The effect of KL-VS gene on medial temporal lobe volume in patients with mild cognitive impairment： A study based on MRI

doi:10.16150/j.1671-2870.2026.02.008

Abstract

Abstract:

Objective Based on magnetic resonance imaging (MRI), this study aims to explore the impact of the KL-VS functional haplotype heterozygous gene (KL-VS^het+) in the Klotho gene on the subregion structure of the medial temporal lobe,which presents abnormal in the brain region in the earliest progression of Alzheimer's disease (AD), as well as its relationship with the decline in cognitive function associated with AD pathology. Methods A total of 48 participants from the AD Neuroimaging Initiative database (with genome-wide association analysis data and high-resolution magnetic resonance ima-ging data from October 2018 to June 2024) were enrolled, comprising 16 KL-VS^het+ carriers [8 cognitively normal, CN; 8 amnestic mild cognitive impairment (MCI), aMCI] and 32 non-carriers (KL-VS^het-) (16 CN and 16 aMCI). Structural MRI data were analyzed using automatic segmentation of hippocampal subfields to calculate medial temporal lobe subregion volumes. Group differences in medial temporal lobe subregion volume, cognitive function, and pathological proteins (amyloid β- protein, Aβ/tau protein) were compared using analysis of variance. Moderation analysis was conducted with SPSS 27 (PROCESS v4.1). Results Significant differences were observed between KL-VS^het+ and KL-VS^het- individuals in medial temporal lobe subregion volumes, cognitive function, and pathological protein (Aβ/tau) burden (P<0.05). In the MCI group, KL-VS^het+ carriers showed significantly larger volumes in the left hippocampal subfield cornu ammonis 3 (CA3) (79.80±29.75 mm³) and dentate gyrus (755.19±186.68 mm³) compared to KL-VS^het- individuals (52.46±15.53 mm³, 710.09±146.09 mm³) (P<0.05). Tau protein deposition was significantly lower in KL-VS^het+ individuals than in KL-VS^het- individuals (P<0.05), and Aβ deposition showed a lower trend, although the difference did not reach statistical significance (P=0.054). Moderation analysis showed that, among KL-VS^het+ individuals, the volumes of multiple medial temporal lobe subregions had significant positive moderating effects on the relationship between AD-related pathology and cognitive performance, mainly reflected in memory scores. The volume of the left CA3 subregion significantly moderated the relationship between Aβ deposition and memory function scores, while the volumes of multiple bilateral medial temporal lobe subregions significantly moderated the relationship between tau deposition and memory scores (interaction term β ranged from 0.000 5 to 0.074 5, and the 95% confidence interval ranged from -0.002 0 to 0.172 3, P<0.05). Conclusions The KL-VS^het+ gene product may exert a neuroprotective effect by slowing down the volume atrophy of medial temporal lobe regions, such as the hippocampus, thereby mitigating the damage to cognitive function caused by pathological protein deposition in patients with mild cognitive impairment (MCI). KL-VS^het may serve as a novel therapeutic target for Alzheimer's disease (AD).

Key words: Alzheimer's disease, Mild cognitive impairment, Magnetic resonance imaging, Medial temporal lobe subregions, Klotho gene

CLC Number:

R741
R445

LIU Xiaocao, ZENG Qingze, LI Yixia, LI Kaicheng, LUO Xiao, YAN Shaozhen, LU Jie. The effect of KL-VS gene on medial temporal lobe volume in patients with mild cognitive impairment： A study based on MRI[J]. Journal of Diagnostics Concepts & Practice, 2026, 25(02): 174-182.

