www.gu.s

e

Preclinical dementia –

Implications for prevention

Ingmar Skoog

Föreståndare för AGECAP Centrum i Göteborg

Neuropsykiatrisk Epidemiologi

Institutionen för Klinisk Neurovetenskap och Fysiologi

Sahlgrenska Akademin

Göteborgs Universitet

Sahlgrenska akademin

Neuropsychiatric Epidemiology

EPINEP

www.gu.se

CENTRE FOR AGEING AND HEALTH

- AGECAP

EPINEP Neuropsychiatric

Epidemiology Department of Psychiatry and Neurochemistry

Institute of Neuroscience and Physiology

Sahlgrenska Academy

University of Gothenburg

Research Group Leader: Ingmar Skoog

www.epinep.gu.se

Seniora Forskare

Margda Waern

Svante Östling

Anna Zettergren

Silke Kern

Hanna Falk

Elisabet Rothenberg

Kerstin Frändin

Tore Hällström

Ingvar Karlsson

Deborah Gustafson

Disputerade forskare

Pia Gudmundsson

Xinxin Guo

Helena Hörder

Lena Johansson

Jürgen Kern

Madeleine Mellqvist Fässberg

Simona Sacuíu

Robert Sigström

Stefan Wiktorsson

Daniel Jaraj

Doktorander

Jenna Al-Najjar

Erik Joas

Isak Fredén Klenfeldt

Johan Nilsson

Mats Ribbe

Therese Rydberg

Johan Skoog

Felicia Nord

Hanna Wetterberg

Lina Rydén

Jessica Samuelsson

Vetenskaplig koordinator

Anna Zettergren

Administrativ koordinator

Tina Jacobsson

Statistiker

Valter Sundh

Erik Joas

Yadi Nejad

Nazib Seidu

Gothenburg

NEUROPSYCHIATRIC EPIDEMIOLOGY

THE GOTHENBURG H70 BIRTH COHORT STUDIES

Demented

(N) %

Men (N=75) 37

Women (N=263) 56 *

•H70-study

•H85-study

•The 95+ Study

•The Prospective Population Study of Women (PPSW)

•Representative samples based on birth dates

H70

(Total N=6200)

Ålder 70 75 79 81 83 85 88 90 92 95 97 99 100 101

1901-02 + + + + + + + + + + + + + +

1906-07 + + +

1911-12 + +

1922 + + + +

1930 + + + + (+)

1944 + (+)(+) (+)

Systematic samples of 70-year-olds living in Gothenburg sampled from the Swedish

Population Register selected based on birth dates (e.g. 2, 5, 8, 12, 15, 18 etc)

H85 GÖTEBORG

(Total N=1556)

Age 85 88 90 92 95 97 99

1901-02 + + + + + + +

1923-24 + + + +

1930 + (+) (+)

Systematic samples from the Swedish Population Register

selected based on birth dates (e.g. 2, 5, 8, 12, 15, 18 etc)

Prospective Population Study of Women

in Gothenburg

Year of examination and ages studied

Cohort 1968 1974 1981 1992 2000 2005 2010 2016

1908 60 66 73 84 92 97 101 108

1914 54 60 67 78 86 91 95 102

1918 50 56 63 74 82 87 91 98

1922 46 52 59 70 78 83 87 94

1930 38 44 51 62 70 75 79 86

N 1462 661 580 450 250

•Neuropsychiatric examination

•Key informant interview

•Medical examination (somatic disorders, alcohol, smoking)

•Functional ability (ADL, iADL)

•Anthropometry (length, weight etc)

•Social interview (social network, physical, social and cultural activities, life

events, working life etc)

•Psychometric testings

•Personality (Eysenck, Five Factor, KASAM)

•Focus groups

•Gender

•Blood, serum, plasma

•Genetic analyses

•ECG, blood pressure

•Lung function

•Physical function (walking speed, hand grip, balance, chair stand etc)

•Audiology

•Ophtalmology

•Dietary examination, DEXA (bone, muscle, fat)

•CT and MRI of brain

•Lumbar puncture/ Neurochemistry

General examinations

MRI (N=850)

3 teslas MRI

Usual MR-sequences (T1, T2, FLAIR)

Newer techniques

Susceptibility weighted imaging

Diffusion tension imaging

Resting state fMRI (‘default mode network’)

