The diagnosis of Alzheimer's disease (AD) is a clinical diagnosis, focusing on the exclusion of other causes of senile dementia.
Both the tau and BA-42 molecules are components of the neurofibrillary tangles associated with AD. Levels of these molecules found in the cerebro-spinal fluid (CSF) have been investigated as a diagnostic test for AD. Additionally, there is an association between the apolipoprotein E (apoE) epsilon 4 genotype and AD. The apoE genotype consists of one of several different combinations of the 3 different alleles, which are labeled 2, 3 or 4. It has been shown that the presence of one allele (apoE4) is over-represented in patients with late onset AD.
There is inadequate data regarding the positive and negative predictive values of CSF levels of tau and BA-42 in the diagnosis of AD in patients with clinical symptoms consistent with possible AD. While the presence of an apoE4 allele may be associated with an increased risk of AD, the associated positive and negative predictive values are inadequate to validate apoE genotyping as a diagnostic test for AD. Additionally, there is no information regarding how such testing would influence the management of the patient. A high positive predictive value may not be clinically useful since the diagnosis can be made clinically.
The Agency for Health Care Policy and Research Clinical Practice Guideline addressed the diagnosis and assessment of AD and related dementias. The guideline stated that “it is not yet possible to depend on apoE genotyping for definitive guidance about diagnosis or treatment of Alzheimer's disease” (Costa et al, 1996). Furthermore, the algorithm presented in the Guideline for the recognition and initial assessment of AD did not incorporate measurement of CSF levels of the peptides tau and BA-42. The Alzheimer's Disease Guidelines Panel concluded that the role of these markers in the diagnosis and management of patients with AD are questions for further research.
Genetic screening for persons who may be at high risk for AD, such as those with the apolipoprotein E 4 gene locus on chromosome 19, is a highly debated issue, particularly because currently no demonstrated intervention can prevent or delay the dementing process, and no evidence exists about predicting age of onset for person with this genotype.
Identifiable genetic mutations are rare causes of AD. Persons with early onset of AD (before age 65) may show an autosomal dominant pattern of inheritance. Nearly all of the autosomal dominant familial forms of AD are related to mutations in one of three different genes: mutations of the amyloid precursor protein (APP) gene on chromosome 21 and genes encoding presenilin 1 (PS1) on chromosome 14 and presenilin 2 (PS2) on chromosome 1. However, only 2 to 10 % of all persons with AD have early onset disease, and genetic mutations have been identified in 30 to 50 % of these patients. In addition, although detection of genetic mutations may have prognostic significance, there is no evidence that genetic testing for AD would alter the management of patients such that clinical outcomes are improved.
The PS-1 DNA Sequencing Test, replacing the Symptomatic PS-1 Analysis and Interpretation Test (Athena Diagnostics), is used for evaluating patients with progressive demential with onset before age 65 with a positive family history of early-onset AD. It detects sequence variations in the presenilin 1 (PS-1) gene by means of polymerase chain reaction and DNA sequencing. However, there is insufficient evidence to support its clinical value at this time.
Efforts to develop biologic markers for the presence of AD, such as tests that could be performed on samples of blood or CSF, are important research topics for confirming a suspected diagnosis of AD.
According to the Canadian Consensus Conference on Dementia (1999) and the American Academy of Neurology's practice parameter on Diagnosis of Dementia (2001), the usefulness of tests for tau, BA-42, and apoE for the diagnosis of AD has not been established.
The AD-associated neuronal thread protein (AD7c-NTP) gene encodes an approximately 41 kD membrane-spanning phosphoprotein that causes apoptosis and neuritic sprouting in transfected neuronal cells. The AD7c-NTP gene is over-expressed in AD beginning early in the course of disease. The levels of neuronal thread protein in post-mortem brain tissue correlate with the levels measured in paired ventricular fluid samples, suggesting that the protein is secreted or released by dying cells into CSF. Recent studies have suggested that urine test for AD7c-NTP could be used to assess the risk of developing AD. de la Monte and Wands (2002) reported that elevated levels of AD7c-NTP can be detected in both CSF and urine of patients with early or moderately severe AD, and the CSF and urinary levels of AD7c-NTP correlate with the severity of dementia. The authors reported that the newest configuration of the AD7c-NTP assay, termed “7c Gold”, has greater than 90 % sensitivity and specificity for detecting early AD. Munzar et al (2002) reported that the competitive ELISA-format AD7C-NTP test in urine is an accurate method for determining AD7c-NTP levels in AD and could be used as a biochemical marker for AD. Additional studies are needed to validate these preliminary results and to demonstrate the impact of AD7c-NTP screening on clinical outcomes.
