Identification of new genetic variants that modify Alzheimer’s disease (AD) risk will elucidate novel targets for curbing the disease progression or delaying symptom onset.
Objective:
To examine whether the functionally advantageous KLOTHO gene KL-VS variant attenuates age-related alteration in cerebrospinal fluid (CSF) biomarkers or cognitive function in middle-aged and older adults enriched for AD risk.
Methods:
Sample included non-demented adults (N = 225, mean age = 63±8, 68% women) from the Wisconsin Registry for Alzheimer’s Prevention and the Wisconsin Alzheimer’s Disease Research Center who were genotyped for KL-VS, underwent CSF sampling and had neuropsychological testing data available proximal to CSF draw. Covariate-adjusted multivariate regression examined relationships between age group (Younger versus Older; mean split at 63 years), AD biomarkers, and neuropsychological performance tapping memory and executive function, and whether these relationships differed between KL-VS non-carriers (KL-VSNC) and heterozygote (KL-VSHET).
Results:
In the pooled analyses, older age was associated with higher levels of total tau (tTau), phosphorylated tau (pTau), and their respective ratios to amyloid-β (Aβ)42 (ps ≤ 0.002), and with poorer performance on neuropsychological tests (ps ≤ 0.001). In the stratified analyses, KL-VSNC exhibited this age-related pattern of associations with CSF biomarkers (all ps ≤ 0.001), and memory and executive function (ps ≤ 0.003), which were attenuated in KL-VSHET (ps ≥ 0.14).
Conclusion:
Worse memory and executive function, and higher tau burden with age were attenuated in carriers of a functionally advantageous KLOTHO variant. KL-VS heterozygosity seems to be protective against age-related cognitive and biomolecular alterations that confer risk for AD.
Van CauwenbergheC, Van BroeckhovenC, SleegersK (2016) The genetic landscape of Alzheimer disease: Clinical implications and perspectives. Genet Med18, 421.
4.
SternY, BarnesCA, GradyC, JonesRN, RazN (2019) Brain reserve, cognitive reserve, compensation, and maintenance: Operationalization, validity, and mechanisms of cognitive resilience. Neurobiol Aging83, 124–129.
5.
GallagherM, OkonkwoOC, ResnickSM, JagustWJ, BenzingerTLS, RappPR (2019) What are the threats to successful brain and cognitive aging?Neurobiol Aging83, 130–134.
6.
DriscollI, ResnickSM, TroncosoJC, AnY, O’BrienR, ZondermanAB (2006) Impact of Alzheimer’s pathology on cognitive trajectories in nondemented elderly. Ann Neurol60, 688–695.
7.
DriscollI, TroncosoJ (2011) Asymptomatic Alzheimer’s disease: A prodrome or a state of resilience?Curr Alzheimer Res8, 330–335.
8.
SingerB, FriedmanE, SeemanT, FavaGA, RyffCD (2005) Protective environments and health status: Cross-talk between human and animal studies. Neurobiol AgingS26, S113–118.
9.
ChateauMT, AraizC, DescampsS, GalasS (2010) Klotho interferes with a novel FGF-signalling pathway and insulin/Igf-like signalling to improve longevity and stress resistance in Caenorhabditis elegans. Aging2, 567–581.
10.
KurosuH, YamamotoM, ClarkJD, PastorJV, NandiA, GurnaniP, McGuinnessOP, ChikudaH, YamaguchiM, KawaguchiH, ShimomuraI, TakayamaY, HerzJ, KanCR, RosenblattKP, Kuro-oM (2005) Suppression of aging in mice by the hormone Klotho. Science309, 1829–1833.
ArkingDE, KrebsovaA, MacekMSr., MacekMJr., ArkingA, MianIS, FriedL, HamoshA, DeyS, McIntoshI, DietzHC (2002) Association of human aging with a functional variant of klotho. Proc Natl Acad Sci U S A99, 856–861.
14.
CheikhiA, BarchowskyA, SahuA, ShindeSN, PiusA, ClemensZJ, LiH, KennedyCA, HoeckJD, FrantiM, AmbrosioF (2019) Klotho: An elephant in aging research. J Gerontol A Biol Sci Med Sci74, 1031–1042.
15.
Di BonaD, AccardiG, VirrusoC, CandoreG, CarusoC (2014) Association of Klotho polymorphisms with healthy aging: A systematic review and meta-analysis. Rejuvenation Res17, 212–216.
16.
MontesantoA, DatoS, BellizziD, RoseG, PassarinoG (2012) Epidemiological, genetic and epigenetic aspects of the research on healthy ageing and longevity. Immunity Ageing9, 6–17.
17.
RevelasM, ThalamuthuA, OldmeadowC, EvansTJ, ArmstrongNJ, KwokJB, BrodatyH, SchofieldPR, ScottRJ, SachdevPS, AttiaJR, MatherKA (2018) Review and meta-analysis of genetic polymorphisms associated with exceptional human longevity. Mech Ageing Dev175, 24–34.
18.
