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We examined the interactions between educational attainment and genetic susceptibility on dementia risk among adults over 60 years old. A total of 174,161 participants were free of dementia at baseline. The APOE ε4-related genetic risk was evaluated by the number of APOE ε4 alleles. The overall genetic susceptibility of dementia was evaluated by polygenetic risk score (PRS). Cox proportional hazards models were used to estimate the association between educational attainment and incident dementia. During a median of 8.9 years of follow-up, a total of 1482 incident cases of dementia were documented. After adjustment for covariates, we found that low education attainment was significantly associated with higher dementia risk in the APOE ε4 carriers, and such relation appeared to be stronger with the increasing number of ε4 alleles. In contrast, educational attainment was not associated with dementia risk in non-APOE ε4 carriers (P for multiplicative interaction = 0.006). In addition, we observed that the dementia risk associated with a combination of low educational attainment and high APOE ε4-related genetic risk was more than the addition of the risk associated with each of these factors (P for additive interaction < 0.001). We found similar significant interactions between educational attainment and PRS on both the multiplicative and additive scales on the dementia risk, mainly driven by the APOE genotype. These data indicate that higher educational attainment in early life may attenuate the risk for dementia, particularly among people with high genetic predisposition., (© 2022. The Author(s), under exclusive licence to American Aging Association.)

With vast amounts ofpatients' medical information, electronic health records (EHRs) are becoming one of the most important data sources in biomedical and health care research. Effectively integrating data from multiple clinical sites can help provide more generalized real-world evidence that is clinically meaningful. To analyze the clinical data from multiple sites, distributed algorithms are developed to protect patient privacy without sharing individual-level medical information. In this paper, we applied the One-shot Distributed Algorithm for Cox proportional hazard model (ODAC) to the longitudinal data from the OneFlorida Clinical Research Consortium to demonstrate the feasibility of implementing the distributed algorithms in large research networks. We studied the associations between the clinical risk factors and Alzheimer's disease and related dementia (ADRD) onsets to advance clinical research on our understanding of the complex risk factors of ADRD and ultimately improve the care of ADRD patients., (©2020 AMIA - All rights reserved.)

Lewy pathology occurs in 8-17% of neurologically normal people age >60, termed incidental Lewy body disease (iLBD). It is often assumed to represent preclinical Parkinson disease (PD). However, some iLBD cases have diffuse pathology inconsistent with preclinical PD. We analyzed iLBD cases (α-synuclein immunohistochemistry) using the Braak PD staging scheme and determined if some had a neuropathological pattern suggestive of preclinical dementia with Lewy bodies (DLB). Of the 235 brains examined, 34 had iLBD (14.5%) and all but one could be assigned a Braak PD stage. The distribution of α-synuclein pathology in the 33 cases fell into three patterns: (1) diffuse cortical and subcortical α-synuclein pathology; (2) no cortical α-synuclein pathology, but a caudal-to-rostral ascending pattern, primarily involving brainstem; and (3) intermediate between these two categories. Also, 6/33 cases failed to follow the pattern of contiguous spread proposed by Braak. These findings suggest dichotomy in the distribution of iLBD: some cases fit the Braak ascending scheme, conceptually consistent with preclinical PD, whereas others displayed prominent cortical involvement that might represent preclinical DLB., (Copyright © 2009 Elsevier Inc. All rights reserved.)

