementia, presence of an APOE-4 allele, or polygenic risk for AD), and 3) subjective memory functioning judgments about the past. We found that both MCI subgroups exhibited impaired RM-NET Lifespan accuracy scores together with temporally-limited retrograde amnesia. For the aMCI group amnesia extended back 45 years prior to testing, but not beyond that time frame. The extent of retrograde amnesia could not be reliably estimated in the small non-aMCI group. The effect sizes of having MCI on the RM-NET were medium for the non-aMCI group and large for the aMCI group, whereas the effect sizes of participant characteristics on RM-NET accuracy scores were small. For the combined MCI group (N = 37), news event memory was significantly related to positive family history of dementia but was not related to the more specific genetic markers of AD risk. For the NC group, news event memory was not related to any measure of genetic risk. Objective measures of past memory from the RM-NET were not related to subjective memory judgements about the present or the recent past in either group. By contrast, when individuals subjectively compared their present versus past memory abilities, there was a significant association between this judgment and objective measures of the past from the RM-NET (direct association for the NC group and inverse for the MCI group). The RM-NET holds significant promise for early identification of those with cognitive and genetic risk factors for AD and non-AD dementias.

Data-driven classification of cognitively normal and mild cognitive impairment subtypes predicts progression in the NACC dataset.

INTRODUCTION: Data-driven neuropsychological methods can identify mild cognitive impairment (MCI) subtypes with stronger associations to dementia risk factors than conventional diagnostic methods. METHODS: Cluster analysis used neuropsychological data from participants without dementia (mean age = 71.6 years) in the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (n = 26,255) and the "normal cognition" subsample (n = 16,005). Survival analyses examined MCI or dementia progression. RESULTS: Five clusters were identified: "Optimal" cognitively normal (oCN; 13.2%), "Typical" CN (tCN; 28.0%), Amnestic MCI (aMCI; 25.3%), Mixed MCI-Mild (mMCI-Mild; 20.4%), and Mixed MCI-Severe (mMCI-Severe; 13.0%). Progression to dementia differed across clusters (oCN < tCN < aMCI < mMCI-Mild < mMCI-Severe). Cluster analysis identified more MCI cases than consensus diagnosis. In the "normal cognition" subsample, five clusters emerged: High-All Domains (High-All; 16.7%), Low-Attention/Working Memory (Low-WM; 22.1%), Low-Memory (36.3%), Amnestic MCI (16.7%), and Non-amnestic MCI (naMCI; 8.3%), with differing progression rates (High-All < Low-WM = Low-Memory < aMCI < naMCI). DISCUSSION: Our data-driven methods outperformed consensus diagnosis by providing more precise information about progression risk and revealing heterogeneity in cognition and progression risk within the NACC "normal cognition" group.

Pulse pressure and APOE ε4 dose interact to affect cerebral blood flow in older adults without dementia.

This study assessed whether the effect of vascular risk on cerebral blood flow (CBF) varies by gene dose of apolipoprotein (APOE) ε4 alleles. 144 older adults without dementia from the Alzheimer's Disease Neuroimaging Initiative underwent arterial spin labeling and T1-weighted MRI, APOE genotyping, fluorodeoxyglucose positron emission tomography (FDG-PET), lumbar puncture, and blood pressure (BP) assessment. Vascular risk was assessed using pulse pressure (systolic BP - diastolic BP). CBF was examined in six AD-vulnerable regions: entorhinal cortex, hippocampus, inferior temporal cortex, inferior parietal cortex, rostral middle frontal gyrus, and medial orbitofrontal cortex. Linear regressions tested the interaction between APOE ε4 dose and pulse pressure on CBF in each region, adjusting for age, sex, cognitive classification, antihypertensive medication use, FDG-PET, reference CBF region, and AD biomarker positivity. There was a significant interaction between pulse pressure and APOE ɛ4 dose on CBF in the entorhinal cortex, hippocampus, and inferior parietal cortex, such that higher pulse pressure was associated with lower CBF only among ε4 homozygous participants. These findings demonstrate that the association between pulse pressure and regional CBF differs by APOE ε4 dose, suggesting that targeting modifiable vascular risk factors may be particularly important for those genetically at risk for AD.

