Effects of APOE2 and APOE4 on brain microstructure in older adults: modification by age, sex, and cognitive status.

BACKGROUND: APOE4 is the strongest genetic risk factor for sporadic Alzheimer's disease (AD), whereas APOE2 confers protection. However, effects of APOE on neurodegeneration in cognitively intact individuals, and how these associations evolve with cognitive decline, are unclear. Furthermore, few studies have evaluated whether effects of APOE on neurodegenerative changes are modified by other AD key risk factors including age and sex. METHODS: Participants included older adults (57% women; 77 ± 7 years) from the Rancho Bernardo Study of Health Aging and the University of California San Diego Alzheimer's Disease Research Center, including 192 cognitively normal (CN) individuals and 33 with mild cognitive impairment. Participants underwent diffusion MRI, and multicompartment restriction spectrum imaging (RSI) metrics were computed in white matter, gray matter, and subcortical regions of interest. Participants were classified as APOE4 carriers, APOE2 carriers, and APOE3 homozygotes. Analysis of covariance among CN (adjusting for age, sex, and scanner) assessed differences in brain microstructure by APOE, as well as interactions between APOE and sex. Analyses across all participants examined interactions between APOE4 and cognitive status. Linear regressions assessed APOE by age interactions. RESULTS: Among CN, APOE4 carriers showed lower entorhinal cortex neurite density than non-carriers, whereas APOE2 carriers showed lower cingulum neurite density than non-carriers. Differences in entorhinal microstructure by APOE4 and in entorhinal and cingulum microstructure by APOE2 were present for women only. Age correlated with lower entorhinal restricted isotropic diffusion among APOE4 non-carriers, whereas age correlated with lower putamen restricted isotropic diffusion among APOE4 carriers. Differences in microstructure between cognitively normal and impaired participants were stronger for APOE4-carriers in medial temporal regions, thalamus, and global gray matter, but stronger for non-carriers in caudate. CONCLUSIONS: The entorhinal cortex may be an early target of neurodegenerative changes associated with APOE4 in presymptomatic individuals, whereas APOE2 may support beneficial white matter and entorhinal microstructure, with potential sex differences that warrant further investigation. APOE modifies microstructural patterns associated with aging and cognitive impairment, which may advance the development of biomarkers to distinguish microstructural changes characteristic of normal brain aging, APOE-dependent pathways, and non-AD etiologies.

Elevated Pure Tone Thresholds Are Associated with Altered Microstructure in Cortical Areas Related to Auditory Processing and Attentional Allocation.

BACKGROUND: Hearing loss is associated with cognitive decline and increased risk for Alzheimer's disease, but the basis of this association is not understood. OBJECTIVE: To determine whether hearing impairment is associated with advanced brain aging or altered microstructure in areas involved with auditory and cognitive processing. METHODS: 130 participants, (mean 76.4±7.3 years; 65% women) of the Rancho Bernardo Study of Healthy Aging had a screening audiogram in 2003-2005 and brain magnetic resonance imaging in 2014-2016. Hearing ability was defined as the average pure tone threshold (PTA) at 500, 1000, 2000, and 4000 Hz in the better-hearing ear. Brain-predicted age difference (Brain-pad) was calculated as the difference between brain-predicted age based on a validated structural imaging biomarker of brain age, and chronological age. Regional diffusion metrics in temporal and frontal cortex regions were obtained from diffusion-weighted MRIs. Linear regression analyses adjusted for age, gender, education, and health-related measures. RESULTS: PTAs were not associated with brain-PAD (ß= 0.09; 95% CI: -0.084 to 0.243; p = 0.34). PTAs were associated with reduced restricted diffusion and increased free water diffusion primarily in right hemisphere temporal and frontal areas (restricted diffusion: ßs = -0.21 to -0.30; 95% CIs from -0.48 to -0.02; ps < 0.03; free water: ßs = 0.18 to 0.26; 95% CIs 0.01 to 0.438; ps < 0.04). CONCLUSIONS: Hearing impairment is not associated with advanced brain aging but is associated with differences in brain regions involved with auditory processing and attentional control. It is thus possible that increased dementia risk associated with hearing impairment arises, in part, from compensatory brain changes that may decrease resilience.

Sex Differences in the Associations of Obesity with Tau, Amyloid PET, and Cognitive Outcomes in Preclinical Alzheimer's Disease: Cross-Sectional A4 Study.

