Abstract
Apolipoprotein E (APOE) genotype was determined in a population of patients with dementia, including 735 patients with Alzheimer's disease (AD), 75 with Frontotemporal Lobar Degeneration (FTLD), 97 with Vascular Dementia (VaD) and 40 with Lewy Body Dementia (LBD), as well as in 506 age- and gender-matched controls (CON). APOE ε2 allele frequency was lower in patients with AD (2.8%) than in CON (6.4%, P≤0.001, OR: 0.41). Similar results were obtained comparing AD with FTLD (6.7%, P≤0.01, OR: 0.37), at difference from VaD (5.6%, P>0.05) or LBD (5.0%, P>0.05). The frequency of the APOE ε4 allele was increased in patients with AD (25.1%) as compared with CON (8.2%, P≤0.001, OR: 4.24), FTLD (11.3%, P≤0.001, OR: 2.67), VaD (11.8%, P≤0.001, OR: 3.02), or LBD (13.8%, P=0.048, OR: 2.07). The frequency of the ε4/ε4 genotype was increased in AD patients compared with controls (6.3 versus 0.8%, P≤0.001, OR: 8.38). The presence of the ε2 allele is a protective factor for AD, whereas the ε4 allele acts as a risk factor for the disease. Both alleles do not influence the susceptibility to FTLD, LBD and VaD.
Keywords: Apolipoprotein E (APOE), Alzheimer's disease (AD), Frontotemporal Lobar Degeneraton (FTLD), Vascular dementia (VaD), Lewy body dementia (LBD), risk factor
Introduction
Current research on neurodegenerative diseases is focused on two main and inter-related objectives: identification of pathogenic mechanisms and therapeutic approaches. Although a cause for most neurodegenerative disease is not known, a multifactorial origin is often the case, involving mainly genetic, environmental, and nutritional factors. As concerns Alzheimer's disease (AD, OMIM #104300), the most common degenerative dementia, the known predisposing role of a particular genotype for the gene that encodes apolipoprotein E (APOE, OMIM #107741) makes the presence of APOE ε4 allele a candidate marker for the disease [1]. APOE is involved in the uptake of lipids generated after neuronal degeneration and in their redistribution to proliferating and repairing cells [2, 3]. Enhanced synthesis of APOE E3, but not APOE E4, was demonstrated to stimulate repair of local hippocampal damage [4].
Whereas the presence of APOE ε4 allele is associated with a significantly greater risk of developing AD [5–11], the ε2 allele seems to have a somewhat protective role towards the disease, even if some discordant data exist [12–15]. In this regard, the paucity of data is probably due, at least in part, to the very low frequency of ε2 allele. A neuropathological study on 296 AD brains [16] evidenced that, whereas the APOE ε4/ε4 genotype was associated with a higher tissue load of neuritic plaques and neurofibrillary tangles, the presence of the ε2 allele was protective against the formation of neuritic plaques.
In vitro studies demonstrated that APOE E3 stimulates, but APOE E4 inhibits neuronal sprouting in murine hippocampal cultures [17]. In addition, APOE has been shown to bind beta amyloid (Aβ) and can therefore be important in the clearance of Aβ [17]. The binding capacity for Aβ is much greater for APOE E2 than for the other isoforms, and this could explain the protection exerted against AD [17]. Other experimental evidence strongly suggests that both protection by APOE E2 and pathogenetic role of APOE E4 are in strict relationship with amyloid processing [18].
To date, the effect of the APOE genotype on the development of other types of dementia is still controversial. A number of studies suggested an association between Frontotemporal Lobar Degeneration (FTLD, OMIM #600274) and APOE ε4 allele [19, 20]. Other Authors [21, 22] however, did not replicate these data, possibly due to the small sample size analyzed in their study. Recent findings demonstrated an association between the APOE ε4 allele and FTLD in males, but not females [23], possibly explaining the discrepancies previously reported. Concerning the e2 allele in the development of FTLD, heterogeneous data have been obtained in different populations. Bernardi et al. [19] showed a protective effect of this allele towards FTLD, whereas other Authors failed to do so [22–24]. Despite these results, a recent meta-analysis comprising a total of 364 FTD patients and 2671 controls (CON) demonstrated an increased susceptibility to FTD in ε2 carriers [25].
Additional studies demonstrated an increased APOE ε4 frequency in Vascular Dementia (VaD), similar to that found in AD [26–28], whereas more recent findings did not replicate such association [29–31].
To further study the role of APOE in the development of AD and other forms of dementia, we genotyped for APOE a large population of CON and patients with different types of dementia (AD, FTLD, LBD – OMIM #127750 - and VaD) and compared the APOE distribution in the different subgroups in order to assess the possible effect of ε2 and ε4 alleles upon the susceptibility to develop these dementias.
