Blood pressure variability is linked to Alzheimer’s disease (AD) risk and MRI-based markers of cerebrovascular disease. Less is known about the role of blood pressure variability in postmortem evaluation of cerebrovascular disease and AD.
Objective:
To determine whether antemortem blood pressure variability predicts cerebrovascular and AD pathology and follow-up cognitive change in autopsy-confirmed AD.
Methods:
National Alzheimer’s Coordinating Center participants (n = 513) underwent 3-4 approximately annual blood pressure measurements and were confirmed to have AD at postmortem evaluation. A subset (n = 493) underwent neuropsychological evaluation at follow-up. Regression models examined relationships between blood pressure variability and cerebrovascular and AD pathological features and follow-up cognitive change.
Results:
Elevated blood pressure variability predicted increased postmortem cerebrovascular lesion burden (ß = 0.26 [0.10, 0.42]; p = 0.001; R2 = 0.12). Increased blood pressure variability predicted specific cerebrovascular lesion severity, including atherosclerosis in the Circle of Willis (OR = 1.22 [1.03, 1.44]; p = 0.02) and cerebral arteriolosclerosis (OR = 1.32 [1.04, 1.69]; p = 0.03). No significant relationships were observed between blood pressure variability and AD pathological findings, including Braak & Braak stage, neuritic plaques or diffuse plaques, or cerebral amyloid angiopathy, or follow-up cognitive decline.
Conclusion:
Findings suggest that elevated blood pressure variability is related to postmortem cerebrovascular lesion burden in autopsy-confirmed AD, independent of average blood pressure and AD neuropathology. Blood pressure fluctuation may selectively promote atherosclerotic and arteriolosclerotic brain lesions with potential implications for cognitive impairment and dementia.
ChoN, HoshideS, NishizawaM, FujiwaraT, KarioK (2018) Relationship between blood pressure variability and cognitive function in elderly patients with good blood pressure control. Am J Hypertens31, 293–298.
MaY, WoltersFJ, ChibnikLB, LicherS, IkramMA, HofmanA, IkramMK (2019) Variation in blood pressure and long-term risk of dementia: A population-based cohort study. PLoS Med16, e1002933.
6.
MaY, TullyPJ, HofmanA, TzourioC (2020) Blood pressure variability and dementia: A state-of-the art review. Am J Hypertens33, 1059–1066.
RouchL, CestacP, SallerinB, PiccoliM, Benattar-ZibiL, BertinP, BerrutG, CorrubleE, DerumeauxG, FalissardB, ForetteF, PasquierF, PingetM, OurabahR, DanchinN, HanonO, VidalJS (2020) Visit-to-visit blood pressure variability is associated with cognitive decline and incident dementia: The S.AGES cohort. Hypertension76, 1280–1288.
10.
AlpérovitchA, BlachierM, SoumaréA, RitchieK, DartiguesJF, Richard-HarstonS, TzourioC (2014) Blood pressure variability and risk of dementia in an elderly cohort, the Three-City Study. Alzheimers Dement10, S330–S337.
11.
de HeusRAA, Olde RikkertMGM, TullyPJ, LawlorBA, ClaassenJAHR (2019) Blood pressure variability and progression of clinical Alzheimer disease. Hypertension74, 1172–1180.
12.
QinB, VieraAJ, MuntnerP, PlassmanBL, EdwardsLJ, AdairLS, PopkinBM, MendezMA (2016) Visit-to-visit variability in blood pressure is related to late-life cognitive decline. Hypertension68, 106–113.
SibleIJ, NationDA, Alzheimer’s Disease Neuroimaging Initiative (2020) Long-term blood pressure variability across the clinical and biomarker spectrum of Alzheimer’s disease. J Alzheimers Dis77, 1655–1669.
15.
JenningsJR, MuldoonMF, RyanC, PriceJC, GreerP, Sutton-TyrrellK, Van Der VeenFM, MeltzerCC (2005) Reduced cerebral blood flow response and compensation among patients with untreated hypertension. Neurology64, 1358–1365.
16.
NovakV, HajjarI (2010) The relationship between blood pressure and cognitive function. Nat Rev Cardiol7, 686–698.
17.
MaY, SongA, ViswanathanA, BlackerD, VernooijMW, HofmanA, PapatheodorouS (2020) Blood pressure variability and cerebral small vessel disease: A systematic review and meta-analysis of population-based cohorts. Stroke51, 82–89.
18.
CecchiE, GiglioliC, ValenteS, LazzeriC, GensiniGF, AbbateR, ManniniL (2011) Role of hemodynamic shear stress in cardiovascular disease. Atherosclerosis214, 249–256.
19.
MaY, YilmazP, BosD, BlackerD, ViswanathanA, IkramMA, HofmanA, VernooijMW, IkramMK (2020) Blood pressure variation and subclinical brain disease. J Am Coll Cardiol75, 2387–2399.