BACKGROUND: The association between obesity and Alzheimer's disease (AD) is complex. Recent studies indicated the relationships between obesity and AD may differ by sex, and women may benefit from being overweight in terms of AD risk. OBJECTIVE: We investigated whether sex modifies the associations of obesity with tau positron emission tomography (PET), amyloid PET, and cognition in preclinical AD. METHODS: We included 387 cognitively-unimpaired amyloid-positive participants (221 women, 166 men, 87.6% non-Hispanic White) with available 18F-flortaucipir PET, 18F-florbetapir PET, and completed the Preclinical Alzheimer Cognitive Composite (PACC) tests from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study. Participants were categorized based on body mass index (BMI: kg/m2): normal-weight (BMI: 18.5-25), overweight (BMI: 25-30), and obese (BMI≥30). RESULTS: Significant sex by BMI category interactions on PACC and its components: Mini-Mental State Examination (MMSE) and Reminding Test-Free+Total Recall (FCSRT96) revealed that overweight and obese women outperformed normal-weight women on FCSRT96, while obese men showed poorer MMSE performance than normal-weight men. These interactions were independent of APOE4. There were no significant interactions of sex by BMI category on tau and amyloid PET. However, sex-stratified analyses observed obesity was associated with less regional tau and mean cortical amyloid in women, not in men. CONCLUSION: This study found that in preclinical AD, overweight and obesity were associated with better verbal memory in women, whereas obesity was associated with worse global cognition among men. Future studies focusing on the mechanism for this relationship may inform sex-specific interventions for AD prevention.

Improved multimodal prediction of progression from MCI to Alzheimer's disease combining genetics with quantitative brain MRI and cognitive measures.

INTRODUCTION: There is a pressing need for non-invasive, cost-effective tools for early detection of Alzheimer's disease (AD). METHODS: Using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), Cox proportional models were conducted to develop a multimodal hazard score (MHS) combining age, a polygenic hazard score (PHS), brain atrophy, and memory to predict conversion from mild cognitive impairment (MCI) to dementia. Power calculations estimated required clinical trial sample sizes after hypothetical enrichment using the MHS. Cox regression determined predicted age of onset for AD pathology from the PHS. RESULTS: The MHS predicted conversion from MCI to dementia (hazard ratio for 80th versus 20th percentile: 27.03). Models suggest that application of the MHS could reduce clinical trial sample sizes by 67%. The PHS alone predicted age of onset of amyloid and tau. DISCUSSION: The MHS may improve early detection of AD for use in memory clinics or for clinical trial enrichment. HIGHLIGHTS: A multimodal hazard score (MHS) combined age, genetics, brain atrophy, and memory. The MHS predicted time to conversion from mild cognitive impairment to dementia. MHS reduced hypothetical Alzheimer's disease (AD) clinical trial sample sizes by 67%. A polygenic hazard score predicted age of onset of AD neuropathology.

Neuroimaging-Derived Predicted Brain Age and Alcohol Use Among Community-Dwelling Older Adults.

OBJECTIVES: Observational studies have suggested that moderate alcohol use is associated with reduced risk of dementia. However, the nature of this association is not understood. We investigated whether light to moderate alcohol use may be associated with slower brain aging, among a cohort of older community-dwelling adults using a biomarker of brain age based on structural neuroimaging measures. DESIGN: Cross-sectional observational study. PARTICIPANTS: Well-characterized members of a longitudinal cohort study who underwent neuroimaging. We categorized the 163 participants (mean age 76.7 ± 7.7, 60% women) into current nondrinkers, light drinkers (1-7 drinks/week) moderate drinkers (>7-14 drinks/week), or heavier drinkers (>14 drinks/week). MEASUREMENTS: We calculated brain-predicted age using structural MRIs processed with the BrainAgeR program, and calculated the difference between brain-predicted age and chronological age (brain-predicted age difference, or brain-PAD). We used analysis of variance to determine if brain-PAD differed across alcohol groups, controlling for potential confounders. RESULTS: Brain-PAD differed across alcohol groups (F[3, 150] = 4.02; p = 0.009) with heavier drinkers showing older brain-PAD than light drinkers (by about 6 years). Brain-PAD did not differ across light, moderate, and nondrinkers. Similar results were obtained after adjusting for potentially mediating health-related measures, and after excluding individuals with a history of heavier drinking. DISCUSSION: Among this sample of healthy older adults, consumption of more than 14 drinks/week was associated with a biomarker of advanced brain aging. Light and moderate drinking was not associated with slower brain aging relative to non-drinking.

