White matter hyperintensities are a prominent feature of autosomal dominant Alzheimer’s disease that emerge prior to dementia

Ask your doctor EXACTLY what to do to prevent problems from these white matter hyperintensities.

My doctor told me I had a bunch of white matter hyperintensities but never showed me them on any scan, so I don't know the size, location or any intervention needed, because my doctor knew nothing and did nothing. I have zero cognitive impairment and I'm 16 years out.

White matter hyperintensities are a prominent feature of autosomal dominant Alzheimer’s disease that emerge prior to dementia

• Dorothee Schoemaker,
• Maria Clara Zanon Zotin,
• Kewei Chen,
• Kay C. Igwe,
• Clara Vila-Castelar,
• Jairo Martinez,
• Ana Baena,
• Joshua T. Fox-Fuller,
• Francisco Lopera,
• Eric M. Reiman,
• Adam M. Brickman &
• Yakeel T. Quiroz 

Alzheimer's Research & Therapy volume 14, Article number: 89 (2022) Cite this article

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Abstract

Background

To promote the development of effective therapies, there is an important need to characterize the full spectrum of neuropathological changes associated with Alzheimer’s disease. In line with this need, this study examined white matter abnormalities in individuals with early-onset autosomal dominant Alzheimer’s disease, in relation to age and symptom severity.

Methods

This is a cross-sectional analysis of data collected in members of a large kindred with a PSEN1 E280A mutation. Participants were recruited between September 2011 and July 2012 from the Colombian Alzheimer’s Prevention Initiative registry. The studied cohort comprised 50 participants aged between 20 and 55 years, including 20 cognitively unimpaired mutation carriers, 9 cognitively impaired mutation carriers, and 21 non-carriers. Participants completed an MRI, a lumbar puncture for cerebrospinal fluid collection, a florbetapir PET scan, and neurological and neuropsychological examinations. The volume of white matter hyperintensities (WMH) was compared between cognitively unimpaired carriers, cognitively impaired carriers, and non-carriers. Relationships between WMH, age, and cognitive performance were further examined in mutation carriers.

Results

The mean (SD) age of participants was 35.8 (9.6) years and 64% were women. Cardiovascular risk factors were uncommon and did not differ across groups. Cognitively impaired carriers [median, 6.37; interquartile range (IQR), 9.15] had an increased volume of WMH compared to both cognitively unimpaired carriers [median, 0.85; IQR, 0.79] and non-carriers [median, 1.07; IQR, 0.71]. In mutation carriers, the volume of WMH strongly correlated with cognition and age, with evidence for an accelerated rate of changes after the age of 43 years, 1 year earlier than the estimated median age of symptom onset. In multivariable regression models including cortical amyloid retention, superior parietal lobe cortical thickness, and cerebrospinal fluid phospho-tau, the volume of WMH was the only biomarker independently and significantly contributing to the total explained variance in cognitive performance.

Conclusions

The volume of WMH is increased among individuals with symptomatic autosomal-dominant Alzheimer’s disease, begins to increase prior to clinical symptom onset, and is an independent determinant of cognitive performance in this group. These findings suggest that WMH are a key component of autosomal-dominant Alzheimer’s disease that is closely related to the progression of clinical symptoms.

Background

Cerebrovascular changes, including white matter hyperintensities (WMH), cerebral microbleeds, and lacunar infarcts, are prominent features of Alzheimer’s disease (AD) [1], contributing to the rate of cognitive decline across disease stages [2,3,4]. In patients with AD, WMH typically precede the onset of clinical symptoms [5, 6] and become more prominent over time, with advancing disease severity [5, 7]. White matter hyperintensities are also observed in individuals with early-onset autosomal-dominant AD (ADAD) [5, 8,9,10], a population characterized by a younger age of symptom onset and a low frequency of vascular risk factors. This evidence suggests that the presence of WMH is not solely explained by aging or age-related comorbidities but is rather implicated in AD pathogenesis [11].

Yet, little is known about the trajectory of WMH from the asymptomatic to symptomatic disease stages. Past efforts to characterize relationships among age, cognitive symptoms, and WMH in patients with late-onset sporadic AD are confounded by the high frequency of age-related comorbidities in this population [12]. Investigating these associations in younger individuals with a deterministic genetic mutation for AD, presenting low levels of cardiovascular risk factors, offers a unique opportunity to determine whether the presence of WMH is a core independent feature of AD and characterize the temporal relationship between the emergence of WMH and clinical symptom onset.

Relying on data from a homogeneous cohort of individuals carrying the Presenilin 1 (PSEN1) E280A mutation leading to ADAD, this study examined the severity of WMH in relation to age and cognitive symptoms. Carriers of the PSEN1 E280A have a well-defined and relatively homogenous disease course, with a median age of cognitive impairment at 44 years (95% C.I. = 43, 45 years) [13]. We hypothesized that carriers of the PSEN1 E280A mutation would have greater WMH volume than non-carriers, which would relate to both older age and worsening cognitive performance.

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