Association of Vascular Risk Factors and CSF and Imaging Biomarkers With White Matter Hyperintensities in Former American Football Players.

BACKGROUND AND OBJECTIVES: Recent data link exposure to repetitive head impacts (RHIs) from American football with increased white matter hyperintensity (WMH) burden. WMH might have unique characteristics in the context of RHI beyond vascular risk and normal aging processes. We evaluated biological correlates of WMH in former American football players, including markers of amyloid, tau, inflammation, axonal injury, neurodegeneration, and vascular health. METHODS: Participants underwent clinical interviews, MRI, and lumbar puncture as part of the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy Research Project. Structural equation modeling tested direct and indirect effects between log-transformed total fluid-attenuated inversion recovery (FLAIR) lesion volumes (TLV) and the revised Framingham stroke risk profile (rFSRP), MRI-derived global metrics of cortical thickness and fractional anisotropy (FA), and CSF levels of amyloid ß1-42, p-tau181, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), and neurofilament light. Covariates included age, race, education, body mass index, APOE ε4 carrier status, and evaluation site. Models were performed separately for former football players and a control group of asymptomatic men unexposed to RHI. RESULTS: In 180 former football players (mean age = 57.2, 36% Black), higher log(TLV) had direct associations with the following: higher rFSRP score (B = 0.26, 95% CI 0.07-0.40), higher p-tau181 (B = 0.17, 95% CI 0.01-0.43), lower FA (B = -0.28, 95% CI -0.42 to -0.13), and reduced cortical thickness (B = -0.25, 95% CI -0.45 to -0.08). In 60 asymptomatic unexposed men (mean age = 59.3, 40% Black), there were no direct effects on log(TLV) (rFSRP: B = -0.03, 95% CI -0.48 to 0.57; p-tau181: B = -0.30, 95% CI -1.14 to 0.37; FA: B = -0.07, 95% CI -0.48 to 0.42; or cortical thickness: B = -0.28, 95% CI -0.64 to 0.10). The former football players showed stronger associations between log(TLV) and rFSRP (1,069% difference in estimates), p-tau181 (158%), and FA (287%) than the unexposed men. DISCUSSION: Risk factors and biological correlates of WMH differed between former American football players and asymptomatic unexposed men. In addition to vascular health, p-tau181 and diffusion tensor imaging indices of white matter integrity showed stronger associations with WMH in the former football players. FLAIR WMH may have specific risk factors and pathologic underpinnings in RHI-exposed individuals.

Comparing neuropsychological, typical, and ADNI criteria for the diagnosis of mild cognitive impairment in Vietnam-era veterans.

OBJECTIVE: Neuropsychological criteria for mild cognitive impairment (MCI) more accurately predict progression to Alzheimer's disease (AD) and are more strongly associated with AD biomarkers and neuroimaging profiles than ADNI criteria. However, research to date has been conducted in relatively healthy samples with few comorbidities. Given that history of traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) are risk factors for AD and common in Veterans, we compared neuropsychological, typical (Petersen/Winblad), and ADNI criteria for MCI in Vietnam-era Veterans with histories of TBI or PTSD. METHOD: 267 Veterans (mean age = 69.8) from the DOD-ADNI study were evaluated for MCI using neuropsychological, typical, and ADNI criteria. Linear regressions adjusting for age and education assessed associations between MCI status and AD biomarker levels (cerebrospinal fluid [CSF] p-tau181, t-tau, and Aß42) by diagnostic criteria. Logistic regressions adjusting for age and education assessed the effects of TBI severity and PTSD symptom severity simultaneously on MCI classification by each criteria. RESULTS: Agreement between criteria was poor. Neuropsychological criteria identified more Veterans with MCI than typical or ADNI criteria, and were associated with higher CSF p-tau181 and t-tau. Typical and ADNI criteria were not associated with CSF biomarkers. PTSD symptom severity predicted MCI diagnosis by neuropsychological and ADNI criteria. History of moderate/severe TBI predicted MCI by typical and ADNI criteria. CONCLUSIONS: MCI diagnosis using sensitive neuropsychological criteria is more strongly associated with AD biomarkers than conventional diagnostic methods. MCI diagnostics in Veterans would benefit from incorporation of comprehensive neuropsychological methods and consideration of the impact of PTSD.

