A multilayer network analysis of Alzheimer's disease pathogenesis: Roles for p-tau, synaptic peptides, and physical activity.

INTRODUCTION: In the aging brain, cognitive abilities emerge from the coordination of complex pathways arising from a balance between protective lifestyle and environmental factors and accumulation of neuropathologies. METHODS: As part of the Rush Memory and Aging Project (n = 440), we measured accelerometer-based actigraphy, cognitive performance, and after brain autopsy, selected reaction monitoring mass spectrometry. Multilevel network analysis was used to examine the relationships among the molecular machinery of vesicular neurotransmission, Alzheimer's disease (AD) neuropathology, cognition, and late-life physical activity. RESULTS: Synaptic peptides involved in neuronal secretory function were the most influential contributors to the multilayer network, reflecting the complex interdependencies among AD pathology, synaptic processes, and late-life cognition. Older adults with lower physical activity evidenced stronger adverse relationships among phosphorylated tau peptides, markers of synaptic integrity, and tangle pathology. DISCUSSION: Network-based approaches simultaneously model interdependent biological processes and advance understanding of the role of physical activity in age-associated cognitive impairment. HIGHLIGHTS: Network-based approaches simultaneously model interdependent biological processes. Secretory synaptic peptides were influential contributors to the multilayer network. Older adults with lower physical activity had adverse relationships among pathology. There was interdependence among phosphorylated tau, synaptic integrity, and tangles. Network methods elucidate the role of physical activity in cognitive impairment.

Better cardiovascular health is associated with slowed clinical progression in autosomal dominant frontotemporal lobar degeneration variant carriers.

INTRODUCTION: Cardiovascular health is important for brain aging, yet its role in the clinical manifestation of autosomal dominant or atypical forms of dementia has not been fully elucidated. We examined relationships between Life's Simple 7 (LS7) and clinical trajectories in individuals with autosomal dominant frontotemporal lobar degeneration (FTLD). METHODS: Two hundred forty-seven adults carrying FTLD pathogenic genetic variants (53% asymptomatic) and 189 non-carrier controls completed baseline LS7, and longitudinal neuroimaging and neuropsychological testing. RESULTS: Among variant carriers, higher baseline LS7 is associated with slower accumulation of frontal white matter hyperintensities (WMHs), as well as slower memory and language declines. Higher baseline LS7 associated with larger baseline frontotemporal volume, but not frontotemporal volume trajectories. DISCUSSION: Better baseline cardiovascular health related to slower cognitive decline and accumulation of frontal WMHs in autosomal dominant FTLD. Optimizing cardiovascular health may be an important modifiable approach to bolster cognitive health and brain integrity in FTLD. HIGHLIGHTS: Better cardiovascular health associates with slower cognitive decline in frontotemporal lobar degeneration (FTLD). Lifestyle relates to the accumulation of frontal white matter hyperintensities in FTLD. More optimal cardiovascular health associates with greater baseline frontotemporal lobe volume. Optimized cardiovascular health relates to more favorable outcomes in genetic dementia.

Predicting brain atrophy and cognitive aging trajectories with baseline subjective cognitive concerns in cognitively normal older adults.

Subjective cognitive concerns (SCC) are common even in cognitively normal older adults who lack objectively-detectable deficits on standard neuropsychological evaluation. The clinical relevance of these concerns, particularly considering the nature of concerns (e.g., memory versus non-memory), remains unclear. Thus, we examined whether baseline memory and non-memory SCC relate to longitudinal change in brain volume and neuropsychological test performance in 476 functionally-intact, objectively unimpaired older adults (Mage = 72y, 56 % female, follow-up time = 1 - 9 years). Mixed-effects models revealed that both higher baseline memory and non-memory SCC predicted greater atrophy in total gray matter and dorsolateral prefrontal cortex atrophy over time, while only memory SCC predicted steeper medial temporal lobe atrophy. Regarding neuropsychological performance, higher non-memory SCC predicted decline in processing speed performance, while memory SCC did not predict neuropsychological trajectories. SCC are a risk factor for more adverse brain and cognitive aging trajectories, even in functionally-intact, seemingly cognitively normal older adults.

Clinical implications of head trauma in frontotemporal dementia and primary progressive aphasia.