Background: The evidence for increased risk of dementia in relatives of patients with Parkinson disease (PD) remains conflicting., Objective: To study the risk of cognitive impairment or dementia in first-degree relatives of patients with PD., Design, Setting, and Participants: We conducted a historical cohort study of 1019 first-degree relatives of 162 patients with PD and of 858 relatives of 147 matched controls representative of the population of Olmsted County, Minnesota. In addition, we studied 2716 first-degree relatives of 411 patients with PD referred to Mayo Clinic., Main Outcome Measures: We administered via telephone a cognitive test directly to relatives or a dementia questionnaire to proxies. For relatives reported by proxies to have dementia, we obtained copies of their medical records to confirm the diagnosis. We also obtained dementia information from a medical records-linkage system., Results: In the overall population-based sample, the risk of cognitive impairment or dementia was increased in relatives of patients with PD compared with relatives of controls (hazard ratio, 1.37; 95% confidence interval, 1.03-1.81; P = .03) and was particularly increased in relatives of patients with onset of PD at age 66 years or younger (youngest tertile; hazard ratio, 1.73; 95% confidence interval, 1.21-2.46; P = .003). The findings were consistent in several sensitivity analyses. In the referral-based sample, the risk of cognitive impairment or dementia in relatives increased with younger age at onset of PD but did not vary by other clinical characteristics., Conclusion: Cognitive impairment or dementia may share familial susceptibility factors with PD (genetic or nongenetic).

In an inception cohort of 196 Olmsted County, Minnesota, residents with Parkinson's disease (PD) first recognized in 1976 to 1995, we tested whether the increased risk of bone fractures is associated with concomitant dementia. Using the data resources of the Rochester Epidemiology Project, information about PD, dementia, other clinical risk factors for fracture and fracture events was obtained from review of complete inpatient and outpatient medical records spanning each subject's residence in the community. Compared to an equal number of age- and sex-matched non-PD referent subjects from the community, PD patients were at a 2.2-fold increased risk of fractures generally and a 3.2-fold greater risk of hip fractures specifically. Adjusting for age, the independent predictors of overall fracture risk in the PD subjects included female sex (hazard ratio [HR] 1.6; 95% confidence interval [CI], 1.1-2.3), dementia (HR, 1.6; 95% CI, 1.1-2.4) and chronic depression, which was associated with a reduced risk (HR, 0.4; 95% CI, 0.2-0.8). Hip fractures were predicted by dementia (HR, 2.2; 95% CI, 1.2-4.1). The increased fracture risk in patients with PD is not entirely explained by concomitant dementia, and additional study is needed to determine the relative contributions to fracture risk of falls versus bone loss in these patients., ((c) 2006 Movement Disorder Society.)

Objective: The objective of this study was to assess clinical decision-making associated with the use of a multi-analyte blood biomarker (BBM) test among patients presenting with signs or symptoms of mild cognitive impairment or dementia. Methods: The Quality Improvement PrecivityAD2 (QUIP II) Clinician Survey (NCT06025877) study evaluated the clinical utility of the PrecivityAD2™ blood test in a prospective, single cohort of 203 patients presenting with symptoms of Alzheimer's disease (AD) or other causes of cognitive decline across 12 memory specialists. The PrecivityAD2 blood test (C2N Diagnostics, St. Louis, MO) combines the plasma Aβ42/Aβ40 ratio and the p-tau217/np-tau217 ratio (%p-tau217) measurements in a statistical algorithm to yield an Amyloid Probability Score 2 (APS2) that informs on the likelihood of brain amyloid plaques. After receiving the BBM test results, clinicians completed surveys on management strategies for each patient. Results: Patients had a median age of 74, 53% were female, and 28% were traditionally under-represented in Black, Hispanic, and Asian groups. The composite primary endpoint, defined as a change in AD diagnostic certainty, drug therapy, or additional brain amyloid evaluation pre- and post-BBM testing, was 75% (p < 0.0001 versus the pre-specified threshold of 20% clinically meaningful change). Anti-AD medication orders decreased among negative APS2 patients and increased among positive APS2 patients (p < 0.0001). Additional brain amyloid testing decreased among negative APS2 patients (p < 0.0001). Conclusions: This blood biomarker test can help memory specialists guide patients to anti-AD therapies as well as rule out AD to allow for other diagnostic considerations. [ABSTRACT FROM AUTHOR]

