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AbstractBackgroundThe relation between cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD) and neurodegeneration and brain regions of relevance for very early pathological processes in AD is poorly understood. This study aims to investigate cross‐sectional associations between the CSF biomarkers amyloid‐β1‐42 (Aβ42), total‐tau (T‐tau), phosphorylated‐tau (P‐tau), neurogranin (Ng) and neurofilament light (NfL) protein and normalized intracranial volumes of the hippocampus, amygdala, entorhinal cortex and basal forebrain observed on structural magnetic resonance imaging (MRI) in cognitively healthy 70‐year olds from the general population.MethodThe analyses included 226 cognitively normal individuals (clinical dementia rating of zero), examined during 2014‐2016 as part of the population‐based Gothenburg H70 Birth Cohort Studies in Sweden. The study participants had undergone lumbar puncture examination to extract CSF samples for biomarker measurements (pg/mL), MRI scan (volumes in mm³), and apolipoprotein E (APOE) genotyping. Linear regressions, adjusted for sex, were used to examine potential associations.ResultElevated CSF T‐tau, P‐tau, and Ng concentrations were associated with smaller volumes of the hippocampus, amygdala, and entorhinal cortex among individuals with amyloid pathology (p = 8×10−8 – 0.04) and among APOE ε4 carriers (p = 8×10−5 – 0.04). In addition, elevated CSF T‐tau, P‐tau, and Ng concentrations were associated with larger basal forebrain among individuals without pathological Aβ42 (p = 0.001 – 0.01) and among APOE ε4 non‐carriers (p = 0.004 – 0.02).ConclusionThe results of our study suggest that among cognitively normal adults who have amyloid pathology or genetic susceptibility to AD, there are associations between axonal degeneration, tangle pathology, and synapse loss and decreased volumes of AD vulnerable brain regions. The associations between elevated CSF biomarkers and larger basal forebrain in cognitively normal individuals were unexpected, but could possibly be explained by compensatory mechanisms or an inflammatory response (generating neuronal or glial swelling) as a very early reaction to the presence of increased levels of tau and Ng. Our findings highlight the clinical pathophysiological relevance of CSF biomarkers of AD and neurodegeneration and how they relate to AD specific brain regions seen on structural MRI in 70‐year‐olds that may be at risk to develop dementia.

AbstractBackgroundTamoxifen is used as a selective estrogen receptor modifier (SERM) to treat hormone receptor‐positive breast cancer. Raloxifene, another SERM, has been used for the treatment of osteoporosis in post‐menopausal women. The aim of this cross‐sectional study was to examine whether a history of tamoxifen or raloxifene use was associated with cognitive performance, odds of mild cognitive impairment (MCI), or structural neurodegenerative MRI markers.MethodThe study included women with and without a personal history of breast cancer enrolled in the Mayo Clinic Study of Aging (MCSA). A history of breast cancer and use of SERMs before the MCSA enrollment visit was abstracted using the Rochester Epidemiology Project medical‐linkage system. Participants had a diagnosis of MCI (prevalent) at the time of enrollment into the MCSA. Logistic regression was used to examine associations of SERMs with odds of MCI. Linear regression models were used to examine associations of SERMs with cognitive measures z‐scores (Memory, Executive Function, Language, Visuospatial Skills, Global Cognition), hippocampal volume, and Alzheimer’s disease signature cortical thickness.ResultAmong the women aged ≥ 50 at enrollment in the MCSA, 151 had a history of breast cancer, and 2235 had no prior history of any cancer. Of the 151 women with a history of breast cancer, 42 (28%) had taken tamoxifen and 109 (72%) had not at enrollment in the MCSA; 54 had neuroimaging data (tamoxifen = 16; no tamoxifen = 38). Among the women without prior history of cancer at enrollment in the MCSA, 76 (3%) had taken raloxifene and 2159 (97%) had not; 755 had neuroimaging data (raloxifene = 25; no raloxifene = 730). No significant associations between tamoxifen with global or domain‐specific cognition or odds of MCI were observed among women with a history of breast cancer after adjusting for confounders (Table 1). Likewise raloxifene was not significantly associated with global or domain‐specific cognition or odds of MCI in women without a history of cancer after adjusting for confounders (Table 2). We did not find significant associations between SERMs and any neuroimaging outcome (Table 3).ConclusionOur results suggest use of tamoxifen or raloxifene is not significantly associated with cognition in postmenopausal women.

