Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene result in typical late-onset Parkinson disease (PD).1,2 Yet the neuropathological heterogeneity observed in such patients (eg, nigral degeneration alone or in combination with tau pathology, diffuse Lewy bodies, brainstem Lewy bodies, or anterior horn cell loss) suggests that LRRK2 might be involved in the pathogenesis of several neurodegenerative diseases.1,2 The potential role of LRRK2 in Alzheimer disease (AD) is of particular interest because the gene resides within a region on chromosome 12 previously linked to late-onset AD.3 The aim of this study was to screen a large sample of patients with AD for the presence of the LRRK2 mutation most common in PD (G2019S).4
Methods
We studied 754 subjects who met the NINCDS-ADRDA criteria (National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association) for probable or definite AD. These individuals were participants in the National Cell Repository for Alzheimer’s Disease at Indiana University, Indianapolis, or in ongoing studies at the Oregon Health and Science University Layton Aging and Alzheimer’s Disease Center, Portland, and University of Washington Alzheimer’s Disease Research Center, Seattle. All subjects (or their representatives) provided written informed consent according to procedures approved by the institutional review board at each participating site.
Standard methods were used to extract DNA, and genotyping was performed by TaqMan assay on an ABI PRISM 7900HT Sequence Detection system (Applied Biosystems, Foster City, Calif). The DNA from subjects known to be heterozygous for G2019S was included in all assays as a control. Power calculations were performed using Power and Precision software (Biostat, Englewood, NJ).
Results
The demographic and clinical characteristics of the study group are presented in the Table. Histopathologic data sufficient for a diagnosis of definite AD were available for 47.1% of the subjects. The mean±SD age at onset was 67.5±10.2 years (range, 30–95 years). Approximately two thirds of the subjects had a family history of dementia (in at least 1 first-degree relative) and 96% were Caucasian.
Table 1.
Characteristics of Subjects With Alzheimer Disease by Site
| Site | Subjects, No. |
Age at Onset, Mean ± SD, y* |
Men, No. (%) |
Autopsy Confirmed, No. (%) |
Family History of Dementia, No. (%)† |
|---|---|---|---|---|---|
| OHSU LAADC | 200 | 68.1 ± 9.9 | 103 (51.5) | 72 (36.0) | 102 (51.0) |
| NCRAD | 305 | 67.8 ± 10.4 | 105 (34.4) | 203 (66.6) | 296 (97.0) |
| UW ADRC | 249 | 66.8 ± 10.1 | 125 (50.2) | 80 (32.1) | 96 (38.6) |
| Total | 754 | 67.5 ± 10.2 | 333 (44.2) | 355 (47.1) | 494 (65.5) |
Abbreviations: OHSU LAADC, Oregon Health and Science University Layton Aging and Alzheimer’s Disease Center, Portland; NCRAD, National Cell Repository for Alzheimer’s Disease at Indiana University, Indianapolis; UW ADRC, University of Washington Alzheimer’s Disease Research Center, Seattle.
Age at onset was not known for 6 subjects.
Defined as having 1 or more first-degree relatives with dementia.
We did not detect the G2019S mutation in any of the 754 subjects genotyped. Our analysis of 1508 chromosomes provided greater than 95% power (α=.05) to detect G2019 in the sample, assuming a frequency greater than or equal to 0.25% for the mutation in patients with AD in the population.
Comment
Our data suggest that G2019S, which occurs at a frequency of approximately 1% in sporadic5 and 3% in familial4,5 PD, is not a common cause of AD. We had adequate power to detect G2019S in our sample, which predominantly comprised cases with a family history of dementia, even if the true frequency of the mutation in AD was nearly 10-fold less than that in PD. Our findings are consistent with recent studies6,7 and argue that the concomitant AD pathology observed in some mutation-positive patients1 might simply be a chance occurrence rather than a direct result of dysfunction of the LRRK2-encoded product (dardarin) itself.
This study did not assess the frequency of less common PD-related LRRK2 mutations in AD nor did it address the existence of pathogenic mutations specific to AD. Furthermore, the role of LRRK2 in determining susceptibility to disorders other than AD and PD is not yet clear. Comprehensive studies of the gene in large samples of patients with other parkinsonian disorders, motor neuron disease, and non-AD dementing illnesses will be necessary to determine whether LRRK2 truly represents a molecular link between neurodegenerative diseases.
Acknowledgment
We thank the patients and their families for participating in the study and Dr William Lee, Stephen Ayres, Jason Isabelle, Erica Martinez, and Dora Yearout for technical support and assistance with data preparation.
Funding/Support: This study was supported by grants P01 AG017586, K08 NS044138, P30 AG008017, P50 AG005136, R01 NS036960, R01 NS048595, and U24 AG021886 from the National Institutes of Health, Bethesda, Md; a Research Enhancement Award Program grant and the Veterans Integrated Service Network 20 (VISN 20) Geriatric and Mental Illness Research, Education, and Clinical Centers, Department of Veterans Affairs, Washington, DC; and the New York State Department of Health Wadsworth Center, Albany.
References
- 1.Zimprich A, Biskup S, Leitner P, et al. Mutations in LRRK2 causeautosomal-dominant parkinsonism with pleomorphic pathology. Neuron. 2004;44:601–607. doi: 10.1016/j.neuron.2004.11.005. [DOI] [PubMed] [Google Scholar]
- 2.Paisan-Ruiz C, Jain S, Evans EW, et al. Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron. 2004;44:595–600. doi: 10.1016/j.neuron.2004.10.023. [DOI] [PubMed] [Google Scholar]
- 3.Pericak-Vance MA, Bass MP, Yamaoka LH, et al. Complete genomic screen in late-onset familial Alzheimer disease: evidence for a new locus on chromosome 12. JAMA. 1997;278:1237–1241. [PubMed] [Google Scholar]
- 4.Kachergus J, Mata IF, Hulihan M, et al. Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations. Am J Hum Genet. 2005;76:672–680. doi: 10.1086/429256. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Kay DM, Zabetian CP, Factor SA, et al. Parkinson’s disease and LRRK2: frequency of a common mutation in U.S. movement disorder clinics. [Accessed on November 7, 2005];Mov Disord. 2005 Oct 25; doi: 10.1002/mds.20751. [Epub ahead of print]. Available at: http://dx.doi.org/10.1002/mds.20751. [DOI] [PubMed] [Google Scholar]
- 6.Toft M, Sando SB, Melquist S, et al. LRRK2 mutations are not common in Alzheimer’s disease. Mech Ageing Dev. 2005;126:1201–1205. doi: 10.1016/j.mad.2005.06.010. [DOI] [PubMed] [Google Scholar]
- 7.Hernandez D, Paisan Ruiz C, Crawley A, et al. The dardarin G2019S mutation is a common cause of Parkinson’s disease but not other neurodegenerative diseases. Neurosci Lett. 2005;389:137–139. doi: 10.1016/j.neulet.2005.07.044. [DOI] [PubMed] [Google Scholar]