Figures/Tables 7

Figure 1

Table 1

Table 2

Comparison of medial temporal lobe subregional volumes between KL-VShet⁺ and KL-VShet⁻ groups （$\bar{x}±s$）

Item	KL-VS^het-CN	KL-VS^het-MCI	KL-VS^het+CN	KL-VS^het+MCI	F（χ²）	P
L_CA1	1287.70±114.45	1191.64±211.91	1324.33±200.95	1118.70±208.09	2.303	0.091^c,f
L_CA2	1.57±1.26	1.11±0.61	1.53±1.21	0.74±0.46	1.275	0.300
L_CA3	56.37±16.37	52.46±15.53	56.88±20.81	72.80±29.75	1.799	0.162^e
L_DG	782.93±68.93	710.09±146.09	797.66±98.31	755.19±186.68	1.234	0.309^c,e
L_SUB	447.20±83.46	403.47±52.35	447.50±87.31	382.98±69.07	1.959	0.135
L_ERC	456.30±66.04	369.30±79.03	398.13±101.39	387.99±128.81	2.671	0.060
L_BA35	531.47±89.16	472.24±92.27	496.34±117.24	452.86±90.28	1.475	0.235
L_BA36	1824.36±305.82	1605.57±266.88	1655.54±295.64	1599.68±448.21	1.502	0.228
L_PHC	757.33±165.20	722.16±164.32	713.10±140.74	693.08±143.82	0.317	0.813
L_CA	1346.21±123.47	1245.00±220.02	1382.17±192.91	1148.32±244.44	2.717	0.056^c,f
L_HIPP	2129.15±150.98	1955.09±358.11	2179.83±261.27	1859.12±441.02	2.283	0.093^f
R_CA1	1173.77±119.59	1158.21±230.51	1266.84±162.16	1118.00±267.69	0.823	0.489
R_CA2	7.84±3.27	8.19±4.12	9.38±2.72	6.68±1.04	0.778	0.513
R_CA3	62.04±27.89	56.02±16.18	65.20±26.54	72.71±38.17	0.716	0.548
R_DG	792.12±99.14	788.20±165.25	852.15±73.66	751.24±140.99	0.803	0.499
R_SUB	443.26±85.09	434.48±75.11	477.25±80.70	387.62±48.23	1.750	0.171^f
R_ERC	491.23±102.61	415.65±98.74	433.40±101.50	464.73±167.08	1.262	0.300
R_BA35	512.29±101.25	487.86±87.79	483.05±65.29	437.77±152.33	0.873	0.463
R_BA36	1805.15±450.28	1574.03±250.67	1752.69±267.92	1591.25±510.68	1.225	0.313
R_PHC	774.14±126.18	787.02±125.03	759.42±110.75	764.08±283.94	0.069	0.976
R_CA	1243.64±136.95	1222.42±242.02	1341.42±154.19	1157.59±296.30	1.065	0.378
R_HIPP	2035.76±204.99	2010.62±400.06	2193.57±213.55	1882.69±430.93	1.225	0.312

