Looking Behind the Curtain: Patient Stratification According to Genetic or Demographic Factors May Yield Unexpected Results in Studies of Neurodegenerative Diseases
Restricted accessArticle commentaryFirst published online July 18, 2023
Looking Behind the Curtain: Patient Stratification According to Genetic or Demographic Factors May Yield Unexpected Results in Studies of Neurodegenerative Diseases
Amyloid-PET studies of neurodegenerative diseases may yield inconclusive findings due to lacking stratification according to genetic or demographic variants. APOEɛ4 alleles are the major variants to increase disease susceptibility and cause earlier onset and more behavioral features in patients with late-onset Alzheimer’s disease, but have no linear effects on cognitive or functional decline; thus, sample stratification according to APOEɛ4 carrier status may be the best option. Interactions among APOEɛ4 alleles, sex, and age on amyloid-β deposition may reveal even more innovative findings with sufficiently large samples, suggesting variable genomic effects of cognitive reserve, sex differences, and cerebrovascular risk on neurodegeneration.
BlossCS, DelisDC, SalmonDP, BondiMW (2010) APOE genotype is associated with left-handedness and visuospatial skills in children. Neurobiol Aging31, 787–795.
2.
GozalD, CapdevilaOS, Kheirandish-GozalL, McLaughlin CrabtreeV (2007) ɛ4 allele, cognitive dysfunction, and obstructive sleep apnea in children. Neurology69, 243–249.
3.
RosenAC, AriasJJ, AshfordJW, BlackerD, ChhatwalJP, ChinNA, ClarkL, DennySS, GoldmanJ, GleasonCE, GrillJD, HeidebrinkJL, HendersonVW, LavacotJA, LinglerJH, MenonM, NoshenyRL, OliveiraFF, ParkerMW, Rahman-FilipiakA, RevooriA, RumbaughM, SanchezD, SchindlerSE, SchwarzCG, ToyL, TyroneJ, WalterS, WangLS, WijsmanEM, ZallenDT, AggarwalNT (2022) The advisory group on risk evidence education for dementia: Multidisciplinary and open to all. J Alzheimers Dis90, 953–962.
4.
De OliveiraFF, BertolucciPHF, ChenES, SmithMC (2014) Risk factors for age at onset of dementia due to Alzheimer’s disease in a sample of patients with low mean schooling from São Paulo, Brazil. Int J Geriatr Psychiatry29, 1033–1039.
5.
SilvaNCBS, BrackoO, NelsonA, OliveiraFF, RobisonL, ShaabanCE, HainsworthAH, PriceBR (2022) Vascular cognitive impairment and dementia: An early career researcher perspective. Alzheimers Dement (Amst)14, e12310.
6.
ScheltensP, De StrooperB, KivipeltoM, HolstegeH, ChetélatG, TeunissenCE, CummingsJ, van der FlierWM (2021) Alzheimer’sdisease. Lancet397, 1577–1590.
7.
MartinsCAR, OulhajA, de JagerCA, WilliamsJH (2005) APOE alleles predict the rate of cognitive decline in Alzheimer disease - A nonlinear model, Neurology65, 1888–1893.
8.
SelkoeDJ, HardyJ (2016) The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med8, 595–608.
9.
De OliveiraFF, PiviGAK, ChenES, SmithMC, BertolucciPHF (2015) Risk factors for cognitive and functional change in one year in patients with Alzheimer’s disease dementia from São Paulo, Brazil. J Neurol Sci359, 127–132.
10.
De OliveiraFF, PereiraFV, PiviGAK, SmithMC, BertolucciPHF (2018) Effects of APOE haplotypes and measures of cardiovascular risk over gender-dependent cognitive and functional changes in one year in Alzheimer’s disease. Int J Neurosci128, 472–476.
11.
OliveiraFF, ChenES, SmithMC, BertolucciPH (2017) Associations of cerebrovascular metabolism genotypes with neuropsychiatric symptoms and age at onset of Alzheimer’s disease dementia. Rev Bras Psiquiatr39, 95–103.
12.
OliveiraFF, ChenES, SmithMC, BertolucciPHF (2016) Predictors of cognitive and functional decline in patients with Alzheimer disease dementia from Brazil. Alzheimer Dis Assoc Disord30, 243–250.
WangJ, WangM, RenS, HuangL, HeK, LiJ, HuaF, GuanY, GuoQ, HuangQ, XieF (2023) The effect of gender and APOEɛ4 status on brain amyloid-β deposition in different age groups of mild cognitively impaired individuals: A PET-CT study. J Alzheimers Dis94, 763–775.
15.
VisserPJ, KnopmanDS (2009) Amyloid imaging in the prediction of Alzheimer-type dementia in subjects with amnestic MCI. Neurology73, 744–745.
16.
NordbergA (2004) PET imaging of amyloid in Alzheimer’s disease. Lancet Neurol3, 519–527.
17.
MoscosoA, GrotheMJ, AshtonNJ, KarikariTK, RodriguezJL, SnellmanA, Suárez-CalvetM, ZetterbergH, BlennowK, SchöllM (2021) Time course of phosphorylated-tau181 in blood across the Alzheimer’sdisease spectrum. Brain144, 325–329.
18.
De OliveiraFF, ChenES, SmithMC, BertolucciPHF (2020) Selected LDLR and APOE polymorphisms affect cognitive and functional response to lipophilic statins in Alzheimer’s disease. J Mol Neurosci70, 1574–1588.
19.