BACKGROUND: Traumatic brain injury (TBI) and repetitive head impacts (RHI) have been linked to increased risk for multiple types of neurodegenerative disease, higher dementia risk, and earlier age of dementia symptom onset, suggesting transdiagnostic implications for later-life brain health. Frontotemporal dementia (FTD) and primary progressive aphasia (PPA) represent a spectrum of clinical phenotypes that are neuropathologically diverse. FTD/PPA diagnoses bring unique challenges due to complex cognitive and behavioral symptoms that disproportionately present as an early-onset dementia (before age 65). We performed a detailed characterization of lifetime head trauma exposure in individuals with FTD and PPA compared to healthy controls to examine frequency of lifetime TBI and RHI and associated clinical implications. METHODS: We studied 132 FTD/PPA (age 68.9 ± 8.1, 65% male) and 132 sex-matched healthy controls (HC; age 73.4 ± 7.6). We compared rates of prior TBI and RHI (contact/collision sports) between FTD/PPA and HC (chi-square, logistic regression, analysis of variance). Within FTD/PPA, we evaluated associations with age of symptom onset (analysis of variance). Within behavioral variant FTD, we evaluated associations with cognitive function and neuropsychiatric symptoms (linear regression controlling for age, sex, and years of education). RESULTS: Years of participation were greater in FTD/PPA than HC for any contact/collision sport (8.5 ± 6.7yrs vs. 5.3 ± 4.5yrs, p = .008) and for American football (6.2yrs ± 4.3yrs vs. 3.1 ± 2.4yrs; p = .003). Within FTD/PPA, there were dose-dependent associations with earlier age of symptom onset for TBI (0 TBI: 62.1 ± 8.1, 1 TBI: 59.9 ± 6.9, 2 + TBI: 57.3 ± 8.4; p = .03) and years of American football (0yrs: 62.2 ± 8.7, 1-4yrs: 59.7 ± 7.0, 5 + yrs: 55.9 ± 6.3; p = .009). Within bvFTD, those who played American football had worse memory (z-score: -2.4 ± 1.2 vs. -1.4 ± 1.6, p = .02, d = 1.1). CONCLUSIONS: Lifetime head trauma may represent a preventable environmental risk factor for FTD/PPA. Dose-dependent exposure to TBI or RHI influences FTD/PPA symptom onset and memory function in bvFTD. Clinico-pathological studies are needed to better understand the neuropathological correlates linking RHI or TBI to FTD/PPA onset and symptoms.

Visual Impairment, Eye Conditions, and Diagnoses of Neurodegeneration and Dementia.

Importance: Vision and eye conditions are associated with increased risk for Alzheimer disease and related dementias (ADRDs), but the nature of the association and the underlying biological pathways remain unclear. If causal, vision would be an important modifiable risk factor with viable population-level interventions. Objective: To evaluate potentially causal associations between visual acuity, eye conditions (specifically cataracts and myopia), neuroimaging outcomes, and ADRDs. Design, Setting, and Participants: A cohort and 2-sample bidirectional mendelian randomization (MR) study was conducted using UK Biobank participants and summary statistics from previously published genome-wide association studies on cataract, myopia, and AD. The participants included in the analysis were aged 55 to 70 years without dementia at baseline (calendar years 2006 to 2010), underwent genotyping, and reported on eye conditions; a subset completed visual acuity examinations (n = 69 852-71 429) or brain imaging (n = 36 591-36 855). Data were analyzed from August 15, 2022, through November 28, 2023. Exposure: Self-reported cataracts, visual acuity, and myopia measured by refraction error. Main Outcomes and Measures: ADRD, AD, and vascular dementia were identified from electronic medical records. Total and regional brain volumes were determined using magnetic resonance imaging. Results: The sample included 304 953 participants (mean [SD] age, 62.1 (4.1) years; 163 825 women [53.72%]); 14 295 (4.69%) had cataracts and 2754 (3.86%) had worse than 20/40 vision. Cataracts (hazard ratio [HR], 1.18; 95% CI, 1.07-1.29) and myopia (HR, 1.35; 95% CI, 1.06-1.70) were associated with a higher hazard of ADRD. In MR analyses to estimate potential causal effects, cataracts were associated with increased risk of vascular dementia (inverse variance-weighted odds ratio [OR], 1.92; 95% CI, 1.26-2.92) but were not associated with increased dementia (OR, 1.21; 95% CI, 0.98-1.50). There were no associations between myopia and dementia. In MR for potential reverse causality, AD was not associated with cataracts (inverse variance-weighted OR, 0.99; 95% CI, 0.96-1.01). Genetic risk for cataracts was associated with smaller total brain (ß = -597.43 mm3; 95% CI, -1077.87 to -117.00 mm3) and gray matter (ß = -375.17 mm3; 95% CI, -680.10 to -70.24 mm3) volumes, but not other brain regions. Conclusions and Relevance: In this cohort and MR study of UK Biobank participants, cataracts were associated with increased risk of dementia, especially vascular dementia, and reduced total brain volumes. These findings lend further support to the hypothesis that cataract extraction may reduce the risk for dementia.

