The neuropathology of Alzheimer’s disease (AD) has previously been shown to be rather common among the elderly.
Objective:
The aim of this study was to inspect the associations between cerebrospinal fluid (CSF) AD biomarker concentrations, age, the APOEɛ4 allele, cardiovascular diseases, diabetes, and cognitive performance in a cohort of a neurologically healthy population.
Methods:
This study included 93 subjects (42 men, mean age 67 years) without previous neurological symptoms or subjective cognitive complaints. Their cognition was assessed, and CSF biomarkers and APOEɛ4 status were analyzed.
Results:
Of the studied subjects, 8.6% (n = 8) had a pathological CSF AD biomarker profile. An increase in age correlated positively with CSF tau pathology and negatively with global cognitive performance.
Conclusion:
AD-type pathological changes in CSF and subtle cognitive impairment are common within a population with no previous memory complaints. Age was the main risk factor for the changes.
HuletteCM, Welsh-BohmerKA, MurrayMG, SaundersAM, MashDC, McIntyreLM (1998) Neuropathological and neuropsychological changes in “normal” aging: Evidence for preclinical Alzheimer disease in cognitively normal individuals. J Neuropathol Exp Neurol57, 1168–1174.
7.
DavisDG, SchmittFA, WeksteinDR, MarkesberyWR (1999) Alzheimer neuropathologic alterations in aged cognitively normal subjects. J Neuropathol Exp Neurol58, 376–388.
8.
JackCRJr, KnopmanDS, JagustWJ, PetersenRC, WeinerMW, AisenPS, ShawLM, VemuriP, WisteHJ, WeigandSD, LesnickTG, PankratzVS, DonohueMC, TrojanowskiJQ (2013) Tracking pathophysiological processes in Alzheimer’s disease: An updated hypothetical model of dynamic biomarkers. Lancet Neurol12, 207–216.
9.
TapiolaT, AlafuzoffI, HerukkaSK, ParkkinenL, HartikainenP, SoininenH, PirttilaT (2009) Cerebrospinal fluid {beta}-amyloid 42 and tau proteins as biomarkers of Alzheimer-type pathologic changes in the brain. Arch Neurol66, 382–389.
10.
StrozykD, BlennowK, WhiteLR, LaunerLJ (2003) CSF Abeta 42 levels correlate with amyloid-neuropathology in a population-based autopsy study. Neurology60, 652–656.
11.
FaganAM, RoeCM, XiongC, MintunMA, MorrisJC, HoltzmanDM (2007) Cerebrospinal fluid tau/β-amyloid42 ratio as a prediction of cognitive decline in nondemented older adults. Arch Neurol64, 343–349.
12.
RoeCM, FaganAM, GrantEA, HassenstabJ, MoulderKL, Maue DreyfusD, SutphenCL, BenzingerTL, MintunMA, HoltzmanDM, MorrisJC (2013) Amyloid imaging and CSF biomarkers in predicting cognitive impairment up to 7.5 years later. Neurology80, 1784–1791.
13.
LiG, MillardSP, PeskindER, ZhangJ, YuC, LeverenzJB, MayerC, ShoferJS, RaskindMA, QuinnJF (2014) Cross-sectional and longitudinal relationships between cerebrospinal fluid biomarkers and cognitive function in people without cognitive impairment from across the adult life span. JAMA Neurol71, 742–751.
14.
SteenlandK, ZhaoL, GoldsteinF, CellarJ, LahJ (2014) Biomarkers for predicting cognitive decline in those with normal cognition. J Alzheimers Dis40, 587–594.
15.
PeskindER, LiG, ShoferJ, QuinnJF, KayeJA, ClarkCM, FarlowMR, DeCarliC, RaskindMA, SchellenbergGD, LeeVM, GalaskoDR (2006) Age and apolipoprotein E*4 allele effects on cerebrospinal fluid beta-amyloid 42 in adults with normal cognition. Arch Neurol63, 936–939.
16.