De OliveiraFF, BertolucciPHF, ChenES, SmithMC (2022) Pharmacogenetic analyses of therapeutic effects of lipophilic statins on cognitive and functional changes in Alzheimer’s disease. J Alzheimers Dis87, 359–372.
20.
De OliveiraFF, ChenES, SmithMC, BertolucciPHF (2018) Pharmacogenetics of angiotensin-converting enzyme inhibitors in patients with Alzheimer’s disease dementia. Curr Alzheimer Res15, 386–398.
21.
De OliveiraFF, ChenES, SmithMC, BertolucciPHF (2016) Associations of blood pressure with functional and cognitive changes in patients with Alzheimer’s disease. Dement Geriatr Cogn Disord41, 314–323.
22.
De OliveiraFF, ChenES, SmithMC, BertolucciPHF (2017) Longitudinal lipid profile variations and clinical change in Alzheimer’s disease dementia. Neurosci Lett646, 36–42.
23.
De OliveiraFF, de AlmeidaSS, ChenES, SmithMC, BertolucciPHF (2022) APOE ɛ4 carrier status as mediator of effects of psychotropic drugs on clinical changes in patients with Alzheimer’s disease. J Neuropsychiatry Clin Neurosci34, 351–360.
24.
YangHS, YuL, WhiteCC, ChibnikLB, ChhatwalJP, SperlingRA, BennettDA, SchneiderJA, De JagerPJ (2018) Evaluation of TDP-43 proteinopathy and hippocampal sclerosis in relation to APOEɛ4 haplotype status: A community-based cohort study. Lancet Neurol17, 773–781.
25.
De OliveiraFF, MiraldoMC, De Castro-NetoEF, AlmeidaSS, MatasSLA, BertolucciPHF, Naffah-MazzacorattiMG (2021) Associations of neuropsychiatric features with cerebrospinal fluid biomarkers of amyloidogenesis and neurodegeneration in dementia with Lewy bodies compared with Alzheimer’s disease and cognitively healthy people. J Alzheimers Dis81, 1295–1309.
26.
OliveiraFF, AlmeidaSS, SmithMAC, BertolucciPHF (2021) Behavioural effects of the ACE insertion/deletion polymorphism in Alzheimer’s disease depend upon stratification according toAPOE-ɛ4 carrier status. Cogn Neuropsychiatr26, 293–305.
27.
MartersteckA, MurphyC, RademakerA, WienekeC, WeintraubS, ChenK, MesulamMM, RogalskiE (2016) Is in vivo amyloid distribution asymmetric in primary progressive aphasia?Ann Neurol79, 496–501.
28.
Garnier-CroussardA, BougachaS, WirthM, DautricourtS, SherifS, LandeauB, GonneaudJ, De FloresR, de la SayetteV, VivienD, Krolak-SalmonP, ChételatG (2022) White matter hyperintensity topography in Alzheimer’s disease and links to cognition. Alzheimers Dement18, 422–433.
29.
LehmannM, GhoshPM, MadisonC, LaforceRJr, Corbetta-RastelliC, WeinerMW, GreiciusMD, SeeleyWW, Gorno-TempiniML, RosenHJ, MillerBL, JagustWJ, RabinoviciGD (2013) Diverging patterns of amyloid deposition and hypometabolism in clinical variants of probable Alzheimer’s disease. Brain136, 844–858.
30.
SintiniI, Graff-RadfordJ, JonesDT, BothaH, MartinPR, MachuldaMM, SchwarzCG, SenjemML, GunterJL, JackCRJr, LoweVJ, JosephsKA, WhitwellJL (2021) Tau and amyloid relationships with resting-state functional connectivity in atypical Alzheimer’s disease. Cereb Cortex31, 1693–1706.
31.
FranzmeierN, DewenterA, FrontzkowskiL, DichgansM, RubinskiA, NeitzelJ, SmithR, StrandbergO, OssenkoppeleR, BuergerK, DueringM, HanssonO, EwersM (2020) Patient-centered connectivity-based prediction of tau pathology spread in Alzheimer’s disease. Sci Adv6, eabd1327.
32.
MeccaAP, O’DellRS, SharpES, BanksER, BartlettHH, ZhaoW, LipiorS, DiepenbrockNG, ChenMK, NaganawaM, ToyonagaT, NabulsiNB, WykBCV, ArnstenAFT, HuangY, CarsonRE, van DyckCH (2022) Synaptic density and cognitive performance in Alzheimer’s disease: A PET imaging study with [11C]UCB-J. Alzheimers Dement18, 2527–2536.
33.
YoungCB, WinerJR, YounesK, CodyKA, BetthauserTJ, JohnsonSC, SchultzA, SperlingRA, GreiciusMD, CobosI, PostonKL, MorminoEC (2022) Divergent cortical tau positron emission tomography patterns among patients with preclinical Alzheimer disease. JAMA Neurol79, 592–603.
StageE, RisacherSL, LaneKA, GaoS, NhoK, SaykinAJ, ApostolovaLG (2022) Association of the top 20 Alzheimer’s disease risk genes with [18F]flortaucipir PET. Alzheimers Dement (Amst)14, e12308.
36.
BetthauserTJ, BilgelM, KoscikRL, JedynakBM, AnY, KellettKA, MoghekarA, JonaitisEM, StoneCK, EngelmanCD, AsthanaS, ChristianBT, WongDF, AlbertM, ResnickSM, JohnsonSC (2022) Multi-method investigation of factors influencing amyloid onset and impairment in three cohorts. Brain145, 4065–4079.