In a 2001 American Academy of Neurology's practice parameter for the diagnosis of dementia (Knopman et al, 2001) stated that “no laboratory tests have yet emerged that are appropriate for routine use in the clinical evaluation of patients with suspected AD”. The practice parameter concluded that further research is needed to improve clinical definitions of dementia and its subtypes, as well as to determine the utility of various instruments of neuroimaging, biomarkers, and genetic testing in increasing diagnostic accuracy.
The tropicamide drop test has been proposed as a rapid, non-invasive method for the early diagnosis of AD based on the observation that patients with AD exhibit greater pupillary dilation following administration of a diluted solution (0.01 %) of the cholinergic antagonist, tropicamide. However, subsequent studies reported that pupillary response to tropicamide does not differentiate between AD patients and healthy subjects. The tropicamide drop test is associated with high individual variability in the pupillary response to topically applied drugs. Furthermore, the reliability (test-retest) of the tropicamide drop test is questionable.
Mild cognitive impairment is a transition period between physiological aging and dementia. Each year more than 12 % of individuals with mild cognitive impairment develop AD. In a controlled study, Eibenstein and colleagues (2005) assessed the presence of an olfactory deficit in patients with amnesic mild cognitive impairment (aMCI). A total of 29 subjects diagnosed with aMCI and a homogeneous control group of 29 subjects were enrolled in the study. Olfactory function was assessed by the Sniffin' Sticks Screening Test (SSST) and the Mini Mental State Examination, the Clinical Dementia Rating, the Geriatric Depression Scale and the Mental Deterioration Battery were used to evaluate the neurocognitive status. Individuals with aMCI showed a significant impairment of their olfactory identification compared to controls (SSST score: 8.3 +/- 2.1 versus 10.8 +/- 0.9; p < 0.001). These results suggested that olfactory tests should be part of the diagnostic armamentarium of pre-clinical dementia. They noted that a long-term follow-up might confirm the olfactory identification function as an early and reliable marker in the diagnosis of pre-clinical dementia.
Hampel and Shen (2009) noted that AD is characterized by the progressive formation of insoluble amyloid plaques and vascular deposits consisting of the amyloid beta-peptide (Abeta) in the brain. Pathological mechanisms are already active early in the pre-symptomatic stage of AD. Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), also known as beta-secretase, is one of the 2 key enzymes in APP processing; the other being gamma-secretase. The Abeta peptide results from cleavage of APP initially by BACE1 to produce the C99 fragment and releases soluble APPbeta (sAPPbeta); C99 is then further cleaved by gamma-secretase leading to the Abeta peptide. Increased BACE1 activity and elevated levels of insoluble Abeta peptide have been shown in brain tissue of patients with sporadic AD. Since the CSF is in direct contact with the extra-cellular space of the central nervous system, biochemical changes in the brain can potentially be reflected in CSF. Thus, CSF-based detection of BACE1 levels and activity might be valuable in aiding early detection and prediction, particularly in pre-clinical or even pre-symptomatic subjects who are at risk of AD. Recently, these researchers were among the first groups to quantitatively analyze the enzymatic activities and protein levels of BACE1 in the CSF. Preliminary research using recently developed BACE1 ELISAs, BACE1 enzymatic activity, sAPPbeta and total Abeta1-x ELISAs were used by examining these hypothesis driven functional candidate markers in subjects with clinically diagnosed AD and amnestic mild cognitive impairment (MCI). Two sandwich ELISAs were used and BACE1 enzymatic activities were seen by synthetic fluorescence substrate and total Abeta levels by sandwich-ELISA. Moreover, elevated CSF levels of BACE1 protein were associated with an increased risk ratio in MCI. Interestingly, amnestic MCI subjects showed increased levels of BACE1 activity compared to healthy controls (HC) and AD patients. For total Abeta and tau, increased CSF levels were associated with a higher risk of MCI compared to HC as well. BACE1 activity was significantly correlated with BACE1 protein concentration and total Abeta levels, with Abeta being itself correlated with the BACE1 protein level. The authors concluded that currently, independent studies are ongoing to validate BACE1 and functionally associated proteins as candidate biomarkers for early detection, prediction, progression as well as for biological activity in AD.
