Association of Alzheimer's Disease and Other Neuropathologies with Functional Disability in Persons With and Without Dementia.

BACKGROUND: Dementia results from multiple neuropathologies causing cognitive impairment sufficiently severe to impact functional status. However, these pathologies and functional impairment are common in persons without dementia. We examined the association of AD and multiple other neuropathologies with instrumental and basic activities of daily living in persons with and without dementia. METHODS: Participants were 1,509 deceased from the Religious Orders Study or Rush Memory and Aging Project. Pathologic AD and three other AD indices were examined, in addition to four non-AD neurodegenerative pathologies: cerebral amyloid angiopathy (CAA), hippocampal sclerosis, TDP-43 and Lewy bodies, and four cerebrovascular pathologies: gross- and microinfarctions, athero- and arteriolosclerosis. Functional assessment included Lawton and Katz Index Instrumental and Basic Activities of Daily Living (IADL and BADL). Ordinal regression models adjusted for age, sex, and education were used to examine the association of neuropathologies with IADL and BADL. RESULTS: AD and the other neuropathologies were associated with impaired IADL (all Ps<0.001) and with impaired BADL (Ps<0.01), except for atherosclerosis and CAA which were not associated with BADL. The effects of most neuropathologies were largely affected by dementia. However, small effects on IADL remained for PHFtau tangles after adjusting models for dementia. Direct effects of gross infarcts on IADL and BADL, and of microinfarcts on BADL remained unchanged after adjusting the models for dementia. CONCLUSION: AD and all other neuropathologies are strongly associated with functional disability. The association of most neuropathologies with disability was eliminated or attenuated by dementia, except for gross infarcts and microinfarcts.

Mercury and selenium distribution in human brain tissue using synchrotron micro-X-ray fluorescence.

Mercury is a well-recognized environmental contaminant and neurotoxin, having been associated with a number of deleterious neurological conditions including neurodegenerative diseases, such as Alzheimer's disease. To investigate how mercury and other metals behave in the brain, we used synchrotron micro-X-ray fluorescence to map the distribution pattern and quantify concentrations of metals in human brain. Brain tissue was provided by the Rush Alzheimer's Disease Center and samples originated from individuals diagnosed with Alzheimer's disease and without cognitive impairment. Data were collected at the 2-ID-E beamline at the Advanced Photon Source at Argonne National Laboratory with an incident beam energy of 13 keV. Course scans were performed at low resolution to determine gross tissue features, after which smaller regions were selected to image at higher resolution. The findings revealed (1) the existence of mercury particles in the brain samples of two subjects; (2) co-localization and linear correlation of mercury and selenium in all particles; (3) co-localization of these particles with zinc structures; and (4) association with sulfur in some of these particles. These results suggest that selenium and sulfur may play protective roles against mercury in the brain, potentially binding with the metal to reduce the induced toxicity, although at different affinities. Our findings call for further studies to investigate the relationship between mercury, selenium, and sulfur, as well as the potential implications in Alzheimer's disease and related dementias.

Genetic associations with dementia-related proteinopathy: Application of item response theory.

INTRODUCTION: Although dementia-related proteinopathy has a strong negative impact on public health, and is highly heritable, understanding of the related genetic architecture is incomplete. METHODS: We applied multidimensional generalized partial credit modeling (GPCM) to test genetic associations with dementia-related proteinopathies. Data were analyzed to identify candidate single nucleotide variants for the following proteinopathies: Aß, tau, α-synuclein, and TDP-43. RESULTS: Final included data comprised 966 participants with neuropathologic and WGS data. Three continuous latent outcomes were constructed, corresponding to TDP-43-, Aß/Tau-, and α-synuclein-related neuropathology endophenotype scores. This approach helped validate known genotype/phenotype associations: for example, TMEM106B and GRN were risk alleles for TDP-43 pathology; and GBA for α-synuclein/Lewy bodies. Novel suggestive proteinopathy-linked alleles were also discovered, including several (SDHAF1, TMEM68, and ARHGEF28) with colocalization analyses and/or high degrees of biologic credibility. DISCUSSION: A novel methodology using GPCM enabled insights into gene candidates for driving misfolded proteinopathies. HIGHLIGHTS: Latent factor scores for proteinopathies were estimated using a generalized partial credit model. The three latent continuous scores corresponded well with proteinopathy severity. Novel genes associated with proteinopathies were identified. Several genes had high degrees of biologic credibility for dementia risk factors.