AbstractBackgroundTwo pathways that help explain cognitive health are 1) brain maintenance – referring to the relative absence of brain changes over time; 2) cognitive reserve – a property of the brain that allows for sustained cognitive ability in the presence of brain pathology. Both pathways influence cognitive aging and are best understood using longitudinal data. Our goal was to assess the effect of modifiable vascular/metabolic and lifestyle enrichment factors on these pathways using longitudinal brain changes measured on structural magnetic resonance imaging (MRI) and longitudinal cognitive decline. Lastly, we combined these pathways and their relationships in the same model.MethodWe identified 1250 participants from a well‐characterized sample of older adults from the Mayo Clinic Study of Aging with both longitudinal MRI and cognitive data. Linear mixed models were performed to assess the impact of modifiable factors on brain maintenance and cognitive reserve. Latent growth curve models (SEM) were used to assess the impact of brain structure and cognitive reserve on longitudinal cognition.ResultThe mean age of our sample was 78.8 years, with 45.4% female, and 27.1% APOE4 carriers. Mean follow‐up time was 4.0 years with a mean of 3.2 MRI scans per participant. Linear mixed models showed that poorer vascular/metabolic health (presence of vascular/metabolic conditions) was associated with lower cross‐sectional temporal region cortical thickness (‐0.014 (0.003), p<0.001) and lower global cognition (‐0.042 (0.018), p = 0.024). Higher estimated cognitive reserve at baseline as assessed by education/occupation composite (0.103 (0.01), p<0.001) was associated with higher global cognition. Unexpectedly, late‐life physical activities were related to lower global cognition (‐0.05 (0.007), p = 0.004). Our final latent growth curve SEM fit the data well showing temporal associations between unmodifiable characteristics, cognitive reserve, and brain structural pathways, as well as the influence of modifiable vascular/metabolic factors.ConclusionWe found that brain maintenance and cognitive reserve pathways were related to better cognition over time. We further showed that vascular/metabolic health impacts long‐term cognitive outcomes (i.e. cognitive aging) primarily through the brain maintenance pathway. These data provide a modeling scheme for future studies and can aid in assessing the pathways by which individual factors may influence cognitive aging.

AbstractBackgroundWomen have higher rates of hypertension at the time of menopausal transition than men. Although elevated systolic and diastolic blood pressures (SBP and DBP) are risk factors for white matter (WM) injury both in women and men, WM hyperintensities (WMH), a marker of WM injury, are more common in women than in men after the age of 60. Thus, women may be vulnerable to the effects of elevated BP on WM integrity during menopausal transition. We investigated the association of BP in recently postmenopausal women with good cardiovascular health with WMH volume assessed 13 years later.MethodWomen (n = 212; median age = 67; range 58‐72), who were previously enrolled in a multi‐site randomized menopausal hormone therapy trial, Kronos Early Estrogen Prevention Study (KEEPS), participated in the present observational KEEPS Continuation Study. SBP and DBP were measured at KEEPS baseline (median age = 54 years; range 44‐59). Participants who were on antihypertensive medications at KEEPS baseline were excluded from the analysis (n = 34). Approximately 9 years after the end of KEEPS menopausal hormones versus placebo 4‐year interventions, WM integrity was assessed with automated WMH volume measurements from 3D‐FLAIR MRI. Associations of baseline SBP and DBP with logWMH volume measured 13 years later were tested by linear regression analyses. Model 1 was adjusted for age, study site, and total intracranial volume. Model 2 was adjusted for covariates of model 1, triglycerides, low density lipoproteins, and waist/hip ratio.ResultThe median SBP was 116 (range 83‐158) and DBP was 74 (range 56‐98). Higher SBP was associated with greater WMH volume (model 1:p = 0.005; model 2:p = 0.005). Similarly, higher DBP was associated with greater WMH volume (model 1:p = 0.008; model 2:p = 0.006) (Figure 1). Neither menopausal hormone therapies versus placebo, nor having high/low SBP (≥120/<120) modified these associations. Voxel‐based analyses demonstrate the association of BPs with the spatial distribution of WMHs (Figure 2).ConclusionHigher BPs in recently menopausal women were associated with greater WM injury more than a decade later after adjusting for CVD risk factors. Early postmenopausal stage is a critical time for BP control in women, which may reduce the risk of WM injury later in life.