Identifying and distinguishing cognitive profiles among virally suppressed people with HIV.

OBJECTIVE: Cognitive deficits are common among people with HIV (PWH), even when virally suppressed. We identified cognitive profiles among virally suppressed PWH and determined how sociodemographic, clinical/behavioral, and HIV disease characteristics distinguish profile membership. METHOD: Participants included 704 virally suppressed PWH (Mage = 43.9 [SD = 10.2], 88% male, 58.9% non-Hispanic White) from the HIV Neurobehavioral Research Program. Demographically adjusted T scores were derived from a neuropsychological evaluation comprised of 13 tests. We implemented a pipeline involving dimension reduction and clustering to identify profiles of cognitive performance. Random forest models on a 70/30 training/testing set with internal cross-validation were used to identify sociodemographic, clinical/behavioral, and HIV disease correlates of profile membership. RESULTS: Six cognitive profiles were identified: (a) "unimpaired" (19.9%); (b) weakness in verbal learning and memory (15.5%); (c) weakness in executive function and learning (25.8%); (d) weakness in motor, processing speed, and executive function (8.1%); (e) impaired learning and recall with weak-to-impaired motor, processing speed, and executive function (13.1%); (f) global deficits (17.6%). The most discriminative sociodemographic, clinical/behavioral, and HIV disease characteristics varied by profile with self-reported mood symptoms and cognitive/functional difficulties (e.g., language/communication, memory, and overall everyday function complaints) most consistently associated with profile membership. CONCLUSIONS: Cognitive profiles and their associated factors among PWH are heterogeneous, but learning/memory deficits were most common and self-reported mood, and cognitive/functional difficulties were most consistently related to profile membership. This heterogeneity in cognitive profiles and their correlates in PWH suggests that differing mechanisms contribute to cognitive deficits and, thus, underscores the need for personalized risk reduction and therapeutic strategies among PWH. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

White Matter Hyperintensity Volume and Amyloid-PET Synergistically Impact Memory Independent of Tau-PET in Older Adults Without Dementia.

BACKGROUND: Alzheimer's disease (AD) and cerebrovascular disease are common, co-existing pathologies in older adults. Whether the effects of cerebrovascular disease and AD biomarkers on cognition are additive or synergistic remains unclear. OBJECTIVE: To examine whether white matter hyperintensity (WMH) volume moderates the independent association between each AD biomarker and cognition. METHODS: In 586 older adults without dementia, linear regressions tested the interaction between amyloid-ß (Aß) positron emission tomography (PET) and WMH volume on cognition, independent of tau-PET. We also tested the interaction between tau-PET and WMH volume on cognition, independent of Aß-PET. RESULTS: Adjusting for tau-PET, the quadratic effect of WMH interacted with Aß-PET to impact memory. There was no interaction between either the linear or quadratic effect of WMH and Aß-PET on executive function. There was no interaction between WMH volume and tau-PET on either cognitive measure. CONCLUSION: Results suggest that cerebrovascular lesions act synergistically with Aß to affect memory, independent of tau, highlighting the importance of incorporating vascular pathology into biomarker assessment of AD.