Sleep quality and sleep duration predict brain microstructure among community-dwelling older adults.

Although poor sleep quality and extreme sleep durations have been associated with brain atrophy and dementia, it is unclear whether sleep disturbances contribute to neural injury in the absence of neurodegeneration and cognitive impairment. In 146 dementia-free older adults of the Rancho Bernardo Study of Healthy Aging (76.7 ± 7.8 years at MRI), we examined associations of restriction spectrum imaging metrics of brain microstructure with self-reported sleep quality 6.3 ± 0.7 years prior, and with sleep duration reported 25, 15 and 9 years prior. Worse sleep quality predicted lower white matter restricted isotropic diffusion and neurite density and higher amygdala free water, with stronger associations between poor sleep quality and abnormal microstructure for men. Among women only, short or long sleep duration 25 and 15 years before MRI predicted lower white matter restricted isotropic diffusion and increased free water. Associations persisted after accounting for associated health and lifestyle factors. Sleep patterns were not related to brain volume or cortical thickness. Optimizing sleep behaviors throughout the life-course may help to preserve healthy brain aging.

Midlife omega-3 fatty acid intake predicts later life white matter microstructure in an age- and APOE-dependent manner.

Omega-3 intake has been positively associated with healthy brain aging, yet it remains unclear whether high omega-3 intake beginning early in life may optimize its protective effects against brain aging. We examined whether omega-3 intake is associated with brain microstructure over 2 decades later among dementia-free older adults. The 128 participants (62% women; age at magnetic resonance imaging: 76.6 ± 7.9) from the Rancho Bernardo Study of Healthy Aging completed at least 1 dietary assessment between 1984 and 1996 and underwent restriction spectrum imaging (RSI) 22.8 ± 3.1 years later. We evaluated associations between prior omega-3 intake and RSI metrics of gray and white matter (WM) microstructure. Higher prior omega-3 intake was associated with greater restricted diffusion in the superior cortico-striatal fasciculus. A correlation between higher prior omega-3 intake and greater cingulum restricted diffusion was stronger among participants >80 years old. Higher omega-3 intake correlated with greater restricted diffusion in the inferior longitudinal and inferior fronto-occipital fasciculus more strongly for apolipoprotein E (APOE) ε4 carriers than noncarriers. Associations were not modified by adjustment for dietary pattern, health, or lifestyle. High omega-3 intake in midlife may help to maintain WM integrity into older age, particularly in the latest decades of life and among APOE ε4 carriers.

Pulse pressure trajectories predict brain microstructure in community-dwelling older adults: Associations with executive function and modification by APOE.

INTRODUCTION: Effects of chronic arterial stiffness on brain aging remain unclear. We, therefore, examined whether long-term trajectories of pulse pressure (PP) predicted brain microstructure, microstructure mediated PP-executive function associations, and APOE genotype modified PP-microstructure associations. METHODS: We examined associations of PP trajectories with brain microstructure measured using restriction spectrum imaging in 146 community-dwelling older adults, whether microstructure mediated PP trajectory-executive function associations, and whether PP-restriction spectrum imaging correlations were modified by APOE-ε4 status. RESULTS: Participants with trajectories of high PP had lower restricted isotropic diffusion (RI) compared to those with low PP trajectories and PP-executive function associations were mediated by subcortical and white matter RI. High PP more strongly correlated with lower RI and higher hindered diffusion among APOE-ε4 carriers than non-carriers. DISCUSSION: Prolonged elevated PP predicts microstructural abnormalities which may contribute to impaired executive function. APOE-ε4 carriers may be most vulnerable to the adverse effects of PP on brain microstructure.

Sex differences in Alzheimer's disease: plasma MMP-9 and markers of disease severity.