AbstractBackgroundUnderstanding mortality risk across the Alzheimer’s disease (AD) clinical stages is essential for resource planning and estimating the value of disease modifying therapies (DMTs), which may slow progression. Such studies are lacking.MethodThe study used the Uniform Data Set of the National Alzheimer’s Coordinating Center (NACC) from September 1, 2005 to March 1, 2021 to assess mortality risk across the AD clinical stages. It included 12,414 participants aged ≥ 50 years, who contributed to the following stages: cognitively unimpaired (CU n = 11,458), incident prodromal AD (n = 937), and AD dementia (n = 745). AD etiology and stage were established based on clinical evaluation and cognitive, behavioral, and functional scores. Study centers report mortality for actively followed participants. Participants contributed observation time until all‐cause death, disease progression, discontinuation, loss to follow‐up, data cutoff or the last visit before a longer than 36‐month gap in visits or recorded scores.Hazard ratios for each AD stage versus CU were estimated using Cox proportional hazards models. Least absolute shrinkage and selection operator facilitated final predictor selection.ResultParticipants’ mean age (SD) at study entry was 71.0 years (SD 9.2) (34.9% males). Participants with incident mild, moderate, and severe AD had increased mortality risk relative to CU after controlling for age, sex, education, apolipoprotein E ε4 genotype status, BMI, and residence type. Relative all‐cause mortality risk by AD stage decreased with increasing age; the HRs (95% CI) for mortality at 65 years of age were 6.7 (2.7‐16.9), 14.8 (8.8‐24.8), and 30.1 (16.7‐56.8) for mild, moderate and severe AD respectively; at 80 years of age, the corresponding HR (95% CI) were 2.4 (1.7‐3.3), 3.1 (2.4‐3.9), and 6.6 (4.8‐9.1). Male sex (HR = 1.75, 95% CI 1.52‐2.04) and residing in an institution (vs. private residence; HR = 3.11, 95% CI 2.28‐4.25) significantly increased relative all‐cause mortality risk.ConclusionRelative all‐cause mortality risk increases with AD severity, and more so at younger ages. Despite data limitations, findings are significant as efforts to delay disease, for instance with DMTs, could not only improve patient and caregiver quality of life and reduce costs, but also extend the lives of patients with AD.NIA/NIH Grant U24 AG072122 funds the NACC database.

AbstractBackgroundParadoxical lucidity is characterized by spontaneous mental clarity with verbal or non‐verbal communication or behavior among people with AD who had previously been thought to lack the cognitive capacity to do so. With a paucity of data available, family caregivers (FCGs) provide critical perspectives on characteristics of these episodes of lucidity (EL).MethodTwenty‐four FCGs who witnessed at least one EL were interviewed about the experience. Qualitative data were transcribed, double coded, and analyzed to help characterize ELs.ResultFCGs described ELs as indelible moments, possibly triggered by music, food, holidays, or impending death. The spontaneity of the EL, its duration, the connectedness with FCGs, and coherence of communication varied. Instead of seeing them as cognitive fluctuations, FCGs often assigned metaphysical meaning to ELs.ConclusionFCG descriptions of ELs had few common patterns, suggestions they are heterogenous. Their impact on FCGs, however, was enduring.