Schmand and colleagues (2010) noted that abnormal levels of biomarkers in CSF and atrophy of medial temporal lobe (MTL) structures on magnetic resonance imaging (MRI) are being used increasingly to diagnose early AD. These investigators evaluated the claim that these biomarkers can detect pre-clinical AD before behavioral (i.e., memory) symptoms arise. They included all relevant longitudinal studies of CSF and MRI biomarkers published between January 2003 and November 2008. Subjects were not demented at baseline but some declined to MCI or to AD during follow-up. Measures of tau and beta-amyloid in CSF, MTL atrophy on MRI, and performance on delayed memory tasks were extracted from the papers or obtained from the investigators. A total of 21 MRI studies and 14 CSF studies were retrieved. The effect sizes of total tau, phosphorylated tau and amyloid beta 42 ranged from 0.91 to 1.11. The effect size of MTL atrophy was 0.75. Memory performance had an effect size of 1.06. Atrophy of MTL and memory impairment tended to increase when assessed closer to the moment of diagnosis, whereas effect sizes of CSF biomarkers tended to increase when assessed longer before the diagnosis. The authors concluded that memory impairment is a more accurate predictor of early AD than atrophy of MTL on MRI, whereas CSF abnormalities and memory impairment are about equally predictive. Consequently, the CSF and MRI biomarkers are not very sensitive to pre-clinical AD. Cerebro-spinal fluid markers remain promising, but studies with long follow-up periods in elderly subjects who are normal at baseline are needed to evaluate this promise.
In a cross-sectional study, Carlesimo et al (2010) examined the relationship between age-related memory decline and MRI hippocampal anatomical changes in a cohort of healthy individuals. A total of 76 healthy individuals (44 males and 32 females), ranging in age from 20 to 80 years, were recruited. These individuals were submitted to a 3-T MRI protocol with a whole-brain T1-weighted and diffusion-weighted scanning and a neuropsychological assessment. For each subject, these researchers calculated the volumes of the total brain (gray + white matter) and hippocampi. The segmented hippocampi defined the binary masks where mean values of mean diffusivity (MD) and fractional anisotropy (FA) were calculated. Neuropsychological evaluation included tests of verbal memory (15-min delayed recall of a 15-word list) and visuospatial memory (20-min delayed reproduction of Rey complex figure). Hippocampal MD, but not hippocampal FA, hippocampal volume, or total brain volume, predicted performance of individuals beyond their 50s on tests of verbal as well as visuo-spatial memory. The author concluded that high mean diffusivity values in the hippocampal formation of healthy elderly individuals predict memory decline, as reflected by performance on tests of declarative verbal and visual-spatial memory.
In the present study, none of the subjects fulfilled the clinical or neuropsychological criteria for MCI. Nevertheless, in a number of subjects beyond their 50s, high MD values in the hippocampal formation were accompanied by performance scores that were not truly pathological, but fell in the lower portion of the normal range on tests of declarative memory. The relevant question is if these individuals represent a very early stage in the progression of AD, anterior to the development of an aMCI, or whether, instead, they represent the lower portion of the normal distribution formed by aged individuals who will not develop dementia. The authors stated that longitudinal studies that follow the outcome of these individuals are needed to discriminate between these 2 alternative hypotheses.
In an editorial that accompanied the afore-mentioned article, Schuff (2010) noted that these findings by Carlesimo et al raise several important issues such as (i) they imply that memory deficits in healthy individuals have a biologic underpinning without apparent tissue loss, though the processes underlying the variations in diffusivity are largely unclear, and (ii) alterations in the brain's microstructure may potentially provide new clues for a separation of normal aging from pathology. However, unless prospective studies are conducted, the issue remains open whether mean diffusivity is better as early predictor of AD than volume. It also would be premature to dismiss the value of anatomical MRI, because new developments in MRI have led to improvements in mapping the anatomy of the hippocampus, including differentiation of the subfields.
