Interactions between Atrial Fibrillation,Cardiovascular Risk Factors,and ApoE Genotype in Promoting Cognitive Decline in Patients with Alzheimer’s Disease: A Prospective Cohort Study
Restricted accessResearch articleFirst published online February 20, 2018
Interactions between Atrial Fibrillation,Cardiovascular Risk Factors,and ApoE Genotype in Promoting Cognitive Decline in Patients with Alzheimer’s Disease: A Prospective Cohort Study
An association between non-valvular atrial fibrillation (NVAF) and cognitive impairment has been hypothesized.
Objective:
We sought to evaluate whether and how permanent NVAF (pNVAF) is associated with progression of cognitive impairment in patients with Alzheimer’s disease (AD) in the presence of vascular or genetic risk factors.
Methods:
310 consecutive patients affected by mild-moderate AD were included and followed for a 24-month period. At the end of the follow-up, based on the results of the neuropsychological evaluation patients were classified as stable or deteriorated to severe AD. Clinical history, therapy, time in therapeutic range for anticoagulation, Framingham cardiovascular risk profile (FCRP), CHA2DS2-VASc score, Mini-Mental State Examination (MMSE), ApoE genotype, brain CT-scan, carotid ultrasound, and ECG were collected. Binary logistic and path analysis were adopted to assess relationships between pNVAF, ApoE, and cognitive outcome.
Results:
Despite anticoagulant therapy, pNVAF was associated with lower entry MMSE, higher mean intima-media thickness (mIMT) and higher FCRP. Among patients carrying ApoE ɛ4 allele and affected by pNVAF, the lowest MMSE (14.90±7.62) and the highest mIMT (1.16±0.17 mm) and FCRP (26.24±3.96) values were detected. In this group, the risk of cognitive deterioration reached the highest probability. pNVAF was associated with an increased cognitive deterioration in subjects with high FCRP, CHA2DS2-VASc, or mIMT.
Conclusions:
pNVAF seems to identify AD patients with a significant atherosclerotic burden and reduced cognitive performances. The interaction between pNVAF and ApoE ɛ4 genotype, especially with aggregated risk factors and an advanced stage of vascular damage is associated with higher risk of fast cognitive deterioration.
MarijonE, Le HeuzeyJ-Y, ConnollyS, YangS, PogueJ, BrueckmannM, EikelboomJ, ThemelesE, EzekowitzM, WallentinL, YusufS (2013) Causes of death and influencing factors in patients with atrial fibrillation: A competing-risk analysis from the randomized evaluation of long-term anticoagulant therapy study. Circulation128, 2192–2201.
2.
ViticchiG, FalsettiL, VernieriF, AltamuraC, AltavillaR, LuzziS, BartoliniM, ProvincialiL, SilvestriniM (2014) Apolipoprotein E genotype and cerebrovascular alterations can influence conversion to dementia in patients with mild cognitive impairment. J Alzheimers Dis41, 401–410.
3.
CorraoS, ArganoC, NobiliA, MarcucciM, DjadeCD, TettamantiM, PasinaL, FranchiC, MarengoniA, SalernoF, VioliF, MannucciPM, PerticoneF (2015) Brain and kidney, victims of atrial microembolism in elderly hospitalized patients? Data from the REPOSI study. Eur J Intern Med26, 243–249.
4.
GranzieraS, BertozzoG, PengoV, MarigoL, DenasG, PetruzzellisF, RossiK, InfanteT, PadayattilSJ, PerissinottoE, ManzatoE, NanteG (2015) To treat or not to treat very elderly naïve patients with atrial fibrillation with vitamin K antagonists (VKA): Results from the VENPAF cohort. Intern Emerg Med10, 795–804.
5.
ProiettiM, CalvieriC, MalatinoL, SignorelliS, CorazzaGR, PerticoneF, VestriAR, LoffredoL, DavíG, VioliF, BasiliS (2015) Relationship between carotid intima-media thickness and non valvular atrial fibrillation type. Atherosclerosis238, 350–355.
6.
SafourisA, PsaltopoulouT, SergentanisTN, BoutatiE, KapakiE, TsivgoulisG (2015) Vascular risk factors and Alzheimer’s disease pathogenesis: Are conventional pharmacological approaches protective for cognitive decline progression?CNS Neurol Disord Drug Targets14, 257–269.