Glodzik-SobanskaL, PirragliaE, BrysM, de SantiS, MosconiL, RichKE, SwitalskiR, Saint LouisL, SadowskiMJ, MartiniukF, MehtaP, PraticoD, ZinkowskiRP, BlennowK, de LeonMJ (2009) The effects of normal aging and ApoE genotype on the levels of CSF biomarkers for Alzheimer’s disease. Neurobiol Aging30, 672–681.
17.
ShojiM, MatsubaraE, KanaiM, WatanabeM, NakamuraT, TomidokoroY, ShizukaM, WakabayashiK, IgetaY, IkedaY (1998) Combination assay of CSF Tau, Aβ1-40 and Aβ1-42 (43) as a biochemical marker of Alzheimer’s disease. J Neurol Sci158, 134–140.
18.
GuillozetAL, WeintraubS, MashDC, MesulamMM (2003) Neurofibrillary tangles, amyloid, and memory in aging and mild cognitive impairment. Arch Neurol60, 729–736.
19.
StomrudE, HanssonO, ZetterbergH, BlennowK, MinthonL, LondosE (2010) Correlation of longitudinal cerebrospinal fluid biomarkers with cognitive decline in healthy older adults. Arch Neurol67, 217–223.
20.
VemuriP, WisteHJ, WeigandSD, ShawLM, TrojanowskiJQ, WeinerMW, KnopmanDS, PetersenRC, JackCRJr, Alzheimer’s Disease Neuroimaging Initiative (2009) MRI and CSF biomarkers in normal, MCI, and AD subjects: Diagnostic discrimination and cognitive correlations. Neurology73, 287–293.
21.
RamiL, ForteaJ, BoschB, Sole-PadullesC, LladoA, IranzoA, Sanchez-ValleR, MolinuevoJL (2011) Cerebrospinal fluid biomarkers and memory present distinct associations along the continuum from healthy subjects to AD patients. J Alzheimers Dis23, 319–326.
22.
SchottJM, BartlettJW, FoxNC, BarnesJ (2010) Increased brain atrophy rates in cognitively normal older adults with low cerebrospinal fluid Aβ1-42. Ann Neurol68, 825–834.
23.
PettigrewC, SoldanA, MoghekarA, WangM, GrossAL, O’BrienR, AlbertM (2015) Relationship between cerebrospinal fluid biomarkers of Alzheimer’s disease and cognition in cognitively normal older adults. Neuropsychologia78, 63–72.
24.
RaberJ, HuangY, AshfordJW (2004) ApoE genotype accounts for the vast majority of AD risk and AD pathology. Neurobiol Aging25, 641–650.
25.
FarrerLA, CupplesLA, HainesJL, HymanB, KukullWA, MayeuxR, MyersRH, Pericak-VanceMA, RischN, Van DuijnCM (1997) Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: A meta-analysis. JAMA278, 1349–1356.
26.
MorrisJC, RoeCM, XiongC, FaganAM, GoateAM, HoltzmanDM, MintunMA (2010) APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. Ann Neurol67, 122–131.
27.
TervoS, KivipeltoM, HanninenT, VanhanenM, HallikainenM, MannermaaA, SoininenH (2004) Incidence and risk factors for mild cognitive impairment: A population-based three-year follow-up study of cognitively healthy elderly subjects. Dement Geriatr Cogn Disord17, 196–203.
28.
WilsonRS, SchneiderJA, BarnesLL, BeckettLA, AggarwalNT, CochranEJ, Berry-KravisE, BachJ, FoxJH, EvansDA (2002) The apolipoprotein E ɛ4 allele and decline in different cognitive systems during a 6-year period. Arch Neurol59, 1154–1160.
29.
LiuY, PaajanenT, WestmanE, WahlundL, SimmonsA, TunnardC, SobowT, ProitsiP, PowellJ, MecocciP (2010) Effect of APOE ɛ4 allele on cortical thicknesses and volumes: The AddNeuroMed study. J Alzheimers Dis21, 947–966.
30.
KivipeltoM, HelkalaEL, LaaksoMP, HanninenT, HallikainenM, AlhainenK, SoininenH, TuomilehtoJ, NissinenA (2001) Midlife vascular risk factors and Alzheimer’s disease in later life: Longitudinal, population based study. BMJ322, 1447–1451.