Evaluating genomic signatures of aging in brain tissue as it relates to Alzheimer's disease.

Telomere length (TL) attrition, epigenetic age acceleration, and mitochondrial DNA copy number (mtDNAcn) decline are established hallmarks of aging. Each has been individually associated with Alzheimer's dementia, cognitive function, and pathologic Alzheimer's disease (AD). Epigenetic age and mtDNAcn have been studied in brain tissue directly but prior work on TL in brain is limited to small sample sizes and most studies have examined leukocyte TL. Importantly, TL, epigenetic age clocks, and mtDNAcn have not been studied jointly in brain tissue from an AD cohort. We examined dorsolateral prefrontal cortex (DLPFC) tissue from N = 367 participants of the Religious Orders Study (ROS) or the Rush Memory and Aging Project (MAP). TL and mtDNAcn were estimated from whole genome sequencing (WGS) data and cortical clock age was computed on 347 CpG sites. We examined dementia, MCI, and level of and change in cognition, pathologic AD, and three quantitative AD traits, as well as measures of other neurodegenerative diseases and cerebrovascular diseases (CVD). We previously showed that mtDNAcn from DLPFC brain tissue was associated with clinical and pathologic features of AD. Here, we show that those associations are independent of TL. We found TL to be associated with ß-amyloid levels (beta = - 0.15, p = 0.023), hippocampal sclerosis (OR = 0.56, p = 0.0015) and cerebral atherosclerosis (OR = 1.44, p = 0.0007). We found strong associations between mtDNAcn and clinical measures of AD. The strongest associations with pathologic measures of AD were with cortical clock and there were associations of mtDNAcn with global AD pathology and tau tangles. Of the other pathologic traits, mtDNAcn was associated with hippocampal sclerosis, macroscopic infarctions and CAA and cortical clock was associated with Lewy bodies. Multi-modal age acceleration, accelerated aging on both mtDNAcn and cortical clock, had greater effect size than a single measure alone. These findings highlight for the first time that age acceleration determined on multiple genomic measures, mtDNAcn and cortical clock may have a larger effect on AD/AD related disorders (ADRD) pathogenesis than single measures.

Brain autopsies of critically ill COVID-19 patients demonstrate heterogeneous profile of acute vascular injury, inflammation and age-linked chronic brain diseases.

BACKGROUND: This study examined neuropathological findings of patients who died following hospitalization in an intensive care unit with SARS-CoV-2. METHODS: Data originate from 20 decedents who underwent brain autopsy followed by ex-vivo imaging and dissection. Systematic neuropathologic examinations were performed to assess histopathologic changes including cerebrovascular disease and tissue injury, neurodegenerative diseases, and inflammatory response. Cerebrospinal fluid (CSF) and fixed tissues were evaluated for the presence of viral RNA and protein. RESULTS: The mean age-at-death was 66.2 years (range: 26-97 years) and 14 were male. The patient's medical history included cardiovascular risk factors or diseases (n = 11, 55%) and dementia (n = 5, 25%). Brain examination revealed a range of acute and chronic pathologies. Acute vascular pathologic changes were common in 16 (80%) subjects and included infarctions (n = 11, 55%) followed by acute hypoxic/ischemic injury (n = 9, 45%) and hemorrhages (n = 7, 35%). These acute pathologic changes were identified in both younger and older groups and those with and without vascular risk factors or diseases. Moderate-to-severe microglial activation were noted in 16 (80%) brains, while moderate-to-severe T lymphocyte accumulation was present in 5 (25%) brains. Encephalitis-like changes included lymphocytic cuffing (n = 6, 30%) and neuronophagia or microglial nodule (most prominent in the brainstem, n = 6, 30%) were also observed. A single brain showed vasculitis-like changes and one other exhibited foci of necrosis with ball-ring hemorrhages reminiscent of acute hemorrhagic leukoencephalopathy changes. Chronic pathologies were identified in only older decedents: 7 brains exhibited neurodegenerative diseases and 8 brains showed vascular disease pathologies. CSF and brain samples did not show evidence of viral RNA or protein. CONCLUSIONS: Acute tissue injuries and microglial activation were the most common abnormalities in COVID-19 brains. Focal evidence of encephalitis-like changes was noted despite the lack of detectable virus. The majority of older subjects showed age-related brain pathologies even in the absence of known neurologic disease. Findings of this study suggest that acute brain injury superimposed on common pre-existing brain disease may put older subjects at higher risk of post-COVID neurologic sequelae.