Associations of cerebrovascular disease and Alzheimer's disease pathology with cognitive decline: Analysis of the National Alzheimer's Coordinating Center Uniform Data Set.

Cerebrovascular disease (CVD) and Alzheimer's disease (AD) often co-occur and may impact specific cognitive domains. This study's goal was to determine effects of CVD and AD burden on cross-sectional and longitudinal executive function (EF) and memory in older adults. Longitudinally followed participants from the National Alzheimer Coordinating Center database (n = 3342) were included. Cognitive outcomes were EF and memory composite scores. Baseline CVD presence was defined by moderate-to-severe white matter hyperintensities or lacunar infarct on MRI. Baseline AD pathology was defined by amyloid positivity via PET or CSF. Linear mixed models examined effects of CVD, AD, and time on cognitive outcomes, controlling for sex, education, baseline age, MoCA score, and total number of study visits. At baseline, CVD associated with lower EF (p < 0.001), while AD associated with lower EF and memory (ps < 0.001). Longitudinally only AD associated with faster declines in memory and EF (ps < 0.001). These results extend our understanding of CVD and AD pathology, highlighting that CVD does not necessarily indicate accelerated decline.

Sex and gender differences in cognitive resilience to aging and Alzheimer's disease.

Sex and gender-biological and social constructs-significantly impact the prevalence of protective and risk factors, influencing the burden of Alzheimer's disease (AD; amyloid beta and tau) and other pathologies (e.g., cerebrovascular disease) which ultimately shape cognitive trajectories. Understanding the interplay of these factors is central to understanding resilience and resistance mechanisms explaining maintained cognitive function and reduced pathology accumulation in aging and AD. In this narrative review, the ADDRESS! Special Interest Group (Alzheimer's Association) adopted a multidisciplinary approach to provide the foundations and recommendations for future research into sex- and gender-specific drivers of resilience, including a sex/gender-oriented review of risk factors, genetics, AD and non-AD pathologies, brain structure and function, and animal research. We urge the field to adopt a sex/gender-aware approach to resilience to advance our understanding of the intricate interplay of biological and social determinants and consider sex/gender-specific resilience throughout disease stages. HIGHLIGHTS: Sex differences in resilience to cognitive decline vary by age and cognitive status. Initial evidence supports sex-specific distinctions in brain pathology. Findings suggest sex differences in the impact of pathology on cognition. There is a sex-specific change in resilience in the transition to clinical stages. Gender and sex factors warrant study: modifiable, immune, inflammatory, and vascular.

Examining Associations Between Smartphone Use and Clinical Severity in Frontotemporal Dementia: Proof-of-Concept Study.