HofmanA, OttA, BretelerMMB, BotsML, SlooterAJC, Van HarskampF, Van DuijnCN, Van BroeckhovenC, GrobbeeDE (1997) Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer’s disease in the Rotterdam Study. Lancet349, 151–154.
22.
WhiteLR, PetrovitchH, HardmanJ, NelsonJ, DavisDG, RossGW, MasakiK, LaunerLJ, MarkesberyWR (2002) Cerebrovascular pathology and dementia in autopsied Honolulu-Asia Aging Study participants. Ann N Y Acad Sci977, 9–23.
23.
ArvanitakisZ, CapuanoAW, LeurgansSE, BennettDA, SchneiderJA (2016) Relation of cerebral vessel disease to Alzheimer’s disease dementia and cognitive function in older adults: A cross-sectional study. Lancet Neurol15, 934–943.
24.
ToledoJB, ArnoldSE, RaibleK, BrettschneiderJ, XieSX, GrossmanM, MonsellSE, KukullWA, TrojanowskiJQ (2013) Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer’s Coordinating Centre. Brain136, 2697–2706.
25.
SchneiderJA, ArvanitakisZ, BangW, BennettDA (2007) Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology69, 2197–2204.
26.
BrickmanAM, ReitzC, LuchsingerJA, ManlyJJ, SchupfN, MuraskinJ, DeCarliC, BrownTR, MayeuxR (2010) Long-term blood pressure fluctuation and cerebrovascular disease in an elderly cohort. Arch Neurol67, 564–569.
O’CaoimhR, GaoY, SvendrovskiA, IllarioM, IaccarinoG, YavuzBB, KehoePG, MolloyDW (2019) Effect of visit-to-visit blood pressure variability on cognitive and functional decline in mild to moderate Alzheimer’s disease. J Alzheimers Dis68, 1499–1510.
32.
The NIA Alzheimer’s Disease Research Centers Program, National Alzheimer’s Coordinating Center.
33.
BeeklyDL, RamosEM, LeeWW, DeitrichWD, JackaME, WuJ, HubbardJL, KoepsellTD, MorrisJC, KukullWA (2007) The National Alzheimer’s Coordinating Center (NACC) database: The uniform data set. Alzheimer Dis Assoc Disord21, 249–258.
34.
MorrisJC, WeintraubS, ChuiHC, CummingsJ, DecarliC, FerrisS, FosterNL, GalaskoD, Graff-RadfordN, PeskindER, BeeklyDL, RamosEM, KukullWA (2006) The uniform data set (UDS): Clinical and cognitive variables and descriptive data from Alzheimer Disease Centers. Alzheimer Dis Assoc Disord20, 210–216.
35.
BesserL, KukullW, KnopmanDS, ChuiH, GalaskoD, WeintraubS, JichaG, CarlssonC, BurnsJ, QuinnJ, SweetRA, RascovskyK, TeylanM, BeeklyD, ThomasG, BollenbeckM, MonsellS, MockC, ZhouXH, ThomasN, RobichaudE, DeanM, HubbardJ, JackaM, Schwabe-FryK, WuJ, PhelpsC, MorrisJC (2018) Version 3 of the national Alzheimer’s coordinating center’s uniform data set. Alzheimer Dis Assoc Disord32, 351–358.
36.
MirraSS, HeymanA, McKeelD, SumiSM, CrainBJ, BrownleeLM, VogelFS, HughesJP, van BelleG, BergL, BallMJ, BiererLM, ClaasenD, HansenLR, HartM, HedreenJ, BaltimoreB, Hen DersonV, HymanBT, JoachimC, Mark-EsberyW, Mar TinezAJ, McKeeA, MillerC, MoossyJ, NochlinD, PerlD, PetitoC, RaoGR, SchelperRL, SlagerU, TerryRD (1991) The consortium to establish a registry for Alzheimer’s disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology41, 479–486.
37.
EglitGML, WeigandAJ, NationDA, BondiMW, BangenKJ (2020) Hypertension and Alzheimer’s disease: Indirect effects through circle of Willis atherosclerosis. Brain Commun2, 1–13.
38.
MoroneyJT, BagiellaE, DesmondDW, HachinskiVC, MölsäPK, GustafsonL, BrunA, FischerP, ErkinjunttiT, RosenW, PaikMC, TatemichiTK (1997) Meta-analysis of the Hachinski Ischemic Score in pathologically verified dementias. Neurology49, 1096–1105.
39.
StorandtM, BotwinickJ, DanzigerWL, BergL, HughesCP (1984) Psychometric differentiation of mild senile dementia of the Alzheimer type. Arch Neurol41, 497–499.
40.
AshendorfL, JeffersonAL, O’ConnorMK, ChaissonC, GreenRC, SternRA (2008) Trail Making Test errors in normal aging, mild cognitive impairment, and dementia. Arch Clin Neuropsychol23, 129–137.
41.
RothwellPM, HowardSC, DolanE, O’BrienE, DobsonJE, DahlöfB, SeverPS, PoulterNR (2010) Prognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hypertension. Lancet375, 895–905.
42.