Table 2

Figure 2

Figure 3

Figure 4

Table 3

Interactive moderating effects

Subre- gions	Independent variable	Dependent variable	β（subregions× pathology× KL-VS）	SE	t	P	LLCI	ULCI	∆R2	KL-VS^het-		KL-VS^het+
Subre- gions	Independent variable	Dependent variable	β（subregions× pathology× KL-VS）	SE	t	P	LLCI	ULCI	∆R2	β	P	β	P
L_CA3	Aβ-CL	MEM	0.0005	0.000 2	2.710 0	0.010 3	0.000 1	0.000 8	0.112 9	-0.000 1	0.702 3	0.000 4	0.001 0
L_CA3	Aβ-CL	MoCA	0.002 5	0.001 2	2.033 1	0.049 7	0.000 0	0.005 0	0.076 0	-0.001 0	0.272 1	0.001 5	0.082 0
L_DG	tau Braak Ⅲ-Ⅳ SUVR	MEM	0.028 1	0.009 5	2.974 6	0.005 5	0.008 9	0.047 4	0.120 4	-0.004 9	0.179 7	0.023 3	0.012 3
L_ERC	tau Braak Ⅲ-Ⅳ SUVR	MEM	0.026 5	0.012 4	2.142 7	0.039 8	0.001 3	0.051 7	0.056 1	-0.004 5	0.276 3	0.022 0	0.068 8
L_PHC	tau Braak Ⅲ-Ⅳ SUVR	MEM	0.034 1	0.017 7	1.923 5	0.063 3	-0.002 0	0.070 2	0.062 5	-0.000 8	0.080 4	0.033 3	0.065 4
R_CA1	tau Braak Ⅲ-Ⅳ SUVR	MEM	0.019 1	0.008 4	2.260 5	0.030 7	0.001 9	0.036 3	0.082 9	-0.003 3	0.168 6	0.015 8	0.060 6
R_DG	tau Braak Ⅲ-Ⅳ SUVR	MEM	0.038 5	0.014 9	2.587 5	0.014 4	0.008 2	0.068 8	0.099 9	-0.005 6	0.039 6	0.032 9	0.031 9
R_SUB	tau Braak Ⅲ-Ⅳ SUVR	MEM	0.087 3	0.041 7	2.091 4	0.044 5	0.002 3	0.172 3	0.073 9	-0.003 9	0.606 0	0.083 4	0.050 7
R_BA35	tau Braak Ⅲ-Ⅳ SUVR	MEM	0.038 1	0.014 3	2.670 4	0.011 8	0.009 0	0.067 2	0.110 4	-0.012 0	0.084 3	0.026 1	0.046 2
L_DG	tau meta temporal SUVR	MEM	0.018 8	0.007 7	2.435 0	0.020 6	0.003 1	0.034 5	0.083 3	-0.003 1	0.275 5	0.015 7	0.036 6
R_DG	tau meta temporal SUVR	MEM	0.026 4	0.012 5	2.123 2	0.041 6	0.001 1	0.051 8	0.070 0	-0.004 0	0.067 3	0.022 5	0.076 5
R_BA35	tau meta temporal SUVR	MEM	0.031 2	0.126 0	2.471 2	0.019 0	0.005 5	0.056 8	0.095 1	-0.007 5	0.169 0	0.023 7	0.046 5
L_CA1	tau Braak Ⅴ-Ⅵ SUVR	MEM	0.016 3	0.006 7	2.440 9	0.020 4	0.002 7	0.029 9	0.077 6	-0.004 4	0.206 7	0.011 9	0.046 3
L_DG	tau Braak Ⅴ-Ⅵ SUVR	MEM	0.028 1	0.007 9	3.535 9	0.001 3	0.011 9	0.044 2	0.160 5	-0.007 7	0.072 7	0.020 4	0.005 1
L_Sub	tau Braak Ⅴ-Ⅵ SUVR	MEM	0.052 7	0.023 0	2.295 6	0.028 4	0.005 9	0.099 5	0.076 4	-0.009 8	0.408 5	0.042 9	0.037 3
L_ERC	tau Braak Ⅴ-Ⅵ SUVR	MEM	0.034 1	0.011 0	3.095 2	0.004 1	0.011 6	0.056 5	0.109 0	-0.010 0	0.134 2	0.024 0	0.010 6
L_PHC	tau Braak Ⅴ-Ⅵ SUVR	MEM	0.035 2	0.016 3	2.152 6	0.039 0	0.001 9	0.068 4	0.079 7	-0.002 9	0.537 6	0.032 2	0.047 6
R_CA1	tau Braak Ⅴ-Ⅵ SUVR	MEM	0.016 8	0.006 9	2.432 6	0.020 8	0.002 7	0.030 8	0.093 1	-0.002 6	0.315 0	0.014 2	0.034 2
R_DG	tau Braak Ⅴ-Ⅵ SUVR	MEM	0.032 9	0.010 5	3.115 2	0.003 9	0.011 4	0.054 3	0.138 6	-0.005 0	0.089 9	0.027 9	0.009 9
R_SUB	tau Braak Ⅴ-Ⅵ SUVR	MEM	0.074 5	0.029 1	2.558 8	0.015 4	0.015 2	0.133 9	0.105 4	-0.008 3	0.353 2	0.066 2	0.023 2
R_ERC	tau Braak Ⅴ-Ⅵ SUVR	MEM	0.0280	0.012 2	2.287 0	0.029 0	0.003 1	0.052 8	0.084 7	-0.006 9	0.306 6	0.021 0	0.048 4
R_BA35	tau Braak Ⅴ-Ⅵ SUVR	MEM	0.039 3	0.012 1	3.257 5	0.002 7	0.014 7	0.063 9	0.148 7	-0.009 8	0.178 3	0.029 5	0.004 8
R_BA36	tau Braak Ⅴ-Ⅵ SUVR	MEM	0.010 9	0.004 5	2.430 5	0.020 9	0.001 8	0.020 0	0.100 4	-0.002 2	0.348 7	0.008 7	0.030 8
R_HIPP	tau Braak Ⅴ-Ⅵ SUVR	MEM	0.009 5	0.004 2	2.285 3	0.028 9	0.001 0	0.018 0	0.079 1	-0.001 8	0.193 9	0.007 7	0.058 9