BACKGROUND: Frontotemporal lobar degeneration (FTLD) is a leading cause of dementia in individuals aged <65 years. Several challenges to conducting in-person evaluations in FTLD illustrate an urgent need to develop remote, accessible, and low-burden assessment techniques. Studies of unobtrusive monitoring of at-home computer use in older adults with mild cognitive impairment show that declining function is reflected in reduced computer use; however, associations with smartphone use are unknown. OBJECTIVE: This study aims to characterize daily trajectories in smartphone battery use, a proxy for smartphone use, and examine relationships with clinical indicators of severity in FTLD. METHODS: Participants were 231 adults (mean age 52.5, SD 14.9 years; n=94, 40.7% men; n=223, 96.5% non-Hispanic White) enrolled in the Advancing Research and Treatment of Frontotemporal Lobar Degeneration (ARTFL study) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS study) Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Mobile App study, including 49 (21.2%) with mild neurobehavioral changes and no functional impairment (ie, prodromal FTLD), 43 (18.6%) with neurobehavioral changes and functional impairment (ie, symptomatic FTLD), and 139 (60.2%) clinically normal adults, of whom 55 (39.6%) harbored heterozygous pathogenic or likely pathogenic variants in an autosomal dominant FTLD gene. Participants completed the Clinical Dementia Rating plus National Alzheimer's Coordinating Center Frontotemporal Lobar Degeneration Behavior and Language Domains (CDR+NACC FTLD) scale, a neuropsychological battery; the Neuropsychiatric Inventory; and brain magnetic resonance imaging. The ALLFTD Mobile App was installed on participants' smartphones for remote, passive, and continuous monitoring of smartphone use. Battery percentage was collected every 15 minutes over an average of 28 (SD 4.2; range 14-30) days. To determine whether temporal patterns of battery percentage varied as a function of disease severity, linear mixed effects models examined linear, quadratic, and cubic effects of the time of day and their interactions with each measure of disease severity on battery percentage. Models covaried for age, sex, smartphone type, and estimated smartphone age. RESULTS: The CDR+NACC FTLD global score interacted with time on battery percentage such that participants with prodromal or symptomatic FTLD demonstrated less change in battery percentage throughout the day (a proxy for less smartphone use) than clinically normal participants (P<.001 in both cases). Additional models showed that worse performance in all cognitive domains assessed (ie, executive functioning, memory, language, and visuospatial skills), more neuropsychiatric symptoms, and smaller brain volumes also associated with less battery use throughout the day (P<.001 in all cases). CONCLUSIONS: These findings support a proof of concept that passively collected data about smartphone use behaviors associate with clinical impairment in FTLD. This work underscores the need for future studies to develop and validate passive digital markers sensitive to longitudinal clinical decline across neurodegenerative diseases, with potential to enhance real-world monitoring of neurobehavioral change.

Targeting complement C3a receptor resolves mitochondrial hyperfusion and subretinal microglial activation in progranulin-deficient frontotemporal dementia.

Mutations in progranulin ( GRN ) cause frontotemporal dementia ( GRN -FTD) due to deficiency of the pleiotropic protein progranulin. GRN -FTD exhibits diverse pathologies including lysosome dysfunction, lipofuscinosis, microgliosis, and neuroinflammation. Yet, how progranulin loss causes disease remains unresolved. Here, we report that non-invasive retinal imaging of GRN -FTD patients revealed deficits in photoreceptors and the retinal pigment epithelium (RPE) that correlate with cognitive decline. Likewise, Grn -/- mice exhibit early RPE dysfunction, microglial activation, and subsequent photoreceptor loss. Super-resolution live imaging and transcriptomic analyses identified RPE mitochondria as an early driver of retinal dysfunction. Loss of mitochondrial fission protein 1 (MTFP1) in Grn -/- RPE causes mitochondrial hyperfusion and bioenergetic defects, leading to NF-kB-mediated activation of complement C3a-C3a receptor signaling, which drives further mitochondrial hyperfusion and retinal inflammation. C3aR antagonism restores RPE mitochondrial integrity and limits subretinal microglial activation. Our study identifies a previously unrecognized mechanism by which progranulin modulates mitochondrial integrity and complement-mediated neuroinflammation.

Unveiling the proteome-wide autoreactome enables enhanced evaluation of emerging CAR T cell therapies in autoimmunity.

Given the global surge in autoimmune diseases, it is critical to evaluate emerging therapeutic interventions. Despite numerous new targeted immunomodulatory therapies, comprehensive approaches to apply and evaluate the effects of these treatments longitudinally are lacking. Here, we leveraged advances in programmable-phage immunoprecipitation methodology to explore the modulation, or lack thereof, of autoantibody profiles, proteome-wide, in both health and disease. Using a custom set of over 730,000 human-derived peptides, we demonstrated that each individual, regardless of disease state, possesses a distinct and complex constellation of autoreactive antibodies. For each individual, the set of resulting autoreactivites constituted a unique immunological fingerprint, or "autoreactome," that was remarkably stable over years. Using the autoreactome as a primary output, we evaluated the relative effectiveness of various immunomodulatory therapies in altering autoantibody repertoires. We found that therapies targeting B cell maturation antigen (BCMA) profoundly altered an individual's autoreactome, while anti-CD19 and anti-CD20 therapies had minimal effects. These data both confirm that the autoreactome comprises autoantibodies secreted by plasma cells and strongly suggest that BCMA or other plasma cell-targeting therapies may be highly effective in treating currently refractory autoantibody-mediated diseases.

Development and validation of a nonverbal consensus-based semantic memory paradigm in patients with epilepsy.