Materials and methods
Subjects
Nine-hundred forty-seven patients were consecutively recruited at the Alzheimer Units of Ospedale Maggiore Policlinico-IRCCS and Ospedale Sacco (Milan) and at the Presidio Ospedaliero di Magenta (Milan). All patients underwent a standard battery of examinations, including medical history, physical and neurological examination, screening laboratory tests, neurocognitive evaluation (to assess memory, language and constructional praxis), brain Magnetic Resonance Imaging (MRI) or Computed Tomography (CT) and, if indicated, Positron Emission Computed Tomography (PET). Dementia severity was assessed by the Clinical Dementia Rating (CDR) and the Mini Mental State Examination (MMSE) score. Seven-hundred thirty-five patients (206 males and 529 females, mean age at disease onset ±S.E.M.: 73.8± 0.36 years) were diagnosed by exclusion as affected by probable AD, according to NINCDS-ADRDA criteria [32]. One hundred-seven AD patients had an onset of the disease before age 65 (EOAD). For this subjects the possible presence of familial AD was excluded as no first-degree relative was affected by AD. Seventy-five patients (34 males and 41 females, mean age at onset ±S.E.M.: 68.7±1.97 years) were diagnosed as sporadic FTLD in accordance with consensus criteria proposed by Neary et al. [33]. These consensus criteria identify three clinical syndromes: Frontotemporal dementia (FTD), Progressive nonfluent Aphasia (PA) and Semantic Dementia (SD), which reflect the clinical heterogeneity of FTLD. Five out of 75 patients with FTLD had PA, 2 had SD and the remainder were diagnosed as FTD.
Forty patients (19 males and 21 females, mean age at onset ±S.E.M.: 74.5±1.18 years) were diagnosed as LBD according to McKeith et al. criteria [34]. Diagnosis of VaD was formulated in 97 patients (52 males and 45 females, mean age at onset ±S.E.M.: 73.0±1.03 years) according to NINDS-AIREN criteria [35]. The control group consisted of 506 subjects matched to patients for ethnic background and age (175 males and 331 females; mean age±S.E.M: 68.7±0.59 years, P>0.05 versus patients), without memory complaints (MMSE score ranging from 28 to 30), including healthy age-matched volunteers recruited either at nursing homes or at the Centers involved in this study (non-consanguineous patients' kindreds). An informed consent to participate in this study, performed in accordance with the Helsinki Declaration of 1975, was given by all individuals or their caregivers.
APOE genotyping
High-molecular weight DNA was isolated from whole blood using a Flexigene Kit (Qiagen, Hildren, Gemany), as described by the manufacturer. The amount of DNA for each sample was determined by measuring the optical density at 260 nm wavelengths using a spectrophotometer (Eppendorf AG, Germany). APOE genotype was determined by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) assay. DNA was amplified using specific primers and then digested with HhaI, as previously described [36].
Statistical analysis
Allelic and genotypic frequencies were obtained by direct counting. χ2 test was used to test for Hardy-Weinberg equilibrium and for differences in allele distribution among groups. The odds ratio (OR) was calculated along with its 95% confidence interval (CI).
Results
APOE ε2 distribution
APOE allelic and genotypic frequencies in patients and controls are summarized in Table 1. The allelic frequency of the ε2 allele was significantly decreased in patients with AD (2.8%) as compared with either controls (6.4%, P≤0.001, OR: 0.41, CI: 0.27-0.62) or patients with other types of dementia (5.9%, P≤0.01, OR: 0.45, CI: 0.26-0.77). When comparing AD patients with FTLD, a statistically significant difference was found (2.8 versus 6.7%, P≤0.01, OR: 0.37, CI: 0.18-0.77), while the same comparison between AD and VaD or LBD was not significant (5.6 and 5.0%, respectively, P>0.05, Table 2). None of patients with PA and SD was a carrier of the ε2 allele. No significant differences in ε2 distribution were found between controls and FTLD, LBD or VaD. The calculation of the mean age at onset according to APOE genotype in AD patients highlighted a significant increase of age at onset for cases with ε2/ε4 or ε2/ε3 genotypes in comparison to age at onset for the ε3/ε3 group. No differences in allelic and genotypic frequencies of ε2 were observed after stratifying patients according to gender (data not shown).
Table 1.
