Of the 283 Hispanic subjects (72.6% of Puerto Rican heritage, 27.4% from 16 other countries of origin), for whom DNA had been collected, 20 were found to carry the PSEN1 Gly206Ala mutation. Nineteen of these were diagnosed with dementia (17 AD, 1 vascular dementia, 1 frontotemporal dementia), while one was diagnosed as having normal cognitive function at age 58 but had major depression and cognitive complaints (and was subsequently lost to follow-up). Of the 263 non-carriers, 111 were diagnosed with AD, 19 with other neurodegenerative dementias, 56 with MCI, 33 with miscellaneous other non-neurodegenerativc disease conditions affecting cognition (depression, head trauma, etc.), and 44 were normal control recruits.
Demographic, clinical, and biomarker data for the PSEN1 Gly206Ala dementia subjects and non-carrier AD subjects are compared in along with data from normal control subjects for contrast. An illustrative case is presented in . Compared to non-carriers with AD, PSEN1 Gly206Ala carriers had younger age of onset, lower frequency of APOE ε4 genotype, and lower rates of hypertension. The mean age of onset for carriers was 59.6 (range 46–67 with one outlier whose onset was 81), ten years younger than that of non-carriers whose mean age of onset was 69.2 (range=45–90). Among the 19 PSEN1 carriers, only 3/19 (16%) were also apolipoprotein E ε4 carriers and their ages of onset were 46 (ε4/ε4), 59 (ε3/ε4), and 65 (ε3/ε4). In contrast, 41 % of PSEN1 non-carriers were apolipoprotein E ε4 carriers and their mean age of onset was 68.8 (range 47–94).
Demographic, clinical, and biomarker characteristics of PSEN1 Gly206Ala mutation carriers with dementia and non-carriers with Alzheimer’s disease
Fig. 1 Illustrative case of Alzheimer’s disease (AD) due to PSEN1 G206A: 56 year-old woman born in Puerto Rico who presented with at least one year of progressive forgetfulness, spatial and temporal disorientation, frequent confusion, prominent depression, (more ...)
Analyses of domain-specific psychometric test performances in the CERAD battery revealed no differences between carriers and non-carriers with AD in memory, language, visuoconstructional abilities, speed of processing or executive functions, except for marginally worse word-list recall in the PSEN1 Gly206Ala carriers (t[1,94] = 1.98, p<0.05). No differences were observed in rates of head injury, alcohol/other substance abuse, or use of medications including antidepressants, antipsychotics, anxiolytics, cholinesterase inhibitors, memantine, or statins.
Quantitative AD biochemical biomarkers were obtained in three carriers and 13 non-carriers. All three carriers exhibited abnormally elevated total tau and phospho-tau levels and two of the three had abnormally low amyloid-β levels. SPARE-AD, an index of AD-pattern cortical atrophy measured with volumetric MRI, was abnormally elevated in all three. 18FDG-PET was abnormal in all three with a characteristic temporo-parietal hypometabolism pattern. One carrier died with autopsy, which confirmed the diagnosis of AD with severe plaque and tangle pathology, as portrayed in .
Genotyping of 3 microsatellite markers was performed in 19 cases with Gly206Ala and 54 individuals lacking the mutation to determine whether there may have been a common ancestor of the Gly206Ala mutation by haplotype analysis. The following alleles were identified among the samples tested: 11 to 27 CA repeats, 15 to 25 GT repeats, and 9 to 24 repeats at D14S53. The CA(19) (allele frequency (AF) = 0.55), GT(22) (AF=0.5), and D14S53 14 repeat (AF=0.31) alleles were the most common among the mutation cases. PHASE 2.1 analysis for microsatellite markers segregating with the Gly206Ala identified the haplotype containing the Gly206Ala mutation: (CA)19, and (GT)22. This was present in all Gly206Ala carriers, while none of the non-carriers had both (CA)19 and (GT)22 alleles at the same time and hence did not carry the (CA)19-(GT)22 haplotype. This supports the hypothesis that all Gly206Ala mutations originated from the same common ancestral haplotype inherited by Puerto Rican Gly206Ala carriers [5