Alzheimer's Disease Pathology in Middle Aged and Older People with HIV: Comparisons with Non-HIV Controls on a Healthy Aging and Alzheimer's Disease Trajectory and Relationships with Cognitive Function.

We determined the prevalence of Alzheimer's disease (AD) pathological hallmarks, amyloid-ß and phosphorylated-Tau, in autopsied brains of 49 people with HIV (PWH) (ages: 50-68; mean age = 57.0) from the National NeuroAIDS Tissue Consortium and in a comparative cohort of 55 people without HIV (PWoH) from the UC San Diego Alzheimer's Disease Research Center (17 controls, 14 mild cognitive impairment, 24 AD; ages: 70-102, mean age = 88.7). We examined how AD pathology relates to domain-specific cognitive functions in PWH overall and in sex-stratified samples. Amyloid-ß and phosphorylated-Tau positivity (presence of pathology of any type/density) was determined via immunohistochemistry in AD-sensitive brain regions. Among PWH, amyloid-ß positivity ranged from 19% (hippocampus) to 41% (frontal neocortex), and phosphorylated-Tau positivity ranged from 47% (entorhinal cortex) to 73% (transentorhinal cortex). Generally, AD pathology was significantly less prevalent, and less severe when present, in PWH versus PWoH regardless of cognitive status. Among PWH, positivity for AD pathology related most consistently to memory-related domains. Positivity for p-Tau pathology related to memory-related domains in women with HIV only, although the sample size of women with HIV was small (n = 10). Results indicate that AD pathology is present in a sizable portion of middle aged and older PWH, although not to the extent in older PWoH. Studies with better age-matched PWoH are needed to examine the effect of HIV status on AD pathology.

Decreased myelin proteins in brain donors exposed to football-related repetitive head impacts.

American football players and other individuals exposed to repetitive head impacts can exhibit a constellation of later-life cognitive and neuropsychiatric symptoms. While tau-based diseases such as chronic traumatic encephalopathy can underpin certain symptoms, contributions from non-tau pathologies from repetitive head impacts are increasingly recognized. We examined cross-sectional associations between myelin integrity using immunoassays for myelin-associated glycoprotein and proteolipid protein 1 with risk factors and clinical outcomes in brain donors exposed to repetitive head impacts from American football. Immunoassays for myelin-associated glycoprotein and proteolipid protein 1 were conducted on dorsolateral frontal white matter tissue samples of 205 male brain donors. Proxies of exposure to repetitive head impacts included years of exposure and age of first exposure to American football play. Informants completed the Functional Activities Questionnaire, Behavior Rating Inventory of Executive Function-Adult Version (Behavioral Regulation Index), and Barratt Impulsiveness Scale-11. Associations between myelin-associated glycoprotein and proteolipid protein 1 with exposure proxies and clinical scales were tested. Of the 205 male brain donors who played amateur and professional football, the mean age was 67.17 (SD = 16.78), and 75.9% (n = 126) were reported by informants to be functionally impaired prior to death. Myelin-associated glycoprotein and proteolipid protein 1 correlated with the ischaemic injury scale score, a global indicator of cerebrovascular disease (r = -0.23 and -0.20, respectively, Ps < 0.01). Chronic traumatic encephalopathy was the most common neurodegenerative disease (n = 151, 73.7%). Myelin-associated glycoprotein and proteolipid protein 1 were not associated with chronic traumatic encephalopathy status, but lower proteolipid protein 1 was associated with more severe chronic traumatic encephalopathy (P = 0.03). Myelin-associated glycoprotein and proteolipid protein 1 were not associated with other neurodegenerative disease pathologies. More years of football play was associated with lower proteolipid protein 1 [beta = -2.45, 95% confidence interval (CI) [-4.52, -0.38]] and compared with those who played <11 years of football (n = 78), those who played 11 or more years (n = 128) had lower myelin-associated glycoprotein (mean difference = 46.00, 95% CI [5.32, 86.69]) and proteolipid protein 1 (mean difference = 24.72, 95% CI [2.40, 47.05]). Younger age of first exposure corresponded to lower proteolipid protein 1 (beta = 4.35, 95% CI [0.25, 8.45]). Among brain donors who were aged 50 or older (n = 144), lower proteolipid protein 1 (beta = -0.02, 95% CI [-0.047, -0.001]) and myelin-associated glycoprotein (beta = -0.01, 95% CI [-0.03, -0.002]) were associated with higher Functional Activities Questionnaire scores. Lower myelin-associated glycoprotein correlated with higher Barratt Impulsiveness Scale-11 scores (beta = -0.02, 95% CI [-0.04, -0.0003]). Results suggest that decreased myelin may represent a late effect of repetitive head impacts that contributes to the manifestation of cognitive symptoms and impulsivity. Clinical-pathological correlation studies with prospective objective clinical assessments are needed to confirm our findings.