R Core Team (2018) R: A language and environment for statistical computing.
43.
BesserLM, KukullWA, TeylanMA, BigioEH, CairnsNJ, KoflerJK, MontineTJ, SchneiderJA, NelsonPT (2018) The revised national Alzheimer’s coordinating center’s neuropathology form-available data and new analyses. J Neuropathol Exp Neurol77, 717–726.
44.
UmegakiH, KhookhorO (2013) The response of the autonomic nervous system to the cholinesterase inhibitor, donepezil. Neuroendocrinol Lett34, 383–387.
45.
RoherAE, EshC, KokjohnTA, KalbackW, LuehrsDC, SewardJD, SueLI, BeachTG (2003) Circle of Willis atherosclerosis is a risk factor for sporadic Alzheimer’s disease. Arterioscler Thromb Vasc Biol23, 2055–2062.
46.
IadecolaC (2004) Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat Rev Neurosci5, 347–360.
47.
LaneCA, BarnesJ, NicholasJM, SudreCH, CashDM, ParkerTD, MaloneIB, LuK, JamesSN, KeshavanA, Murray-SmithH, WongA, BuchananSM, KeussSE, GordonE, CoathW, BarnesA, DicksonJ, ModatM, ThomasD, CrutchSJ, HardyR, RichardsM, FoxNC, SchottJM (2019) Associations between blood pressure across adulthood and late-life brain structure and pathology in the neuroscience substudy of the 1946 British birth cohort (Insight 46): An epidemiological study. Lancet Neurol18, 942–952.
48.
NationDA, EdmondsEC, BangenKJ, Delano-WoodL, ScanlonBK, HanSD, EdlandSD, SalmonDP, GalaskoDR, BondiMW (2015) Pulse pressure in relation to tau-mediated neurodegeneration, cerebral amyloidosis, and progression to dementia in very old adults. JAMA Neurol72, 546–553.
49.
KitamuraJ, NagaiM, UenoH, OhshitaT, KikumotoM, TokoM, KatoM, DoteK, YamashitaH, KarioK (2020) The insular cortex, Alzheimer disease pathology, and their effects on blood pressure variability. Alzheimer Dis Assoc Disord34, 282–291.
50.
QiuC, von StraussE, WinbladB, FratiglioniL (2004) Decline in blood pressure over time and risk of dementia: A longitudinal study from the Kungsholmen project. Stroke35, 1810–1815.
51.
WrightJT, WilliamsonJD, WheltonPK, SnyderJK, SinkKM, RoccoM V., ReboussinDM, RahmanM, OparilS, LewisCE, KimmelPL, JohnsonKC, GoffDC, FineLJ, CutlerJA, CushmanWC, CheungAK, AmbrosiusWT (2015) A randomized trial of intensive versus standard blood-pressure control. N Engl J Med373, 2103–2116.
52.
WebbAJ, FischerU, MehtaZ, RothwellPM (2010) Effects of antihypertensive-drug class on interindividual variation in blood pressure and risk of stroke: A systematic review and meta-analysis. Lancet375, 906–915.
53.
AmentaF, MigniniF, RabbiaF, TomassoniD, VeglioF (2002) Protective effect of anti-hypertensive treatment on cognitive function in essential hypertension: Analysis of published clinical data. J Neurol Sci203-204, 147–151.
54.
Levi MarpillatN, Macquin-MavierI, TropeanoA-I, Levi-BachoudA-C, MaisonP (2013) Antihypertensive classes, cognitive decline and incidence of dementia: A network meta-analysis. J Hypertens31, 1073–1082.
55.
DingJ, Davis-PlourdeKL, SedaghatS, TullyPJ, WangW, PhillipsC, PaseMP, HimaliJJ, Gwen WindhamB, GriswoldM, GottesmanR, MosleyTH, WhiteL, Guo*nasonV, DebetteS, BeiserAS, SeshadriS, IkramMA, MeirellesO, TzourioC, LaunerLJ (2020) Antihypertensive medications and risk for incident dementia and Alzheimer’s disease: A meta-analysis of individual participant data from prospective cohort studies. Lancet Neurol19, 61–70.
BiloG, ParatiG (2018) Blood pressure variability and kidney disease: Another vicious circle?J Hypertens36, 1019–1021.
59.
QiuC, WinbladB, FratiglioniL (2005) The age-dependent relation of blood pressure to cognitive function and dementia. Lancet Neurol4, 487–499.
60.
LimHM, ChiaYC, ChingSM, ChinnaK (2019) Number of blood pressure measurements needed to estimate long-term visit-to-visit systolic blood pressure variability for predicting cardiovascular risk: A 10-year retrospective cohort study in a primary care clinic in Malaysia. BMJ Open9, e025322.
61.
JohnsonLA, CushingB, RohlfingG, EdwardsM, DavenlooH, D’AgostinoD, HallJR, O’BryantSE (2014) The Hachinski Ischemic Scale and cognition: The influence of ethnicity. Age Ageing43, 364–369.