Table 3

References 33

[1]	2023 Alzheimer's disease facts and figures[J]. Alzheimers Dement, 2023, 19(4):1598-1695. doi: 10.1002/alz.13016 pmid: 36918389
[2]	DUBAL D B, YOKOYAMA J S, ZHU L, et al. Life extension factor klotho enhances cognition[J]. Cell Rep, 2014, 7(4):1065-1076. doi: 10.1016/j.celrep.2014.03.076 pmid: 24813892
[3]	LEON J, MORENO A J, GARAY B I, et al. Peripheral elevation of a klotho fragment enhances brain function and resilience in young, aging, and α-synuclein transgenic mice[J]. Cell Rep, 2017, 20(6):1360-1371. doi: S2211-1247(17)30990-7 pmid: 28793260
[4]	LATHE R, ST CLAIR D. Programmed ageing: decline of stem cell renewal, immunosenescence, and Alzheimer's disease[J]. Biol Rev Camb Philos Soc, 2023, 98(4):1424-1458. doi: 10.1111/brv.12959 pmid: 37068798
[5]	WALCZAK K, KOŁODZIEJCZYK W, PSZCZOŁOWSKA M, et al. Klotho protein in Alzheimer's disease: Diet leading to immortality?[J]. J Alzheimers Dis, 2025, 106(3):823-831. doi: 10.1177/13872877251350125 pmid: 40598860
[6]	ABRAHAM C R, MULLEN P C, TUCKER-ZHOU T, et al. Klotho is a neuroprotective and cognition-enhancing protein[J]. Vitam Horm, 2016,101:215-238.
[7]	BELLOY M E, NAPOLIONI V, HAN S S, et al. Association of KLOTHO-VS heterozygosity with risk of Alzheimer disease in individuals who carry APOE4[J]. JAMA Neurol, 2020, 77(7):849-862. doi: 10.1001/jamaneurol.2020.0414 pmid: 32282020
[8]	ERICKSON C M, SCHULTZ S A, OH J M, et al. KLOTHO heterozygosity attenuates APOE4-related amyloid burden in preclinical AD[J]. Neurology, 2019, 92(16):e1878-e1889.
[9]	KATONOVA A, ANDEL R, JURASOVA V, et al. Associations of KLOTHO-VS heterozygosity and α-klotho protein with cerebrospinal fluid Alzheimer's disease biomarkers[J]. J Alzheimers Dis, 2025, 105(1):159-171. doi: 10.1177/13872877251326199 URL
[10]	CHEN X R, SHAO Y, SADOWSKI M J, et al. Interaction between KLOTHO-VS heterozygosity and APOE ε4 allele predicts rate of cognitive decline in late-onset Alzheimer's disease[J]. Genes (Basel), 2023, 14(4):917. doi: 10.3390/genes14040917 URL
[11]	SORRENTINO F, FENOGLIO C, SACCHI L, et al. KLOTHO gene expression is decreased in peripheral blood mononuclear cells in patients with Alzheimer's di-sease and frontotemporal dementia[J]. J Alzheimers Dis, 2023, 94(3):1225-1231. doi: 10.3233/JAD-230322 URL
[12]	YOKOYAMA J S, MARX G, BROWN J A, et al. Systemic klotho is associated with KLOTHO variation and predicts intrinsic cortical connectivity in healthy human aging[J]. Brain Imaging Behav, 2017, 11(2):391-400. doi: 10.1007/s11682-016-9598-2 pmid: 27714549
[13]	DE VRIES C F, STAFF R T, HARRIS S E, et al. Klotho, APOEε4, cognitive ability, brain size, atrophy, and survival: a study in the Aberdeen Birth Cohort of 1936[J]. Neurobiol Aging, 2017,55:91-98.
[14]	CAI Y, DU J, LI A, et al. Initial levels of β-amyloid and tau deposition have distinct effects on longitudinal tau accumulation in Alzheimer's disease[J]. Alzheimers Res Ther, 2023, 15(1):30. doi: 10.1186/s13195-023-01178-w pmid: 36750884
[15]	李雨航, 肖世富, 岳玲. 轻度行为损害与阿尔茨海默病相关研究的进展[J]. 诊断学理论与实践, 2025, 24(5):548-554.
	LI Y H, XIAO S F, YUE L. Advances in research on association between mild behavioral impairment and Alzheimer's disease[J]. J Diagn Concepts Pract, 2025, 24(5):548-554.
[16]	BERRON D, VAN WESTEN D, OSSENKOPPELE R, et al. Medial temporal lobe connectivity and its associations with cognition in early Alzheimer's disease[J]. Brain, 2020, 143(4):1233-1248. doi: 10.1093/brain/awaa068 pmid: 32252068
[17]	HARRISON T M, MAASS A, ADAMS J N, et al. Tau deposition is associated with functional isolation of the hippocampus in aging[J]. Nat Commun, 2019, 10(1):4900. doi: 10.1038/s41467-019-12921-z pmid: 31653847