Hooshmand et al (2010) examined the relation between serum levels of homocysteine (tHcy) and holotranscobalamin (holoTC), the active fraction of vitamin B12, and risk of incident AD in a sample of Finnish community-dwelling elderly. A dementia-free sample of 271 subjects aged 65 to 79 years derived from the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study was followed-up for 7 years to detect incident AD. The association between serum tHcy and holoTC with AD was analyzed with multiple logistic regression after adjusting for several potential confounders, including common vascular risk factors. The odds ratios (ORs) (95 % confidence interval [CI]) for AD were 1.16 (1.04 to 1.31) per increase of 1 μmol/L of tHcy at baseline and 0.980 (0.965 to 0.995) for each increase of 1 pmol/L baseline holoTC. Adjustment for several potential confounders including age, sex, education, APOE ε4 allele, body mass index, Mini-Mental State Examination, smoking, stroke, and blood pressure did not alter the associations: ORs (95 % CI) for AD became 1.19 (1.01 to 1.39) for tHcy and 0.977 (0.958 to 0.997) for holoTC. Adjusting for holoTC attenuated the tHcy-AD link (OR changed from 1.16 to 1.10, 95 % CI: 0.96 to 1.25). The holoTC-AD relationship was less influenced by controlling for tHcy (OR changed from 0.980 to 0.984, 95 % CI: 0.968 to 1.000). Addition of folate did not change any of the results. The authors concluded that these findings suggested that both tHcy and holoTC may be involved in the development of AD. The tHcy-AD link may be partly explained by serum holoTC. The authors stated that the role of holoTC in AD should be further investigated; further studies on the role of sensitive markers of B12 status in identifying individuals who are at increased risk of AD are needed.
In an editorial that accompanied the afore-mentioned study, Seshadri (2010) stated that observational studies and larger clinical trials are indicated, targeting older persons with MCI, simultaneously assessing holoTC (and B12) and plasma tHcy (and folate, methylmalonic acid). Careful examination of the evidence is needed to ascertain who is the perpetrator in the complex pathology of AD and other dementias.
Perneczky et al (2011) examined if soluble amyloid precursor proteins (sAPP) in CSF improve the identification of patients with incipient AD in a group of patients with MCI. A cohort study with follow-up assessments of 58 patients with MCI with baseline CSF sampling was conducted: 21 patients had progressed to probable AD (MCI-AD), 27 still had MCI, 8 had reverted to normal (MCI-NAD), and 2 patients with fronto-temporal dementia (FTD) were excluded. Sixteen additional patients with FTD were included to explore the specificity of the CSF markers. Cerebro-spinal fluid concentrations of sAPPα, sAPPβ, tau, and Aβ(1-42) were measured with sensitive and specific ELISAs. Associations between diagnostic status, CSF protein concentrations, and other patient characteristics were explored using multiple logistic regression analyses with stepwise variable selection. The optimal sensitivity and specificity of the best models were derived from receiver operating characteristic curves. The MCI-AD group had significantly higher sAPPβ concentrations than the MCI-NAD and the FTD groups. A combination of sAPPβ, tau, and age differentiated the MCI-AD and the MCI-NAD groups with a sensitivity of 80.0 % and a specificity of 81.0 %. The best model for the differentiation of the MCI-AD and the FTD groups included sAPPβ and tau, and showed a sensitivity of 95.2 % and a specificity of 81.2 %. Aβ(1-42) and sAPPα did not significantly contribute to the models. The authors concluded that these findings suggested that sAPPβ may be clinically useful, and superior to Aβ(1-42), in the early and differential diagnosis of incipient AD. Limitations of this study included patient recruitment at a specialized memory clinic, which may restrict the generalization of the results to the general population with incipient AD and the lack of pathologic confirmation of AD and FTD. Also, the recruitment of a modest number of patients and the relatively short follow-up period may have under-estimated the predictive value of sAPPβ. The authors stated that replications of these findings in larger multi-center studies are needed. Further studies are needed to examine the clinical value of sAPPβ for the differentiation of AD from healthy aging and from other neurodegenerative disorders, and to investigate its use as a marker for anti-amyloid treatment response.