Cognitive reserve moderates the association between cerebral blood flow and language performance in older adults with mild cognitive impairment.

Higher cognitive reserve (CR) may offer protection from cognitive changes associated with reduced cerebral blood flow (CBF). We investigated CR as a moderator of the effect of CBF on cognition in older adults with mild cognitive impairment (MCI; N = 46) and those who are cognitively unimpaired (CU; N = 101). Participants underwent arterial spin labeling MRI, which was used to quantify CBF in 4 a priori regions. Estimated verbal intelligence quotient (VIQ) served as a proxy for CR. Multiple linear regressions examined whether VIQ moderated associations between CBF and cognition and whether this differed by cognitive status. Outcomes included memory and language performance. There were 3-way interactions (CBF*VIQ*cognitive status) on category fluency when examining hippocampal, superior frontal, and inferior frontal CBF. Follow-up analyses revealed that, within the MCI but not CU group, there were CBF*VIQ interactions on fluency in all a priori regions examined, where there were stronger, positive associations between CBF and fluency at higher VIQ. Conclusion: In MCI, higher CR plays a role in strengthening CBF-fluency associations.

Brain Derived Neurotrophic Factor Interacts with White Matter Hyperintensities to Influence Processing Speed and Hippocampal Volume in Older Adults.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays an important role in regulating synaptic activity and plasticity. OBJECTIVE: Given that type-2 diabetes (T2DM) increases the risk of cognitive decline, and studies have suggested lower BDNF levels may be a risk factor of diabetic neurovascular complications, we sought to investigate total white matter hyperintensities (WMH) as a moderator of the effect of BDNF on hippocampal volume and cognition. METHODS: Older adults without dementia from the Alzheimer's Disease Neuroimaging Initiative (N = 454 including 49 with T2DM and 405 without diabetes) underwent neuropsychological evaluation, magnetic resonance imaging to quantify hippocampal and WMH volumes, and blood draw to assess BDNF. RESULTS: Adjusting for age, sex, and APOE ɛ4 carrier status, there was a significant interaction between total WMH and BDNF on bilateral hippocampal volume in the non-T2DM group (t = 2.63, p = 0.009). Examination of main effect models with a dichotomous high/low BNDF group revealed a significant main effect for low BDNF (t = -4.98, p < 0.001), such that as WMH increased, bilateral hippocampal volume decreased. There was also a significant interaction between total WMH and BDNF on processing speed in the non-T2DM group (t = 2.91, p = 0.004). There was a significant main effect for low BDNF (t = -3.55, p < 0.001) such that as WMH increased, processing speed decreased. The interactions were not significant in the T2DM group. CONCLUSION: These results further elucidate the protective role that BDNF plays on cognition, as well as the cognitive effects of WMH.

APOE differentially moderates cerebrospinal fluid and plasma phosphorylated tau181 associations with multi-domain cognition.

