This is a brief summary of the findings from the Swedish study on familial Alzheimer’s disease (FAD). Similar to other FAD studies, it includes prospective assessments of cognitive function, tissue sampling, and technical analyses such as MRI and PET. This 24-year-old study involves 69 individuals with a 50% risk of inheriting a disease-causing mutation in presenilin 1 (PSEN1 H163Y or I143T), or amyloid precursor protein (the Swedish APP or the arctic APP mutation) who have made a total of 169 visits. Our results show the extraordinary power in this study design to unravel the earliest changes in preclinical AD. The Swedish FAD study will continue and future research will focus on disentangling the order of pathological change using longitudinal data as well as modeling the changes in patient derived cell systems.
GoateA, ChartierharlinMC, MullanM, BrownJ, CrawfordF, FidaniL, GiuffraL, HaynesA, IrvingN, JamesL, MantR, NewtonP, RookeK, RoquesP, TalbotC, PericakvanceM, RosesA, WilliamsonR, RossorM, OwenM, HardyJ (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease, Nature349, 704–706.
2.
ChartierharlinMC, CrawfordF, HouldenH, WarrenA, HughesD, FidaniL, GoateA, RossorM, RoquesP, HardyJ, MullanM (1991) Early-onset Alzheimer’s disease caused by mutations at codon-717 of the beta-amyloid precursor protein gene, Nature353, 844–846.
3.
MurrellJ, FarlowM, GhettiB, BensonMD (1991) A mutation in the amyloid precursor protein associated with hereditary Alzheimer’s disease, Science254, 97–99.
Bird T. Early-onset familial Alzheimer disease. GeneReviews. https://www.ncbi.nlm.nih.gov/books/NBK1236/
7.
WahlundLO, BasunH, AlmkvistO, JulinP, AxelmanK, ShigetaM, JelicV, NordbergA, LannfeltL (1999) A follow-up study of the family with the Swedish APP 670/671 Alzheimer’s disease mutation, Dement Geriatr Cogn Disord10, 526–533.
8.
AlmkvistO, AxelmanK, BasunH, JensenM, ViitanenM, WahlundLO, LannfeltL (2003) Clinical findings in nondemented mutation carriers predisposed to Alzheimer’s disease: A model of mild cognitive impairment, Acta Neurol Scand107, 77–82.
9.
KellerL, WelanderH, ChiangHH, TjernbergLO, NennesmoI, WallinAK, GraffC (2010) The PSEN1 I143T mutation in a Swedish family with Alzheimer’s disease: Clinical report and quantification of A beta in different brain regions, Eur J Hum Genet18, 1202–1208.
10.
BlennowK, HampelH, WeinerM, ZetterbergH (2010) Cerebrospinal fluid and plasma biomarkers in Alzheimer disease, Nat Rev Neurol6, 131–144.
11.
ThordardottirS, StahlbomAK, FerreiraD, AlmkvistO, WestmanE, ZetterbergH, EriksdotterM, BlennowK, GraffC (2015) Preclinical cerebrospinal fluid and volumetric magnetic resonance imaging biomarkers in Swedish familial Alzheimer’s disease, J Alzheimers Dis43, 1393–1402.
RingmanJM, CoppolaG, ElashoffD, Rodriguez-AgudeloY, MedinaLD, GylysK, CummingsJL, ColeGM (2012) Cerebrospinal fluid biomarkers and proximity to diagnosis in preclinical familial Alzheimer’s disease, Dement Geriatr Cogn Disord33, 1–5.
15.
WahlundLO, JulinP, JohanssonSE, ScheltensP (2000) Visual rating and volumetry of the medial temporal lobe on magnetic resonance imaging in dementia: A comparative study, J Neurol Neurosurg Psychiatry69, 630–635.
16.
DuaraR, LoewensteinDA, PotterE, AppelJ, GreigMT, UrsR, ShenQ, RajA, SmallB, BarkerW, SchofieldE, WuY, PotterH (2008) Medial temporal lobe atrophy on MRI scans and the diagnosis of Alzheimer disease, Neurology71, 1986–1992.
17.
ScheltensP, LaunerLJ, BarkhofF, WeinsteinHC, VangoolWA (1995) Visual assessment of medial temporal-lobe atrophy on magnetic-resonance-imaging - interobserver reliability, J Neurol242, 557–560.
LiX, WestmanE, StahlbomAK, ThordardottirS, AlmkvistO, BlennowK, WahlundLO, GraffC (2015) White matter changes in familial Alzheimer’s disease, J Intern Med278, 211–218.
20.
GreiciusMD, SrivastavaG, ReissAL, MenonV (2004) Default-mode network activity distinguishes Alzheimer’s disease from healthy aging: Evidence from functional MRI, Proc Natl Acad Sci U S A101, 4637–4642.
21.
ShelineYI, RaichleME (2013) Resting state functional connectivity in preclinical Alzheimer’s disease, Biol Psychiatry74, 340–347.
22.
BinnewijzendMAA, SchoonheimMM, Sanz-ArigitaE, WinkAM, van der FlierWM, TolboomN, AdriaanseSM, DamoiseauxJS, ScheltensP, van BerckelBNM, BarkhofF (2012) Resting-state fMRI changes in Alzheimer’s disease and mild cognitive impairment, Neurobiol Aging33, 2018–2028.
23.
LiXZ, WestmanE, ThordardottirS, StahlbomAK, AlmkvistO, BlennowK, WahlundLO, GraffC (2017) The effects of gene mutations on default mode network in familial Alzheimer’s disease, J Alzheimers Dis56, 327–334.
24.
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.
25.
SchollM, AlmkvistO, AxelmanK, StefanovaE, WallA, WestmanE, LangstromB, LannfeltL, GraffC, NordbergA (2011) Glucose metabolism and PIB binding in carriers of a His163Tyr presenilin 1 mutation, Neurobiol Aging32, 1388–1399.
PeraniD, GrassiF, SorbiS, NacmiasB, PiacentiniS, PiersantiP, ProvincialiL, AmaducciL, FazioF (1997) PET study in subjects from two Italian FAD families with APP717 Val to Ileu mutation, Eur J Neurol4, 214–220.
28.
MarutleA, GillbergPG, BergforsA, YuWF, NiRQ, NennesmoI, VoytenkoL, NordbergA (2013) H-3-Deprenyl and H-3-PIB autoradiography show different laminar distributions of astroglia and fibrillar beta-amyloid in Alzheimer brain, J Neuroinflammation10, 15.
29.
JossanSS, GillbergPG, DargyR, AquiloniusSM, LangstromB, HalldinC, OrelandL (1991) Quantitative localization of human brain monoamine oxidase-b by large section autoradiography using L- H-3 deprenyl, Brain Res547, 69–76.
30.
KadirA, MarutleA, GonzalezD, SchollM, AlmkvistO, MousaviM, MustafizT, Darreh-ShoriT, NennesmoI, NordbergA (2011) Positron emission tomography imaging and clinical progression in relation to molecular pathology in the first Pittsburgh Compound B positron emission tomography patient with Alzheimer’s disease, Brain134, 301–317.
31.
TongJC, MeyerJH, FurukawaY, BoileauI, ChangLJ, WilsonAA, HouleS, KishSJ (2013) Distribution of monoamine oxidase proteins in human brain: Imlications for brain imaging studies. J Cereb Blood Flow Metab33, 863–871.