[18]	GORDON B A, BLAZEY T M, SU Y, et al. Spatial patterns of neuroimaging biomarker change in individuals from families with autosomal dominant Alzheimer's disease: a longitudinal study[J]. Lancet Neurol, 2018, 17(3):241-250. doi: S1474-4422(18)30028-0 pmid: 29397305
[19]	DRISCOLL I F, LOSE S, MA Y, et al. KLOTHO KL-VS heterozygosity is associated with diminished age-related neuroinflammation, neurodegeneration, and synaptic dysfunction in older cognitively unimpaired adults[J]. Alzheimers Dement, 2024, 20(8):5347-5356. doi: 10.1002/alz.13912 pmid: 39030746
[20]	JACK C R JR, BENNETT D A, BLENNOW K, et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease[J]. Alzheimers Dement, 2018, 14(4):535-562. doi: S1552-5260(18)30072-4 pmid: 29653606
[21]	BRAAK H, ALAFUZOFF I, ARZBERGER T, et al. Sta-ging of Alzheimer disease-associated neurofibrillary patho-logy using paraffin sections and immunocytochemistry[J]. Acta Neuropathol, 2006, 112(4):389-404. doi: 10.1007/s00401-006-0127-z URL
[22]	GIULIANO A, DONATELLI G, COSOTTINI M, et al. Hippocampal subfields at ultra high field MRI: An overview of segmentation and measurement methods[J]. Hippocampus, 2017, 27(5):481-494. doi: 10.1002/hipo.22717 pmid: 28188659
[23]	YOKOYAMA J S, STURM V E, BONHAM L W, et al. Variation in longevity gene KLOTHO is associated with greater cortical volumes[J]. Ann Clin Transl Neurol, 2015, 2(3):215-230. doi: 10.1002/acn3.161 URL
[24]	ZHAO Y, ZENG C Y, LI X H, et al. Klotho overexpression improves amyloid-β clearance and cognition in the APP/PS1 mouse model of Alzheimer's disease[J]. Aging Cell, 2020, 19(10): e13239. doi: 10.1111/acel.v19.10 URL
[25]	ULLAH M, SUN Z. Klotho deficiency accelerates stem cells aging by impairing telomerase activity[J]. J Gerontol A Biol Sci Med Sci, 2019, 74(9):1396-1407. doi: 10.1093/gerona/gly261 URL
[26]	ZENG Q, LI K, LUO X, et al. Distinct atrophy pattern of hippocampal subfields in patients with progressive and stable mild cognitive impairment: A longitudinal MRI study[J]. J Alzheimers Dis, 2021, 79(1):237-247. doi: 10.3233/JAD-200775 pmid: 33252076
[27]	ROIG-SORIANO J, EDO Á, VERDÉS S, et al. Long-term effects of s-KL treatment in wild-type mice: Enhancing longevity, physical well-being, and neurological resilience[J]. Mol Ther, 2025, 33(8):4007. doi: 10.1016/j.ymthe.2025.06.046 URL
[28]	HUIJBERS W, MORMINO E C, SCHULTZ A P, et al. Amyloid-β deposition in mild cognitive impairment is associated with increased hippocampal activity, atrophy and clinical progression[J]. Brain, 2015, 138(Pt 4):1023-1035. doi: 10.1093/brain/awv007 pmid: 25678559
[29]	KAZIM S F, SEO J H, BIANCHI R, et al. Neuronal network excitability in Alzheimer's disease: The puzzle of similar versus divergent roles of amyloid β and tau[J]. eNeuro, 2021, 8(2):ENEURO.0418-20.2020.
[30]	KANG D W, CHOI W H, JUNG W S, et al. Impact of amyloid burden on regional functional synchronization in the cognitively normal older adults[J]. Sci Rep, 2017, 7(1):14690. doi: 10.1038/s41598-017-15001-8 pmid: 29089631
[31]	DAS S R, PLUTA J, MANCUSO L, et al. Increased functional connectivity within medial temporal lobe in mild cognitive impairment[J]. Hippocampus, 2013, 23(1):1-6. doi: 10.1002/hipo.22051 pmid: 22815064
[32]	TAHMASIAN M, PASQUINI L, SCHERR M, et al. The lower hippocampus global connectivity, the higher its local metabolism in Alzheimer disease[J]. Neurology, 2015, 84(19):1956-1963. doi: 10.1212/WNL.0000000000001575 pmid: 25878180
[33]	PATTEN K T, VALENZUELA A E, WALLIS C, et al. The effects of chronic exposure to ambient traffic-related air pollution on Alzheimer's disease phenotypes in wildtype and genetically predisposed male and female rats[J]. Environ Health Perspect, 2021, 129(5):57005. doi: 10.1289/EHP8905 URL