Multiple gene variants linked to Alzheimer's-type clinical dementia via GWAS are also associated with non-Alzheimer's neuropathologic entities.

The classic pathologic hallmarks of Alzheimer's disease (AD) are amyloid plaques and neurofibrillary tangles (AD neuropathologic changes, or ADNC). However, brains from individuals clinically diagnosed with "AD-type" (amnestic) dementia usually harbor heterogeneous neuropathologies in addition to, or other than, ADNC. We hypothesized that some AD-type dementia associated genetic single nucleotide variants (SNVs) identified from large genomewide association studies (GWAS) were associated with non-ADNC neuropathologies. To test this hypothesis, we analyzed data from multiple studies with available genotype and neuropathologic phenotype information. Clinical AD/dementia risk alleles of interest were derived from the very large GWAS by Bellenguez et al. (2022) who reported 83 clinical AD/dementia-linked SNVs in addition to the APOE risk alleles. To query the pathologic phenotypes associated with variation of those SNVs, National Alzheimer's disease Coordinating Center (NACC) neuropathologic data were linked to AD Sequencing Project (ADSP) and AD Genomics Consortium (ADGC) data. Separate data were obtained from the harmonized Religious Orders Study and the Rush Memory and Aging Project (ROSMAP). A total of 4811 European participants had at least ADNC neuropathology data and also genotype data available; data were meta-analyzed across cohorts. As expected, a subset of dementia-associated SNVs were associated with ADNC risk in Europeans-e.g., BIN1, PICALM, CR1, MME, and COX7C. Other gene variants linked to (clinical) AD dementia were associated with non-ADNC pathologies. For example, the associations of GRN and TMEM106B SNVs with limbic-predominant age-related TDP-43 neuropathologic changes (LATE-NC) were replicated. In addition, SNVs in TNIP1 and WNT3 previously reported as AD-related were instead associated with hippocampal sclerosis pathology. Some genotype/neuropathology association trends were not statistically significant at P < 0.05 after correcting for multiple testing, but were intriguing. For example, variants in SORL1 and TPCN1 showed trends for association with LATE-NC whereas Lewy body pathology trended toward association with USP6NL and BIN1 gene variants. A smaller cohort of non-European subjects (n = 273, approximately one-half of whom were African-Americans) provided the basis for additional exploratory analyses. Overall, these findings were consistent with the hypothesis that some genetic variants linked to AD dementia risk exert their affect by influencing non-ADNC neuropathologies.

Relationship of Purpose in Life to Dementia in Older Black and White Brazilians.