AbstractBackgroundPhysical activity is associated with reduced risk for Alzheimer’s disease (AD). Aerobic exercise produced modest‐to‐moderate cognitive gains in older adults with mild cognitive impairment or AD dementia. In animal models, aerobic exercise modifies AD’s AT(N) biomarkers of Amyloid‐beta (Aβ), hyperphosphorylated Tau, and Neurodegeneration. However, most observational studies didn’t find significant associations between physical activity and AT(N) biomarkers. Few exercise trials included biomarkers, partially attributable to the prohibitive cost and invasiveness of cerebrospinal fluid or PET biomarkers and reported mixed effects on central AT(N) biomarkers. Plasma Aβ42/40 ratio, phosphorylated tau 181 (p‐tau181), and total tau (t‐tau) demonstrate robust correlations with central amyloid and tau levels and offer an opportunity for inclusion in exercise trials.MethodThis pilot study examined the preliminary effects of 6‐month aerobic exercise on plasma Aβ42/40 ratio, p‐tau181, and t‐tau in older adults with mild‐to‐moderate AD dementia. Twenty‐six participants were eligible, and all consented to enroll (8 in stretching, 18 in cycling). Plasma Aβ42/40 ratio, p‐tau181, and t‐tau were measured using Simoa™ assays at baseline, 3, and 6 months. Data were analyzed using Cohen’s d, multilevel model, and intention‐to‐treat.ResultThe sample averaged 77.58±6.99 years old, 15.44±3.00 years of education, 65% male, and 96.2% carrying an APOE e4 allele. The 6‐month within‐group trajectories of changes in outcomes trended differently but were not statistically significant. Aβ42/40 ratio (mean ± standard deviation) increased by 0.001±0.012, p‐tau181 increased by 0.609±1.417 pg/ml, and t‐tau decreased by 0.020±0.279 ng/ml in the stretching group, while Aβ42/40 ratio decreased by 0.001±0.010, p‐tau181 increased by 0.101±1.579 pg/ml, and t‐tau decreased by 0.075±0.215 pg/ml in the cycling group. Between‐group differences were not significant. Effect sizes for 6‐month within‐group changes were small except for p‐tau181 in stretching (d = 0.43 [‐.65, 1.45]) and t‐tau in cycling (‐0.35 [‐0.87, 0.17]). Most 6‐month between‐group effect sizes were also small except for p‐tau181 (d = .40 [‐.70, 1.51]) and t‐tau (d = .53 [‐.40, 1.46]), a trend favoring cycling.ConclusionBlood biomarkers are highly feasible and tolerable. Exercise modalities may affect AD plasma biomarkers differently. Aerobic exercise may reduce p‐tau181 levels and stretching exercise may improve Aβ42/40 ratio, which need to be validated in future trials.

AbstractBackgroundPartners of persons with mild cognitive impairment (pwMCI) show increased rates of depression and other mental health problems compared to the general population. While dyadic behavioral interventions such as cognitive rehabilitation have shown beneficial effects in reducing caregiver burden, research to date lacks consistent outcome measures and rarely focuses on distressed partners. Therefore, this study explored the longitudinal effect of the Healthy Action to Benefit Independence & Thinking® (HABIT) program on partners with relatively low initial adjustment level. We hypothesized that the HABIT program would improve partner adjustment in those who were distressed.MethodData from 322 pwMCI and partners were utilized from the HABIT IRB research registry. Among them, 240 completed HABIT while 82 served as an untreated control group. Consistent with our previous exploratory factor analysis, a composite partner adjustment score was calculated using the Center for Epidemiologic Studies Depression scale (CES‐D), the REACH Anxiety Inventory Form, and the Quality of Life scale for adults with Alzheimer’s Disease (QOL‐AD). We included partners with an adjustment score below the median of each group to focus on partners with low levels of baseline adjustment. Latent growth curve models were conducted at baseline, 3‐month, 6‐month, and 1‐year follow‐ups to investigate the trajectories of partner adjustment level.ResultIn the low adjustment subsample, no between group difference was found at baseline. An overall improvement in partner adjustment scores was observed only in the treatment group (b = 5.00, p<.001). The slope of change was larger (b = 3.75, p = .016) in the treatment group, indicating a faster improvement in adjustment level in HABIT partners with marginally lower baseline and higher follow‐up scores. This difference in the improvement rates was most evident at the 3‐month follow‐up (t(1, 94) = ‐2.63, p = .010) and gradually reduced in subsequent visits.ConclusionIn partners of those with MCI who have low levels of emotional adjustment, behavioral interventions like HABIT can be beneficial in accelerating improvement in their overall adjustment level and facilitate adaptation to their loved ones’ MCI symptoms compared to untreated controls. Techniques taught in dyadic interventions may serve as protective factors for mental health problems in primary caregivers of pwMCI.