31.
NotkolaI, SulkavaR, PekkanenJ, ErkinjunttiT, EhnholmC, KivinenP, TuomilehtoJ, NissinenA (1998) Serum total cholesterol, apolipoprotein E ɛ4 Allele, and Alzheimer’s disease. Neuroepidemiology17, 14–20.
32.
DeCarliC, MillerBL, SwanGE, ReedT, WolfPA, CarmelliD (2001) Cerebrovascular and brain morphologic correlates of mild cognitive impairment in the National Heart, Lung, and Blood Institute Twin Study. Arch Neurol58, 643–647.
33.
BedseG, Di DomenicoF, ServiddioG, CassanoT (2015) Aberrant insulin signaling in Alzheimer’s disease: Current knowledge. Front Neurosci9, 204.
34.
de la MonteSM (2012) Brain insulin resistance and deficiency as therapeutic targets in Alzheimer’s disease. Curr Alzheimer Res9, 35–66.
35.
GatzM, ReynoldsC, NikolicJ, LoweB, KarelM, PedersenN (1995) An empirical test of telephone screening to identify potential dementia cases. Int Psychogeriatr7, 429–438.
36.
JarvenpaaT, RinneJO, RaihaI, KoskenvuoM, LopponenM, HinkkaS, KaprioJ (2002) Characteristics of two telephone screens for cognitive impairment. Dement Geriatr Cogn Disord13, 149–155.
37.
HanninenT, PulliainenV, SotaniemiM, HokkanenL, SaloJ, HietanenM, PirttilaT, PoyhonenM, JuvaK, RemesA, ErkinjunttiT (2010) Early detection of cognitive changes in memory diseases: New cut-off scores for the Finnish version of CERAD neuropsychological battery. Duodecim126, 2013–2021.
38.
SeoEH, LeeDY, LeeJH, ChooIH, KimJW, KimSG, ParkSY, ShinJH, DoYJ, YoonJC (2010) Total scores of the CERAD neuropsychological assessment battery: Validation for mild cognitive impairment and dementia patients with diverse etiologies. Am J Geriatr Psychiatry18, 801–809.
39.
ChandlerMJ, LacritzLH, HynanLS, BarnardHD, AllenG, DeschnerM, WeinerMF, CullumCM (2005) A total score for the CERAD neuropsychological battery. Neurology65, 102–106.
40.
HerukkaSK, HallikainenM, SoininenH, PirttilaT (2005) CSF Abeta42 and tau or phosphorylated tau and prediction of progressive mild cognitive impairment. Neurology64, 1294–1297.
41.
FranciscoM, LazarukKD, RhodesMD, WenzMH (2005) Assessment of two flexible and compatible SNP genotyping platforms: TaqMan® SNP Genotyping Assays and the SNPlex™ Genotyping System. Mutat Res573, 111–135.
42.
BennettDA, SchneiderJA, ArvanitakisZ, KellyJF, AggarwalNT, ShahRC, WilsonRS (2006) Neuropathology of older persons without cognitive impairment from two community-based studies. Neurology66, 1837–1844.
43.
RiedelBC, ThompsonPM, BrintonRD (2016) Age, APOE and sex: Triad of risk of Alzheimer’s disease. J Steroid Biochem Mol Biol160, 134–147.
44.
LindsayJ, LaurinD, VerreaultR, HebertR, HelliwellB, HillGB, McDowellI (2002) Risk factors for Alzheimer’s disease: A prospective analysis from the Canadian Study of Health and Aging. Am J Epidemiol156, 445–453.
JansenWJ, OssenkoppeleR, KnolDL, TijmsBM, ScheltensP, VerheyFR, VisserPJ, AaltenP, AarslandD, AlcoleaD (2015) Prevalence of cerebral amyloid pathology in persons without dementia: A meta-analysis. JAMA313, 1924–1938.
48.