OBJECTIVE: Brain areas implicated in semantic memory can be damaged in patients with epilepsy (PWE). However, it is challenging to delineate semantic processing deficits from acoustic, linguistic, and other verbal aspects in current neuropsychological assessments. We developed a new Visual-based Semantic Association Task (ViSAT) to evaluate nonverbal semantic processing in PWE. METHOD: The ViSAT was adapted from similar predecessors (Pyramids & Palm Trees test, PPT; Camels & Cactus Test, CCT) comprised of 100 unique trials using real-life color pictures that avoid demographic, cultural, and other potential confounds. We obtained performance data from 23 PWE participants and 24 control participants (Control), along with crowdsourced normative data from 54 Amazon Mechanical Turk (Mturk) workers. RESULTS: ViSAT reached a consensus >90% in 91.3% of trials compared to 83.6% in PPT and 82.9% in CCT. A deep learning model demonstrated that visual features of the stimulus images (color, shape; i.e., non-semantic) did not influence top answer choices (p = 0.577). The PWE group had lower accuracy than the Control group (p = 0.019). PWE had longer response times than the Control group in general and this was augmented for the semantic processing (trial answer) stage (both p < 0.001). CONCLUSIONS: This study demonstrated performance impairments in PWE that may reflect dysfunction of nonverbal semantic memory circuits, such as seizure onset zones overlapping with key semantic regions (e.g., anterior temporal lobe). The ViSAT paradigm avoids confounds, is repeatable/longitudinal, captures behavioral data, and is open-source, thus we propose it as a strong alternative for clinical and research assessment of nonverbal semantic memory.

Neuropsychiatric Profiles and Cerebral Amyloid Burden in Adults without Dementia.

INTRODUCTION: We comprehensively evaluated how self- and informant-reported neuropsychiatric symptoms (NPS) were differentially associated with cerebral amyloid-beta (Aß) PET levels in older adults without dementia. METHODS: Two hundred and twenty-one participants (48% female, age = 73.4 years ± 8.4, Clinical Dementia Rating = 0 [n = 184] or 0.5 [n = 37]) underwent an Aß-PET scan (florbetapir or PIB), comprehensive neuropsychological testing, and self-reported (Geriatric Depression Scale - 30 item [GDS-30]) and informant-reported interview (Neuropsychiatric Inventory Questionnaire [NPI-Q]) of NPS. Cerebral Aß burden was quantified using centiloids (CL). NPI-Q and GDS-30 queried the presence of NPS within 4 subdomains and 6 subscales, respectively. Regression models examined the relationship between NPS and Aß-PET CL. RESULTS: Both higher self- and informant-reported NPS were associated with higher Aß burden. Among specific NPI-Q subdomains, informant-reported changes in depression, anxiety, and irritability were all associated with higher Aß-PET. Similarly, self-reported (GDS-30) subscales of depression, apathy, anxiety, and cognitive concern were associated with higher Aß-PET. When simultaneously entered, only self-reported cognitive concern was associated with Aß-PET in the GDS-30 model, while both informant-reported anxiety and depression were associated with Aß-PET in the NPI-Q model. Clinical status moderated the association between self-reported NPS and Aß-PET such that the positive relationship between self-perceived NPS and Aß burden strengthened with increasing functional difficulties. CONCLUSIONS: In a cohort of older adults without dementia, both self- and informant-reported measures of global NPS, particularly patient-reported cognitive concerns and informant-reported anxiety and depression, corresponded with cerebral Aß burden. NPS may appear early in the prodromal disease state and relate to initial AD proteinopathy burden, a relationship further exaggerated in those with greater clinical severity.

Linking Type and Extent of Head Trauma to Cavum Septum Pellucidum in Older Adults With and Without Alzheimer Disease and Related Dementias.