MRI CSF Cognitive function Psychiatric disorders Personality

Dexa (fat, muscle, bones) ECG Blood samples Genetic factors

External factors

www.gu.se

Preclinical dementia

Life-course epidemiology

0 100

= risk factor

= protective Preclinical

AD Dementia

CLINICAL COURSE OF ALZHEIMERS DISEASE

Dementia

Memory

Language

ADL

Social ability

Spatial ability

Aggressivness

Apathy

Personality changes

Cerebrospinal fluid markers in

Alzheimer’s disease

Low beta-amyloid-42

High total tau

High phospho-tau

Jack et al. Lancet Neurology 2013

Temporal ordering of the pathological processes of AD

CSF-abeta

CSF-tau

MRI atrophy

Memory

MCI

Dementia

PET amyloid

PET tau

0 20 Duration years

Preclinical AD

Jack et al. Lancet Neurology 2013

Risk factors and

initiators

Accelerators

Deaccelerators

Time line of pathological processes in AD

How common is preclinical AD?

Preclinical dementia in CSF (Dubois criteria)

in a population sample of 70-year-olds

with CDR 0

%

Pathological beta-amyloid-42 23

Pathological total-tau 33

Pathological p-tau 7

Precliniscal Alzheimer

(amyloid AND tau pathology)

10

Any Alzheimerpathology 46

Kern, Skoog et al Neurology 2018

Venn diagram of the ATN distribution of amyloid and tau pathology of 70-year-

olds with CDR 0.

CENTRE FOR AGEING AND HEALTH

- AGECAP

Kern et al. Neurology 2018

Kern, Skoog et al Neurology 2018

ApoE e4 Low beta-amyloid 42

70-year-olds born 1944 with CDR 0

Male sex Higher total-tau

Poor sleep Low CSF Beta-amyloid 42

Skoog J et al 2018

70-year-olds born 1944

Higher

CSF t-tau, p-tau, neurogranin

Lower CSF Beta-amyloid 42

Individuals with ApoE e4

Poor sleep

When does AD start?

And when is it a disorder?

The Prospective Population Study of

Women

Ages at examination

Year of examination and ages of participants

Cohort 1968 1974 1981 1992 2000 2005 2009

1908 60 66 73 84 92 97 101

1914 54 60 67 78 86 91 95

1918 50 56 63 74 82 87 91

1922 46 52 59 70 78 83 87

1930 38 44 51 62 70 75 79

N 1462 86

CSF-biomarkers in 1992 in relation to

dementia during 18-year follow-up

No

dementia

Dementia onset

Year of follow-

up

0-18 years

(N=62)

0-8

years

(N=6)

9-13

years

(N=10)

14-18

years

(N=8)

Beta-amyloid

1-42

865.2 655.2* 648.0** 767.5*

Total tau 321.3 546.3* 311.5 235.3

Skoog, Kern, Blennow, Zetterberg 2018

Red squares=Alzheimer's, Green=vascular dementia, circles=not dementia

0

200

400

600

800

1000

1200

1400

0 20 40 60 80 100 120 140

Am

ylo

id-β

42

Tau

Amyloid-β 42 and t-Tau from CSF 1992 and development of dementia until 2009

Dementia Alzheimer’s disease

1992-2000 1992-2005 1992-2010 1992-2000 1992-2005 1992-2010

Sensitivity 83.3 83.3 73.1 100.0 100 94.1

Specificity 60.0 60.0 60.0 60.0 60.0 60.0

PPV 17.2 38.5 44.2 17.2 33.3 40.0

NPV 97.3 92.3 83.7 100.0 100.0 97.3

Skoog et al 2018

Sensitivity, specificity, PPV and NPV

for below median of beta-amyloid in

relation to dementia during 18 years

follow-up

Pathological beta-amyloid 5/12 became demented

What happens very early in the

disease process?

