Legend to Supplementary Figure 1.
A presentation of the clinical characteristics of two example pedigrees belonging to the subset
of 18 families with mixed Alzheimer disease and vascular dementia. Every generation is
represented by a Roman numeral, and each member of the generation by an Arabic numeral.
Males are represented by a square and females by a circle. Affected individuals have filled
symbols.
Supplementary Figure 1a. Pedigree A
Parents of the third generation lived until ages 81 years and 93 years without known cognitive
dysfunction.
III:1 (DZ twin)
Pernicous anemia treated with vitamin-B injections since 53 years of age and slight
hypertension. Age 65 referred because she disturbs neighbors and appears to have had
hallucinations and paranoia which she denies and she is oriented to time and place. Moves to
home for the elderly at age 70. Five years later at 74 increasing periods of confusion (at times
diagnosed as suspected be cerebral insults) and anxiety, speaks ceaselessly and loudly,
reduced short term memory, turns day into night and disturbs other patients in the service
house but still remarkably oriented to person, time and place. Diagnosed with senile dementia
at age 75. Dies just before her 76th birthday. Hachinski score=4
III:2 (DZ twin)
Onset before age 63 with forgetfulness, absent-mindedness. Since 65 years incapable of
taking care of herself and the household. Husband fed her and helped with hygiene in the
home. Incontinence before age 69. Hospitalized at age 69 with signs of dementia and heart
incompensation. Seizures and TIA at age 69. EEG abnormal with slow rhythm and diagnosis
of dementia senilis since age 69. Diabetes at age 69. Dies at age 83 and autopsy shows
characteristic distribution of plaques and tangles for Definitive AD with severe amyloid
angiopathy, In addition severe vascular changes with multiple infarctions in cortex cerebri and
white matter. The level of degeneration and vascular changes are interpreted by the
neuropathologist to be so severe that each type by itself is sufficient to explain the dementiasymptoms. Hachinski score=0
III:3
Previously healthy except a peptic ulcer. At age 70 onset of disorientation, suspiciousness and
aggressiveness. First contact with health care age 74 after rapid worsening of symptoms and
loss of memory function diagnosed as dementia of Alzheimer type. Institutionalized at age 77.
Increasing apathy. Autospy after death at age 89 shows definite AD (CERAD) with
congophilic amyloid angiopathy and vascular white matter changes. Hachinski score=1
III:4
Onset 76 years, at age 82 increasing anxiety , memory difficulties and confusion and
sometimes paranoia.Fulfils NINCDS-ADRDA criteria for probable AD. Died at age 88
without autopsy. Hachinski score=3
III:5
Previously healthy but at age 65 (according to daughter) cognitive symptoms possibly
hallucinations and at 70 already severely affected with memory difficulties and disorientation
and dismissed from his mason work. One year later anxious, emotional incontinence and
confusion treated as an agitated depression without success. A neurological consultant judges
that the patient has confusion rather than dementia at age 71. Increased memory problems age
72 and EEG shows diffuse slow activity and rare sharp waves. Age 72 diagnosed as presenile
dementia. Seizures developed age 76. Medical journals suggest the dementia to be secondary
to atherosclerosis rather than Alzheimer disease. Died age 78 from pulmonary embolism, no
autopsy. Hachinski score=5
III:6
Treated for hypertension and hypothyroidism since age 70, and diabetes type 2 since age 74
years. Onset 79 years of age memory difficulties and loss of consciousness interpreted as TIA
and CT shows bilateral occipital infarctions but EEG normal. At age 80 years she cannot take
care of herself in her home: cannot cook, gets lost, forgets stove. Gets MID diagnosis but
Mixed dementia cannot be excluded. Dies 84 years old. Hachinski score= 11
Supplementary Figure 1b. Pedigree B
III:1
Referred for dementia investigation at age 75 years with 3 years of memory complaints,
problems with wood crafting and disorientation (onset 72 years). Björk-Shiley aortic-cusp
surgery at 58 years and By-pass surgery at ages 58 and 69 years, chronic obstructive lung
disease (previous smoker). The neuropsychological testing unremarkable except for a discrete
reduction in spatial performance and short-term memory tests. CT shows slight central and
frontal cortical atrophy judged to be normal for his age. EEG: pathological with moderate,
partially episodic abnormalities in frontotemporal regions with a clear dominance on the left.
No general signs of dementia of Alzheimer type but the EEG is interpreted to be in agreement
with a multi-infarction dementia. CSF: Slightly increased T-tau and normal beta-amyloid, no
signs of BBB-dysfunction. Diagnosed with Mild-cognitive impairment at 75 years which is
converted to Alzheimer disease at age 77 years after a slow progression of memory
difficulties. He also has an episode of passing blindness which is interpreted as a TIA. Dies at
age 82 years without autopsy. Hachinski score= 3
III:2
Onset at age 62 with memory complaints (misplaces his tools, doesn’t remember names of
neighbors, and wife also notices memory disturbance). At age 66 a dementia investigation
cannot find evidence of dementia including a slightly abnormal EEG with irregularly and low
amplitude 4-7 Hz activities in lateral hemispheres with left-sided predominance and
maximum over left temporal region and an unremarkable neuropsychological test. 1 year later
a follow-up investigation cannot find any objective memory, spatial or logical impairments.
One and a half years after the original investigation, at age 68, the patient complains of
worsening memory and the neuropsychological test shows a progression of memory
complaints, signs of expressive aphasia, and apraxia i.e., predominantly left-sided signs. The
EEG is unchanged. Imaging is not performed. The clinical diagnosis at age 68 reads:
Subcortical dementia of multi-infarction type. The personality is well-preserved. Dies at age
77 without autopsy. Hachinski score=10
III:3
Wife complains about his memory problems since age 67 years. However, the patient was
knocked unconscious at age 40 in an accident and the wife thinks the patient never recovered
fully (became “slower”). The patient seeks health care for memory problems at age 72 and a
CT shows wide lateral ventricles and third ventricle i.e. cortical and central brain atrophy with
predominance in the frontal lobes and is diagnosed with Alzheimer disease. At age 73 he has
developed incontinence, rigidity and apathy and concentration difficulties and the AD
diagnosis questioned. Dies aged 74 without autopsy. Hachinski score=2.
III:4
Onset of memory complaints and disorientation at age 69 years. At age 73 he, cannot read
news papers, watch TV and has difficulties anxious, cries easily, ataxia, CT: enlarged
ventricles, and third ventricle. EEG marked diffuse abnormality with maximum
frontotemporal, neuropsychology: dementia with language, spatial and visual perception
difficulties suggestive of Alzheimer disease and concomitant frontal signs of anxiety,
restlessness, fidgety, uncritical and preservations probably secondary to subcortical
disturbance. Diagnosed with Alzheimer disease at age 73 years. Dies at age 75 years without
autopsy. Hachinski score = 3.