OBJECTIVES: To test the hypothesis that higher level of purpose in life is associated with lower likelihood of dementia and mild cognitive impairment (MCI) in older Brazilians. METHODS: As part of the Pathology, Alzheimer's and Related Dementias Study (PARDoS), informants of 1,514 older deceased Brazilians underwent a uniform structured interview. The informant interview included demographic data, the Clinical Dementia Rating scale to diagnose dementia and MCI, the National Institute of Mental Health Diagnostic Interview Schedule for depression, and a 6-item measure of purpose in life, a component of well-being. RESULTS: Purpose scores ranged from 1.5 to 5.0 with higher values indicating higher levels of purpose. On the Clinical Dementia Rating Scale, 940 persons (62.1%) had no cognitive impairment, 121 (8.0%) had MCI, and 453 (29.9%) had dementia. In logistic regression models adjusted for age at death, sex, education, and race, higher purpose was associated with lower likelihood of MCI (odds ratio = .58; 95% confidence interval [CI]: .43, .79) and dementia (odds ratio = .49, 95% CI: .41, .59). Results were comparable after adjusting for depression (identified in 161 [10.6%]). Neither race nor education modified the association of purpose with cognitive diagnoses. CONCLUSIONS: Higher purpose in life is associated with lower likelihood of MCI and dementia in older black and white Brazilians.

Dementia and autopsy-verified causes of death in racially-diverse older Brazilians.

BACKGROUND: While dementia has been associated with specific causes of death, previous studies were relatively small autopsy series or population-based studies lacking autopsy confirmation and were restricted to Non-Latinx Whites. Here, we examine the association of dementia with autopsy-verified causes of death in racially-diverse older Brazilians. METHODS: As part of the Pathology, Alzheimer´s and Related Dementias Study (PARDoS), a community-based study in Brazil, we included 1941 racially-diverse deceased, 65 years or older at death. We conducted a structured interview with legal informants including the Clinical Dementia Rating (CDR) Scale for dementia proximate to death. Causes of death were assessed after full-body autopsy and macroscopic examination of the brain, thoracic and abdominal/pelvic organs. Up to four causes of death were reported for each decedent. Causes of death were classified as circulatory, infectious, cancer and other. Logistic regression was used to determine associations of dementia with cause of death, controlling for age, sex, race, and education. RESULTS: Dementia was associated with a higher odds of an infectious cause of death (OR = 1.81, 95%CI:1.45-2.25), and with a lower odds of a circulatory disease as cause of death (OR = 0.69, 95%CI:0.54-0.86) and cancer as cause of death (OR = 0.41, 95%CI:0.24-0.71). Dementia was associated with a higher odds of pneumonia (OR = 1.92, 95%CI:1.53-2.40) and pulmonary embolism (OR = 2.31, 95%CI:1.75-3.05) as causes of death and with a lower odds of acute myocardial infarction (OR = 0.42, 95%CI:0.31-0.56) and arterial disease (OR = 0.76, 95%CI:0.61-0.94) as causes of death. CONCLUSION: Racially-diverse older Brazilians with dementia had a higher odds of an infectious cause of death and a lower odds of cancer and circulatory disease as causes of death than those without dementia.

Neuropsychiatric symptoms in Brazilians with mild cognitive impairment and dementia.

INTRODUCTION: Knowledge is limited about behavioral and psychological symptoms of mild cognitive impairment (MCI) and dementia in racial and ethnic minorities. METHODS: As part of the Pathology, Alzheimer's and Related Dementias Study (PARDoS), we interviewed knowledgeable informants of 2319 older Brazilian decedents (67% white, 11% black, 22% mixed) using the informant portion of the Clinical Dementia Rating Scale to classify MCI and dementia and the Neuropsychiatric Inventory to assess behavioral and psychological symptoms. RESULTS: We identified four clusters of neuropsychiatric symptoms: agitation, affect/apathy, psychosis, and behavioral problems. On the Clinical Dementia Rating Scale, 1407 had no cognitive impairment, 180 had MCI, and 732 had dementia. Both MCI and dementia were associated with symptoms in each behavioral/psychological cluster (all P's < .001). There was little evidence of racial differences in the association of MCI and dementia with these neuropsychiatric symptoms. CONCLUSION: MCI and dementia are associated with elevated behavioral and psychological symptoms in older black and white Brazilians.