APO E allele and genotype frequencies (%) in patients and CON
| APOE | CON n=506 | AD n=735 | Mean age at onset (years±SD) | OTHER DEMENTIAS n=212 |
|---|---|---|---|---|
| Allele | ||||
| ε2 | 65 (6.4) | 41 (2.8)* | - | 25 (5.9) |
| ε3 | 864 (85.4) | 1060 (72.1) | - | 348 (82.0) |
| ε4 | 83 (8.2) | 369 (25.1)** | - | 51 (12.1) |
| Genotype | ||||
| ε2/e2 | 3 (0.6) | 1 (0.1) | NA | 1 (0.5) |
| ε2/e3 | 54 (10.7) | 29 (3.9) | 78.0±3.5# | 22 (10.4) |
| ε2/e4 | 5 (1.0) | 10 (1.4) | 81.3±5.2# | 1 (0.5) |
| ε3/e3 | 370 (73.1) | 382 (52.0) | 74.5±5.0 | 141 (66.5) |
| ε3/e4 | 70 (13.8) | 267 (36.3) | 73.4±7.0 | 44 (20.7) |
| ε4/e4 | 4 (0.8) | 46 (6.3)*** | 72.9±5.2 | 3 (1.4) |
The genotypic distributions of CON and AD respected Hardy-Weinberg equilibrium (p>0.05 for the χ2 test between observed and expected values).
P≤0.001; OR: 0.41, CI: 0.27-0.62, AD versus controls; P≤0.01; OR: 0.45, CI: 0.26-0.77, AD versus other dementias
P≤0.001; OR: 4.24, CI: 3.20-5.61, AD versus controls; P≤0.01; OR: 2.64, CI: 1.88-3.81, AD versus other dementias
P≤0.001; OR: 8.38, CI: 3.00-23.43, AD versus controls; P≤0.01; OR: 4.65, CI: 1.43-15.10, AD verus other dementias
P≤0.01 versus ε3/ε3 genotype, one-way ANOVA followed by Dunnett's post hoc test. SD: standard deviation
Table 2.
APO E allele and genotype frequencies (%) in AD compared with FTLD, LBD and VaD
| Allele | CON n=506 | AD n=735 | OTHER DEMENTIAS n=212 | |||
|---|---|---|---|---|---|---|
| ɛ4− | ɛ4+ | ɛ4− | ɛ4+ | ɛ4− | ɛ4+ | |
| ɛ2− | 370 (73.1) | 74 (14.6) | 382 (52.0) | 313 (42.6)** | 141 (66.5) | 47 (22.2) |
| ɛ2+ | 57 (11.3) | 5 (1.0) | 30 (4.1)* | 10 (1.3) | 23 (10.8) | 1 (0.5) |
The genotypic distributions of AD, FTLD, LBD and VaD respected Hardy-Weinberg equilibrium (p>0.05 for the χ2 test between observed and expected values)
P ≤ 0.01; OR: 0.37, CI: 0.18-0.77, AD versus FTLD
P ≤ 0.001; OR: 2.67, CI: 1.53-4.67, AD versus FTLD; P=0.048; OR: 2.07, CI: 1.02-4.21, AD versus LBD; P ≤ 0.001; OR: 3.02 CI: 1.81-5.04, AD versus VaD
APOE ε4 distribution
The allelic frequency of the ε4 allele was significantly higher in patients with AD (25.1%) than in controls (8.2%, P≤0.001, OR: 4.24, CI: 3.20-5.61) or patients with other kinds of dementia (12.1%, P≤0.01, OR: 2.64, CI: 1.88-3.81; Table 1). Comparing AD patients with the different disorders included in the last group, a statistically significant difference was found between AD and FTLD (25.1 versus 11.3%, P≤0.001, OR: 2.67, CI: 1.53-4.67), as well as between AD and VaD (25.1 versus 11.8%, P≤0.001, OR: 3.02, CI: 1.81-5.04). Concerning LBD, a borderline significance was found when comparing with AD (25.1 versus 13.8%, P=0.048, OR: 2.07, CI: 1.02-4.21, Table 2). No significant differences in ε4 distribution were observed between controls and FTLD or LBD or VaD. The frequency of the APOE ε4/ε4 genotype was significantly increased in AD patients as compared with either controls or other forms of dementia (6.3 versus 0.8%, P≤0.001, OR: 8.38, CI: 3.00-23.43 or versus 1.4%, P≤0.01, OR: 4.65, CI: 1.43-15.10, respectively). No differences in allelic and genotypic frequencies of ε4 were observed stratifying patients according to gender (data not shown). However, the frequency of the ε4/ε4 genotype was markedly high in EOAD (12.1%) compared to controls, with an over 15-fold increased risk to develop AD (P≤0.001, OR: 17.46, CI: 5.57-54.71). The calculation of the mean age at onset according to APOE genotype in AD patients did not find a decrease of age at onset for cases with ε3/ε4 or ε4/ε4 genotypes in comparison to age at onset for the ε3/ε3 group.