BACKGROUND: Studies have reported higher plasma matrix metalloproteinase-9 (MMP-9) levels in mild cognitive impairment (MCI) and Alzheimer's disease (AD). Despite evidence that MMP-9 activity and its influence on AD pathophysiology may be modulated by sex hormones, sex differences in the association between MMP-9 and AD biomarkers and cognition have not been explored. METHODS: Our sample included 238 amyloid-ß (Aß)-positive participants with MCI or AD dementia from the Alzheimer's Disease Neuroimaging Initiative (37.4% women, 74.6 ± 7.3 years). We used linear regression models to examine whether sex modified free and total plasma MMP-9 associations with CSF t-tau, p-tau181, and Aß42. We used linear mixed effects models to examine whether sex modified total and free plasma MMP-9 associations with cognition, using longitudinal Mini-Mental Status Examination (MMSE) and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) data. RESULTS: Total and free MMP-9 levels did not differ by sex, but AD dementia patients had higher total MMP-9 levels than participants with MCI (ß = 0.06 [-0.11 to -0.01], p = 0.031). Sex modified the association of CSF t-tau with total (ß = 128.68 [55.37 to 201.99], p < 0.001) and free MMP-9 (ß = 98.61 [33.61 to 163.62], p = 0.003), whereby higher total and free MMP-9 correlated with higher CSF t-tau in women and lower CSF t-tau in men. Higher free MMP-9 correlated with lower CSF p-tau181 among men (ß = -14.98 [-27.37 to -2.58], p = 0.018), but not women. In participants with MCI, higher free MMP-9 levels were associated with higher CSF Aß42 among men (ß = 26.88 [4.03 to 49.73], p = 0.022) but not women. In the overall sample, higher free and total MMP-9 at baseline predicted worsening MMSE scores in women (ß = -2.10 [-3.97 to -0.27], p = 0.027 and ß = -2.24 [-4.32 to -0.18], p = 0.035) but not men. Higher free MMP-9 correlated with worse ADAS-cog scores (ß = 12.34 [3.02 to 21.65], p = 0.011) in women (ß = 12.34 [3.02 to 21.65], p = 0.011) but not men with AD dementia cross-sectionally but correlated with worsening ADAS-cog scores longitudinally only in men (ß = 8.98 [0.27 to 17.68], p = 0.042). CONCLUSIONS: MMP-9 may have more detrimental effects on AD-related pathological and cognitive changes in women. If replicated, our findings could help uncover potential mechanisms contributing to women's elevated susceptibility to AD.

Sex differences in plasma p-tau181 associations with Alzheimer's disease biomarkers, cognitive decline, and clinical progression.

Studies have shown that women on the Alzheimer's disease (AD) continuum have more pathological tau in the brain and cerebrospinal fluid (CSF), than men. Some studies have found that higher levels of tau biomarkers are more strongly associated with clinical AD, cognitive decline and neurodegeneration in women than in men. Despite major developments in the use of plasma tau phosphorylated at threonine 181 (p-tau181) as an AD biomarker, it is unknown whether these sex differences apply to plasma p-tau181. In 1060 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants (47% women, 73.8 ± 7.6 years old), we examined sex differences in plasma p-tau181 levels and their association with other biomarkers, cognitive decline and incident AD. Linear regressions tested for an effect of sex on plasma p-tau181 levels and for plasma p-tau181 × sex interactions on CSF p-tau181, as well as entorhinal cortex tau, cortical amyloid-ß (Aß) deposition, and brain glucose metabolism, quantified using PET imaging. Linear mixed effects models tested for a sex × baseline plasma p-tau181 interaction on change in cognition over time. Finally, Cox models tested for a sex × plasma p-tau181 interaction on the risk of AD dementia in participants who were free of dementia at baseline. Despite similar plasma p-tau181 levels between sexes, women had lower brain glucose metabolism, greater brain Aß and entorhinal cortex tau deposition, higher CSF p-tau181 and faster cognitive decline in relation to higher baseline plasma p-tau181 levels compared with men. Among Aß positive, dementia-free participants, women had higher rates of incident AD dementia associated with increasing baseline plasma p-tau181 levels, relative to men. Our results suggest that sex may impact the clinical interpretation of plasma p-tau181 concentrations. If replicated, these findings could have important implications for the use of plasma p-tau181 as an accessible AD biomarker and screening tool for preventive and therapeutic clinical trials.

Associations between MRI-assessed locus coeruleus integrity and cortical gray matter microstructure.