Relation of Literacy and Music Literacy to Dementia in Older Black and White Brazilians.

BACKGROUND: Literacy is more consistently reported than education as protective against dementia in developing regions. OBJECTIVE: To study the association of verbal literacy, numeracy, and music literacy with dementia in older Black and White Brazilians with a broad spectrum of education. METHODS: We studied 1,818 Black, Mixed-race, and White deceased Brazilians 65 years or older at death (mean = 79.64). Data were retrospectively obtained within 36 hours after death in a face-to-face interview with an informant, usually a family member. Dementia was classified using the Clinical Dementia Rating (CDR) scale. Three forms of literacy were ascertained: verbal literacy (10 questions: reading and writing), numeracy (3 questions: multiplication, percentages, and use of a calculator), and music literacy (1 question: reading music). Black (11%) and Mixed-race (23%) older adults were combined in analyses. Models adjusted for age and sex. RESULTS: Dementia was identified in 531 people. Participants had 0 to 25 years of education (median = 4). More literacy was associated with lower odds of dementia (all p≤0.039). Participants that read music had about half the odds of having dementia. Participants in the highest quartile of numeracy and verbal literacy had respectively 27%and 15%lower odds of having dementia compared to the lowest quartile. Literacy was lower in Blacks (p < 0.001, except music p = 0.894) but the effect of literacy on dementia was similar (interaction p > 0.237). In secondary analyses, playing instruments without reading music was not associated with dementia (p = 0.887). CONCLUSION: In a large sample of Brazilians, verbal literacy, numeracy, and music literacy were associated with lower odds of dementia. The effect was similar across races.

The link between social and emotional isolation and dementia in older black and white Brazilians.

OBJECTIVE: To examine the link between social and emotional isolation and likelihood of dementia among older black and white Brazilians. DESIGN: Cross-sectional clinical-pathological cohort study. SETTING: Medical center in Sao Paulo, Brazil. PARTICIPANTS: As part of the Pathology, Alzheimer's and Related Dementias Study, we conducted uniform structured interviews with knowledgeable informants (72% children) of 1,493 older (age > 65) Brazilian decedents. MEASUREMENTS: The interview included measures of social isolation (number of family and friends in at least monthly contact with decedent), emotional isolation (short form of UCLA Loneliness Scale), and major depression plus the informant portion of the Clinical Dementia Rating Scale to diagnose dementia and its precursor, mild cognitive impairment (MCI). RESULTS: Decedents had a median social network size of 8.0 (interquartile range = 9.0) and a median loneliness score of 0.0 (interquartile range = 1.0). On the Clinical Dementia Rating Scale, 947 persons had no cognitive impairment, 122 had MCI, and 424 had dementia. In a logistic regression model adjusted for age, education, sex, and race, both smaller network size (odds ratio [OR] = 0.975; 95% confidence interval [CI]: 0.962, 0.989) and higher loneliness (OR = 1.145; 95% CI: 1.060, 1.237) were associated with higher likelihood of dementia. These associations persisted after controlling for depression (present in 10.4%) and did not vary by race. After controlling for depression, neither network size nor loneliness was related to MCI. CONCLUSION: Social and emotional isolation are associated with higher likelihood of dementia in older black and white Brazilians.

Informant-Reported Discrimination, Dementia, and Cognitive Impairment in Older Brazilians.