APOE ε2 and ε4 combination
The lowest OR was found in patients carrying the protective ε2 allele but not the risk ε4 allele as compared with either controls or patients with other types of dementia (4.1 versus 11.3%, P≤0.001, OR: 0.34, CI: 0.22-0.54 or versus 10.8%, P≤0.001, OR: 0.35, CI: 0.20-0.62, respectively, Table 3). Conversely, the highest OR was found comparing patients carrying the ε4 but not the ε2 allele (42.6 versus 14.6%, P≤0.001, OR: 4.33, CI: 3.25-5.77 or versus 22.2%, P≤0.001, OR: 2.60, CI: 1.82-3.71, respectively, Table 3).
Table 3.
Combination of risk ε4 and protective ε2 alleles in patients and controls
| APOE | AD n=735 | FTLD n=75 | LBD n=40 | VaD n=97 |
|---|---|---|---|---|
| Allele | ||||
| ε2 | 41(2.8)* | 10 (6.7) | 4 (5.0) | 11 (5.6) |
| ε3 | 1060 (72.1) | 123 (82) | 65 (81.2) | 160 (82.6) |
| ε4 | 369 (25.1)** | 23 (11.3) | 11 (13.8) | 23 (13.8) |
| Genotype | ||||
| ε2/ε2 | 1 (0.1) | 0(0) | 0(0) | 1 (1.0) |
| ε2/ε3 | 29 (3.9) | 10 (13.3) | 4 (10.0) | 8 (8.3) |
| ε2/ε4 | 10 (1.4) | 0(0) | 0(0) | 1 (0) |
| ε3/ε3 | 382 (52.0) | 48 (64.0) | 25 (62.5) | 68 (70.1) |
| ε3/ε4 | 267 (36.3) | 17 (22.7) | 11(27.5) | 16 (16.5) |
| ε4/ε4 | 46 (6.3) | 0(0) | 0(0) | 3 (3.1) |
P≤0.001; OR: 0.34, CI: 0.22-0.54 ε2+/ε4− carriers, AD versus controls; P≤0.001; OR: 0.35, CI: 0.20-0.62, ε2+/ε4-carriers, AD versus other dementias
P≤0.001; OR: 4.33, CI: 3.25-5.77, ε2−/ε4+ carriers, AD versus controls; P≤0.001; OR: 2.60, CI: 1.82-3.71, ε2−/e4+ carriers, AD versus other dementias
Discussion
According to our results, the effect exerted by APOE alleles is specific for the development of AD, whereas ε2 and ε4 alleles likely do not influence the susceptibility to FTLD, VaD or LBD. The presence of the ε2 allele is a protective factor against the development of AD and also delayed age at onset in comparison to ε3/ε3 carriers; conversely, the ε4 allele is associated to an increased risk for AD, but in this case we did not find a modulation of age at onset among ε3/ε4 or ε4/ε4 carriers in comparison to ε3/ε3 patients. However, the ε4 homozygous status is associated with an almost 10-fold risk to develop AD and this value is even higher (about 15-fold) when considering patients with early-onset AD). In accordance with these data, the lowest OR was found in APOE ε2+/ε4− carriers.
Whereas both ε2 and ε4 alleles have been repeatedly demonstrated to play an opposite role in the development of AD, to date controversial results on such role for other types of dementia have been obtained. Regarding the ε2 allele, Bernardi et al. [19] demonstrated a protective role of this allele in an Italian population with FTD. However, this study was conducted in a population from a region of Southern Italy (Calabria), which can be considered genetically homogeneous due to its geographic and historical isolation, possibly explaining the discrepancies with our results. A recent meta-analysis [25] demonstrated a risk effect of the ε2 on the susceptibility to develop FTLD, but this effect was mainly observed in patients with familial forms of the disease. Concerning the ε4 allele in FTLD, our results are in agreement with previous findings demonstrating an absence of a susceptibility effect [22, 25, 37].
In accordance with previous data [38], the frequency of APOE ε2 allele has been shown to be unchanged in LBD as compared with normal population. Concerning the ε4 allele, its role in LBD is more controversial. Whereas some studies showed a distribution similar to AD [38], others showed an increased frequency of the ε4 allele in patients with coexisting clinical and pathological features of both LBD and AD [37]. However, as the clinical diagnosis of AD+LBD has been criticized [39], in this study we didn't consider the possibility of this diagnostic variant in our patients. This our data are in agreement with previous findings [38], but should be considered cautiously because the sample analyzed is quite small. Therefore, the role of APOE in the susceptibility of LBD remains still debated and further studies on a larger population are certainly needed to clarify this issue.
