Bowirrat, Cui, et al ACE-ID polymorphism is not associated with either DAT or age-related cognitive decline (ARCD) in this Arab community. Methods and results Subjects were sourced from a prevalence study of dementia conducted in Wadi Ara, a geographically defined area in northern Israel comprising three Arab villages (Bowirrat et al 2001). Among the original list of 853 residents aged 65 years and older (prevalence date, October, 1995), 823 (363 males and 460 females) were available and consented to participate in the study. Only 30 patients (23 females and 7 males) were excluded from the original list of the study (853) because they did not fulfill the diagnostic criteria for DAT and ARCD (they were classified with other medical conditions). Among the excluded females (n = 23), 19 suffered from vascular dementia (VaD), 1 patient had Parkinson’s disease (PD), and 3 had pseudodementia. Among the excluded males (n = 7), 5 suffered from PD and 2 patients were diagnosed with VaD. The sex-specific prevalence of DAT among males and females was 53/363 = 14.6% and 115/460 = 25%, respectively; and the sex-specific prevalence of ARCD among males and females was 118/354 = 33.3% and 236/354 = 66.6%, respectively. These subjects were interviewed and examined by an Arabic- speaking neurologist (AB). Each subject underwent a battery of standard cognitive tests modified to fit the cultural and linguistic characteristics of this community (Bowirrat et al 2001). The diagnosis of DAT and ARCD was determined using DSM-IV criteria (APA 1994). Those with a medical history and laboratory or cognitive test results that suggested the presence of other illnesses, such as vascular dementia, Parkinson’s disease, normal-pressure hydrocephalus, or pseudodementia (depression), were excluded. Peripheral blood samples were obtained from the 650 subjects for DNA analysis. To genotype the ACE-ID polymorphism, 2 polymerase chain reactions (PCRs) were performed. In the first reaction, primers that flank the ID polymorphism were used to amplify DNA from each subject (5´-CTGGAGACC ACTCCCATCCTTTCT and 5´-TTGATGAGTTCCAC GTATTTCG). The resulting PCR product was analyzed on a 2% agarose gel for the presence or absence of the 287-bp insertion–deletion polymorphism. Because this reaction frequently fails to detect the insertion variant, a second PCR reaction was performed that specifically amplifies the allele containing the insertion (primers 5´-CTGGGATTA CAGGCGTGATACA and 5´-TTGATGAGTTCCAC 74 5 (5.88) 35 (41.18) 45 (52.94) 45 (26.47) Normal 0.3731 0.9973 Normal 0.2223 0.9559 GTATTTCG). The data from both reactions were used to establish the ACE-ID genotype. For statistical analysis, the Hardy-Weinberg equilibrium (HWE) was assessed for each group (DAT, ARCD, normal). Allele and genotype frequencies were compared among groups by a χ2 test. The results of the ACE (ID) genotyping (Table 1) showed that the frequency of the I allele was 32% in cognitively normal control, 26% in DAT cases (p = 0.2223), and 32% in ARCD cases (p = 0.9559). The genotype frequency distribution in the control groups were also similar to those for DAT cases (p = 0.3731) and ARCD cases (p = 0.9973). Therefore, our results suggest that the ID polymorphism within ACE is not associated with DAT or ARCD in this Arab community (Table 1). Discussion AD is the most overdiagnosed and misdiagnosed disorder of mental functioning in older adults. Part of the problem, is that many other disorders show symptoms that resemble those of AD. The crucial difference, however, is that many of these disorders – unlike AD – may be stopped, reversed, or cured. Based on these findings, clinical diagnosis of AD has been referred to as “a diagnosis by exclusion”, and one that can only be made in the face of clinical deterioration over time. There is no specific clinical test or finding that is unique to AD. Hence, all disorders that can bring on similar symptoms must be systematically excluded. The “classical” senile plaques and the neurofibrillary tangles seen in an AD Table 1 Genotypic and allelic frequencies among ARCD, DAT, and cognitively normal control ACE-ID Normal ARCD DAT II DI DD f(I) 8 (7.14) 56 (50) 48 (42.86) 72 (32.14) 3 (6.82) 22 (50) 19 (43.18) 28 (31.82) Abbreviations: ACE, angiotensin-converting enzyme; I, insertion allele; D, deletion allele; ARCD, age-related cognitive decline; DAT, dementia of Alzheimer’s type; f(I), frequency of the insertion allele. Table 1a Genotypic p-value Group ARCD DAT ARCD Table 1b Allelic p-value Group DAT ARCD 0.5745 – ARCD 0.3660 – Neuropsychiatric Disease and Treatment 2005:1(1)