BACKGROUND: Self-reported discrimination is a source of psychosocial stress that has been previously associated with poor cognitive function in older African Americans without dementia. OBJECTIVE: Here, we examine the association of discrimination with dementia and cognitive impairment in racially diverse older Brazilians. METHODS: We included 899 participants 65 years or older (34.3% Black) from the Pathology, Alzheimer's and Related Dementias Study (PARDoS), a community-based study of aging and dementia. A structured interview with informants of the deceased was conducted. The interview included the Clinical Dementia Rating (CDR) Scale for the diagnosis of dementia and cognitive impairment proximate to death and the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) as a second measure of cognitive impairment. Informant-reported discrimination was assessed using modified items from the Major and Everyday Discrimination Scales. RESULTS: Discrimination was reported by informants of 182 (20.2%) decedents and was more likely reported by informants of Blacks than Whites (25.3% versus 17.6%, p = 0.006). Using the CDR, a higher level of informant-reported discrimination was associated with higher odds of dementia (OR: 1.24, 95% CI 1.08 -1.42, p = 0.002) and cognitive impairment (OR: 1.21, 95% CI: 1.06 -1.39, p = 0.004). Similar results were observed using the IQCODE (estimate: 0.07, SE: 0.02, p = 0.003). The effects were independent of race, sex, education, socioeconomic status, major depression, neuroticism, or comorbidities. CONCLUSION: Higher level of informant-reported discrimination was associated with higher odds of dementia and cognitive impairment in racially diverse older Brazilians.

Neuroticism, negative life events, and dementia in older White and Black Brazilians.

OBJECTIVE: Exposure to negative life events (NLEs) and neuroticism are associated with dementia. It is unknown whether neuroticism explains or modifies the association of NLEs with dementia in older Black and White Brazilians. METHODS: A total of 1747 decedents 65 years and older White and Black (11% Black and 23% Mixed) Brazilians, 53% women, were included in the analyses. Data were obtained in a face-to-face interview with an informant (71% their children) who knew the decedents for 47 years on average. Dementia was classified using the Clinical Dementia Rating. NLEs were assessed with a 10-item scale involving common problems (e.g., death, illness, alcoholism, and financial). Neuroticism was assessed with a 6-item neuroticism scale adapted from the NEO Five-Factor Inventory. Models adjusted for age, sex, and education. Black and mixed-race were combined in the analyses. RESULTS: NLEs (median of 2) were more common in Blacks than Whites (2.04 vs. 1.82, p = 0.007). More NLEs increased the odds of dementia (OR = 1.112, ß = 0.106, p = 0.002), similarly in Blacks and Whites (ß interaction  = 0.046, p = 0.526). More NLEs were also associated with higher neuroticism (ß = 0.071, p < 0.0001), in Whites but not in Blacks (ß interaction  = -0.048, p = 0.006). Neuroticism was associated with higher odds of dementia (OR = 1.658, ß = 0.506, p=<0.001), in Whites but not in Blacks (ß interaction  = -0.420, p = 0.040). Overall, 34% of the effect of NLEs on dementia was associated with the underlying neuroticism trait in Whites (65%, Indirect OR = 1.060, p < 0.001) but no association was evident in Blacks (6%, Indirect OR = 1.008, p = 0.326). Neuroticism did not moderate the association of NLEs with dementia (OR = 0.979, ß = -0.021, p = 0.717). CONCLUSION: The association of NLEs and dementia is partially explained by neuroticism in older White but not in Blacks Brazilians.

Acculturation in Context: The Relationship Between Acculturation and Socioenvironmental Factors With Level of and Change in Cognition in Older Latinos.

OBJECTIVES: Latinos are 1.5 times as likely to develop Alzheimer's dementia as non-Latino Whites. This health disparity may arise from multiple influences with culturally relevant factors receiving increasing attention. Models of acculturation stress the importance of considering acculturation-related factors within the context of socioenvironmental factors to better capture the Latino experience in the United States. METHODS: We measured 10 acculturation and contextually-related variables in 199 Latinos (age 69.7 years) without dementia participating in Rush Alzheimer's Disease Center studies. We tested the relationship between these variables via Principal Component Analysis (PCA), then investigated how resulting components associated with level of and longitudinal change in global and domain-specific cognition using separate linear mixed-effects models adjusted for relevant confounders and their interactions with time. RESULTS: The PCA revealed a 3-factor unrotated solution (variance explained ~70%). Factor 1, representing acculturation-related aspects of nativity, language- and social-based acculturation, was positively associated with level, but not change, in global cognition, semantic memory, and perceptual speed. Factor 2, representing contextually-related socioenvironmental experiences of discrimination, social isolation, and social networks, was negatively associated with level of global cognition, episodic and working memory, and faster longitudinal decline in visuospatial ability. Factor 3 (familism only) did not associate with level or change in any cognitive outcome. DISCUSSION: Acculturation- and contextually-related factors differentiated from each other and differentially contributed to cognition and cognitive decline in older Latinos. Providers should query acculturation and lived experiences when evaluating cognition in older Latinos.