Biofluid markers of phosphorylated tau181 (p-tau181) are increasingly popular for the detection of early Alzheimer's pathologic changes. However, the differential dynamics of cerebrospinal fluid (CSF) and plasma p-tau181 remain under investigation. We studied 727 participants from the Alzheimer's Disease Neuroimaging Initiative with plasma and CSF p-tau181 data, apolipoprotein (APOE) ε4 carrier status, amyloid positron emission tomography (PET) imaging, and neuropsychological data. Higher levels of plasma and CSF p-tau181 were observed among APOE ε4 carriers. CSF and plasma p-tau181 were significantly associated with memory, and this effect was greater in APOE ε4 carriers. However, whereas CSF p-tau181 was not significantly associated with language or attention/executive function among ε4 carriers or non-carriers, APOE ε4 status moderated the association of plasma p-tau181 with both language and attention/executive function. These findings lend support to the notion that p-tau181 biofluid markers are useful in measuring AD pathologic changes but also suggest that CSF and plasma p-tau181 have unique properties and dynamics that should be considered when using these markers in research and clinical practice.

Priorities for research on neuromodulatory subcortical systems in Alzheimer's disease: Position paper from the NSS PIA of ISTAART.

The neuromodulatory subcortical system (NSS) nuclei are critical hubs for survival, hedonic tone, and homeostasis. Tau-associated NSS degeneration occurs early in Alzheimer's disease (AD) pathogenesis, long before the emergence of pathognomonic memory dysfunction and cortical lesions. Accumulating evidence supports the role of NSS dysfunction and degeneration in the behavioral and neuropsychiatric manifestations featured early in AD. Experimental studies even suggest that AD-associated NSS degeneration drives brain neuroinflammatory status and contributes to disease progression, including the exacerbation of cortical lesions. Given the important pathophysiologic and etiologic roles that involve the NSS in early AD stages, there is an urgent need to expand our understanding of the mechanisms underlying NSS vulnerability and more precisely detail the clinical progression of NSS changes in AD. Here, the NSS Professional Interest Area of the International Society to Advance Alzheimer's Research and Treatment highlights knowledge gaps about NSS within AD and provides recommendations for priorities specific to clinical research, biomarker development, modeling, and intervention. HIGHLIGHTS: Neuromodulatory nuclei degenerate in early Alzheimer's disease pathological stages. Alzheimer's pathophysiology is exacerbated by neuromodulatory nuclei degeneration. Neuromodulatory nuclei degeneration drives neuropsychiatric symptoms in dementia. Biomarkers of neuromodulatory integrity would be value-creating for dementia care. Neuromodulatory nuclei present strategic prospects for disease-modifying therapies.

The Independent Walking for Brain Health Intervention for Older Adults: Protocol for a Pilot Randomized Controlled Trial.