The role of APOE ε4 allele in VaD is doubtful as well, with some evidences of an association [27] and others failing to demonstrate a role in the susceptibility to the disease [31]. Interestingly, Engelborghs et al. [24] demonstrated an effect of the ε4 allele on the risk of mixed dementia. The concomitant occurrence of microvascular brain disease in AD is a matter of great debate and represents a yet unsolved dilemma in the pathogenesis of AD [40, 41].
The specificity of the ε4 allele in influencing the susceptibility to AD but not to other types of dementia could be linked to the amyloid-related pathogenetic mechanism at the basis of AD. In fact, compelling in-vitro evidence demonstrates that lipidated APOE E4 binds preferentially to Aβ than APO E2 or E3 isoforms [42]. In addition, several studies confirmed an increased amyloid deposition in APOE E4 carriers [43, 44], thus suggesting a role in AD but not in other types of dementia, in which other proteins are supposed to be responsible for neuronal death [45, 46]. The observation of an association between an increased frequency of the ε4 allele in patients having coexisting clinical and pathological features of AD+LBD, i.e. amyloid plaques and Lewy bodies but not in patients with a pure neuropa-thological form of LBD [37] strongly supports an amyloid-related mechanism at the basis of the observed association between APOE alleles and the development of AD.
In accordance with previous findings, carriers of the ε4/ε4 genotype have the greatest risk to develop AD. Moreover, this genotype seems correlated with an earlier onset of the disease, as also previously suggested [8]. Conversely, the effect of carrying the ε2/ε2 genotype is hard to evaluate given the very low frequency of this genotype in our as well in other populations.
In conclusion, our findings confirm that the APOE ε2 allele has a protective role towards the development of AD, where it can also delay the age at onset, but has no effect in other forms of dementia. Nevertheless, its role in VaD and LBD remains questionable, because of the small sample analyzed with respect to the very low frequency of this allelic variant. The APOE ε4 allele is a strong susceptibility factor for AD, particularly in the homozygous ε4/ε4 form, whereas it does not influence the risk to develop other types of dementia. Again, the borderline significance obtained between AD and LBD does not allow to draw reliable conclusions on a possible role of APOE ε4 allele in LBD.
Acknowledgments
This work was supported by grants from Associazione “Amici del Centro Dino Ferrari”, Monzino Foundation, IRCCS Ospedale Maggiore Milano, Associazione per la Ricerca sulle Demenze (ARD), Associazione per la Ricerca Geriatrica e lo Studio della Longevità (AGER), Milan, and Ing. Cesare Cusan.
References
- 1.Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993;261:921–923. doi: 10.1126/science.8346443. [DOI] [PubMed] [Google Scholar]
- 2.Boyles JK, Zoellner CD, Anderson LJ, Kosik LM, Pitas RE, Weisgraber KH, Hui 2DY, Mahley RW, Gebicke-Haerter PJ, Ignatius MJ. A role for apolipoprotein E, apolipoprotein A-I, and low density lipoprotein receptors in cholesterol transport during regeneration and remyelination of the rat sciatic nerve. J Clin Invest. 1989;83:1015–1031. doi: 10.1172/JCI113943. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Ignatius MJ, Shooter EM, Pitas RE, Mahley RW. Lipoprotein uptake by neuronal growth cones in vitro. Science. 1987;236:959–962. doi: 10.1126/science.3576212. [DOI] [PubMed] [Google Scholar]
- 4.Poirier J, Baccichet A, Dea D, Gauthier S. Cholesterol synthesis and lipoprotein reuptake during synaptic remodelling in hippocampus in adult rats. Neuroscience. 1993;55:81–90. doi: 10.1016/0306-4522(93)90456-p. [DOI] [PubMed] [Google Scholar]
