Application of Cerebrospinal Fluid AT(N) Framework on the Diagnosis of AD and Related Cognitive Disorders in Chinese Han Population

Figures & data

Table 1 Biomarker Profiles and Pathological Interpretations

AT(N) Profiles	Biomarker Category	Pathological Interpretation
A+T+(N)+	Alzheimer’s disease	Alzheimer’s continuum ^a
A+T+(N)-	Alzheimer’s disease
A+T-(N)+	Alzheimer’s and concomitant suspected non-Alzheimer’s pathologic change
A+T-(N)-	Alzheimer’s pathologic change
A-T+(N)+	Non-AD pathologic change	Non-Alzheimer’s disease pathologic changes ^b
A-T+(N)-	Non-AD pathologic change
A-T-(N)+	Non-AD pathologic change
A-T-(N)-	Normal AD biomarkers	Normal AD biomarker ^c

Notes: Each biomarker category is binarized as positive (+) or negative (-), resulting in eight different AT(N) biomarker profiles; Every individual can be classified into one of the three categories based on biomarker profiles: those who are in the Alzheimer’s continuum (dark grey), those with non-AD pathologic changes (light grey), and those with normal AD biomarkers (no color); ^aWhen only abnormal level of CSF Aβ₄₂ is present, the AT(N) profile should be classified into the “Alzheimer’s continuum” group, which is an umbrella term comprised of three pathological conditions including “AD pathology,” “Alzheimer’s and concomitant suspected non-Alzheimer’s pathologic change,” and “Alzheimer’s pathologic change;” ^bWhen levels of CSF tau are abnormal while CSF Aβ₄₂ was normal, the AT(N) profile should be classified into the “Non-Alzheimer’s disease pathologic changes” group; ^cWhen all 3 biomarkers are normal, the AT(N) profile should be classified into the “Normal AD biomarker” group.

Abbreviation: AD, Alzheimer’s disease.

Table 2 Demographic Characteristic and Clinical Data at Baseline

Initial Diagnosis	AD (n=79)	NAD (n=58)	Total (n=137)
Sex, Male%	49.4%	50.6%	48.2%
Age, years	62.2 ± 9.9	60.7 ± 9.7	61.6 ± 9.8
Age at onset, years	59.4 ± 10.3	58.2 ± 10.3	58.9 ± 10.2
Duration, years	2.9 ± 2.4	2.5 ± 2.3	2.7 ± 2.3
Education, years	7.6 ± 4.2	7.5 ± 3.7	7.6 ± 4.0
MMSE score	13.3 ± 7.1	17.2 ± 8.9 ^a	14.9 ± 8.1
CSF Aβ42 (pg/mL)	619 ± 268	703 ± 382	655 ± 322
CSF t-tau (pg/mL)	448 ± 292 ^b	276 ± 246	375 ± 286
CSF p-tau181 (pg/mL)	72 ± 44 ^c	51 ± 33	63 ± 41

Notes: Data are presented as mean ± S.D. or percentage (%); ^aAD < NAD (p<0.01); ^bAD > NAD (p<0.001); ^cAD > NAD (p<0.01).

Abbreviations: AD, Alzheimer’s disease; CSF, cerebrospinal fluid; MMSE, Mini-Mental State Examination; NAD, non-Alzheimer’s disease.

Table 3 Distribution of Cerebrospinal Fluid Biomarker AT(N) Profiles in Groups

Biomarker Category	AT(N) Profile	AD (n=79)	NAD (n=58)	Total (n=137)
Alzheimer’s continuum	A+T+(N)+	11	4	15
	A+T+(N)-	2	0	2
	A+T-(N)+	5	2	7
	A+T-(N)-	24	17	41
	Number (%)	42 (64.6)	23 (35.4)	65
NAD pathologic change	A-T+(N)+	20	6	26
	A-T+(N)-	3	1	4
	A-T-(N)+	4	3	7
	Number (%)	27 (73.0)	10 (27.0)	37
Normal AD biomarker	A-T-(N)-	10	25	35
	Number (%)	10 (28.6)	25 (71.4)	35

Note: Data expressed as integral numbers and percentage (exhibited with brackets, the respective proportion of AD group and NAD group in the total participants).

Abbreviations: AD, Alzheimer’s disease; NAD, non-Alzheimer’s disease.

Figure 1 Revision of initial diagnosis post-CSF biomarker disclosure based on the AT(N) framework.

Figure 2 Distribution of cerebrospinal fluid (CSF) biomarker profiles based on the AT(N) framework in different diagnostic groups. (A) Distribution in five diagnostic subgroups: Group Stable AD, Group Change AD to NAD, Group Change NAD to AD, Group Stable NAD, Group Change NAD to NAD; (B) Distribution in Group Final AD; (C) Distribution in Group Final NAD. Notes: Alzheimer’s continuum (orange), Non-AD pathologic changes (yellow), normal AD biomarkers (light green).