In a case-cohort study, Schrijvers et al (2011) evaluated the potential of plasma clusterin as a biomarker of the presence, severity, and risk of AD. Plasma levels of clusterin were measured at baseline (1997 to 1999) in 60 individuals with prevalent AD, a random subcohort of 926 participants, and an additional 156 participants diagnosed with AD during follow-up until January 1, 2007 (mean [SD], 7.2 [2.3] years). Main outcome measures included prevalent AD, severity of AD measured by the Mini-Mental State Examination (MMSE) score, and the risk of developing AD during follow-up. The likelihood of prevalent AD increased with increasing plasma levels of clusterin (OR per SD increase of plasma clusterin level, 1.63; 95 % CI: 1.21 to 2.20; adjusted for age, sex, education level, apolipoprotein E status, diabetes, smoking, coronary heart disease, and hypertension). Among patients with AD, higher clusterin levels were associated with more severe disease (adjusted difference in MMSE score per SD increase in clusterin levels, -1.36; 95 % CI: -2.70 to -0.02; p = 0.047). Plasma clusterin levels were not related to the risk of incident AD during total follow-up (adjusted hazard ratio [HR], 1.00; 95 % CI: 0.85 to 1.17; p for trend = 0.77) or within 3 years of baseline (adjusted HR, 1.09; 95 % CI: 0.84 to1.42; p for trend = 0.65). The authors concluded that plasma clusterin levels were significantly associated with baseline prevalence and severity of AD, but not with incidence of AD. They stated that increased clusterin levels do not precede development of AD and thus are not a potential early marker of subclinical disease.
Tan and colleagues (2012) stated that higher dietary intake and circulating levels of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have been related to a reduced risk for dementia, but the pathways underlying this association remain unclear. These investigators examined the cross-sectional relation of red blood cell (RBC) fatty acid levels to subclinical imaging and cognitive markers of dementia risk in a middle-aged to elderly community-based cohort. They related RBC DHA and EPA levels in dementia-free Framingham Study participants (n = 1,575; 854 women, age 67 +/- 9 years) to performance on cognitive tests and to volumetric brain MRI, with serial adjustments for age, sex, and education (model A, primary model), additionally for APOE ε4 and plasma homocysteine (model B), and also for physical activity and body mass index (model C), or for traditional vascular risk factors (model D). Participants with RBC DHA levels in the lowest quartile (Q1) when compared to others (Q2-4) had lower total brain and greater white matter hyper-intensity volumes (for model A: β +/- SE = -0.49 +/- 0.19; p = 0.009, and 0.12 +/- 0.06; p = 0.049, respectively) with persistence of the association with total brain volume in multi-variable analyses. Participants with lower DHA and ω-3 index (RBC DHA+EPA) levels (Q1 versus Q2-4) also had lower scores on tests of visual memory (β +/- SE = -0.47 +/- 0.18; p = 0.008), executive function (β +/- SE = -0.07 +/- 0.03; p = 0.004), and abstract thinking (β +/- SE = -0.52 +/- 0.18; p = 0.004) in model A, the results remaining significant in all models. The authors concluded that lower RBC DHA levels are associated with smaller brain volumes and a "vascular" pattern of cognitive impairment even in persons free of clinical dementia. Moreover, they stated that "the association between lower RBC omega-3 fatty acid levels and markers of accelerated cognitive and structural brain aging observed here should be confirmed in other populations and extended in the future to include dementia outcomes".