- 5.Khachaturian AS, Corcoran CD, Mayer LS, Zandi PP, Breitner JC, Cache County Study Investigators Apolipoprotein E epsilon4 count affects age at onset of Alzheimer disease, but not lifetime susceptibility: The Cache County Study. Arch Gen Psychiatry. 2004;61:518–524. doi: 10.1001/archpsyc.61.5.518. [DOI] [PubMed] [Google Scholar]
- 6.Myers RH, Schaefer EJ, Wilson PW, D'Agostino R, Ordovas JM, Espino A, Au R, White RF, Knoefel JE, Cobb JL, McNulty KA, Beiser A, Wolf PA. Apolipoprotein E epsilon4 association with dementia in a population-based study: The Framingham study. Neurology. 1996;46:673–677. doi: 10.1212/wnl.46.3.673. [DOI] [PubMed] [Google Scholar]
- 7.Rebeck GW, Reiter JS, Strickland DK, Hyman BT. Apolipoprotein E in sporadic Alzheimer's disease: allelic variation and receptor interactions. Neuron. 1993;11:575–580. doi: 10.1016/0896-6273(93)90070-8. [DOI] [PubMed] [Google Scholar]
- 8.Saunders AM. Apolipoprotein E and Alzheimer disease: an update on genetic and functional anayses. J Neuropathol Exp Neurol. 2000;59:751–758. doi: 10.1093/jnen/59.9.751. [DOI] [PubMed] [Google Scholar]
- 9.Saunders AM, Schmader K, Breitner JC, Benson MD, Brown WT, Goldfarb L, Goldgaber D, Manwaring MG, Szymanski MH, McCown N. Apolipoprotein E epsilon 4 allele distributions in late-onset Alzheimer's disease and in other amyloid-forming diseases. Lancet. 1993;342:710–711. doi: 10.1016/0140-6736(93)91709-u. [DOI] [PubMed] [Google Scholar]
- 10.Scott J. Apolipoprotein E and Alzheimer's disease. Lancet. 1993;342:696. doi: 10.1016/0140-6736(93)91704-p. [DOI] [PubMed] [Google Scholar]
- 11.Strittmatter WJ, Roses AD. Apolipoprotein E and Alzheimer's disease. Annual Rev Neurosci. 1996;19:53–77. doi: 10.1146/annurev.ne.19.030196.000413. [DOI] [PubMed] [Google Scholar]
- 12.Corder EH, Saunders AM, Risch NJ, Strittmatter WJ, Schmechel DE, Gaskell PC, Jr, Rimmler JB, Locke PA, Conneally PM, Schmader KE. Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat Genet. 1994;7:180–184. doi: 10.1038/ng0694-180. [DOI] [PubMed] [Google Scholar]
- 13.Berlau DJ, Corrada MM, Head E, Kawas CH. APOE epsilon2 is associated with intact cognition but increased Alzheimer pathology in the oldest old. Neurology. 2009;72:829–34. doi: 10.1212/01.wnl.0000343853.00346.a4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Borenstein AR, Mortimer JA, Ding D, Schellenberg GD, Decarli C, Zhao Q, Copenhaver C, Guo Q, Chu S, Galasko D, Salmon DP, Dai Q, Wu Y, Petersen R, Hong Z. Effects of Apolipoprotein E-E4 and -E2 in Amnestic Mild Cognitive Impairment and Dementia in Shanghai: SCOBHI-P. Am J Alzheimers Dis Other Demen. 2010 doi: 10.1177/1533317509357736. Feb 8. [Epub ahead of print] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Ignatov I, Belden C, Jacobson S, Connor D, Sabbagh MN. Possible Alzheimer's disease in an apolipoprotein E2 homozygote. J Alzheimers Dis. 2009;16(1):35–8. doi: 10.3233/JAD-2009-0932. Jan. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Tiraboschi P, Hansen LA, Masliah E, Alford M, Thai U, Corey-Bloom J. Impact of APOE genotype on neuropathologic and neurochemical markers of Alzheimer disease. Neurology. 2004;62:1977–1983. doi: 10.1212/01.wnl.0000128091.92139.0f. [DOI] [PubMed] [Google Scholar]
- 17.Aleshkov S, Abraham CR, Zannis VI. Interaction of nascent ApoE2, ApoE3, and ApoE4 isoforms expressed in mammalian cells with amyloid peptide beta (1-40). Relevance to Alzheimer's disease. Biochemistry. 1997;36:10571–10580. doi: 10.1021/bi9626362. [DOI] [PubMed] [Google Scholar]
- 18.Maezawa I, Jin LW, Woltjer RL, Maeda N, Martin GM, Montine TJ, Montine KS. Apolipoprotein E isoforms and apolipoprotein AI protect from amyloid precursor protein carboxy terminal fragment-associated cytotoxicity. J Neurochem. 2004;91:1312–1321. doi: 10.1111/j.1471-4159.2004.02818.x. [DOI] [PubMed] [Google Scholar]