Table 4 Influence of Cerebrospinal Fluid AT(N) Framework on Diagnostic Confidence

Final Diagnosis		Final AD			Final NAD				Total
		Stable AD	Change NAD to AD	Total	Stable NAD	Change AD to NAD	Change NAD to NAD	Total
Number		58	16	74	41	21	1	63	137
^aPre-CSF DC (%) *		73.4 ± 4.6	66.4 ± 5.7	71.9 ± 5.6 ^#	69.4 ± 5.6	68.5 ± 6.4	75.0	69.2 ± 5.9	70.6 ± 5.9
Confidence Interval (%)		[72.2, 74.6]	[63.3, 69.4]	[70.6, 73.2]	[67.6, 71.2]	[65.5, 71.4]	NA	[67.7, 70.7]	[69.6, 71.6]
^bPost-CSF DC (%) *		84.0 ± 10.0	84.9 ± 5.5	84.2 ± 9.2 ^#	77.6 ± 8.9	72.5 ± 10.1	85.0	76.0 ± 9.5	80.4 ± 10.2
Confidence Interval (%)		[81.4, 86.6]	[81.9, 87.8]	[82.1, 86.3]	[74.8, 80.4]	[67.9, 77.1]	NA	[73.6, 78.4]	[78.7, 82.1]
^cΔDC (%) *		10.6 ± 10.8	18.5 ± 8.3	12.3 ± 10.7 ^#	8.2 ± 8.0	4.0 ± 11.0	10.0	6.8 ± 9.2	9.8 ± 10.4
Confidence Interval (%)		[7.8, 13.4]	[14.1, 22.9]	[9.8, 14.8]	[5.7, 10.7]	[−1.0, 9.0]	NA	[4.5, 9.1]	[8.0, 11.5]
CSF biomarker category
Alzheimer’s continuum	Number	38	15	53	7	4	1	12	65
	^dΔDC (%) *	17.0 ± 5.6	18.8 ± 8.4	17.5 ± 6.5 ^#	−5.0 ± 7.5	5.3 ± 4.1	10.0	−0.3 ± 8.4	14.2 ± 9.8
	Confidence Interval (%)	[15.2, 18.9]	[14.1, 23.5]	[15.7, 19.3]	[−12.0, 2.0]	[−1.3, 11.8]	NA	[−5.7, 5.0]	[11.8, 16.6]
NAD pathologic change	Number	16	0	16	10	11	0	21	37
	^eΔDC (%) *	−0.4 ± 5.2	NA	−0.4 ± 5.2	11.5 ± 2.7	8.3 ± 11.3	NA	9.8 ± 8.4 ^#	5.4 ± 8.8
	Confidence Interval (%)	[−3.2, 2.3]	NA	[−3.2, 2.3]	[9.6, 13.4]	[0.6, 15.9]	NA	[6.0, 13.6]	[2.5, 8.3]
Normal AD biomarker	Number	4	1	5	24	6	0	30	35
	^fΔDC (%) *	−6.3 ± 11.2	14.0	−2.2 ± 13.3	10.7 ± 5.4	−4.7 ± 9.4	NA	7.6 ± 8.8 ^#	6.2 ± 9.9
	Confidence Interval (%)	[−24.1, 11.6]	NA	[−18.7, 14.3]	[8.4, 13.0]	[−14.5, 15.2]	NA	[4.3, 10.9]	[2.8, 9.6]

Notes: Groups with only one sample or with no samples are excluded from statistical analysis; *Indicates statistical significance in comparison between these multi-subgroups; ^#Indicates statistical significance in comparison between Group Final AD and Group Final NAD; ^aStable AD > Change NAD to AD/Stable NAD/Change AD to NAD (p<0.0001; p<0.001; p<0.001); ^bStable AD > Stable NAD/Change AD to NAD (p<0.01; p<0.0001); Change NAD to AD > Change AD to NAD/Stable NAD (p<0.0001; p<0.01); ^cChange NAD to AD > Stable AD/Change AD to NAD/Stable NAD (p<0.01; p<0.0001; p<0.0001); ^dStable AD > Change AD to NAD/Stable NAD (p<0.0001; p<0.0001); Change NAD to AD > Stable NAD/Change AD to NAD (p<0.0001; p<0.01); ^eStable NAD > Stable AD (p<0.0001); Change AD to NAD > Stable AD (p=0.012<0.016); ^fStable NAD > Stable AD/Change AD to NAD (p<0.0001; p<0.0001).

Abbreviations: ΔDC, changes in diagnostic confidence; AD, Alzheimer’s disease; CSF, cerebrospinal fluid; DC, diagnostic confidence; NA, not available; NAD, non-Alzheimer’s disease.

Figure 3 Different changes in diagnostic confidence post-CSF AT(N) profile disclosure compared to pre-CSF disclosure in five diagnostic subgroups. (A) Alzheimer’s continuum; (B) Non-AD pathologic change; (C) Normal AD biomarkers. Notes: Group Stable AD (dark blue line), Group Change NAD to AD (orange line), Group Stable NAD (grey line), Group Change AD to NAD (yellow line), Group Change NAD to NAD (light blue line). “*” and “****” stand for p<0.05 and p<0.0001, respectively.

Figure 4 Different changes in diagnostic confidence due to three pathological interpretations of the AT(N) framework and total changes both in Group Final AD and Group Final NAD. In the upper two boxes: Alzheimer’s continuum (orange line), Non-AD pathologic changes (yellow line), Normal AD biomarker (light green line). In the lower box: Final AD (red line), Final NAD (dark green line). (A) Group Final AD; (B) Group Final NAD; (C) Total participants. “***” and “****” stand for p<0.001 and p<0.0001, respectively.