The locus coeruleus (LC) is one of the earliest sites of tau pathology, making it a key structure in early Alzheimer's disease (AD) progression. As the primary source of norepinephrine for the brain, reduced LC integrity may have negative consequences for brain health, yet macrostructural brain measures (e.g. cortical thickness) may not be sensitive to early stages of neurodegeneration. We therefore examined whether LC integrity was associated with differences in cortical gray matter microstructure among 435 men (mean age = 67.5; range = 62-71.7). LC structural integrity was indexed by contrast-to-noise ratio (LCCNR) from a neuromelanin-sensitive MRI scan. Restriction spectrum imaging (RSI), an advanced multi-shell diffusion technique, was used to characterize cortical microstructure, modeling total diffusion in restricted, hindered, and free water compartments. Higher LCCNR (greater integrity) was associated with higher hindered and lower free water diffusion in multiple cortical regions. In contrast, no associations between LCCNR and cortical thickness survived correction. Results suggest lower LC integrity is associated with patterns of cortical microstructure that may reflect a reduction in cytoarchitectural barriers due to broader neurodegenerative processes. These findings highlight the potential utility for LC imaging and advanced diffusion measures of cortical microstructure in assessing brain health and early identification of neurodegenerative processes.

Sex differences in Alzheimer's disease: do differences in tau explain the verbal memory gap?

To determine if sex differences in verbal memory in AD are related to differences in extent or distribution of pathological tau, we studied 275 participants who were amyloid PET positive and carried clinical classifications of normal cognition, mild cognitive impairment (MCI) or dementia, and had tau (AV1451) PET. We compared tau distribution between men and women, and as a function of genetic risk. In MCI we further explored the relationship between quantity and distribution of tau in relation to verbal memory scores. Women had more tau burden overall, but this was driven by sex differences at the MCI stage. There was no significant difference in tau load by APOE e4 status. Within the MCI group the association between tau and performance in verbal memory tasks was stronger in women than men. The topography of the associations between tau and verbal memory also differed in MCI; women demonstrated stronger relationships between tau distribution and verbal memory performance, especially in the left hemisphere. These findings have implications for understanding tau distribution and spread, and in interpretation of verbal memory performance.

Age and Sex Differences in the Associations of Pulse Pressure With White Matter and Subcortical Microstructure.

Midlife vascular disease increases risk for dementia and effects of vascular dysfunction on brain health differ between men and women. Elevated pulse pressure, a surrogate for arterial stiffness, contributes to cerebrovascular pathology and white matter damage that may advance cognitive aging; however, it remains unclear how associations between pulse pressure and neural integrity differ by sex and age. This study used restriction spectrum imaging to examine associations between pulse pressure and brain microstructure in community-dwelling women (N=88) and men (N=55), aged 56 to 97 (mean, 76.3) years. Restricted isotropic (presumed intracellular), hindered isotropic (presumed extracellular), neurite density, and free water diffusion were computed in white matter tracts and subcortical regions. After adjustment for age and sex, higher pulse pressure correlated with lower restricted isotropic diffusion in global white matter, with more pronounced associations in parahippocampal cingulum, as well as in thalamus and hippocampus. Subgroup analyses demonstrated stronger correlations between pulse pressure and restricted isotropic diffusion in association fibers for participants ≤75 years than for older participants, with stronger effects for women than men of this age group. Microstructure in parahippocampal cingulum and thalamus differed by pulse pressure level regardless of antihypertensive treatment. Increased pulse pressure may lead to widespread injury to white matter and subcortical structures, with greatest vulnerability for women in late middle to early older age. Restriction spectrum imaging could be useful for monitoring microstructural changes indicative of neuronal loss or shrinkage, demyelination, or inflammation that accompany age-related cerebrovascular dysfunction.

Brain microstructure mediates sex-specific patterns of cognitive aging.

Normal brain aging is characterized by declining neuronal integrity, yet it remains unclear how microstructural injury influences cognitive aging and whether such mechanisms differ between sexes. Using restriction spectrum imaging (RSI), we examined sex differences in associations between brain microstructure and cognitive function in 147 community-dwelling older men and women (56-99 years). Gray and white matter microstructure correlated with global cognition, executive function, visuospatial memory, episodic memory, and logical memory, with the strongest associations for restricted, hindered and free isotropic diffusion. Associations were stronger for women than for men, a difference likely due to greater age-related variability in cognitive scores and microstructure in women. Isotropic diffusion mediated effects of age on cognition for both sexes, though distinct mediation patterns were present for women and men. For women, hippocampal and corpus callosum microstructure mediated age effects on verbal and visuospatial memory, respectively, whereas for men fiber microstructure (mainly fornix and corpus callosum) mediated age effects on executive function and visuospatial memory. These findings implicate sex-specific pathways by which changing brain cytoarchitecture contributes to cognitive aging, and suggest that RSI may be useful for evaluating risk for cognitive decline or monitoring efficacy of interventions to preserve brain health in later life.