Person-Specific Contributions of Brain Pathologies to Progressive Parkinsonism in Older Adults.

BACKGROUND: Mixed-brain pathologies are the most common cause of progressive parkinsonism in older adults. We tested the hypothesis that the impact of individual pathologies associated with progressive parkinsonism differs among older adults. METHODS: Data were from 1089 decedents who had undergone annual clinical testing and autopsy. Parkinsonism was based on a modified United Parkinson's Disease Rating Scale. Linear mixed-effects models were employed, to investigate the combinations of 9 pathologies related to progressive parkinsonism. Then we estimated the person-specific contributions of each pathology for progressive parkinsonism. RESULTS: The average participant showed 3 pathologies. Parkinson's disease (PD) and 4 cerebrovascular pathologies (macroinfarcts, atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy [CAA]), but not Alzheimer's disease, TDP-43, hippocampal sclerosis, and microinfarcts, were independently associated with progressive parkinsonism. These pathologies accounted for 13% of additional variance of progressive parkinsonism. Thirty-one different combinations of these 5 pathologies were observed to be associated with progressive parkinsonism observed. On average, PD and CAA accounted, respectively, for 66% and 65% of person-specific progression of parkinsonism, while macroinfarcts, atherosclerosis, and arteriolosclerosis accounted for 41%-48%. CONCLUSION: There is much greater heterogeneity in the comorbidity and relative impact of individual brain pathologies affecting progressive parkinsonism than previously recognized and this may account in part for its phenotypic heterogeneity in older adults.

Alzheimer's disease frequency peaks in the tenth decade and is lower afterwards.

Age is the most robust risk factor for Alzheimer's dementia, however there is little data on the relation of age to Alzheimer's disease (AD) and other common neuropathologies that contribute to Alzheimer's dementia. We use data from two community-based, clinical-pathologic cohorts to examine the association of age with AD and other common pathologies. Participants were 1420 autopsied individuals from the Religious Orders Study or Rush Memory and Aging Project who underwent annual clinical evaluations for diagnosis of Alzheimer's dementia, mild cognitive impairment (MCI), and level of cognition. The neuropathologic traits of interest were pathologic AD according to modified NIA-Reagan criteria, three quantitative measures of AD pathology (global AD pathology score, ß-amyloid load and PHFtau tangle density), macro- and micro-scopic infarcts, neocortical Lewy bodies, TDP-43 and hippocampal sclerosis. Semiparametric generalized additive models examined the nonlinear relationship between age and the clinical and pathological outcomes. The probability of Alzheimer's dementia at death increased with age such that for every additional year of age, the log odds of Alzheimer's dementia was 0.067 higher, corresponding to an odds ratio of 1.070 (p < 0.001). Results were similar for cognitive impairment and level of cognition. By contrast, a nonlinear relationship of age with multiple indices of AD pathology was observed (all ps < 0.05), such that pathologic AD reached a peak around 95 years of age and leveled off afterwards; the quantitative measures of AD pathology were significantly lower at ages above 95. The association of age with other neuropathologies was quite distinct from that of AD in that most increased with advancing age. AD pathology appears to peak around 95 years of age while other common pathologies continue to increase with age.

Lower mitochondrial DNA content but not increased mutagenesis associates with decreased base excision repair activity in brains of AD subjects.