BACKGROUND AND OBJECTIVES: Cavum septum pellucidum (CSP) is a common but nonspecific MRI finding in individuals with prior head trauma. The type and extent of head trauma related to CSP, CSP features specific to head trauma, and the impact of brain atrophy on CSP are unknown. We evaluated CSP cross-sectionally and longitudinally in healthy and clinically impaired older adults who underwent detailed lifetime head trauma characterization. METHODS: This is an observational cohort study of University of California, San Francisco Memory and Aging Center participants (healthy controls [HCs], those with Alzheimer disease or related dementias [ADRDs], subset with traumatic encephalopathy syndrome [TES]). We characterized traumatic brain injury (TBI) and repetitive head impacts (RHI) through contact/collision sports. Study groups were no RHI/TBI, prior TBI only, prior RHI only, and prior RHI + TBI. We additionally looked within TBI (1, 2, or 3+) and RHI (1-4, 5-10, and 11+ years). All underwent baseline MRI, and 67% completed a second MRI (median follow-up = 5.4 years). CSP measures included grade (0-4) and length (millimeters). Groups were compared on likelihood of CSP (logistic regression, odds ratios [ORs]) and whether CSP length discriminated groups (area under the curve [AUC]). RESULTS: Our sample included 266 participants (N = 160 HCs, N = 106 with ADRD or TES; age 66.8 ± 8.2 years, 45.3% female). Overall, 123 (49.8%) participants had no RHI/TBI, 52 (21.1%) had TBI only, 41 (16.6%) had RHI only, 31 (12.6%) had RHI + TBI, and 20 were classified as those with TES (7.5%). Compared with no RHI/TBI, RHI + TBI (OR 3.11 [1.23-7.88]) and TES (OR 11.6 [2.46-54.8]) had greater odds of CSP. Approximately 5-10 years (OR 2.96 [1.13-7.77]) and 11+ years of RHI (OR 3.14 [1.06-9.31]) had higher odds of CSP. CSP length modestly discriminated participants with 5-10 years (AUC 0.63 [0.51-0.75]) and 11+ years of prior RHI (AUC 0.69 [0.55-0.84]) from no RHI/TBI (cut point = 6 mm). Strongest effects were noted in analyses of American football participation. Longitudinally, CSP grade was unchanged in 165 (91.7%), and length was unchanged in 171 (95.5%) participants. DISCUSSION: Among older adults with and without neurodegenerative disease, risk of CSP is driven more by duration (years) of RHI, especially American football, than number of TBI. CSP length (≥6 mm) is relatively specific to individuals who have had substantial prior RHI. Neurodegenerative disease and progressive atrophy do not clearly influence development or worsening of CSP.

KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss.

Synaptic plasticity is obstructed by pathogenic tau in the brain, representing a key mechanism that underlies memory loss in Alzheimer's disease (AD) and related tauopathies. Here, we found that reduced levels of the memory-associated protein KIdney/BRAin (KIBRA) in the brain and increased KIBRA protein levels in cerebrospinal fluid are associated with cognitive impairment and pathological tau levels in disease. We next defined a mechanism for plasticity repair in vulnerable neurons using the C-terminus of the KIBRA protein (CT-KIBRA). We showed that CT-KIBRA restored plasticity and memory in transgenic mice expressing pathogenic human tau; however, CT-KIBRA did not alter tau levels or prevent tau-induced synapse loss. Instead, we found that CT-KIBRA stabilized the protein kinase Mζ (PKMζ) to maintain synaptic plasticity and memory despite tau-mediated pathogenesis. Thus, our results distinguished KIBRA both as a biomarker of synapse dysfunction and as the foundation for a synapse repair mechanism to reverse cognitive impairment in tauopathy.

Sex Differences in Association of Physical Activity With All-Cause and Cardiovascular Mortality.

BACKGROUND: Although physical activity is widely recommended for reducing cardiovascular and all-cause mortality risks, female individuals consistently lag behind male individuals in exercise engagement. OBJECTIVES: The goal of this study was to evaluate whether physical activity derived health benefits may differ by sex. METHODS: In a prospective study of 412,413 U.S. adults (55% female, age 44 ± 17 years) who provided survey data on leisure-time physical activity, we examined sex-specific multivariable-adjusted associations of physical activity measures (frequency, duration, intensity, type) with all-cause and cardiovascular mortality from 1997 through 2019. RESULTS: During 4,911,178 person-years of follow-up, there were 39,935 all-cause deaths including 11,670 cardiovascular deaths. Regular leisure-time physical activity compared with inactivity was associated with 24% (HR: 0.76; 95% CI: 0.73-0.80) and 15% (HR: 0.85; 95% CI: 0.82-0.89) lower risk of all-cause mortality in women and men, respectively (Wald F = 12.0, sex interaction P < 0.001). Men reached their maximal survival benefit of HR 0.81 from 300 min/wk of moderate-to-vigorous physical activity, whereas women achieved similar benefit at 140 min/wk and then continued to reach a maximum survival benefit of HR 0.76 also at ∼300 min/wk. Sex-specific findings were similar for cardiovascular death (Wald F = 20.1, sex interaction P < 0.001) and consistent across all measures of aerobic activity as well as muscle strengthening activity (Wald F = 6.7, sex interaction P = 0.009). CONCLUSIONS: Women compared with men derived greater gains in all-cause and cardiovascular mortality risk reduction from equivalent doses of leisure-time physical activity. These findings could enhance efforts to close the "gender gap" by motivating especially women to engage in any regular leisure-time physical activity.