Tarawneh et al (2012) stated that measures of neuronal damage/dysfunction are likely good surrogates for disease progression in AD. Cerebro-spinal fluid markers of neuronal injury may offer utility in predicting disease progression and guiding prognostic and outcome assessments in therapeutic trials. Visinin-like protein-1 (VILIP-1) has demonstrated potential utility as a marker of neuronal injury. These researchers investigated the utility of VILIP-1 and VILIP-1/Aβ42 in predicting rates of cognitive decline in early AD. Individuals with a clinical diagnosis of very mild or mild AD (n = 60) and baseline CSF measures of VILIP-1, tau, p-tau181, and Aβ42 were followed longitudinally for an average of 2.6 years. Annual assessments included the Clinical Dementia Rating (CDR), CDR-sum of boxes (CDR-SB), and global composite scores. Mixed linear models assessed the ability of CSF biomarker measures to predict rates of cognitive decline over time. Baseline CSF VILIP-1 and VILIP-1/Aβ42 levels predicted rates of future decline in CDR-SB and global composite scores over the follow-up period. Individuals with CSF VILIP-1 greater than or equal to 560 pg/ml (corresponding to the upper tercile) progressed much more rapidly in CDR-SB (1.61 boxes/year; p = 0.0077) and global scores (-0.53 points/year; p = 0.0002) than individuals with lower values (0.85 boxes/year and -0.15 points/year, respectively) over the follow-up period. Cerebro-spinal fluid tau, p-tau181, tau/Aβ42, and p-tau181/Aβ42 also predicted more rapid cognitive decline in CDR-SB and global scores over time. The authors concluded that these findings suggested that CSF VILIP-1 and VILIP-1/Aβ42 predict rates of global cognitive decline similarly to tau and tau/Aβ42, and may be useful CSF surrogates for neurodegeneration in early AD. Drawbacks of this study included relatively small sample size and short follow-up period. These findings need to be validated in well-designed studies with standardized assay, larger sample size and longer durations of follow-up.
Watabe-Rudolph et al (2012) analyzed the level of novel biomarkers of DNA damage and telomere dysfunction (chitinase activity, N-acetyl-glucosaminidase activity, stathmin, and EF-1α) in CSF of 94 patients with AD, 41 patients with non-AD dementia, and 40 control patients without dementia. Enzymatic activity of chitinase (chitotriosidase activity) and stathmin protein level were significantly increased in CSF of patients with AD and non-AD dementia compared with that of no dementia control patients. As a single marker, chitinase activity was most powerful for distinguishing patients with AD from no dementia patients with an accuracy of 85.8 % using a single threshold. Discrimination was even superior to clinically standard CSF markers that showed an accuracy of 78.4 % (β-amyloid) and 77.6 % (tau). Combined analysis of chitinase with other markers increased the accuracy to a maximum of 91 %. The biomarkers of DNA damage were also increased in CSF of patients with non-AD dementia compared with no dementia patients, and the new biomarkers improved the diagnosis of non-AD dementia as well as the discrimination of AD from non-AD dementia. The authors concluded that taken together, the findings in this study provided experimental evidence that DNA damage markers are significantly increased in AD and non-AD dementia. Moreover, they stated that prospective clinical trials are needed to evaluate whether determination of chitinase enzyme activity and stathmin protein level in CSF could improve the diagnosis and prediction of disease progression of AD.
Hudson et al (2012) noted that although several studies have described an association between AD and genetic variation of mitochondrial DNA (mtDNA), each has implicated different mtDNA variants, so the role of mtDNA in the etiology of AD remains uncertain. These researchers tested 138 mtDNA variants for association with AD in a powerful sample of 4,133 AD case patients and 1,602 matched controls from 3 Caucasian populations. Of the total population, 3,250 case patients and 1,221 elderly controls met the quality control criteria and were included in the analysis. In the largest study to-date, these investigators failed to replicate the published findings. Meta-analysis of the available data showed no evidence of an association with AD. The authors concluded that the current evidence linking common mtDNA variations with AD is not compelling.
Mielke et al (2012) examined if serum ceramides and sphingomyelins (SM) were associated with an increased risk of all-cause dementia and AD. Participants included 99 women without dementia aged 70 to 79, with baseline serum SM and ceramides, enrolled in a longitudinal population-based study and followed for up to 6 visits over 9 years. Baseline lipids, in tertiles, were examined in relation to all-cause dementia and AD using discrete time Cox proportional survival analysis. Lipids were analyzed using electrospray ionization tandem mass spectrometry. A total of 27 (27.3 %) of the 99 women developed incident dementia. Of these, 18 (66.7 %) were diagnosed with probable AD. Higher baseline serum ceramides, but not SM, were associated with an increased risk of AD; these relationships were stronger than with all-cause dementia. Compared to the lowest tertile, the middle and highest tertiles of ceramide d18:1-C16:0 were associated with a 10-fold (95 % CI: 1.2 to 85.1) and 7.6-fold increased risk of AD (95 % CI: 0.9 to 62.1), respectively. The highest tertiles of ceramide d18:1-C24:0 (HR = 5.1, 95 % CI: 1.1 to 23.6) and lactosylceramide (HR = 9.8, 95 % CI: 1.2 to 80.1) were also associated with risk of AD. Total and high-density lipoprotein cholesterol and triglycerides were not associated with dementia or AD. The authors concluded that results from this preliminary study suggested that particular species of serum ceramides are associated with incident AD and warrant continued examination in larger studies. Drawbacks of this study include a small sample size of women only, as well as a single baseline measurement of the biomarker.