VoHT, LaszczykAM, KingGD (2018) Klotho, the key to healthy brain aging?Brain3, 183–194.
19.
BelloyME, NapolioniV, HanSS, Le GuenY, GreiciusMD, for the Alzheimer’s Disease Neuroimaging Initiative (2020) Associations of Klotho-KS heterozygosity with risk of Alzheimer’s disease in individuals who carry APOE4. JAMA Neurol77, 849–862.
20.
BlackerD, LeeH, MuzikanskyA, MartinEC, TanziR, McArdleJJ, MossM, AlbertM (2007) Neuropsychological measures in normal individuals that predict subsequent cognitive decline. Arch Neurol64, 862–871.
21.
JohnsonSC, KoscikRL, JonaitisEM, ClarkLR, MuellerKD, BermanSE, BendlinBB, EngelmanCD, OkonkwoOC, HoganKJ, AsthanaS, CarlssonCM, HermannBP, SagerMA (2018) The Wisconsin Registry for Alzheimer’s Prevention: A review of findings and current directions. Alzheimers Dement (Amst)10, 130–142.
22.
DarstBF, KoscikRL, RacineAM, OhJM, KrauseRA, CarlssonCM, ZetterbergH, BlennowK, ChristianBT, BendlinBB, OkonkwoOC, HoganKJ, HermannBP, SagerMA, AsthanaS, JohnsonSC, EngelmanCD (2017) Pathway-specific polygenic risk scores as predictors of amyloid-beta deposition and cognitive function in a sample at increased risk for Alzheimer’s disease. J Alzheimers Dis55, 473–484.
23.
ArkingDE, AtzmonG, ArkingA, BarzilaiN, DietzHC (2005) Association between a functional variant of the KLOTHO gene and high-density lipoprotein cholesterol, blood pressure, stroke, and longevity. Circ Res96, 412–418.
24.
YokoyamaJS, SturmVE, BonhamLW, KleinE, ArfanakisK, YuL, CoppolaG, KramerJH, BennettDA, MillerBL, DubalDB (2015) Variation in longevity gene KLOTHO is associated with greater cortical volumes. Ann Clin Transl Neurol2, 215–230.
25.
PalmqvistS, ZetterbergH, BlennowK, VestbergS, AndreassonU, BrooksDJ, OweniusR, HägerströmD, WollmerP, MinthonL, HanssonO (2014) Accuracy of brain amyloid detection in clinical practice using cerebrospinal fluid beta-amyloid 42: A cross-validation study against amyloid positron emission tomography. JAMA Neurol71, 1282–1289.
26.
SagerMA, HermannB, LaRue A (2005) Middle-aged children of persons with Alzheimer’s disease: APOE genotypes and cognitive function in the Wisconsin Registry for Alzheimer’s Prevention. J Geriatr Psychiatry Neurol18, 245–249.
27.
WeintraubS, SalmonD, MercaldoN, FerrisS, Graff-RadfordNR, ChuiH, CummingsJ, DeCarliC, FosterNL, GalaskoD, PeskindE, DietrichW, BeeklyDL, KukullWA, MorrisJC (2009) The Alzheimer’s Disease Centers’ Uniform Data Set (UDS): The neuropsychologic test battery. Alzheimer Dis Assoc Disord23, 91–101.
28.
SchmidtM (1996) Rey Auditory Verbal Learning Test: A Handbook, Western Psychological Services, Torrance, CA.
29.
ReitanR, WolfsonD (1993) Halstead-Reitan Neuropsychological Test Battery: Theory and clinical interpretation, Neuropsychology Press, Tucson.
30.
BehrensG, WinklerTW, GorskiM, LeitzmannMF, HeidIM (2011) To stratify or not to stratify: Power considerations for population-based genome-wide association studies of quantitative traits. Genet Epidemiol35, 867–879.
31.
PorterT, BurnhamSC, MilicicL, SavageG, MaruffP, LimYY, AmesD, MastersCL, MartinsRN, Rainey-SmithS, RoweCC, SalvadoO, GrothD, VerdileG, VIllemagneVL, LawsSM (2019) Klotho allele status is not associated with Aβ and APOE ɛ4-related cognitive decline in preclinical Alzheimer’s disease. Neurobiol Aging76, 162–165.
DuyckaertsC, BennecibM, GrignonY, UchiharaT, HeY, PietteF, HauwJJ (1997) Modeling the relation between neurofibrillary tangles and intellectual status. Neurobiol Aging18, 267–273.
37.
BennettDA, SchneiderJA, ArvanitakisZ, KellyJF, AggarwalNT, ShahRC, WilsonRS (2006) Neuropathology of older persons without cognitive impairment from two community-based studies. Neurology66, 1837–1844.
38.
LeonJ, MorenoAJ, GarayBI, ChalkleyRJ, BurlingameAL, WangD, DubalDB (2017) Peripheral elevation of a Klotho fragment enhances brain function and resilience in young, aging, and α-synuclein transgenic mice. Cell Rep20, 1360–1371.