Associations of Polycystic Ovary Syndrome With Indicators of Brain Health at Midlife in the CARDIA Cohort.

BACKGROUND AND OBJECTIVES: Polycystic ovary syndrome (PCOS) is a common reproductive disorder associated with an adverse cardiometabolic profile early in life. Increasing evidence links cardiovascular risk factors, such as diabetes and hypertension, to accelerated cognitive aging. However, less is known about PCOS and its relationship to brain health, particularly at midlife. Our goal was to investigate possible associations between PCOS and midlife cognitive function and brain MRI findings in an ongoing prospective study. METHODS: We used data from the Coronary Artery Risk Development in Young Adults (CARDIA) study, a geographically diverse prospective cohort study of individuals who were 18-30 years at baseline (1985-1986) and followed for 30 years. We identified women with PCOS from an ancillary study (CARDIA Women's study (CWS); n = 1,163) as those with elevated androgen levels and/or hirsutism in conjunction with symptoms of oligomenorrhea. At year 30, participants completed cognitive testing, including the Montreal Cognitive Assessment, Rey Auditory Verbal Learning Test (RAVLT) (verbal learning and memory), Digit Symbol Substitution Test (processing speed and executive function), Stroop test (attention and cognitive control), and category and letter fluency tests (semantics and attention). A subset completed brain MRI to assess brain structure and white matter integrity. Multivariable linear regression models estimated the association between PCOS and outcomes, adjusting for age, race, education, and study center. RESULTS: Of the 1163 women in CWS, 907 completed cognitive testing, and of these, 66 (7.1%) met criteria for PCOS (age 54.7 years). Women with and without PCOS were similar for age, BMI, smoking/drinking status, and income. At year 30, participants with PCOS performed lower (mean z score; 95% CI) on Stroop (-0.323 (-0.69 to -7.37); p = 0.008), RAVLT (-0.254 (-0.473 to -0.034); p = 0.002), and category fluency (-0.267 (-0.480 to -0.040); p = 0.02) tests. Of the 291 participants with MRI, 25 (8.5%) met PCOS criteria and demonstrated lower total white matter fractional anisotropy, a measure of white matter integrity (coefficient (95% CI) -0.013 (-0.021 to -0.005); p = 0.002), though not abnormal white matter. DISCUSSION: Our results suggest that women with PCOS have lower cognitive performance and lower white matter integrity at midlife. Additional research is needed to confirm these findings and to determine potential mechanistic pathways including potential modifiable factors.

Plasma phosphorylated tau-217 exhibits sex-specific prognostication of cognitive decline and brain atrophy in cognitively unimpaired adults.

INTRODUCTION: Accumulating evidence indicates disproportionate tau burden and tau-related clinical progression in females. However, sex differences in plasma phosphorylated tau (p-tau)217 prediction of subclinical cognitive and brain changes are unknown. METHODS: We measured baseline plasma p-tau217, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) in 163 participants (85 cognitively unimpaired [CU], 78 mild cognitive impairment [MCI]). In CU, linear mixed effects models examined sex differences in plasma biomarker prediction of longitudinal domain-specific cognitive decline and brain atrophy. Cognitive models were repeated in MCI. RESULTS: In CU females, baseline plasma p-tau217 predicted verbal memory and medial temporal lobe trajectories such that trajectories significantly declined once p-tau217 concentrations surpassed 0.053 pg/ml, a threshold that corresponded to early levels of cortical amyloid aggregation in secondary amyloid positron emission tomography analyses. CU males exhibited similar rates of cognitive decline and brain atrophy, but these trajectories were not dependent on plasma p-tau217. Plasma GFAP and NfL exhibited similar female-specific prediction of medial temporal lobe atrophy in CU. Plasma p-tau217 exhibited comparable prediction of cognitive decline across sex in MCI. DISCUSSION: Plasma p-tau217 may capture earlier Alzheimer's disease (AD)-related cognitive and brain atrophy hallmarks in females compared to males, possibly reflective of increased susceptibility to AD pathophysiology.

Multimodal lifestyle engagement patterns support cognitive stability beyond neuropathological burden.

