From the larger cohort of 110 subjects with a diagnosis of normal cognition and complete CSF examinations, 31 subjects were excluded because of incomplete FH information. An additional 20 subjects were excluded: 4 subjects with both mother and father affected, 5 with only siblings affected, 2 with a parent who had not lived to age 65, 2 with a parent who was not yet 65 year old, 2 with aunts/uncles affected, and 5 who reported a FH of an unspecified dementia.
A total of 59 subjects fulfilled our study criteria and were examined in this study, including 22 NH, 14 PH and 23 MH. For 4 subjects (2 MH and 2 PH), the parents’ AD diagnosis was confirmed at autopsy. For all other subjects, the parents’ diagnosis was clinician certified. The groups did not differ for age, gender, education, frequency of ApoE-4 carriers, presence of subjective memory complaints, MMSE and neuropsychological measures (). Clinical data of demographically matched groups are found in .
Subject characteristics and CSF data by family history group
Subject characteristics and CSF data by demographically matched family history group
For the entire sample, significant group effects were found for Aβ42/40 (F(2,56)=4.1, P=0.02) and IsoP (F(2,56)=7.4, P=0.001). On post-hoc examination, these effects were driven by the MH group that showed lower Aβ42/40 compared to NH and to PH (16%, and 25%, respectively) and higher IsoP levels compared to NH and to PH (18% and 11%) (P’s≤0.05, ). These results were confirmed with the log-transformed Aβ42/40 (F(2,56)=4.9, P=0.005) and IsoP values (F(2,56)=6.8, P=0.002). On post-hoc examination, the MH group showed lower log-transformed Aβ42/40 compared to NH and PH (9%, and 16%) and higher log-transformed IsoP levels compared to NH and PH (24% and 13%) (). All results remained significant controlling for age, gender, education, and ApoE genotype (P<0.05; and ). Although there were no significant main group effects for Aβ42, on post-hoc examination the MH group showed a linear trend towards lower Aβ42 compared to NH (P=0.07), which was still evident on analysis of the log-transformed Aβ42 values, and accounting for age, gender, education and ApoE (P’s≥0.11) ().
CSF measures by family history group. Legend: white = NH, grey = PH, black = MH. Horizontal bars indicate mean group values. Only significant P values are reported.
With and without correcting for age, gender, education and ApoE, there were no significant group differences for P-Tau231, T-Tau, raw and log-transformed Aβ40 measures across groups (). There were no differences between PH and NH for any measures ().
Significant correlations between P-Tau231 and T-Tau measures were found for all groups, as were correlations across Aβ40, Aβ42, and Aβ42/40, using both the raw and log-transformed Aβ data (P≤0.05). All correlations remained significant accounting for age, gender, education and ApoE. Accounting for these same confounds, additional significant associations between IsoP and Aβ42/40 (R2=0.32, P=0.005) and between IsoP and T-Tau measures R2=0.25, P=0.017) were found only for the MH group. These associations remained significant by using log-transformed IsoP and Aβ42/40 measures (IsoP and Aβ42/40: R2=0.29, P=0.008, IsoP and T-Tau: R2=0.20, P=0.039). There were no significant associations across CSF markers for NH and PH groups, with or without controlling for the above confounds.
As reported in , both IsoP and Aβ42/40 discriminated MH from the other groups with accuracies of 68% and 66%, respectively (P’s≤0.007). IsoP added to the accuracy if Aβ42/40 (Pincrement=0.003), and Aβ42/40 added to that of IsoP (Pincrement=0.006), indicating that the two measures provided complementary information. When both markers were included in the model, the accuracy increased to 70% (). Analysis of log-transformed data confirmed results from raw data, yielding 66% accuracy for log-transformed IsoP, 66% accuracy for log-transformed Aβ42/40, and 63% accuracy for the two measures combined (P’s≤0.01, and ). Results remained unchanged controlling for age, gender, education and ApoE (). Aβ40, Aβ42, P-Tau231 and T-Tau measures were not significant predictors of group membership.
CSF biomarkers accuracy and relative risk in discriminating NL MH from the other subjects.
CSF IsoP and Aβ42/40 levels as discriminators of NL MH (black) from NH (white) and PH (grey). CSF measures are raw (top panel) and log-transformed data (bottom panel).
Comparison of demographically matched groups confirmed results with the entire group. The MH group showed lower Aβ42/40 and higher IsoP levels compared to NH and PH (P’s≤0.05), and a trend towards lower Aβ42 levels compared to NH (P’s≥0.09), using both raw and log-transformed measures. Results remained significant controlling for ApoE (). With and without accounting for ApoE, there were no group differences for P-Tau231, T-tau, raw and log-transformed Aβ40, and there were no differences between PH and NH ().
With and without controlling for ApoE, correlations between P-Tau231 and T-Tau measures were found for all groups, as were correlations across Aβ40, Aβ42, and Aβ42/40 (P≤0.05). Within the MH group, there was a significant association between IsoP and Aβ42/40 (raw data: R2=0.29, P=0.04, log-transformed data: R2=0.32, P=0.03), and a trend between IsoP and T-Tau, using either raw or log-transformed IsoP (R2=0.16, P’s=0.15). There were no significant associations across the other CSF markers for NH and PH groups.
On logistic regression, both IsoP and Aβ42/40 discriminated MH from the other groups with accuracies of 69% and 57%, respectively (P’s≤0.004, ). IsoP added to the accuracy if Aβ42/40 (Pincrement=0.007), and Aβ42/40 added to that of IsoP (Pincrement=0.004), for a combined overall accuracy of 69% (P=0.001). Log-transformed data yielded similar estimates, with 69% accuracy for IsoP and 60% accuracy for Aβ42/40, for a combined accuracy of 71% (P’s≤0.004, ). Results remained unchanged after controlling for ApoE status ().