H85 GÖTEBORG

(Total N=1556)

Age 85 88 90 92 95 97 99

1901-02 + + + + + + +

1923-24 + + + +

1930 + (+) (+)

Systematic samples from the Swedish Population Register

selected based on birth dates (e.g. 2, 5, 8, 12, 15, 18 etc)

THE SAHLGRENSKA ACADEMY

Concomitant pathology biomarkers • Total tau- a marker for neuronal damage

– A microtubule binding protein promoting stability

– Major increases in CSF from patients with CJD

– Increases after acute stroke

– 2-3-fold increased in AD

• Neurogranin- a marker for synaptic degeneration

– a postsynaptic protein involved in the regulation of synaptic signaling

through its binding to calmodulin at low levels of calcium

– CSF levels significantly increased in MCI and AD

- High CSF levels correlate with a more rapid change in cognition during

clinical follow-up (Kvartsberg et al 2014).

31 Höglund et al. Transl Psychiatry 2017

THE SAHLGRENSKA ACADEMY

Concomitant pathology biomarkers

• P-Tau(181)- a marker for tangle pathology

– Phosphorylation of tau regulates binding to microtubule

– Hyperphosphorylation of tau seem to be specific to AD

– 2-3fold increases in CSF in AD

• YKL-40 (chitinase 3-like-1)- a marker for reactive astrocytes

– Increased in CSF in AD and FTD

– Increases in CSF may suggest future cognitive decline (Craig-Shapiro et

al 2011)

Höglund et al. Transl Psychiatry 2017

THE SAHLGRENSKA ACADEMY

Healthy elderly with amyloid pathology also display signs of neuronal damage (total tau) and tangle pathology (p-tau)

Höglund et al. Transl Psychiatry 2017

total tau, p< 0.001 p-tau, p< 0.001

THE SAHLGRENSKA ACADEMY

Healthy elderly with amyloid pathology also display signs of inflammation (YKL-40) and synaptic damage (neurogranin)

Höglund et al. Transl Psychiatry 2017

YKL-40, p< 0.044 Neurogranin, p< 0.011

THE SAHLGRENSKA ACADEMY

Cognitively healthy elderly individuals with amyloid pathology display:

• neuronal damage (t-tau and neurogranin),

• tangle pathology (p-tau) and

• microglial activation (YKL-40).

Höglund et al. Transl Psychiatry 2017

THE SAHLGRENSKA ACADEMY

WHAT ABOUT VASCULAR FACTORS IN PRECLINICAL AD?

Ischemic white matter lesions a

silent disease of the brain

Permission from Philip Scheltens

White matter lesions on MRI

WHITE MATTER LESIONS ON CT

Demented

(N) %

Men (N=75) 37

Women (N=263) 56 *

Permission from Arne Brun

Permission from Arne Brun

Prevalence of WMLs in normal

elderly

MRI: 50-100% depending on age and scale

CT: 55-70% depending on age and scale

White matter lesions on CT and

the development of

dementia during a 10 year follow-up

OR (95%-CI)

Depression 3.8 (1.3-7.2)

Dementia 4.0 (1.2-11.8)

Gudmundsson et al. Eur J Neurol 2015

The relation between CSF beta-amyloid-42 and

severity of WMLs and brain atrophy in individuals

with and without dementia

Individuals

Without dementia

(N=29)

With dementia

(N=22)

Interaction with

dementia

p

Frontal atrophy 0.12 -0.52* 0.02

Temporal atrophy -0.15 -0.70*** 0.03

Parietal atrophy -0.13 -0.59*** 0.11

WMLs -0.39** 0.03 0.10

Skoog, et al. J Alz Dis 2018

DENSITY OF SENILE PLAQUES

IN PARAHIPPOCAMPAL GYRUS (number/mm2) IN

MIDDLE-AGED INDIVIDUALS

Controls 5

Hypertension 17*

Coronary artery 9*

CAD/Hypertension 14*

Alzheimer 34*

Sparks et al J Neurol Sci 1995; 131:162-169

Thus, early interaction between

vascular factors and amyloid

Jack et al. Lancet Neurology 2013

Temporal ordering of the pathological processes of AD

WMLs

Hypertension

?

?