Accumulation of oxidative mitochondrial DNA (mtDNA) damage and impaired base excision repair (BER) in brains have been associated with Alzheimer's disease (AD). However, it is still not clear how these affect mtDNA stability, as reported levels of mtDNA mutations in AD are conflicting. Thus, we investigated whether alterations in BER correlate with mtDNA instability in AD using postmortem brain samples from cognitively normal AD subjects and individuals who show neuropathological features of AD, but remained cognitively normal (high-pathology control). To date, no data on DNA repair and mtDNA stability are available for these individuals. BER activities, mtDNA mutations, and mtDNA copy number were measured in the nuclear and mitochondrial extracts. Significantly lower uracil DNA glycosylase activity was detected in nuclear and mitochondrial extracts from AD subjects, while apurinic/apyrimidinic endonuclease activity was similar in all groups. Although mtDNA mutation frequency was similar in all groups, mtDNA copy number was significantly decreased in the temporal cortex of AD brains but not of high-pathology control subjects. Our results show that lower mitochondrial uracil DNA glycosylase activity does not result in increased mutagenesis, but rather in depletion of mtDNA in early-affected brain regions during AD development.

Morphometric measurements of systemic atherosclerosis and visceral fat: Evidence from an autopsy study.

BACKGROUND: Morphometric measurements of systemic atherosclerosis and direct quantification of visceral fat are only possible using materials from autopsy studies. However, the few autopsy studies that have investigated the association of visceral fat with atherosclerosis had small sample sizes and focused on coronary arteries of young or middle-aged White subjects. We aimed to investigate the association of pericardial fat (PF) and abdominal visceral fat (AVF) with atherosclerosis in the aorta, coronary, carotid, and cerebral arteries in a large autopsy study. MATERIALS AND METHODS: We evaluated deceased subjects aged 30 years or above. We dissected and weighted the PF and the AVF and evaluated the atherosclerotic burden in the aorta, as well as the carotid, coronary, and cerebral arteries using morphometric measurements. We also investigated the interaction of PF and AVF with age regarding the atherosclerotic burden. RESULTS: The mean age of the 240 included subjects was 64.8±15.3 years, and 63% was male. Greater PF was associated with a higher degree of aortic atherosclerosis after adjusting for confounding variables (coefficient = 4.39, 95% CI = 0.83; 7.94, p = 0.02). Greater AVF was associated with a higher coronary stenosis index (coefficient = 1.49, 95% CI = 0.15; 2.83, p = 0.03) and a greater number of coronary plaques (coefficient = 0.71, 95% CI = 0.24; 1.19, p = 0.003). We did not find an association of PF or AVF with carotid or cerebral atherosclerotic burden. We found a significant interaction of AVF (coefficient = -0.08; 95% CI = -0.14; -0.02, p = 0.009) and PF (coefficient = -0.87, 95% CI = -1.70; -0.04, p = 0.04) with age regarding carotid artery atherosclerotic burden. CONCLUSIONS: Greater AVF was associated with greater atherosclerotic burden and extent in coronary arteries, while greater PF correlated with a higher degree of atherosclerosis in the aorta.

Neuropathologic features of TOMM40 '523 variant on late-life cognitive decline.

INTRODUCTION: The study investigated the role of neuropathologies in the relationship between TOMM40 '523 genotype and late-life cognitive decline. METHODS: Participants were community-dwelling older persons who had annual cognitive assessments and brain autopsies after death. Genotyping used DNA from peripheral blood or postmortem brain tissue. Linear mixed models assessed the extent to which the association of '523 genotype with cognitive decline is attributable to neuropathologies. RESULTS: Relative to ε3/ε3 homozygotes with '523-S/VL or '523-VL/VL genotype, both '523-L carriers and ε3/ε3 homozygotes with '523-S/S genotype had faster cognitive decline. The association of '523-L with cognitive decline was attenuated and no longer significant after controlling for Alzheimer's and other neuropathologies. By contrast, the association of '523-S/S was unchanged. DISCUSSION: There are two distinct TOMM40 '523 signals in relation to late-life cognitive decline. One signal primarily acts through AD and other common neuropathologies, whereas the other operates through a different mechanism.