BACKGROUND: Extensive research suggests that physical activity (PA) is important for brain and cognitive health and may help to delay or prevent Alzheimer's disease and related dementias. Most PA interventions designed to improve brain health in older adults have been conducted in laboratory, gym, or group settings that require extensive resources and travel to the study site or group sessions. Research is needed to develop novel interventions that leverage mobile health (mHealth) technologies to help older adults increase their engagement in PA in free-living environments, reducing participant burden and increasing generalizability of research findings. Moreover, promoting engagement in moderate-to-vigorous PA (MVPA) may be most beneficial to brain health; thus, using mHealth to help older adults increase time spent in MVPA in free-living environments may help to offset the burden of Alzheimer's disease and related dementias and improve quality of life in older age. OBJECTIVE: We developed a novel PA intervention that leverages mHealth to help older adults achieve more minutes of MVPA independently. This pilot study was a 12-week randomized controlled trial to investigate the feasibility of providing just-in-time (JIT) feedback about PA intensity during free-living exercise sessions to help older adults meet current PA recommendations (150 minutes per week of MVPA). METHODS: Participants were eligible if they were cognitively healthy English speakers aged between 65 and 80 years without major cardiovascular, neurologic, or mental health conditions; could ambulate independently; and undergo magnetic resonance imaging. Enrollment occurred from October 2017 to March 2020. Participants randomized to the PA condition received an individualized exercise prescription and an mHealth device that provided heart rate-based JIT feedback on PA intensity, allowing them to adjust their behavior in real time to maintain MVPA during exercise sessions. Participants assigned to the healthy aging education condition received a reading prescription consisting of healthy aging topics and completed weekly quizzes based on the materials. RESULTS: In total, 44 participants were randomized to the intervention. A follow-up manuscript will describe the results of the intervention as well as discuss screening, recruitment, adverse events, and participants' opinions regarding their participation in the intervention. CONCLUSIONS: The long-term goal of this intervention is to better understand how MVPA affects brain and cognitive health in the real world and extend laboratory findings to everyday life. This pilot randomized controlled trial was conducted to determine the feasibility of using JIT heart rate zone feedback to help older adults independently increase time spent in MVPA while collecting data on the plausible mechanisms of change (frontal and medial temporal cerebral blood flow and cardiorespiratory fitness) that may affect cognition (memory and executive function) to help refine a planned stage 2 behavioral trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT03058146; https://clinicaltrials.gov/ct2/show/NCT03058146. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/42980.

Sex moderates the association between age and myelin water fraction in the cingulum and fornix among older adults without dementia.

Background: Decreasing white matter integrity in limbic pathways including the fornix and cingulum have been reported in Alzheimer's disease (AD), although underlying mechanisms and potential sex differences remain understudied. We therefore sought to explore sex as a moderator of the effect of age on myelin water fraction (MWF), a measure of myelin content, in older adults without dementia (N = 52). Methods: Participants underwent neuropsychological evaluation and 3 T MRI at two research sites. Multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) quantified MWF in 3 a priori regions including the fornix, hippocampal cingulum (CgH), and cingulate cingulum (CgC). The California Verbal Learning Test-Second Edition assessed learning and delayed recall. Multiple linear regressions assessed for (1) interactions between age and sex on regional MWF and (2) associations of regional MWF and memory. Results: (1) There was a significant age by sex interaction on MWF of the fornix (p = 0.002) and CgC (p = 0.005), but not the CgH (p = 0.192); as age increased, MWF decreased in women but not men. (2) Fornix MWF was associated with both learning and recall (ps < 0.01), but MWF of the two cingulum regions were not (p > 0.05). Results were unchanged when adjusting for hippocampal volume. Conclusion: The current work adds to the literature by illuminating sex differences in age-related myelin decline using a measure sensitive to myelin and may help facilitate detection of AD risk for women.

Comprehensive characterization of elevated tau PET signal in the absence of amyloid-beta.

Recently proposed biomarker-only diagnostic frameworks propose that amyloid-beta is necessary for placement on the Alzheimer's disease continuum, whereas tau in the absence of amyloid-beta is considered to be a non-Alzheimer's disease pathologic change. Similarly, the pathologic designation of tau in the absence of amyloid-beta is characterized as primary age-related tauopathy and separable from Alzheimer's disease. Our study sought to identify an early-to-moderate tau stage with minimal amyloid-beta using PET imaging and characterize these individuals in terms of clinical, cognitive and biological features. Seven hundred and three participants from the Alzheimer's Disease Neuroimaging Initiative were classified into one of the four groups (A-/T-, A-/T+, A+/T- and A+/T+) based on PET positivity or negativity for cortical amyloid-beta (A-/A+) and early-to-moderate stage (i.e. meta-temporal) tau (T-/T+). These groups were then compared on demographic and clinical features, vascular risk, multi-domain neuropsychological performance, multi-domain subjective cognitive complaints, apolipoprotein E epsilon-4 carrier status and cortical thickness across Alzheimer's disease-vulnerable regions. The proportion of participants classified in each group was as follows: 47.23% A-/T-, 13.51% A-/T+, 12.23% A+/T- and 27.03% A+/T+. Results indicated that the A-/T+ and A+/T+ groups did not statistically differ on age, sex, depression levels, vascular risk and cortical thickness across temporal and parietal regions. Additionally, both A-/T+ and A+/T+ groups showed significant associations between memory performance and cortical thickness of temporal regions. Despite the different pathologic terminology used for A-/T+ and A+/T+, these groups did not statistically differ on a number of clinical, cognitive and biomarker features. Although it remains unclear whether A-/T+ reflects a pathologic construct separable from Alzheimer's disease, our results provide evidence that this group typically characterized as 'non-Alzheimer's pathologic change' or 'primary age-related tauopathy' should be given increased attention, given some similarities in cognitive and biomarker characteristics to groups traditionally considered to be on the Alzheimer's continuum.