The familial form of AD is due to mutations in 3 major genes (APP gene, presenilin 1 [PSEN1] gene and presenilin 2 [PSEN2] gene). Chen et al (2012) stated that association studies of presenilin-2 (PSEN2) polymorphisms and sporadic AD have yielded inconsistent results, possibly because single studies often lack sufficient statistical power. These investigators performed a meta-analysis to evaluate the association of the 2 most extensively studied PSEN2 polymorphisms, rs8383 and 5'indel, with the risk of sporadic AD. They systematically reviewed relevant studies retrieved by Medline, Pubmed, Embase, AlzGene, and CNKI. Data were analyzed using the Stata (v11.0) software package. The fixed effects model or random-effects model were applied depending on between-study heterogeneity. Publication bias was evaluated using Egger's test and Begg's funnel plots. Overall, the meta-analysis included 6 case-control studies for each polymorphism with 2,186 confirmed AD cases and 2,507 healthy controls in total. Analysis suggested a significant association between SNP rs8383 polymorphism and AD risk with no evidence of between-study heterogeneity or publication bias. In contrast, these researchers found no evidence for an association between the 5'indel polymorphism and AD risk. Further stratified analyses by apolipoprotein ε4 status or ethnicity also failed to reveal a statistically significant association between the 5'indel polymorphism of PSEN2 and AD risk. The authors concluded that this analysis supported the hypothesis that the PSEN2 rs8383 polymorphism is associated with an enlarged risk of sporadic AD. However, they stated that larger scale association studies are needed to further validate the association of PSEN2 polymorphisms with sporadic AD risk and to define potential gene-gene interactions.
Gerrish et al (2012) noted that rare mutations in AβPP, PSEN1, and PSEN2 cause uncommon early onset forms of AD, and common variants in microtubule-associated protein tau (MAPT) are associated with risk of other neurodegenerative disorders. These researchers sought to establish whether common genetic variation in these genes confer risk to the common form of AD that occurs later in life (greater than 65 years). These investigators therefore tested single-nucleotide polymorphisms at these loci for association with late-onset AD (LOAD) in a large case-control sample consisting of 3,940 cases and 13,373 controls. Single-marker analysis did not identify any variants that reached genome-wide significance, a result that is supported by other recent genome-wide association studies. However, these investigators did observe a significant association at the MAPT locus using a gene-wide approach (p = 0.009). They also observed suggestive association between AD and the marker rs9468, which defines the H1 haplotype, an extended haplotype that spans the MAPT gene and has previously been implicated in other neurodegenerative disorders including Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. The authors concluded that common variants at AβPP, PSEN1, and PSEN2 and MAPT are unlikely to make strong contributions to susceptibility for LOAD. However, the gene-wide effect observed at MAPT indicates a possible contribution to disease risk which requires further study.
Jonsson et al (2013) stated that sequence variants, including the ε4 allele of apolipoprotein E, have been associated with the risk of the common late-onset form of AD. Few rare variants affecting the risk of late-onset AD have been found. These investigators obtained the genome sequences of 2,261 Icelanders and identified sequence variants that were likely to affect protein function. They imputed these variants into the genomes of patients with AD and control participants and then tested for an association with AD. These researchers performed replication tests using case-control series from the United States, Norway, the Netherlands, and Germany. They also tested for a genetic association with cognitive function in a population of unaffected elderly persons. A rare missense mutation (rs75932628-T) in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2), which was predicted to result in an R47H substitution, was found to confer a significant risk of AD in Iceland (OR, 2.92; 95 % CI: 2.09 to 4.09; p = 3.42×10(-10)). The mutation had a frequency of 0.46 % in controls 85 years of age or older. These investigators observed the association in additional sample sets (OR, 2.90; 95 % CI: 2.16 to 3.91; p = 2.1×10(-12) in combined discovery and replication samples). They also found that carriers of rs75932628-T between the ages of 80 and 100 years without AD had poorer cognitive function than non-carriers (p = 0.003). The authors concluded that the findings of this study strongly implicate variant TREM2 in the pathogenesis of AD.