BACKGROUND: Modifiable lifestyle behaviors account for a large proportion of dementia risk. However, the combined contributions of multidomain lifestyle patterns to cognitive aging are poorly understood, as most studies have examined individual lifestyle behaviors in isolation and without neuropathological characterization. This study examined data-driven patterns of lifestyle behaviors across multiple domains among older adults and tested their associations with disease-specific neuropathological burden and cognitive decline. METHODS: Participants included 2059 older adults enrolled in the longitudinal Memory and Aging Project (MAP) at the Rush Alzheimer's Disease Center; none of whom had dementia at baseline (73% no cognitive impairment (NCI), 27% mild cognitive impairment [MCI]). All participants completed cognitive testing annually. Lifestyle factors were measured during at least one visit and included (1) actigraphy-measured physical activity, as well as self-reported (2) sleep quality, (3) life space, (4) cognitive activities, (5) social activities, and (6) social network. A subset of participants (n = 791) had autopsy data for which burden of Alzheimer's disease (AD), cerebrovascular disease (CVD), Lewy body disease, and hippocampal sclerosis/TDP-43 was measured. Latent profile analysis across all 2059 participants identified distinct subgroups (i.e., classes) of lifestyle patterns. Linear mixed-effects models examined relationships between lifestyle classes and global cognitive trajectories, with and without covarying for all neuropathologies. Classes were also compared on rates of incident MCI/dementia. RESULTS: Five classes were identified: Class 1Low Life Space (lowest lifestyle engagement), Class 2PA (high physical activity), Class 3Low Avg (low to average lifestyle engagement), Class 4Balanced (high average lifestyle engagement), and Class 5Social (large social network). Classes 4Balanced and 5Social had the lowest AD burden, and Class 2PA had the lowest CVD burden. Classes 2-5 had significantly less steep global cognitive decline compared to Class 1Low Life Space, with comparable effect sizes before and after covarying for neuropathological burden. Classes 4Balanced and 5Social exhibited the lowest rates of incident MCI/dementia. CONCLUSIONS: Lifestyle behavior patterns among older adults account for differential rates of cognitive decline and clinical progression. Those with at least average engagement across all lifestyle domains exhibit greater cognitive stability after adjustment for neuropathology, highlighting the importance of engagement in multiple healthy lifestyle behaviors for later life cognitive health.

Moderating role of physical activity on hippocampal iron deposition and memory outcomes in typically aging older adults.

Physical activity (PA) is linked to better cognitive and brain health, though its mechanisms are unknown. While brain iron is essential for normal function, levels increase with age and, when excessive, can cause detrimental neural effects. We examined how objectively measured PA relates to cerebral iron deposition and memory functioning in normal older adults. Sixty-eight cognitively unimpaired older adults from the UCSF Memory and Aging Center completed neuropsychological testing and brain magnetic resonance imaging, followed by 30-day Fitbit monitoring. Magnetic resonance imaging quantitative susceptibility mapping (QSM) quantified iron deposition. PA was operationalized as average daily steps. Linear regression models examined memory as a function of hippocampal QSM, PA, and their interaction. Higher bilateral hippocampal iron deposition correlated with worse memory but was not strongly related to PA. Covarying for demographics, PA moderated the relationship between bilateral hippocampal iron deposition and memory such that the negative effect of hippocampal QSM on memory performances was no longer significant above 9120 daily steps. PA may mitigate adverse iron-related pathways for memory health.

KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss.

Synaptic plasticity is obstructed by pathogenic tau in the brain, representing a key mechanism that underlies memory loss in Alzheimer's disease (AD) and related tauopathies. Here, we define a mechanism for plasticity repair in vulnerable neurons using the C-terminus of the KIdney/BRAin (KIBRA) protein (CT-KIBRA). We show that CT-KIBRA restores plasticity and memory in transgenic mice expressing pathogenic human tau; however, CT-KIBRA did not alter tau levels or prevent tau-induced synapse loss. Instead, we find that CT-KIBRA binds to and stabilizes protein kinase Mζ (PKMζ) to maintain synaptic plasticity and memory despite tau-mediated pathogenesis. In humans we find that reduced KIBRA in brain and increased KIBRA in cerebrospinal fluid are associated with cognitive impairment and pathological tau levels in disease. Thus, our results distinguish KIBRA both as a novel biomarker of synapse dysfunction in AD and as the foundation for a synapse repair mechanism to reverse cognitive impairment in tauopathy.