AbstractBackgroundNeuropsychiatric symptoms (NPS) often occur during the prodromal stage of frontotemporal dementia (FTD), as evidenced by the presence of early psychiatric diagnosis in approximately 50% of bvFTD patients prior to their dementia diagnosis. We hypothesized that carriers of mutations in progranulin (GRN+), chromosome 9 open reading frame 72 (C9orf72+) and microtubule associated protein tau (MAPT+) have increased baseline burden and rates of progression of NPS compared to non‐carrier individuals prior to onset of dementia symptoms based on the Clinical Dementia Rating (CDR) scale.MethodParticipants were recruited through the ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Study. NPS were assessed with Neuropsychiatric Inventory‐Questionnaire (NPI‐Q), Geriatric Depression Scale (GDS), Interpersonal Reactivity Index (IRI), Social Behaviour Checklist (SBOCL), and Behavioral Inhibition Scale (BIS) annually for up to five years. We selected participants with CDR scores of 0 and 0.5. If a participant’s CDR changed to above 0.5 during the follow‐up, we only analyzed observations collected before the conversion. We used mixed effects models to compare the baseline burden and the longitudinal progression of NPS measures between carriers and controls, adjusted for baseline age, sex, education, and baseline Montreal Cognitive Assessment (MoCA) scores.ResultWe analyzed data from 607 participants (111 C9orf72+, 47 GRN+, 67 MAPT+ and 382 non‐carrier controls). There were no significant group differences in baseline demographic features, except that MAPT+ was significantly younger than other groups (average age: C9orf72+ = 45, GRN+ = 53, MAPT+ = 41, controls = 54). Baseline NPS scores were not significantly different between carriers and controls, except that C9orf72+ had significantly lower GDS compared to controls (p = 0.002). Longitudinally, GRN+ (p = 0.02) and MAPT+ (p = 0.009) had significantly higher rates of NPI‐Q increases compared to controls, while the progression of NPI‐Q in C9orf72+ was comparable to controls. The rates of GDS, IRI, SBOCL and BIS progression were not significantly different between carriers and controls.ConclusionPrior to the onset of dementia, GRN+ and MAPT+ have a faster progression of NPS, as measured by NPI‐Q, compared to controls. Future work will investigate whether different mutation carriers are affected by specific type/cluster of symptoms.

AbstractBackgroundPreclinical Alzheimer’s cognitive composites (PACC) are designed to detect subtle cognitive changes in clinical trials. PACCs often include measures of memory, attention, and semantic fluency, with variations based on available measures. We created a Mayo Clinic PACC (Mayo‐PACC) to address limitations of existing PACCs by prioritizing parsimony, non‐proprietary measures, clinical applicability, and psychometric properties. We developed a Mayo‐PACC and examined sensitivity to detecting longitudinal cognitive change in amyloid positive (A+) older adults relative to the Preclinical Alzheimer’s Cognitive Composite‐Revised (PACC‐R). Exploratory analyses included comparison to other composites.MethodParticipants included 614 individuals in the Mayo Clinic Study of Aging (428 A‐ and 186 A+) age 65‐85 who were cognitively unimpaired at baseline with 7 years mean follow‐up. A+ was defined as PiB‐PET meta‐ROI SUVR ≥ 1.48 (centiloid 22). The Mayo‐PACC included the AVLT sum of trials (trials 1‐5, short delay, long delay), Trails B and Animal fluency. Measures included in the PACC‐R and other comparison composites are listed in Table 1. We calculated study‐specific z‐scores and examined psychometric properties of component measures including test‐retest reliability, practice effects, and distributional properties (ceiling/floor effects, skew, kurtosis). We examined sensitivity to preclinical cognitive change using slope estimates (difference in annualized change across A+ and A‐ groups) from linear mixed models (LMMs) for each composite. A jackknife procedure was used to calculate the standard error and subsequent confidence intervals of differences in rates of change (A+>A‐ indicating more significant decline in A+). Significance was determined based on whether the 95% Confidence Interval (CI) contained 0 (alpha = .05).ResultAll composites showed sensitivity to amyloid‐related longitudinal cognitive decline (A+>A‐ annualized change p<.05; see Table 2). Jack‐knife comparisons revealed comparable utility of Mayo‐PACC and PACC‐R (CI contained 0, see Table 3). Exploratory analyses revealed Mayo‐PACC performed similarly to an adaptation of the ADCS‐PACC, Global‐z, Memory‐z and Attention‐z. The Mayo‐PACC performed better than a 2‐measure Mayo‐PACC‐remote and a single memory measure.ConclusionThe Mayo‐PACC provides a parsimonious composite score that has comparable utility for detecting A+>A‐ cognitive decline compared to the PACC‐R and other composites and can be widely used in both research and clinical settings.