Guerreiro et al (2013) used genome, exome, and Sanger sequencing to analyze the genetic variability in TREM2 in a series of 1,092 patients with AD and 1,107 controls (the discovery set). These researchers then performed a meta-analysis on imputed data for the TREM2 variant rs75932628 (predicted to cause a R47H substitution) from 3 genome-wide association studies of AD and tested for the association of the variant with disease. These investigators genotyped the R47H variant in an additional 1,887 cases and 4,061 controls. They then assayed the expression of TREM2 across different regions of the human brain and identified genes that are differentially expressed in a mouse model of AD and in control mice. These researchers found significantly more variants in exon 2 of TREM2 in patients with AD than in controls in the discovery set (p = 0.02). There were 22 variant alleles in 1,092 patients with AD and 5 variant alleles in 1,107 controls (p < 0.001). The most commonly associated variant, rs75932628 (encoding R47H), showed highly significant association with AD (p < 0.001). Meta-analysis of rs75932628 genotypes imputed from genome-wide association studies confirmed this association (p = 0.002), as did direct genotyping of an additional series of 1,887 patients with AD and 4,061 controls (p < 0.001). Trem2 expression differed between control mice and a mouse model of AD. The authors concluded that heterozygous rare variants in TREM2 are associated with a significant increase in the risk of AD. Moreover, they stated that “We and others have predicted that heterozygous loss-of-function variants may represent a substantial component of risk for common late-onset diseases. Our findings support this hypothesis, and we believe additional loss-of-function variants will be identified as risk factors for Alzheimer's disease and other late-onset complex disorders”.
In an editorial that accompanied the afore-mentioned studies by Jonsson et al (2013) as well as Guerreiro et al (2013), Neumann and Daly (2013) stated that “Pursuing the hypothesis that low-prevalence variants cause Alzheimer's disease with a moderate-to-high effect size, two groups of researchers convincingly show in the Journal that rare variants in TREM2, encoding triggering receptor expressed on myeloid cells 2 protein, cause susceptibility to late-onset Alzheimer's disease, with an odds ratio similar to that of the apolipoprotein E ε4 allele. Although the most compelling TREM2 variant (encoding a substitution of arginine by histidine at residue 47 [R47H] of the TREM2 protein) is rare, with an allelic prevalence of 0.63 % in Iceland, these findings implicate a gene and naturally arising perturbation that may generate new insights into the pathogenesis of late-onset Alzheimer's disease …. We therefore suggest that the degeneration of neurons in these diseases and in TREM2-associated Alzheimer's disease is driven by a chronic inflammatory process with dysfunction in the microglial phagocytosis or inflammatory pathway. These studies provide a new path for experimental inquiry into the biologic roots of Alzheimer's disease”.
Zhang et al (2013) stated that the association between insulin degrading enzyme (IDE) gene polymorphisms and AD risk has been widely reported, but results were somewhat controversial. To assess the association between IDE polymorphisms and AD risk, a meta-analysis was performed. These investigators systematically reviewed relevant studies retrieved by PubMed, Embase, AlzGene, CNKI and Web of Science. Finally, 8 articles were identified for rs3758505 polymorphism and 5 for rs1832196 polymorphism. The pooled ORs were performed for all the 4 genetic models. Subgroup analysis was also performed by ethnicity. Results suggested that rs3758505 polymorphism was unlikely to be associated with genetic susceptibility of AD based on the current published studies. However, for the rs1832196 polymorphism, significant association with AD was found by the dominant model in overall and subgroup analysis. However, larger scale association studies are necessary to further validate the association of IDE polymorphisms with sporadic AD risk and to define potential gene-gene interactions.