- 19.Bernardi L, Maletta RG, Tomaino C, Smirne N, Di Natale M, Perri M, Longo T, Colao R, Curcio SA, Puccio G, Mirabelli M, Kawarai T, Rogaeva E, St George Hyslop PH, Passarino G, De Benedictis G, Bruni AC. The effects of APOE and tau gene variability on risk of frontotemporal dementia. Neurobiol Aging. 2006;27:702–709. doi: 10.1016/j.neurobiolaging.2005.03.008. [DOI] [PubMed] [Google Scholar]
- 20.Gustafson L, Abrahamson M, Grubb A, Nilsson K, Fex G. Apolipoprotein-E genotyping in Alzheimer's disease and frontotemporal dementia. Dement GeriatrCogn Disord. 1997;8:240–243. doi: 10.1159/000106637. [DOI] [PubMed] [Google Scholar]
- 21.Geschwind D, Karrim J, Nelson SF, Miller B. The apolipoprotein E epsilon4 allele is not a significant risk factor for frontotemporal dementia. Ann Neurol. 1998;44:134–138. doi: 10.1002/ana.410440122. [DOI] [PubMed] [Google Scholar]
- 22.Short RA, Graff-Radford NR, Adamson J, Baker M, Hutton M. Differences in tau and apolipoprotein E polymorphism frequencies in sporadic frontotemporal lobar degeneration syndromes. Arch Neurol. 2002;59:611–615. doi: 10.1001/archneur.59.4.611. [DOI] [PubMed] [Google Scholar]
- 23.Srinivasan R, Davidson Y, Gibbons L, Payton A, Richardson AM, Varma A, Julien C, Stopford C, Thompson J, Horan MA, Pendleton N, Pickering-Brown SM, Neary D, Snowden JS, Mann DM. The apolipoprotein E epsilon4 allele selectively increases the risk of frontotemporal lobar degeneration in males. J Neurol Neurosurg Psychiatry. 2006;77:154–158. doi: 10.1136/jnnp.2005.063966. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Engelborghs S, Dermaut B, Goeman J, Saerens J, Marien P, Pickut BA, Van den Broeck M, Serneels S, Cruts M, Van Broeckhoven C, De Deyn PP. Prospective Belgian study of neurodegenerative and vascular dementia: APOE genotype effects. J Neurol Neurosurg Psychiatry. 2003;74:1148–1151. doi: 10.1136/jnnp.74.8.1148. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Verpillat P, Camuzat A, Hannequin D, Thomas-Anterion C, Puel M, Belliard S, Dubois B, Didic M, Lacomblez L, Moreaud O, Golfier V, Campion D, Brice A, Clerget-Darpoux F. Apolipoprotein E gene in frontotemporal dementia: an association study and meta-analysis. Eur J Hum Genet. 2002;10:399–405. doi: 10.1038/sj.ejhg.5200820. [DOI] [PubMed] [Google Scholar]
- 26.Baum L, Lam LC, Kwok T, Lee J, Chiu HF, Mok VC, Wong A, Chen X, Cheung WS, Pang CP, Ma SL, Tang NL, Wong KS, Ng HK. Apolipoprotein E epsilon4 allele is associated with vascular dementia. Dement Geriatr Cogn Disord. 2006;22:301–305. doi: 10.1159/000095246. [DOI] [PubMed] [Google Scholar]
- 27.Davidson Y, Gibbons L, Purandare N, Byrne J, Hardicre J, Wren J, Payton A, Pendleton N, Horan M, Burns A, Mann DM. Apolipoprotein E epsilon4 allele frequency in vascular dementia. Dement Geriatr Cogn Disord. 2006;22:15–19. doi: 10.1159/000092960. [DOI] [PubMed] [Google Scholar]
- 28.Treves TA, Bornstein NM, Chapman J, Klimovitzki S, Verchovsky R, Asherov A, Veshchev IO, Korczyn AD. APOE-e4 in patients with Alzheimer's disease and vascular dementias. Alzheimer Dis Assoc Disord. 1996;10:189–191. doi: 10.1097/00002093-199601040-00003. [DOI] [PubMed] [Google Scholar]
- 29.Frank A, Diez-Tejedor E, Bullido MJ, Valdivieso F, Barreiro P. APOE genotype in cerebrovascular disease and vascular dementia. J Neurol Sci. 2002:203–204. 173–176. doi: 10.1016/s0022-510x(02)00286-1. [DOI] [PubMed] [Google Scholar]
- 30.Guidi I, Galimberti D, Lonati S, Novembrino C, Bamonti F, Tiriticco M, Fenoglio C, Venturelli E, Baron P, Bresolin N, Scarpini E. Oxidative imbalance in patients with mild cognitive impairment and Alzheimer's disease. Neurobiol Aging. 2006;27:262–269. doi: 10.1016/j.neurobiolaging.2005.01.001. [DOI] [PubMed] [Google Scholar]
- 31.Traykov L, Rigaud AS, Baudic S, Smagghe A, Boller F, Forette F. Apolipoprotein E e4 allele frequency in demented and cognitively impaired patients with and without cerebrovascular disease. J Neurol Sci. 2002:203–204. 177–181. doi: 10.1016/s0022-510x(02)00287-3. [DOI] [PubMed] [Google Scholar]