In the Mayo Clinic Cohort Study of Oophorectomy and Aging, women who had both ovaries removed before reaching natural menopause experienced a long-term increased risk of parkinsonism, cognitive impairment or dementia, and depressive and anxiety symptoms. Here, we discuss five possible mechanistic interpretations of the observed associations; first, the associations may be non-causal because they result from the confounding effect of genetic variants or of other risk factors; second, the associations may be mediated by an abrupt reduction in levels of circulating estrogen; third, the associations may be mediated by an abrupt reduction in levels of circulating progesterone or testosterone; fourth, the associations may be mediated by an increased release of gonadotropins by the pituitary gland; and fifth, genetic variants may modify the hormonal effects of bilateral oophorectomy through simple or more complex interactions. Results from other studies are cited as evidence for or against each possible mechanism. These putative causal mechanisms are probably intertwined, and their clarification is a research priority. [ABSTRACT FROM AUTHOR]

Background: The evidence for a neuroprotective effect of estrogen in women remains controversial. Objective: We studied the long-term risk of parkinsonism and of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Methods: We conducted a historical cohort study among all women residing in Olmsted County, Minn., USA, who underwent unilateral or bilateral oophorectomy before the onset of menopause for a noncancer indication from 1950 through 1987. Each member of the oophorectomy cohort was matched by age to a referent woman from the same population who had not undergone oophorectomy. In total, we studied 1,252 women with unilateral oophorectomy, 1,075 women with bilateral oophorectomy, and 2,368 referent women. Women were followed for a median of 25–30 years. Parkinsonism was assessed using screening and examination, through a medical records- linkage system, and through death certificates. Cognitive status was assessed using a structured questionnaire via a direct or proxy telephone interview. Results: The risk of parkinsonism and of cognitive impairment or dementia increased following oophorectomy. In particular, we observed significant linear trends of increasing risk for either outcome with younger age at oophorectomy. Conclusion: Our findings, combined with previous laboratory and epidemiologic findings, suggest that estrogen may have an age-dependent neuroprotective effect. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The identification of the α-synuclein gene on chromosome 4q as a locus for familial Lewy-body parkinsonism and of α-synuclein as a component of Lewy bodies has heralded a new era in the study of Parkinson’s disease. We have identified a large family with Lewy body parkinsonism linked to a novel locus on chromosome 4p15 that does not have a mutation in the α-synuclein gene. Here we report the clinical and neuropathological findings in an individual from this family and describe unusual high molecular weight α-synuclein-immunoreactive proteins in brain homogenates from brain regions with the most marked neuropathology. Distinctive histopathology was revealed with α-synuclein immunostaining, including pleomorphic Lewy bodies, synuclein-positive glial inclusions and widespread, severe neuritic dystrophy. We also discuss the relationship of this familial disorder to a Lewy body disease clinical spectrum, ranging from Parkinson’s disease to dementia with psychosis. [ABSTRACT FROM AUTHOR]

Autosomal dominant parkinsonism has been attributed to pathogenic amino acid substitutions in leucine-rich repeat kinase 2 (LRRK2). By sequencing multiplex families consistent with a PARK8 assignment, we identified a novel heterozygous LRRK2 mutation. A referral sample of 248 affected probands from families with autosomal dominant parkinsonism was subsequently assessed; 7 (2.8%) were found to carry a heterozygous LRRK2 6055G→A transition (G2019S). These seven patients originate from the United States, Norway, Ireland, and Poland. In samples of patients with idiopathic Parkinson disease (PD) from the same populations, further screening identified six more patients with LRRK2 G2019S; no mutations were found in matched control individuals. Subsequently, 42 family members of the 13 probands were examined; 22 have an LRRK2 G2019S substitution, 7 with a diagnosis of PD. Of note, all patients share an ancestral haplotype indicative of a common founder, and, within families, LRRK2 G2019S segregates with disease (multipoint LOD score 2.41). Penetrance is age dependent, increasing from 17% at age 50 years to 85% at age 70 years. In summary, our study demonstrates that LRRK2 G2019S accounts for parkinsonism in several families within Europe and North America. Our work highlights the fact that a proportion of clinically typical, late-onset PD cases have a genetic basis. [ABSTRACT FROM AUTHOR]