ZwanMD, RinneJO, HasselbalchSG, NordbergA, LleoA, HerukkaSK, SoininenH, LawI, BahlJM, CarterSF, ForteaJ, BlesaR, TeunissenCE, BouwmanFH, van BerckelBN, VisserPJ (2016) Use of amyloid-PET to determine cutpoints for CSF markers: A multicenter study. Neurology86, 50–58.
49.
MistridisP, EgliSC, IversonGL, BerresM, WillmesK, Welsh-BohmerKA, MonschAU (2015) Considering the base rates of low performance in cognitively healthy older adults improves the accuracy to identify neurocognitive impairment with the Consortium to Establish a Registry for Alzheimer’s Disease-Neuropsychological Assessment Battery (CERAD-NAB). Eur Arch Psychiatry Clin Neurosci265, 407–417.
MitchellAJ (2009) A meta-analysis of the accuracy of the mini-mental state examination in the detection of dementia and mild cognitive impairment. J Psychiatr Res43, 411–431.
52.
WoodRY, GiulianoKK, BignellCU, PrithamWW (2006) Assessing cognitive ability in research: Use of MMSE with minority populations and elderly adults with low education levels. J Gerontol Nurs32, 45–54.
53.
MazancovaAF, NikolaiT, StepankovaH, KopecekM, BezdicekO (2017) The reliability of clock drawing test scoring systems modeled on the normative data in healthy aging and nonamnestic mild cognitive impairment. Assessment24, 945–957.
54.
BilgelM, AnY, LangA, PrinceJ, FerrucciL, JedynakB, ResnickSM (2014) Trajectories of Alzheimer disease-related cognitive measures in a longitudinal sample. Alzheimers Dement10, 735–742.e4.
BlennowK, DuboisB, FaganAM, LewczukP, de LeonMJ, HampelH (2015) Clinical utility of cerebrospinal fluid biomarkers in the diagnosis of early Alzheimer’s disease. Alzheimers Dement11, 58–69.
59.
MufsonEJ, Malek-AhmadiM, PerezSE, ChenK (2016) Braak staging, plaque pathology, and APOE status in elderly persons without cognitive impairment. Neurobiol Aging37, 147–153.
60.
AlmeidaRP, SchultzSA, AustinBP, BootsEA, DowlingNM, GleasonCE, BendlinBB, SagerMA, HermannBP, ZetterbergH (2015) Effect of cognitive reserve on age-related changes in cerebrospinal fluid biomarkers of Alzheimer disease. JAMA Neurol72, 699–706.
61.
HerukkaS, HelisalmiS, HallikainenM, TervoS, SoininenH, PirttiläT (2007) CSF Aβ42, Tau and phosphorylated Tau, APOE ɛ4 allele and MCI type in progressive MCI. Neurobiol Aging28, 507–514.
62.
LehtimakiT, MoilanenT, ViikariJ, AkerblomHK, EhnholmC, RonnemaaT, MarniemiJ, DahlenG, NikkariT (1990) Apolipoprotein E phenotypes in Finnish youths: A cross-sectional and 6-year follow-up study. J Lipid Res31, 487–495.
63.
KantarciK, LoweV, PrzybelskiSA, WeigandSD, SenjemML, IvnikRJ, PreboskeGM, RobertsR, GedaYE, BoeveBF, KnopmanDS, PetersenRC, JackCRJr (2012) APOE modifies the association between Abeta load and cognition in cognitively normal older adults. Neurology78, 232–240.
64.
AmarK, WilcockGK, ScottM (1996) The diagnosis of vascular dementia in the light of the new criteria. Age Ageing25, 51–55.
ScottJA, BraskieMN, TosunD, ThompsonPM, WeinerM, DeCarliC, CarmichaelOT, Alzheimer’s Disease Neuroimaging Initiative (2015) Cerebral amyloid and hypertension are independently associated with white matter lesions in elderly. Front Aging Neurosci7, 221.
67.
BurtDB, ZembarMJ, NiedereheG (1995) Depression and memory impairment: A meta-analysis of the association, its pattern, and specificity. Psychol Bull117, 285.