- 32.McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: Report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984;34:939–944. doi: 10.1212/wnl.34.7.939. [DOI] [PubMed] [Google Scholar]
- 33.Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, Freedman M, Kertesz A, Robert PH, Albert M, Boone K, Miller BL, Cummings J, Benson DF. Frontotemporal lobar degeneration. A consensus on clinical diagnostic criteria. Neurology. 1998;51:1546–1554. doi: 10.1212/wnl.51.6.1546. [DOI] [PubMed] [Google Scholar]
- 34.McKeith IG, Perry EK, Perry RH. Report of the second dementia with Lewy body international workshop: diagnosis and treatment. Consortium on Dementia with Lewy Bodies. Neurology. 1999;53:902–905. doi: 10.1212/wnl.53.5.902. [DOI] [PubMed] [Google Scholar]
- 35.Roman GC, Tatemichi TK, Erkinjuntti T, Cummings JL, Masdeu JC, Garcia JH, Amaducci L, Orgogozo JM, Brun A, Hofman A. Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology. 1993;43:250–260. doi: 10.1212/wnl.43.2.250. [DOI] [PubMed] [Google Scholar]
- 36.Del Bo R, Comi GP, Bresolin N, Castelli E, Conti E, Degiuli A, Ausenda CD, Scarlato G. The apoli-poprotein E e4 allele causes a faster decline of cognitive performances in Down's syndrome subjects. J Neurol Sci. 1997;145:87–91. doi: 10.1016/s0022-510x(96)00249-3. [DOI] [PubMed] [Google Scholar]
- 37.Nielsen AS, Ravid R, Kamphorst W, Jorgensen OS. Apolipoprotein E epsilon 4 in an autopsy series of various dementing disorders. J Alzheimer Dis. 2003;5:119–125. doi: 10.3233/jad-2003-5206. [DOI] [PubMed] [Google Scholar]
- 38.Singleton AB, Wharton A, O'Brien KK, Walker MP, McKeith IG, Ballard CG, O'Brien J, Perry RH, Ince PG, Edwardson JA, Morris CM. Clinical and neuropathological correlates of apolipoprotein E genotype in dementia with lewy bodies. Dement Geriatr Cogn Disord. 2002;14:167–175. doi: 10.1159/000066022. [DOI] [PubMed] [Google Scholar]
- 39.McKeith IG. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the Consortium on DLB International Workshop. J Alzheimers Dis. 2006;9(Suppl 3):417–423. doi: 10.3233/jad-2006-9s347. [DOI] [PubMed] [Google Scholar]
- 40.Guidi I, Galimberti D, Venturelli E, Lovati C, Del Bo R, Fenoglio C, Gatti A, Dominici R, Galbiati S, Virgilio R, Pomati S, Comi GP, Mariani C, Forloni G, Bresolin N, Scarpini E. Influence of the Glu298Asp polymorphism of NOS3 on age at onset and homocysteine levels in AD patients. Neurobiol Aging. 2005;26:789–794. doi: 10.1016/j.neurobiolaging.2004.07.003. [DOI] [PubMed] [Google Scholar]
- 41.Jellinger KA. The enigma of mixed dementia. Alzheimer's & Dementia. 2007;3:40–53. doi: 10.1016/j.jalz.2006.09.002. [DOI] [PubMed] [Google Scholar]
- 42.Stratman NC, Castle CK, Taylor BM, Epps DE, Melchior GW, Carter DB. Isoform-specific interactions of human apolipoprotein Eto an intermediate conformation of human Alzheimer amyloid beta peptide. Chem Phys Lipids. 2005;137:52–61. doi: 10.1016/j.chemphyslip.2005.06.005. [DOI] [PubMed] [Google Scholar]
- 43.Gearing M, Schneider JA, Robbins RS, Hollister RD, Mori H, Games D, Hyman BT, Mirra SS. Regional variation in the distribution of apolipoprotein E and A beta in Alzheimer's disease. J Neuropathol Exp Neurol. 1995;54:833–841. doi: 10.1097/00005072-199511000-00010. [DOI] [PubMed] [Google Scholar]
- 44.McNamara MJ, Gomez-Isla T, Hyman BT. Apolipoprotein E genotype and deposits of Abeta40 and Abeta42 in Alzheimer disease. Arch Neurol. 1998;55:1001–1004. doi: 10.1001/archneur.55.7.1001. [DOI] [PubMed] [Google Scholar]
- 45.Scarpini E, Galimberti D, Bresolin N. Genetics and neurobiology of frontotemporal lobar degeneration. Neurol Sci. 2006;27(Suppl 1):S32–34. doi: 10.1007/s10072-006-0543-9. [DOI] [PubMed] [Google Scholar]
- 46.Scarpini E, Galimberti D, Guidi I, Bresolin N, Scheltens P. Progressive, isolated language disturbance: its significance in a 65-year-old-man. A case report with implications for treatment and review of literature. J Neurol Sci. 2006;240:45–51. doi: 10.1016/j.jns.2005.09.006. [DOI] [PubMed] [Google Scholar]