Associations between age and brain microstructure in older community-dwelling men and women: the Rancho Bernardo Study.

Cytoarchitectural brain changes during normal aging remain poorly characterized, and it is unclear whether patterns of brain aging differ by sex. This study used restriction spectrum imaging to examine associations between age and brain microstructure in 147 community-dwelling participants (aged 56-99 years). Widespread associations with age in multiple diffusion compartments, including increased free water, decreased restricted and hindered diffusion, and reduced neurite complexity, were observed in the cortical gray matter, the white matter tracts, and the hippocampus. Age differences in cortical microstructure were largely independent of atrophy. Associations were mostly global, although foci of stronger effects emerged in the fornix, anterior thalamic radiation and commissural fibers, and the medial temporal, orbitofrontal, and occipital cortices. Age differences were stronger and more widespread for women than men, even after adjustment for education, hypertension, and body mass index. Restriction spectrum imaging may be a convenient, noninvasive tool for monitoring changes in diffusion properties that are thought to reflect reduced cellular fractions and neurite density or complexity, which occur with typical aging, and for detecting sex differences in patterns of brain aging.

Hearing Impairment and Cognitive Decline in Older, Community-Dwelling Adults.

BACKGROUND: Hearing impairment is prevalent among older adults and has been identified as a risk factor for cognitive impairment and dementia. We evaluated the association of hearing impairment with long-term cognitive decline among community-dwelling older adults. METHODS: A population-based longitudinal study of adults not using hearing aids who had hearing acuity and cognitive function assessed in 1992-1996, and were followed for a maximum of 24 years with up to five additional cognitive assessments. Hearing acuity was categorized based on pure-tone average (PTA) thresholds: normal (PTA ≤ 25 dB), mild impairment (PTA > 25-40 dB), moderate/severe impairment (PTA > 40 dB). RESULTS: Of 1,164 participants (mean age 73.5 years, 64% women), 580 (49.8%) had mild hearing impairment and 196 (16.8%) had moderate/severe hearing impairment. In fully adjusted models, hearing impairment was associated with steeper decline on the Mini-Mental State Examination (MMSE) (mild impairment ß = -0.04, p = .01; moderate/severe impairment ß = -0.08, p = .002) and Trails B (mild impairment ß = 1.21, p = .003; moderate/severe impairment ß = 2.16, p = .003). Associations did not differ by sex or apolipoprotein E (APOE) ϵ4 status and were not influenced by social engagement. The MMSE-hearing association was modified by education: mild hearing impairment was associated with steeper decline on the MMSE among participants without college education but not among those with college education. Moderate/severe hearing impairment was associated with steeper MMSE decline regardless of education level. CONCLUSIONS: Hearing impairment is associated with accelerated cognitive decline with age, and should be screened for routinely. Higher education may provide sufficient cognitive reserve to counter effects of mild, but not more severe, hearing impairment.

Associations Between Microstructure, Amyloid, and Cognition in Amnestic Mild Cognitive Impairment and Dementia.

BACKGROUND: Although amyloid-ß (Aß) and microstructural brain changes are both effective biomarkers of Alzheimer's disease, their independent or synergistic effects on cognitive decline are unclear. OBJECTIVE: To examine associations of Aß and brain microstructure with cognitive decline in amnestic mild cognitive impairment and dementia. METHODS: Restriction spectrum imaging, cerebrospinal fluid Aß, and longitudinal cognitive data were collected on 23 healthy controls and 13 individuals with mild cognitive impairment or mild to moderate Alzheimer's disease. Neurite density (ND) and isotropic free water diffusion (IF) were computed in fiber tracts and cortical regions of interest. We examined associations of Aß with regional and whole-brain microstructure, and assessed whether microstructure mediates effects of Aß on cognitive decline. RESULTS: Lower ND in limbic and association fibers and higher medial temporal lobe IF predicted baseline impairment and longitudinal decline across multiple cognitive domains. ND and IF predicted cognitive outcomes after adjustment for Aß or whole-brain microstructure. Correlations between microstructure and cognition were present for both amyloid-positive and amyloid-negative individuals. Aß correlated with whole-brain, rather than regional, ND and IF. CONCLUSION: Aß correlates with widespread microstructural brain changes, whereas regional microstructure correlates with cognitive decline. Microstructural abnormalities predict cognitive decline regardless of amyloid, and may inform about neural injury leading to cognitive decline beyond that attributable to amyloid.