7.
ViticchiG, FalsettiL, VernieriF, AltamuraC, BartoliniM, LuzziS, ProvincialiL, SilvestriniM (2012) Vascular predictors of cognitive decline in patients with mild cognitive impairment. Neurobiol Aging33, 1127.e1–9.
8.
PolidoriMC, PientkaL, MecocciP (2012) A review of the major vascular risk factors related to Alzheimer’s disease. J Alzheimers Dis32, 521–530.
GlodzikL, RusinekH, BrysM, TsuiWH, SwitalskiR, MosconiL, MisturR, PirragliaE, de SantiS, LiY, GoldowskyA, de LeonMJ (2011) Framingham cardiovascular risk profile correlates with impaired hippocampal and cortical vasoreactivity to hypercapnia. J Cereb Blood Flow Metab31, 671–679.
11.
IlveskoskiE, PerolaM, LehtimäkiT, LaippalaP, SavolainenV, PajarinenJ, PenttiläA, LaluKH, MännikköA, LiestoKK, KoivulaT, KarhunenPJ (1999) Age-dependent association of apolipoprotein E genotype with coronary and aortic atherosclerosis in middle-aged men: An autopsy study. Circulation100, 608–613.
12.
YuJ-T, TanL, HardyJ (2014) Apolipoprotein E in Alzheimer’s disease: An update. Annu Rev Neurosci37, 79–100.
13.
DavignonJ (2005) Apolipoprotein E and atherosclerosis: Beyond lipid effect. Arterioscler Thromb Vasc Biol25, 267–269.
14.
HeeringaJ, van der Kuip DAM, HofmanA, KorsJA, van RooijFJA, LipGYH, WittemanJCM (2007) Subclinical atherosclerosis and risk of atrial fibrillation: The rotterdam study. Arch Intern Med167, 382–387.
15.
ViticchiG, FalsettiL, BurattiL, LuzziS, BartoliniM, AcciarriMC, ProvincialiL, SilvestriniM (2015) Metabolic syndrome and cerebrovascular impairment in Alzheimer’s disease. Int J Geriatr Psychiatry30, 1164–1170.
16.
SilvestriniM, ViticchiG, FalsettiL, BalucaniC, VernieriF, CerquaR, LuzziS, BartoliniM, ProvincialiL (2011) The role of carotid atherosclerosis in Alzheimer’s disease progression. J Alzheimers Dis25, 719–726.
McKhannGM, KnopmanDS, ChertkowH, HymanBT, JackCR, KawasCH, KlunkWE, KoroshetzWJ, ManlyJJ, MayeuxR, MohsRC, MorrisJC, RossorMN, ScheltensP, CarrilloMC, ThiesB, WeintraubS, PhelpsCH (2011) The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement7, 263–269.
19.
WeyerG, ErzigkeitH, KanowskiS, IhlR, HadlerD (1997) Alzheimer’s Disease Assessment Scale: Reliability and validity in a multicenter clinical trial. Int Psychogeriatr9, 123–138.
20.
ColeyN, AndrieuS, JarosM, WeinerM, CedarbaumJ, VellasB (2011) Suitability of the Clinical Dementia Rating-Sum of Boxes as a single primary endpoint for Alzheimer’s disease trials. Alzheimers Dement7, 602–610.e2.
21.
KaffashianS, DugravotA, ElbazA, ShipleyMJ, SabiaS, KivimäkiM, Singh-ManouxA (2013) Predicting cognitive decline: A dementia risk score vs. the Framingham vascular risk scores. Neurology80, 1300–1306.
22.
D’AgostinoRB, VasanRS, PencinaMJ, WolfPA, CobainM, MassaroJM, KannelWB (2008) General cardiovascular risk profile for use in primary care: The Framingham Heart Study. Circulation117, 743–753.
23.
LipGYH, NieuwlaatR, PistersR, LaneDA, CrijnsHJGM (2010) Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach. Chest137, 263–272.
24.
KochW, EhrenhaftA, GriesserK, PfeuferA, MüllerJ, SchömigA, KastratiA (2002) TaqMan systems for genotyping of disease-related polymorphisms present in the gene encoding apolipoprotein E. Clin Chem Lab Med40, 1123–1131.