Item	KL-VS^het-CN	KL-VS^het-MCI	KL-VS^het+CN	KL-VS^het+MCI	F（χ²）	P
Number	16	16	8	8	/	/
Age(years)	76.36±3.99	74.44±7.49	76.05±5.17	78.36±6.40	0.775	0.514
Female [N (%)]	2(12.5)	9(56.25)	4(50)	1(12.5)	/	0.024
APOE ε4 carrier [N (%)]	6(60)	8(50)	4(50)	3(37.5)	/	0.536
Education(years)	17.88±2.09	16.94±2.32	17.63±2.13	17.29±2.20	0.913	0.443
MMSE (total)	28.94±1.12	26.25±4.48	29.63±1.06	27.13±2.23	3.611	0.02^a,d
MoCA (total)	25.19±2.81	21.94±3.80	24.63±2.88	22.88±2.99	3.123	0.035^a
Memory function (z-score)	0.49±0.33	0.03±0.56	0.73±0.57	0.29±0.35	5.035	0.001^a,c,d,f
Executive function (z-score)	0.70±0.37	0.34±0.75	0.75±0.45	0.45±0.55	1.554	0.214
Language function (z-score)	0.45±0.33	0.34±0.65	0.76±0.41	0.20±0.48	1.956	0.135^f
Aβ PET centiloid unit	27.85±28.43(16)	70.90±54.53(15)	42.59±44.49(7)	41.05±66.23(7)	2.200	0.103^a
tau Braak Ⅰ-Ⅱ SUVR(N)	1.18±0.21(14)	1.45±0.27(15)	1.13±0.08(6)	1.15±0.13(7)	5.946	0.002^a,d,e
tau Braak Ⅲ-Ⅳ SUVR(N)	1.17±0.17(14)	1.31±0.27(15)	1.13±0.03(6)	1.12±0.16(6)	2.096	0.117
tau Braak Ⅴ-Ⅵ SUVR(N)	1.05±0.10(14)	1.17±0.20(15)	1.05±0.06(6)	1.01±0.15(6)	2.63	0.64^a,e
tau META TEMporal SUVR(N)	1.22±0.24(14)	1.42±0.35(15)	1.18±0.02(6)	1.19±0.18(6)	2.106	0.116