Physical Activity and Trajectories of Cognitive Change in Community-Dwelling Older Adults: The Rancho Bernardo Study.

BACKGROUND: Although physical activity has been associated with better cognitive function and reduced dementia risk, its association with cognitive decline in normal aging remains uncertain. OBJECTIVE: To determine whether physical activity in youth and older age are associated with age-related cognitive change. METHODS: Over a period of 27 years, 2,027 community-dwelling adults (mean age 73.5; 60% women) of the Rancho Bernardo Study of Healthy Aging completed up to seven cognitive assessments, including tests of global cognitive function, executive function, verbal fluency, and episodic memory. At each visit, participants reported concurrent physical activity. At baseline (1988- 1992), participants additionally reported physical activity as a teenager and at age 30. For each age period, participants were classified as regularly active (3+ times/week) or inactive. RESULTS: Associations between concurrent physical activity and better cognitive function were stronger with advancing age on all tests, even after accounting for education, health, and lifestyle factors, as well as survival differences (ps < 0.05). Baseline physical activity did not predict rates of cognitive decline (ps > 0.40). Individuals who were physically active at age 30 and older age maintained the highest global cognitive function with advancing age (p = 0.002). CONCLUSION: Regular physical activity is associated with better cognitive function with advancing age. Physical activity in young adulthood may contribute to cognitive reserve, which together with physical activity in later years, may act to preserve cognitive function with age.

Tau and atrophy: domain-specific relationships with cognition.

BACKGROUND: Late-onset Alzheimer's disease (AD) is characterized by primary memory impairment, which then progresses towards severe deficits across cognitive domains. Here, we report how performance in cognitive domains relates to patterns of tau deposition and cortical thickness. METHODS: We analyzed data from 131 amyloid-ß positive participants (55 cognitively normal, 46 mild cognitive impairment, 30 AD) of the Alzheimer's Disease Neuroimaging Initiative who underwent magnetic resonance imaging (MRI), flortaucipir (FTP) positron emission tomography, and neuropsychological testing. Surface-based vertex-wise and region-of-interest analyses were conducted between FTP and cognitive test scores, and between cortical thickness and cognitive test scores. RESULTS: FTP and thickness were differentially related to cognitive performance in several domains. FTP-cognition associations were more widespread than thickness-cognition associations. Further, FTP-cognition patterns reflected cortical systems that underlie different aspects of cognition. CONCLUSIONS: Our findings indicate that AD-related decline in domain-specific cognitive performance reflects underlying progression of tau and atrophy into associated brain circuits. They also suggest that tau-PET may have better sensitivity to this decline than MRI-derived measures of cortical thickness.

Identification of genetic heterogeneity of Alzheimer's disease across age.

The risk of APOE for Alzheimer's disease (AD) is modified by age. Beyond APOE, the polygenic architecture may also be heterogeneous across age. We aim to investigate age-related genetic heterogeneity of AD and identify genomic loci with differential effects across age. Stratified gene-based genome-wide association studies and polygenic variation analyses were performed in the younger (60-79 years, N = 14,895) and older (≥80 years, N = 6559) age-at-onset groups using Alzheimer's Disease Genetics Consortium data. We showed a moderate genetic correlation (rg = 0.64) between the two age groups, supporting genetic heterogeneity. Heritability explained by variants on chromosome 19 (harboring APOE) was significantly larger in younger than in older onset group (p < 0.05). APOE region, BIN1, OR2S2, MS4A4E, and PICALM were identified at the gene-based genome-wide significance (p < 2.73 × 10-6) with larger effects at younger age (except MS4A4E). For the novel gene OR2S2, we further performed leave-one-out analyses, which showed consistent effects across subsamples. Our results suggest using genetically more homogeneous individuals may help detect additional susceptible loci.