25.
TouboulP-J, HennericiMG, MeairsS, AdamsH, AmarencoP, BornsteinN, CsibaL, DesvarieuxM, EbrahimS, Hernandez HernandezR, JaffM, KownatorS, NaqviT, PratiP, RundekT, SitzerM, SchminkeU, TardifJ-C, TaylorA, VicautE, WooKS (2012) Mannheim carotid intima-media thickness and plaque consensus (2004-2006-2011). An update on behalf of the advisory board of the 3rd, 4th and 5th watching the risk symposia, at the 13th, 15th and 20th European Stroke Conferences, Mannheim, Germany, 2004, B. Cerebrovasc Dis34, 290–296.
26.
WahlundLO, BarkhofF, FazekasF, BrongeL, AugustinM, SjögrenM, WallinA, AderH, LeysD, PantoniL, PasquierF, ErkinjunttiT, ScheltensP (2001) A new rating scale for age-related white matter changes applicable to MRI and CT. Stroke32, 1318–1322.
27.
RosendaalFR, CannegieterSC, van derMeer FJ, BriëtE (1993) A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost69, 236–239.
28.
PeduzziP, ConcatoJ, KemperE, HolfordTR, FeinsteinAR (1996) A simulation study of the number of events per variable in logistic regression analysis. J Clin Epidemiol49, 1373–1379.
29.
CohenJ (1977), Statistical power analysis for the behavioral sciencesAcademic Press.
30.
BursacZ, GaussCH, WilliamsDK, HosmerDW (2008) Purposeful selection of variables in logistic regression. Source Code Biol Med3, 17.
31.
AltmanD (1991) Practical Statistics for Medical Research. Chapman & Hall, London.
32.
PoggesiA, InzitariD, PantoniL (2015) Atrial fibrillation and cognition: Epidemiological data and possible mechanisms. Stroke46, 3316–3321.
33.
JeffersonAL, BeiserAS, HimaliJJ, SeshadriS, O’DonnellCJ, ManningWJ, WolfPA, AuR, BenjaminEJ (2015) Low cardiac index is associated with incident dementia and Alzheimer disease: The Framingham Heart Study. Circulation131, 1333–1339.
34.
JacobsV, WollerSC, StevensS, MayHT, BairTL, AndersonJL, CrandallBG, DayJD, JohanningK, LongY, MallenderC, OlsonJL, OsbornJS, WeissJP, BunchTJ (2014) Time outside of therapeutic range in atrial fibrillation patients is associated with long-term risk of dementia. Heart Rhythm11, 2206–2213.
35.
BunchTJ, MayHT, BairTL, CrandallBG, CutlerMJ, DayJD, JacobsV, MallenderC, OsbornJS, StevensSM, WeissJP, WollerSC (2016) Atrial fibrillation patients treated with long-term warfarin anticoagulation have higher rates of all dementia types compared with patients receiving long-term warfarin for other indications. J Am Heart Assoc5, pii: e003932.
36.
YaghiS, BoehmeAK, HazanR, HodEA, CanaanA, AndrewsHF, KamelH, MarshallRS, Elkind MSV (2016) Atrial cardiopathy and cryptogenic stroke: A cross-sectional pilot study. J Stroke Cerebrovasc Dis25, 110–114.
37.
GuerraF, ScappiniL, MaoloA, CampoG, PavasiniR, ShkozaM, CapucciA (2016) CHA2DS2-VASc risk factors as predictors of stroke after acute coronary syndrome: A systematic review and meta-analysis. Eur Heart J Acute Cardiovasc Care. doi: 10.1177/2048872616673536
38.
DavignonJ, GreggRE, SingCF (1988) Apolipoprotein E polymorphism and atherosclerosis. Arterioscler Thromb Vasc Biol8, 1–21.
39.
CostantinoG, PoddaGM, FalsettiL, IannoneP, LagesA, MarraAM, MasalaM, ReiakvamOM, SavvaF, SchovanekJ, van BreeS, da Silva ChoraIJ, PriviteraG, RagozzinoS, von RotzM, WoittiezL, DavidsonC, MontanoN (2017) Guidelines on the management of atrial fibrillation in the emergency department: A critical appraisal. Intern Emerg Med12, 693–703.
