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Objectives: Mutations in the GBA gene occur in 7% of patients with Parkinson disease (PD) and are a well-established susceptibility factor for PD, which is characterized by Lewy body disease (LBD) neuropathologic changes (LBDNCs). We sought to determine whether GBA influences risk of dementia with LBDNCs, Alzheimer disease (AD) neuropathologic changes (ADNCs), or both. Methods: We screened the entire GBA coding region for mutations in controls and in subjects with dementia and LBDNCs and no or low levels of ADNCs (pure dementia with Lewy bodies [pDLB]), LBDNCs and high-level ADNCs (LBD-AD), and high-level ADNCs but without LBDNCs (AD). Results: Among white subjects, pathogenic GBA mutations were identified in 6 of 79 pDLB cases (7.6%), 8 of 222 LBD-AD cases (3.6%), 2 of 243 AD cases (0.8%), and 3 of 381 controls (0.8%). Subjects with pDLB and LBD-AD were more likely to carry mutations than controls (pDLB: odds ratio [OR] = 7.6; 95% confidence interval [CI] = 1.8–31.9; p = 0.006; LBD-AD: OR = 4.6; CI = 1.2–17.6; p = 0.025), but there was no significant difference in frequencies between the AD and control groups (OR = 1.1; CI = 0.2–6.6; p = 0.92). There was a highly significant trend test across groups (χ 2 (1) = 19.3; p = 1.1 × 10 −5 ), with the likelihood of carrying a GBA mutation increasing in the following direction: control/AD Conclusions: GBA is a susceptibility gene across the LBD spectrum, but not in AD, and appears to convey a higher risk for PD and pDLB than for LBD-AD. PD and pDLB might be more similar to one another in genetic determinants and pathophysiology than either disease is to LBD-AD.

Article abstract-Objective: To examine the differences in the pattern of progression between AD and AD with Lewy bodies (AD+LB). Methods: The authors examined predictors of functional and cognitive disability, institutionalization, and death, as well as time to the development of psychosis (e.g., delusions, hallucinations), extrapyramidal signs (EPS), diurnal hypersomnia, and depression in 185 patients with definite AD and 60 with autopsy-confirmed AD+LB. In addition, they analyzed a selected group of patients who did not have comorbid systemic or CNS disease that may have affected progression of the disease (AD = 98 versus AD+LB = 44). The mean follow-up was 58.91 ± 35.2 months. Results: All cases: Patients with AD+LB had faster time to the development of EPS and diurnal hypersomnia, but not to the development of psychosis or depression. The rate of cognitive and functional decline, time to institutionalization, and physical survival was not different between AD+LB and AD. Selected cases: Patients with AD+LB developed earlier EPS and diurnal hypersomnia than AD patients, and there was a trend to develop earlier major depression, but no differences were noted in time to psychosis. Patients with AD+LB had a faster time to institutionalization than those with AD. The rate of cognitive and functional decline and physical survival was not different between AD+LB and AD in these selected cases. Conclusion: Patients with AD+LB can develop EPS and diurnal hypersomnia earlier and have faster time to institutionalization than those with AD alone, but cognitive and functional decline and physical survival are similar between these two entities.

Objective: Recent genome-wide association studies (GWAS) of late-onset Alzheimer disease (LOAD) identified 9 novel risk loci. Discovery of functional variants within genes at these loci is required to confirm their role in Alzheimer disease (AD). Single nucleotide polymorphisms that influence gene expression (eSNPs) constitute an important class of functional variants. We therefore investigated the influence of the novel LOAD risk loci on human brain gene expression. Methods: We measured gene expression levels in the cerebellum and temporal cortex of autopsied AD subjects and those with other brain pathologies (∼400 total subjects). To determine whether any of the novel LOAD risk variants are eSNPs, we tested their cis -association with expression of 6 nearby LOAD candidate genes detectable in human brain ( ABCA7, BIN1, CLU, MS4A4A, MS4A6A, PICALM ) and an additional 13 genes ±100 kb of these SNPs. To identify additional eSNPs that influence brain gene expression levels of the novel candidate LOAD genes, we identified SNPs ±100 kb of their location and tested for cis -associations. Results: CLU rs11136000 ( p = 7.81 × 10 −4 ) and MS4A4A rs2304933/rs2304935 ( p = 1.48 × 10 −4 –1.86 × 10 −4 ) significantly influence temporal cortex expression levels of these genes. The LOAD-protective CLU and risky MS4A4A locus alleles associate with higher brain levels of these genes. There are other cis -variants that significantly influence brain expression of CLU and ABCA7 ( p = 4.01 × 10 −5 –9.09 × 10 −9 ), some of which also associate with AD risk ( p = 2.64 × 10 −2 –6.25 × 10 −5 ). Conclusions: CLU and MS4A4A eSNPs may at least partly explain the LOAD risk association at these loci. CLU and ABCA7 may harbor additional strong eSNPs. These results have implications in the search for functional variants at the novel LOAD risk loci.

Objective: To describe the experience of a research clinic diagnosing possible AD during the last two decades. Background: The National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association criteria for possible AD are generally used to indicate that a patient has AD in association with another disease process that could by itself cause dementia. There are no studies describing how these criteria should be applied, and there are no descriptions of functional and cognitive progression or survival in possible AD. Methods: The authors examined the clinical characteristics of 267 patients diagnosed with possible AD at the AD Research Center of Pittsburgh from 1983 to 2000 and the likelihood of arriving at four endpoints: Mini-Mental State Examination score of ≤ 9, Blessed Dementia Rating Scale for activities of daily living score of ≥ 12, nursing home admission, and death. Results: The possible AD classification has been simplified in six categories: possible AD with cerebrovascular disease (CVD) (69%), with history of alcohol abuse (15%), with history of depression (7%), with thyroid disease (4%), with history of head trauma (6%), with vitamin B12 deficiency (6%), and with other disease process that may have affected the clinical presentation of AD (4%). The presence of CVD, history of alcohol abuse, and history of depression concomitant with the onset of dementia were associated with time to death. Neither thyroid disease, history of head trauma, nor vitamin B12 deficiency were associated with any of the four endpoints. Conclusion: This cohort showed that comorbid conditions that can affect cognition delineate clearly defined subgroups in AD. The presence of environmental or other brain disorders sufficient to produce dementia appears to affect physical survival in patients with AD, but not functional and cognitive decline or institutionalization.