Life-time perspective

Life-course epidemiology

0 100

= risk factor

= protective Preclinical

AD

Severe psychological stress in middle-

aged women 1968-80 in relation to

development of dementia up to 2000

Severe

stress

OR (95%-CI)

1968 1.6 (1.1-2.3)

1974 1.6 (1.1-2.3)

1980 1.6 (1.0-2.6)

Stress

1968-80

2.4 (1.2-4.7)

Johansson et al Brain 2010

Severe psychological stress 1968-80

in relation to WMLs in 2000 Severe

stress

OR (95%-CI)

1968 1.7 (0.8-3.6)

1974 1.2 (0.6-2.4)

1980 3.0 (1.4-6.2)

Stress

1968-80

2.2 (1.0-4.5)

Johansson et al Psychosomatic Med 2012

Midlife psychosocial stress 1968-1980

Higher total-tau, VILIP-1, MBP in 1992

Johansson et al Dement Geriatr Cogn Disord. 2018;46(1-2):90-99

VILIP-1 = visinin-like protein 1

MBP= myelin basic protein

Stress and negative events may lead to a life-

long increased level of cortisol

Increased cortisol may lead to damage in the

brain, especially in the hippocampus

Thus, when does the disease start?

Life-time depression and risk of dementia over 44 years

Dem (N)/Depr (N) Dementia

HR 95%CI

Depression onset <20 year

Depression onset 20-49 year

Depression onset 50-69 year

Depression onset ≥70

12/33 (36%)

63/327 (19%)

8/58 (14%)

22/64 (34%)

3.35 (1.70-6.59)

1.66 (1.06-2.59)

0.97 (0.44-2.13)

2.16 (1.22-3.79)

Table (n=713, AD=133 (18%))

HR compared to persons with no depression (28/248,

11%); Adj to age, education, ApoE4 presence

Johansson, Skoog et al 2018

Dementia

subtypes

Risk

variable

Years Incident

at risk cases HR (95% CI)

All dementia1

Intellectual

Physical

6792 109

0·75 (0·58–0·96)

0·61 (0·39–0·96)

Alzheimer’s

disease2

Artistic

6363 55

0·63 (0·42–0·93)

Vascular

dementia3

Club

Physical

5929 25

1·79 (1·04–3·10)

0·39 (0·16–0·96)

Mixed

dementia4

Intellectual

Physical

5883 19

0·24 (0·08–0·69)

0·32 (0·12–0·85)

Al-Najjar et al. 2018

Relationships between specific cognitive engagements and

physical activity in midlife 1968 and dementia in ages 70-84

years

Working capacity at ergometer bicycle in 1968

in relation to dementia incidence 19868-2012

Working

capacity

Dementia

HR (95%-CI)

High 0.13 (0.03-0.56)

Medium 1.0

Low 3.1 (1.4-6.8)

Hörder et al Neurology 2018

Jack et al. Lancet Neurology 2013

Time line of pathological processes in AD

Risk factors and

initiators

Accelerators

Deaccelerators

Non-brain markers of preclinical

AD

Blood pressure trajectories in relation to

late life dementia in women followed for 38 years

Joas et al. Hypertension 2012

A 15-year follow-up of

blood pressure and Alzheimer’s disease

Demented

(N) %

Men (N=75) 37

Women (N=263) 56 *

Skoog et al. Lancet 1996

Trajectories of BMI over 37 years in women

in relation to late-life dementia

Gustafson et al. J Alz Dis (2012)

CSF-abeta

CSF-tau

MRI atrophy

Memory

MCI

Dementia

PET amyloid

PET tau

0 20 Duration years

Preclinical AD

ApoE e4, poor sleep

Psychosocial stress Vascular factors

Hypertension

WMLs Lower bloood pressure

Life-course perspective Dynamic influences from birth to old age

Windows of oppurtunity for prevention?

Dementia can be prevented

We do not know enough on when, where and how the

effects takes place

Most epidemiological studies on risk factors are less

than 20 years

Most prevention studies are less than 5 years

We need to rely more on data from observational

studies for public prevention programs

RCTs are over-rated and should be used with care

Possible preventive factors

• Treat vascular disorders and risk factors

• Fitness

• Physical activity

• Cognitive activity

• Decrease stress

• Treat neuroticism

• Sleep well

• Healthy diet

• Increase education

Vascular risk factors for AD

ApoE e4 (1993)

Hypertension (1996)

Hypercholesterolemi (1997)

Diabetes mellitus (1997)

Atheroscleros (1997)

Overweight (2003)

Sahlgrenska akademin

Neuropsychiatric Epidemiology

EPINEP

http://iagger2019.se

See you in Gothenburg!