The Retrograde Memory for News Events Test (RM-NET) and the relationship between news event memory and performance on standard neuropsychological tests.

Novel tests of semantic memory (SM)-for example, memory for news events (NE; news facts) or famous personalities-are useful for estimating the severity of retrograde amnesia. Individuals with mild cognitive impairment exhibit relatively intact SM/language on traditional neuropsychological tests but exhibit consistent impairment on novel tests of SM, suggesting novel SM tests are dissimilar from traditional SM tests. To identify the relationship between NE memory and traditional cognitive measures, older adults (N = 51) completed a traditional neuropsychological battery and the Retrograde Memory News Events Test (RM-NET; a new test that robustly measures NE memory across the adult life span with high temporal resolution), and the relationship between performance on these tests was examined. Total RM-NET scores were more closely aligned with episodic memory scores than SM scores. The strength of the association between NE scores and episodic memory scores decreased as the age of NE memory increased. Tests of news events appear to reflect performance on traditional tests of episodic memory rather than SM, especially when recent news events are tested.

Cognitive Heterogeneity and Risk of Progression in Data-Driven Subtle Cognitive Decline Phenotypes.

BACKGROUND: There is increasing recognition of cognitive and pathological heterogeneity in early-stage Alzheimer's disease and other dementias. Data-driven approaches have demonstrated cognitive heterogeneity in those with mild cognitive impairment (MCI), but few studies have examined this heterogeneity and its association with progression to MCI/dementia in cognitively unimpaired (CU) older adults. OBJECTIVE: We identified cluster-derived subgroups of CU participants based on comprehensive neuropsychological data and compared baseline characteristics and rates of progression to MCI/dementia or a Dementia Rating Scale (DRS) of ≤129 across subgroups. METHODS: Hierarchical cluster analysis was conducted on individual baseline neuropsychological test scores from 365 CU participants in the UCSD Shiley-Marcos Alzheimer's Disease Research Center longitudinal cohort. Cox regressions examined the risk of progression to consensus diagnosis of MCI or dementia, or to DRS score ≤129, by cluster group. RESULTS: Cluster analysis identified 5 groups: All-Average (n = 139), Low-Visuospatial (n = 46), Low-Executive (n = 51), Low-Memory/Language (n = 83), and Low-All Domains (n = 46). Subgroups had unique demographic and clinical characteristics. Rates of progression to MCI/dementia or to DRS ≤129 were faster for all subgroups (Low-All Domains progressed the fastest > Low Memory/Language≥Low-Visuospatial and Low-Executive) relative to the All-Average subgroup. CONCLUSION: Faster progression in the Low-Visuospatial, Low-Executive, and Low-Memory/Language groups compared to the All-Average group suggests that there are multiple pathways and/or unique subtle cognitive decline profiles that ultimately lead to a diagnosis of MCI/dementia. Use of comprehensive neuropsychological test batteries that assess several domains may be a key first step toward an individualized approach to early detection and fewer missed opportunities for early intervention.